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CONFIDENTIAL INFORMATION OF DELMAR PHARMACEUTICALS, INC. ©2015 DelMar Pharmaceuticals

VAL-083: GBM

Historical Review &

Strategy for Product Development

CONFIDENTIAL – Updated February 2015

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©2015 DelMar Pharmaceuticals

Contents

1. EXECUTIVE SUMMARY ........................................................................................................... 2

2. Introduction ................................................................................................................................ 3

3. VAL-083 Background ................................................................................................................ 3

4. Glioblastoma Multiforme (GBM) ................................................................................................ 5

5. Alkylating Agent Chemotherapy in the Treatment of GBM ....................................................... 8

6. VAL-083 in GBM: ..................................................................................................................... 10

6.1. VAL-083: Overcoming MGMT Resistance ................................................................... 10

6.2. VAL-083 in GBM: Activity Against Cancer Stem Cells (CSCs) in vitro......................... 11

6.3. VAL-083 in GBM: Activity in Combination with Radiation Therapy .............................. 14

6.4. VAL-083 in GBM: Activity in vivo .................................................................................. 15

6.5. VAL-083 in GBM: Historical Human Clinical Experience ............................................. 16

6.6. VAL-083: Summary of Published Historical Safety & Toxicity Data ............................. 21

6.7. VAL-083: DelMar Pharmaceuticals Current Refractory GBM Clinical Trial .................. 23

6.8. VAL-083: Clinical Pharmacokinetics (PK) and Bio-distribution .................................... 25

6.9. VAL-083: Manufacturing ............................................................................................... 26

6.10. VAL-083: Intellectual Property ...................................................................................... 27

7. Market Opportunity .................................................................................................................. 28

8. DelMar Pharmaceutical’s VAL-083 Development & Commercialization Strategy for GBM ... 29

9. Immunotherapy & GBM: Potential integration with VAL-083 ................................................. 32

10. References .............................................................................................................................. 35


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1. EXECUTIVE SUMMARY

Glioblastoma multiforme (GBM) affects approximately 15,000 patients annually in

the United States;

The global market for GBM therapy currently exceeds $1.3 billion annually, with an

opportunity for significant growth;

In spite of recent advances in cancer therapy, prognosis for GBM patients remains

poor. Most patients fail to respond to today’s standard of care and treatment

options for refractory or relapsed patients are limited;

VAL-083 is a first-in-class alkylating agent with a unique bi-functional DNA cross-

linking mechanism that is distinct from other agents used in the treatment of

GBM;

In historical NCI-sponsored clinical trials VAL-083 demonstrated promising anti-

tumor activity in the treatment of hematologic malignancies and a range of solid

tumors, including brain cancer;

VAL-083 is well tolerated with a favorable safety profile in comparison to other

cytotoxic agents with the only reported dose limiting toxicity of

myelosuppression, which reverses spontaneously following treatment;

VAL-083 readily crosses the blood-brain barrier and has been shown to

preferentially accumulate in brain tumor tissue;

VAL-083 demonstrates more potent activity against GBM cells in comparison to

today’s standard of care and can overcome MGMT-mediated chemo-resistance;

VAL-083 is also active against cancer stem cells, suggesting the potential to

surpass the current standard-of-care in the treatment of GBM;

VAL-083 has been granted orphan drug protection for the treatment of gliomas in

the United States and Europe; and is the subject of three newly issued US patents

and one international patent; and

DelMar Pharmaceuticals is positioned to advance VAL-083 into Phase II/III

registration directed clinical trials as a potential new treatment for GBM patients

who have failed other available treatments during 2015.


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2. Introduction

DelMar Pharmaceuticals, Inc. is investigating VAL-083 (dianhydrogalactitol) in Phase I/II clinical trials in

the United States as a potential treatment for refractory glioblastoma multiforme (clinicaltrials.gov

identifier: NCT01478178). VAL-083 has been granted orphan drug status for the treatment of glioma in

the United States and European Union.

Glioblastoma multiforme (“GBM”) is the most common and most aggressive form of brain cancer,

affecting approximately 15,000 patients annually in the United States. Annual incidence of GBM is

approximately 3 per 100,000-population globally. Renewed attention was drawn to this form of brain

cancer when Senator Ted Kennedy was diagnosed and ultimately died from it.

Without treatment median survival following GBM diagnosis is usually less than six months. Only modest

advancements in the treatment of GBM have occurred in the past 25 years and no contemporary GBM

treatments are curative. Median survival from diagnosis with current standard-of-care is well under two

years.

Upon initial diagnosis, standard treatment consists of maximal surgical resection, radiotherapy, and

concomitant and adjuvant chemotherapy with temozolomide (Temodar®

or “TMZ”). Median time to

recurrence after standard chemo-radiation therapy is 6.9 months. Avastin is used as palliative second-

line therapy, but does not increase survival. Patients with refractory or resistant GBM have limited

therapeutic options.

Novel chemotherapies, particularly those with novel cytotoxic mechanisms of action to overcome chemo

resistance would offer important new treatment options for both newly-diagnosed and recurrent GBM.

VAL-083 is a first-in-class alkylating agent with a unique bi-functional DNA cross-linking mechanism

targeting the N7 position of guanine. This mechanism is distinct from other alkylating agents used in the

treatment of GBM.

In historical studies sponsored by the United States National Cancer Institute (“NCI”), VAL-083 exhibited

clinical activity against a range of tumor types including CNS tumors, solid tumors, and hematologic

malignancies. VAL-083 demonstrated promise in the treatment of GBM both as a single-agent and in

combination regimens in NCI-sponsored clinical trials. VAL-083 is approved in China for the treatment of

chronic myelogenous leukemia (“CML”) and lung cancer (Approval No. Guoyao Zhunzi H45021133;

manufactured by Guangxi Wuzhou Pharmaceutical (Group) Co. Ltd.)

DelMar believes that VAL-083’s unique mechanism of action, in association with newly developed data

positions the drug as a valuable therapy for GBM patients who have failed or are unlikely to respond to

other chemotherapeutic interventions.

VAL-083 is initially being positioned as a new treatment for refractory GBM – a significant unmet medical

need. DelMar’s data also supports VAL-083 as a potentially superior alternative to TMZ – the current

front-line chemotherapy in the treatment of newly diagnosed GBM – representing a potential multi-billion

dollar market opportunity.

3. VAL-083 Background

VAL-083 is DelMar Pharmaceuticals’ development identifier given to 1,2:5,6-dianhydrogalactitol

(dianhydrodulcitol, DAG, NSC-132313), a chemotherapeutic agent that was investigated in NCI-

sponsored research and human clinical trials as a treatment for cancer starting in the late 1970s.

http://clinicaltrials.gov/show/NCT01478178


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NCI-sponsored clinical studies suggested promising anti-tumor activity in with VAL-083 in the treatment of

hematologic malignancies and a range of solid tumors, including brain tumors. Antitumor activity has

been observed in clinical trials following both intravenous and oral administration.

Research was eventually not pursued in the United States due to an increased focus on targeted biologic

therapies during the early 1990s. VAL-083 was subsequently approved in China for the treatment of

chronic myeloid leukemia and lung cancer.1

VAL-083 is a structurally unique bi-functional alkylating agent mediating interstrand DNA crosslinks

targeting N7 of guanine.

VAL-083 Molecular Structure

Molecular Formula

C6H10O4

Molecular Weight

146.14

CAS Registry Number

23261-20-3

The functional groups and cytotoxic mechanism associated with VAL-083 differ from other alkylating

chemotherapeutic agents, such as the platinum-based compounds, nitrosoureas or temozolomide.

The principal mechanism of action is attributed to alkylation via the epoxide groups, which form cross-

links at the N-7 position of guanine leading to double-strand DNA breaks.2 The prevalence of guanine-

rich CpG islands in DNA, particularly within the promoters of genes, provides substantial regions of where

guanine residues are in close proximity for targeting by VAL-083 cross-links.

VAL-083 exhibits a favorable safety profile in human clinical trials. Dose limiting toxicity in humans is

myelosuppression, which has been shown to reverse spontaneously following treatment. Alopecia is not

associated with VAL-083 therapy; gastrointestinal toxicity is limited and no significant target organ

damage has been reported in the literature.3 Cumulative toxicity with long-term treatment has not been

reported.

VAL-083 crosses the blood-brain-barrier (BBB) and preferentially accumulates in tumor tissue4,

suggesting VAL-083 may be a therapeutic option for patients with brain metastasis as well as primary

brain tumors.

1Chinese Product Label for VAL-083 2Institoris et al., Chem.-BioL Interactions (1981) 3Vogel et al., Cancer Treat Rep. (1976) 4Eckhardt et al., Cancer Treat Rep. 61:841-47(1977)


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VAL-083 has demonstrated efficacy in cyclophosphamide, BCNU and phenylanine mustard resistant cell

lines and no evidence of cross-resistance has been encountered in published clinical studies. DelMar

Pharmaceuticals also has demonstrated that VAL-083 anti-cancer activity is independent of prominent

repair and resistance mechanisms such as O6-methylguanine methyltransferase (MGMT)

5, and that the

drug is active against temozolomide and platinum-resistant cell lines in vitro and in vivo. Further, the

combination of VAL-083 + other alkylating agents demonstrates more than additive or potentially

synergistic tumor killing effects.

Historical NCI-sponsored clinical trials in GBM achieved promising results with limited toxicity using a

dosing regimen of 25mg/m2/day for five days every five weeks.

In light of extensive safety data and promising efficacy against GBM in historical NCI-sponsored clinical

trials and data supporting that VAL-083’s unique cytotoxic mechanism can overcome chemo-resistance to

currently approved chemotherapies, DelMar Pharmaceuticals initiated a new Phase I/II clinical study to

establish the maximum tolerated dose (“MTD”) in refractory GBM patients using an optimized dosing

scheme.

The goal of DelMar’s current clinical trial is to determine an appropriate dose for advancement into Phase

II/III registration-directed trials in the United States in order to seek FDA approval as new therapy for the

treatment of refractory GBM.

4. Glioblastoma Multiforme (GBM)

Epidemiology

Worldwide, there are an estimated 240,000 new cases of brain and central nervous system (“CNS”)

tumors each year.

Gliomas are a type of CNS tumor that arises from glial cells in the brain or spine. Glial cells are the cells

surrounding nerves. Their primary function is to provide support and protection for neurons in the CNS.

Gliomas are classified by whether they are low-grade (I or II) — slow or relatively slow growing, or high-

grade (III or IV) – malignant, with fast growth and spread into normal brain tissue.

Glioblastoma multiforme (GBM), also known as Grade IV astrocytoma, is the most common and the most

lethal, of these tumors. The World Health Organization estimates that new cases of GBM occur in

approximately 2-3 per 100,000 people each year. In the US, approximately 15,000 people are diagnosed

with GBM annually.

GBM progresses quickly and patients deteriorate rapidly. Common symptoms include headaches,

seizures, nausea, weakness, paralysis and personality or cognitive changes such as loss of speech or

difficulty in thinking clearly.

The majority of patients do not survive for more than two years following diagnosis, and the median

survival in newly diagnosed patients with best available treatments is 14.6 months. Nearly all patients

diagnosed with GBM will relapse following first-line treatment, with a 1-year survival rate of approximately

25% following failure of front-line therapy, with average 5-year survival rate less than 3%.

5Dunn et al., AACR 2012 Annual Meeting.


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Standard of Care in the Treatment of GBM

Standard treatment following diagnosis includes surgical resection to remove as much of the tumor as possible

(debulking) followed by radiotherapy with concomitant and adjuvant chemotherapy with Temodar®

(temozolomide, “TMZ”).

Unfortunately, in almost all cases, GBM will recur and progress following treatment (known as recurrent

disease). Recurrent tumors may be treated with repeated surgical resection and/or additional

chemotherapy. Avastin® (bevacizumab – an anti-VEGF antibody) is approved as a single agent for

patients with recurrent GBM following prior therapy as an alternative to corticosteroids to relieve disease

symptoms in the US, Canada, Australia and Japan.

Temodar®

Following surgery, the current standard front-line therapy for GBM is Temodar® (TMZ). TMZ is a

nonfunctional alkylating agent that produces methylation of DNA, predominantly on the O6 and N

7

positions of guanine; however, its cytotoxic activity is limited to O6 alkylation.

TMZ was originally approved by the US Food and Drug Administration (FDA) in in 1999 for the treatment

of relapsed refractory anaplastic astrocytoma. The label was expanded in 2005 to include GBM in

combination with radiation therapy (“XRT”).

Treatment of newly diagnosed GBM patients with TMZ+XRT showed a statistically significant

improvement in overall survival compared to XRT alone, with median survival increased by 2.5 months in

the TMZ+XRT arm of the study.6

6Temodar Label


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Avastin®

Avastin (bevacizumab) was approved as a single agent for GBM patients with progressive disease

following prior therapy in the United States (2009) and Canada (2010). Avastin is a recombinant

humanized monoclonal IgG antibody that inhibits the biologic activity of human vascular endothelial

growth factor (“VEGF”) leading to reduced micro vascular growth and inhibition of metastatic disease

progression in other solid tumors.

Approval of Avastin for refractory GBM was based on an independent review of an 85 patient Genentech-

sponsored Phase II clinical trial, the results of which were supported by and a separate, independently-

conducted 56 patient NCI-sponsored study.7 Objective responses were assessed using the Macdonald

criteria which defines a complete response as disappearance of all legions and a partial response as a

>50% reduction in the sum of the product diameters (“SPD”) of any lesions that are >10mm at baseline.

Table 4.1: Efficacy Summary; Basis for Approval of Avastin in refractory GBM

Study Sponsor Genentech NCI

# subjects (n) 85 56

Objective Response Rate 28.2% CR=1 (1.2%);

PR = 23 (27.1%)

19.6% CR = 0;

PR=11 (19.6%)

Median Duration of Response 5.6 months 3.9 months

In the Genentech sponsored study, 46.4% of the patients treated with Avastin as a single-agent therapy

experienced a severe adverse event (Grade 3), life threatening or disabling (Grade 4) and death (Grade

5), with three (2.4%) patient deaths related to Avastin therapy.

Avastin carries a “black-box warning” related to severe, sometimes fatal, side effects related to

gastrointestinal perforations, wound healing complications and hemorrhage. There are no data

demonstrating an improvement in disease-related symptoms or increased survival in refractory GBM with

Avastin.8

Avastin was subsequently studied in two Phase III placebo-controlled trials in newly diagnosed GBM. No

survival benefit was observed in the Avastin treated arms. Avastin was, however, associated with a

higher rate of toxicities, including hypertension, bleeding, deep vein thrombosis, pulmonary embolism,

and gastrointestinal perforation. Patients on Avastin therapy also experienced increase rates of symptom

burden and neurocognitive decline, as well as decreased quality of life, compared to those on placebo.

Based on these data, the FDA and key opinion leaders stated that Avastin should not be used in the

treatment of newly diagnosed GBM.9

7 ODAC Briefing Book for Avastin – Genentech Inc. (2009) 8 Avastin Label 9 Gilbert, et al. N Engl J Med (2014)


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5. Alkylating Agent Chemotherapy in the Treatment of GBM

DNA, or deoxyribonucleic acid, is the hereditary material in humans. The information in DNA is stored as

a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). DNA

bases pair up with each other -- A with T and C with G -- to form units called “base pairs”. Each base is

also attached to a deoxyribose sugar molecule and a phosphate molecule, which are arranged in a

double-helix. The structure of the double helix is somewhat like a twisted ladder, with the base pairs

forming the ladder’s rungs.

An important property of DNA is that it can replicate, or make copies of itself in a process known as

mitosis. Each strand of DNA in the double helix can serve as a template for duplicating the sequence of

bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA

present in the original cell. When a mistake is made in the copying of DNA due to toxins, sunlight (UV)

damage or radiation, the cell is instructed to “die” via a process known as apoptosis. However, cells with

DNA errors sometimes escape the body’s natural defense mechanisms resulting in DNA mutations and

the formation of cancer.

Alkylating agents are among the oldest type of cancer chemotherapies in use today. Alkylating agents

bind to DNA to causing damage to cancer cells. Their anti-tumor mechanism is via alkylation of DNA

resulting in base-pair mismatch or strand-mediated cross links between base pairs. The DNA damage

caused by alkylating agents mimics naturally occurring errors, resulting in apoptosis and tumor cell death.

Temozolomide (TMZ) and the nitrosoureas (BCNU - carmustine; CCNU – lomustine, ACNU - nimustine)

are alkylating agents that readily cross the blood-brain-barrier (BBB) and are used in the treatment of

central nervous system (CNS) cancers, including GBM.

The primary cytotoxic mechanism of TMZ and the nitrosoureas is via alkylation of the O6 position of the

DNA base residue, guanine. TMZ treatment causes DNA damage mainly by methylation at the O6

position of guanine resulting in guanine-thymine base pair mismatches during replication. Nitrosoureas

mediate their cytotoxic effect by ethylation at the O6 position of guanine which produces a cross-link to

cytosine residues resulting in double-strand DNA breaks during mitosis.

Prior to the approval of Temodar, the treatment paradigm for GBM included combination therapy of XRT

plus procarbazine and vincristine with either lomustine (CCNU) or carmustine (BCNU), known as PCV

and BVD, respectively. According to the literature, the median length of survival for XRT+TMZ versus

XRT+PCV and XRT+BVD is not significantly different at approximately 14-16 months.

Jim Wells MD Anderson Cancer Center


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TMZ is widely used in preference to the nitrosoureas based on the convenience of its oral dosage

formulation and lower toxicity.10

The current standard of care for GBM is safe maximal surgical resection

followed by radiotherapy and concurrent TMZ followed by adjuvant (maintenance therapy) with TMZ

alone.

Alkylating agents have been shown to act synergistically with radiation to promote enhanced tumor killing

through alkylation-mediated radiation damage; however, this benefit is limited to effective cytotoxic

alkylation and not maintained in situations of chemo resistance.11

Resistance to alkylating agents is generally mediated by base mismatch repair or excision repair

enzymes, which rapidly repair the chemotherapy damage caused to a tumor cell’s DNA thereby enabling

tumor survival and growth.

MGMT Repair Meditated Chemo-resistance

Chemo-resistance to O6 alkylating agents is mediated predominantly by the naturally occurring O

6-DNA

methylguanine methyl-transferase (“MGMT”) enzyme which repairs O6-guanine lesions. MGMT reverses

the formation of chemotherapy-derived DNA adducts at the O6 position of guanine preventing the

formation of lethal base-pair mismatch and DNA cross-links. This repair mechanism in turn prevents

apoptosis and allows tumor survival and growth.

The expression of MGMT can be monitored in tumor cells by measuring the level of methylation in the

promotor region of the MGMT gene. Highly methylated promotors down-regulate the transcription of the

MGMT gene leading to low expression of the MGMT repair enzyme. Unfortunately, most GBM patients

have unmethylated MGMT promotors and high MGMT expression.

Consistent with the importance of its repair activity, high expression of MGMT is strongly correlated with

poor patient outcomes. Several clinical studies have established that MGMT is an important prognostic

indicator of response to TMZ and patient survival.12

10 Neider et al. Reviews on Recent Clinical Trials (2006) 11 Rivera et al. Neuro. Oncol. (2010) 12 Hegi et al. N Eng. J Med (2005)

Hegi et al NEJM,

2005


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Likewise, GBM tumor cells lacking MGMT expression are significantly more sensitive to the cytotoxic

effects of TMZ than are cells that have high MGMT activity in vitro.

GBM cell line U251 T98G

MGMT expression Low High

TMZ resistance Low High

Dunn et al., AACR 2012 MGMT repair is the single, most important factor responsible for resistance to chemotherapy in the

treatment of GBM. Patients with high expression of MGMT (approximately 2/3 of GBM patients) rarely

survive longer than 2 years.13

6. VAL-083 in GBM:

6.1. VAL-083: Overcoming MGMT Resistance

VAL-083 is an alkylating agent which readily crosses the blood brain barrier. Its primary cytotoxic

mechanism, epoxide derived DNA cross-links at the N7 position of guanine, is distinct from TMZ or the

nitrosoureas.

DelMar’s research demonstrates that VAL-083’s N7 targeting mechanism retains cytotoxic activity

independent of MGMT expression in vitro. The prevalence of guanine-rich CpG islands in DNA,

particularly within the promoters of genes, provides substantial regions of where guanine residues are in

close proximity for targeting by VAL-083 cross-links. For example, the CpG island within

the MGMT promoter region itself contains nearly 100 CpG dinucleotide sites providing substantial

targeting opportunity for VAL-083.14

VAL-083 has more potent activity against brain tumor cells in comparison to TMZ and overcome

resistance associated with MGMT suggesting the potential to surpass the current standard-of-care in the

treatment of GBM.15

13 Hegi et al., N Engl J. Med (2005)(352):997-1003 14 Nakagawachi et al., Oncogene (2003) 22, 8835–8844 15 Dunn et al., AACR Annual Meeting (2012)


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6.2. VAL-083 in GBM: Activity against Cancer Stem Cells (CSCs) in vitro

It has been hypothesized that tumor relapses are driven by brain tumor initiating cells (‘BTICs”) otherwise

known as cancer stem cells (“CSCs”) which escaped or are resistant to initial therapy. This may because

of how a particular chemotherapy targets more differentiated (mature) tumor cells while sparing the

subpopulation of stem-like cells.16

The same hypothesis therefore predicts that only therapies that

efficiently eliminate CSCs would induce long-term tumor responses and eliminate disease recurrence.

Additional support for the differentiated profile of VAL-083 and TMZ comes from the results of studies with

CSCs. GBM CSCs display strong resistance to TMZ, even where MGMT expression is low; however,

DelMar Pharmaceuticals data demonstrates that GBM CSCs are susceptible to VAL-082 independent of

MGMT expression.

DelMar examined VAL-083 and TMZ in neurosphere growth assays. Neurospheres are clusters of

suspected neural stem cells, of which a small fraction are considered secondary neurospheres with

demonstrated cancer-like renewal properties (CSCs). 5 μM VAL-083 effectively depleted all secondary

neurospheres with minimal effect on normal human neural stem cells. In contrast, TMZ was ineffective

against primary and secondary neurospheres.

Notably, where temozolomide had no activity against BITCs, the combination of VAL-083 + temozolomide

was more effective than VAL-083 alone. This suggests the potential for future treatment with VAL-

083+TMZ combination chemotherapy.

16 Beier et al., Molecular Cancer (2011)


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Additional studies with CSCs were undertaken in collaboration with researchers at the University of

California, San Francisco and DelMar. Studies were performed to understand VAL-083’s activity in GBM

CSCs compared to Temodar.17

A panel of primary cancer stem cells (CSC) and their paired primary non-stem (non-CSC) cultures were

characterized for MGMT expression.

Each CSC and non-CSC pair was subsequently exposed to DMSO (control), VAL-083 or temozolomide

and analyzed for cell cycle profile and viability.

Cell cycle progression proceeds from G1 to S to G2 through M (mitosis = cell division) and back to G1.

The G1 phase is a growth portion of the cell cycle and the majority of a cell culture would be expected to

be in the G1 phase at any given time. Agents that interfere with DNA replication or repair, such as VAL-

083 or TMZ, will block cell cycle progression and block cells from moving through mitosis and back into

G1 phase.

Treatment with VAL-083 led to a greater degree of cell cycle arrest as indicated by fewer cells in the G1 phase (indicated by the blue portion of each column).

17 Fouse, et al., Neuro-Oncology (2014)

MGMT western blot analysis of protein extracts from 4 pairs of CSC and non-CSC cultures derived from primary GBM tissue


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Over 40% of the CSCs treated with DMSO control of TMZ are in G1 phase at doses of

5µm, representing a normal cell cycle distribution for viable tumor cells at doses similar to

those achieved clinically in the treatment of glioblastoma.

In contrast, than 10% are in G1 phase after a dose of 5µM with VAL-083, indicating that

progression back into G1 phase has been blocked causing cell cycle arrest and

apoptosis.

Higher doses resulted in cell-cycle arrest for both compounds; however, doses exceeding

CNS tissue exposure higher than 10µM of TMZ or VAL-083 are generally not achievable

in a clinical setting due to toxicity.

In summary, DelMar’s data supports that:

Response to VAL-083 was not dependent on culture type. Both and non-CSC cell

cultures exhibit sensitivity to VAL-083.

VAL-083 killed tumor cells at clinically relevant doses in all CSC and non-CSC cultures

tested independent of MGMT expression.

All CSCs were resistant to TMZ and in non-CSC cultures where MGMT is highly

expressed.

These data suggests that VAL-083 has the potential to surpass TMZ outcomes in the treatment of

GBM.

Cells were treated with either increasing doses of TMZ (5, 50 100 and 200 μM) or VAL-083 (1, 5, 25 and 100 μM) and cell cycle analysis was performed 4 days post treatment. MGMT-expressing and all CSC cultures (A, B, D) were all resistant to TMZ at clinically relevant doses; however, VAL-083 was active against all cell cultures tested even at low (single µM) doses.


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GBM Cancer Cell GBM Cancer Stem Cell

MGMT

Status HIGH

TMZ:

VAL-083:

TMZ:

VAL-083:

LOW TMZ:

VAL-083:

TMZ:

VAL-083:

6.3. VAL-083 in GBM: Activity in Combination with Radiation Therapy

Alkylating agents have been shown to act synergistically with radiation to promote tumor cell killing

through alkylation-mediated radiotherapy enhancement. This benefit with TMZ is specific to those GBMs

that have undetectable MGMT expression, while unmethylated MGMT tumors can actually progress

during radiation treatment.18

To examine this further, MGMT expressing GBM tumor cells and MGMT expressing GBM tumor stem

cells were treated with either TMZ at high doses (50µM) or VAL-083 at a clinically relevant dose of (5µM)

either with or without 2Gy of radiation and compared to untreated control (nul in the graphs below).

As expected, temozolomide exhibited no activity against MGMT expressing GBM tumor cells in

comparison to control with or without radiation. However, VAL-083 was active against both MGMT

expressing GBM tumor cells and MGMT expressing GBM tumor stem cells.

18 Rivera et al. Neuro. Oncol (2010)

Cell viability analysis at day 6 post treatment for the paired CSC and non-CSC MGMT-expressing 7996

cultures.


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VAL-083 at 5uM doses resulted in near-100% tumor cell kill; therefore, radiation had no added benefit.

Notably however, when VAL-083 was added to CSC cultures at low micromolar doses (1, 2.5 µM) with or

without 2Gy radiation, VAL-083 acted as a radio-sensitizer against CSC’s in all cultures tested.

In summary, the addition of radiation to low doses of VAL-083 to both MGMT and non-MGMT expressing

GBM tumor stem cells demonstrates an expected radio-sensitizing effect.

Because VAL-083’s radio-sensitizing effect is seen in MGMT-expressing GBM that are resistant to TMZ +

radiation, VAL-083 has the potential to replace TMZ as the chemotherapy of choice in chemo-radiation

treatment of newly diagnosed GBM.

6.4. VAL-083 in GBM: Activity in vivo

VAL-083 demonstrated clinical activity against GBM as a single agent and in combination with BCNU in

historical NCI-sponsored studies. Further VAL-083 increased the life span of both BCNU-sensitive and -

resistant tumor-bearing mice.19

The absence of cross-resistance is explained by the different kinds of

DNA damage caused by the two alkylating agents and the presumably different defense mechanisms

developed by cells against these lesions.

19 Institoris et al. Cancer Chemother Pharmacol. (1989)

Cell cycle profile analysis at day 4 post treatment and cell viability analysis at day 6 post treatment for two different patient-derived CSC cultures treated with VAL-083 with or without irradiation (2Gy). 7996 (graph A&B) and 8565 (graph C&D).

http://www.ncbi.nlm.nih.gov/pubmed/2758560


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Published observations of VAL-083 activity in animal models are consistent with in vitro reports. VAL-083

is active against a range of tumor types, and demonstrates a lack of cross-resistance maintaining activity

where other chemotherapies fail. For example, in a brain tumor model where BCNU achieved only 4 -

16% survival at 120 days, the combination of VAL-083 with BCNU was curative in 85 - 100% of animals

at 120 days.20

Likewise, tumors from patients resistant to cyclophosphamide were sensitive to VAL-083 in

vitro and in mouse models.21

To further examine the comparative effects of VAL-083 and TMZ, DelMar established a mouse model of

GBM in collaboration with the British Columbia Cancer Agency (BCCA). Female Rag2 mice bearing

intracranial human GBM xenograft tumors of U251 (TMZ-sensitive) or BT74 (TMZ-resistant) origin were

treated with TMZ or VAL-083.

Animals were treated with a dose of 30 mg/kg of TMZ or three different doses of VAL-083 ranging from 3

mg/kg to 5 mg/kg. Disease progression is evaluated by overall survival, clinical observations and body

weight measurements.

As expected, animals bearing intracranial U251 (TMZ-sensitive) tumors were sensitive to both TMZ and

VAL-083. Treatment with either compound resulted in a statistically significant survival benefit. Studies

with BT74 (TMZ-resistant) tumors are ongoing.

6.5. VAL-083 in GBM: Historical Human Clinical Experience

VAL-083 was investigated in a number of clinical trials in the United States and Europe during the 1970s

both as a stand-alone therapy and in combination with other chemotherapeutic regimens.

There are five published peer reviewed Phase II studies of VAL-083 for the treatment of brain tumors. In

general, these studies confirm an objective response of 40% or greater with respect to survival and time

to progression, which is comparable to currently approved therapies.

In summary,

VAL-083 was shown to be active against brain tumors, including GBM, in multiple

Phase II human clinical trials;

VAL-083 was well-tolerated by patients; dose limiting toxicity is

thrombocytopenia, which has been shown to resolve spontaneously following

treatment; and

VAL-083 showed no cross resistance to nitrosoureas (e.g. BCNU), a

topoisomerase II inhibitor, or a RNA/DNA anti-metabolites in the published

studies.

An overview of each randomized and open-label study design and the results are provided in Table 6.5.1

and 6.5.2, respectively. Brief narratives of each are provided below the table and the full publications

referenced and available for further review. VAL-083 is referred to as “DAG” or “dianhydrogalactitol” in

the reference publications.

20 Levin et al., Cancer Chemotherapy and Pharmacology (1982) 21 Helson et al., Cancer Treat Rep. (1980)

http://www.researchgate.net/journal/0344-5704_Cancer_Chemotherapy_and_Pharmacology


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Table 6.5.1 VAL-083 Randomized Clinical Study in Brain Tumors

Ref Enroll

Eval.

Design

Control

Drug Dose and Regimen Diagnosis

Inclusion

Results

Eagan

197922

(Mayo Clinic

Rochester,

MN)

43

42

Open-label

Randomized

2x2

Parallel

4 arms

VAL-083: iv push 25mg/m2/d x 5 d,

every 5 wk/ yr 1; every 10 wk/ yr 2

Cont Radiation: 5,000 rads in 25

fractions in 5w

Split Radiation: 2,500 rads in 10

fractions, 3 wk rest, then 2,500 rads

in 10 fractions

Carmustine: after VAL-083 failure:

iv 70 mg/m2/d x 3 d every 8 wk

Supratentorial

astrocytomas

grades 3-4

Median Survival:

Rad only: 8.8 Mo.

VAL-083+Rad: 16.8 Mo.

Eagan et al., 1979: VAL-083 Potentiates Radiation Therapy

In a prospective, randomized VAL-083 brain tumor study (Eagan et al., 1979), subjects with supratentorial

astrocytomas, grades 3 and 4, were randomized to one of four treatment arms after surgical resection.

Two of the treatment arms only received whole-brain irradiation (XRT), either continuous or split-dose

XRT treatment whereas the other two treatment arms had the same two XRT treatments with concomitant

VAL-083 therapy. Upon treatment failure (defined by tumor progression determined by worsening

neurological results and computerized transaxial tomographic scans) the XRT -only treated subjects

would then be treated with VAL-083 and the XRT + VAL-083-treated subjects (including the previous XRT

-only treatment failures) would then be treated with BCNU (a nitrosourea). The carmustine treatment

was intravenous 70 mg/m2/day for three days every eight weeks.

22 Eagan et al., JAMA (1979)

R

A

N

D

O

M

I

Z

A

T

I

O

N

Continuous XRT

Continuous XRT + DAG

Split XRT

Split XRT + DAG

fail

fail

fail

fail

VAL-083 fail fail BCNU No longer

in study

fail BCNU No longer

in study

fail BCNU No longer

in study

VAL-083 fail fail BCNU No longer

in study

Figure 1 – Schema of Eagan Study Design


P a g e | 18


A total of 42 subjects received therapy as follows:

1) 10 subjects continuous XRT only - 5,000 rads in 25 fractions over five weeks

2) 10 subjects split XRT only - 2,500 rads in ten fractions, three week rest period

followed by 2,500 rads in ten fractions

3) 11 subjects continuous XRT plus VAL-083

4) 11 subjects split XRT plus VAL-083

The VAL-083 chemotherapy consisted of an intravenous push of 25 mg/m2/day for five sequential days,

equivalent to 125 mg/m2

total dose per course, every five weeks in year 1 and every ten weeks in year

two.

There was statistically significant superiority of the median survival of the radiation + VAL-083 treated

subjects versus radiation alone (radiation + VAL-083 – 16.8 months, radiation-only – 8.8 months;

P=0.02).

Essentially, the median survival was doubled by VAL-083 treatment over radiation treatment alone.

These data support anti-GBM activity similar to or better than TMZ.

Treatment of GBM temozolomide

(Phase III Stupp 2005) VAL-083

( Phase II Eagan 1979)

Median Overall Survival RT + Chemo

58 weeks 67 weeks

OS Benefit of adding Chemo: RT & Chemo vs. XRT Only

2.5 months (p<0.01)

8.4 months (p=0.02)

Sample (n=) Randomization

573 1:1

42 1:1

The comparison to TMZ must be considered in the context of the period of the study (1979 vs. 2005).

Undoubtedly, improvements in surgical technique and XRT delivery (e.g. gamma knife) would have

improved survival in the XRT-alone arm. However, an examination of the VAL-083 + XRT data in the

context of 2005-delivered surgery and radiation still demonstrates benefit vs. XRT-alone.

Importantly, the authors noted that the median survival of 16.8 months in the XRT + VAL-083 treated

subjects was longer than what was published in the scientific literature for XRT + nitrosourea treated

subjects during the same era.

XRT + VAL-083 Nitrosourea therapy

BCNU CCNU ACNU

Median survival (months) 16.8 12.5 13.0 8.8

Benefit vs. XRT alone 8.4 2.5 1.2 n/a

These comparison data support superior anti-GBM activity for VAL-083’s N7 DNA cross-linking

mechanism versus nitrosoureas O6 alkylating activity.

VAL-083 was well tolerated by patients, with dose limiting toxicity (DLT) defined by myelosuppression.

Time to nadir WBC or platelet counts was typically 3 - 4 weeks after the start of each course (range 1½ to


P a g e | 19


5 weeks). The typical low WBC count was 2,000 – 3,000/mm3 and for platelets was 100,000/mm

3 (range

50,000 – 130,000/mm3). Some evidence of cumulative myelosuppression was reported: The proportion

of subjects experiencing below normal WBC counts rose from 38% after the first course of treatment up to

82% after the sixth course of treatment, though only 50% of subjects (11 of 22) received their sixth course

of VAL-083 treatment. Other than myelosuppression, VAL-083 treatment only resulted in occasional mild

nausea and vomiting.

Of the 20 subjects in the two radiation-only arms, 18 completed their course of radiation therapy and 21 of

the 22 radiation + VAL-083 subjects received their planned therapy. Of the 20 radiation-only treated

subjects, three received VAL-083 upon tumor progression, one of which experienced tumor regression

(but died after two courses of an infection), another one of the three later received BCNU but did not

respond. Of the 22 XRT + VAL-083 treated subjects, 11 received BCNU upon tumor progression and 2 of

these 11 experienced tumor regression. For the VAL-083-treated subjects, the average number of VAL-

083 courses was six, which would encompass 30 weeks of VAL-083 treatment.

Furthermore, several VAL-083-treated subjects experienced tumor regressions after carmustine treatment

suggesting that the tumors are not cross-resistant to VAL-083 and carmustine. Lack of cross-resistance

between VAL-083 and nitrosoureas has also been reported in preclinical studies.

These observations support the hypothesis that VAL-083 will be a valuable in the treatment of TMZ-failed

GBM because nitrosoureas and TMZ attack the same position on DNA and exhibit cross-resistance.

Table 6.5.2 VAL-083 Open-Label Clinical Studies in Brain Tumors

Ref Enroll

Eval.

Design

Control

Drug Dose and Regimen Diagnosis

Inclusion

Results

Espana 197823

(NCI )

17

14

Open-

label

Single-

arm

VAL-083: 1 hr iv, 130mg/m2/d x 5 d,

every 3wks

XRT: 6,000 rads

Astrocytoma

grades 3-4

Median Survival: 7.1 Mo.

Eagan 198124

(Mayo Clinic)

30

30

Open-

label

Parallel

two-arms

2-drug regimen:

VAL-083 + VP-16

3-drug regimen:

VAL-083 + VP-16 + TZT

Supratentorial

primary brain

tumors

recurrent

after XRT

2-drug Tumor Reg: 40%

3-drug Tumor Reg: 33%

2-drug Med. Surv: 9.8mo.

3-drug Med. Surv: 8.8mo.

Weinblatt198125

(LA Children’s

Hospital)

12

7

Open-

label

Single-

arm

VAL-083: 37.5 or 50 mg/m2 twice a

week

primary brain

tumors all with

prior XRT and

chemotherapy

Med. Prog.: 3.7mo.

Eagan 198226

(Mayo Clinic)

49

43

Open-

label

Single-

arm

Combination chemotherapy of VAL-083

and BCNU every 5-7 wk in year 1 and

every 10-12 wk in year 2

VAL-083: 70 mg/m2 iv over 5 min

BCNU: 90 mg/m2 iv over 45-60 min

primary brain

tumors

with no prior

nitrosourea

Med. Surv: 7.4 Mo.

Med. Prog: 3.6 Mo

47% tumor reg.

37% stab. Dis.

23 Espana et al. Cancer Treatment Reports (1978) 24 Eagan et al. Oncology (1982) 25 Wenblatt et al. Cancer Treatment Reports. (1981) 26 Eagan et al. Cancer Treatment Reports (1982)


P a g e | 20


Espana et al. 1978 Phase II study of VAL-083 in malignant glioma

In this open-label, single-arm, uncontrolled study, 17 subjects with astrocytomas, grades 3 and 4, were

treated with VAL-083 subsequent to surgical resection and concurrent with radiation treatment. Four

subjects also had prior chemotherapy treatment with semustine (meCCNU) and VM-26. Subjects were

given a single 1 hour intravenous infusion of VAL-083, 150 mg/m2/d every 21 days.

Depending on severity of myelosuppression or adverse events, or lack thereof, subjects either had their

doses reduced to 130 mg/m2/d or increased to 170 mg/m

2/d. Three of the subjects were not evaluable

due to either only receiving single doses or being lost to follow-up.

The median duration of survival was 7.1 months from start of VAL-083-treatment and 18 months (range 1

- 52) from diagnosis (surgery). Leukopenia was the most common adverse event in 8 (57%) subjects and

thrombocytopenia in 6 (43%) with nadirs being observed about two weeks after treatment (range 2-3

weeks) after treatment.

Notably, three patients who failed to respond to treatment the nitrosourea meCCNU did responded to

VAL-083. These observations support a lack of cross resistance between VAL-083’s N7 DNA cross-

linking mechanism and the nitrosoureas O6 alkylating activity.

Eagan et al. 1981 Phase II studies of VAL-083 in combination chemotherapy

In an open-label, parallel-group study in subjects with supratentorial brain tumors recurrent after XRT

were treated with experimental therapy:

VAL-083 (NSC 1478178; DAG): Novel N7 DNA cross-linking agent

o i.v. 20mg/m2 for five days every 5-6 weeks

VP-16 (NSC 141540): Semi-synthetic epipodophylotoxin derivative o i.v. 75mg/m

2 on days 1, 3 and 5

Triazinate (NSC 139105; TZT) is a triazine folate antagonist similar to methotrexate o i.v. 75mg/m

2 on days 1 and 3.

Patients were given either a two drug regimen of “VAL-083 + VP-16 (“DV”) or a three drug regimen of

VAL-083 + VP-16 + TZT (“DVT”). A total of 30 subjects were treated, 15 in each arm with similar

demographics.

Tumor regressions were noted in 40% of patients treated with the DV regimen and 33% of patients

treated with the DVT regimen. Myelosuppression was the most frequent toxicity encountered. The

authors note that the 37% overall regression rate for VAL-083-based combination therapy suggest that

VAL-083 is probably effective against primary brain tumors.

Weinblatt et al. 1981 VAL-083 in the treatment of children with brain tumors

Twelve (12) pediatric subjects (mean age 9.3 ± 3.6 years, range 4 to 15 years) with recurrent or

progressive primary brain tumors were treated with VAL-083 in an open-label, single-arm, uncontrolled

study.

Subjects had been heavily pre-treated treated with multiple brain tumor therapies including XRT (12/12),

surgical resection (10/12), CCNU (11/12), vincristine (12/12), procarbazine (11/12), cyclophosphamide

(1/12) and cisplatin (1/12).


P a g e | 21


VAL-083 was administered at 37.5 or 50 mg/m2 twice a week and modified as needed based on

hematologic toxicity (myelosuppression).

Seven (7) subjects experienced disease progression after 3.7 ± 2.0 months (range 1.5 – 7 months). The

remaining five (5) subjects were asymptomatic with no evidence of disease, representing a response rate

of 45%.

Eagan et al. 1982 Combination VAL-083 + BCNU

43 patients (mean age 48 years, range 22 - 74) with primary brain tumors with no prior chemotherapy or

XRT therapy were treated with a combination of VAL-083 and BCNU in an open-label, single arm study

uncontrolled study.

Of the 43 subjects, 32 (74%) were diagnosed with astrocytomas with grades 1 (2, 5%), 2 (13, 30%), 3

(14, 33) and 4 (3, 7%). The remaining subjects had unbiopsied glioma (10, 23%) and one subject with an

oligodendroglioma grade 2. One subject had prior aziridine benzoquinone and three subjects had prior

radiation therapy within 8 weeks due for disease progression.

BCNU was administered at a dose of 90 mg/m2 i.v. over 45-60 minutes; VAL-083 was administered at a

dose of 70 mg/m2 i.v. over 5 minutes every 5-7 weeks in year 1 and every 10-12 weeks in year 2. Drug

doses were modified to maintain sufficient counts above nadirs for white blood cells ≥2750/mm3 and

platelets ≥95,000/mm3.

Results were as follows:

Tumor Regression 20 (47%)

Stable Disease 16 (37%)

Disease progression 7 (16%)

Notably, 57% (8 of 14) of subjects with Grade 3 astrocytomas experienced tumor regression.

Based on a comparison to previously published brain tumor regression response for a BCNU only study,

the authors calculated the contribution of VAL-083 to provide a tumor regression rate of 21% representing

nearly half of the overall 47% tumor regression response rate.

Median survival correlated positively with subjects experiencing tumor regression living the longest with a

median survival of 12.7 months; for subjects with stable disease median survival was 5.2 months; and for

those with immediate progression only 1.9 months.

VAL-083 related toxicity was minor: Nausea and vomiting were mild and infrequent and hematologic

toxicity was noted. The proportion of subjects experiencing leucopenia was 30% (wbc count nadir

<4000/mm3) or thrombocytopenia was 28% (platelet count nadir <100,000/mm

3).

6.6. VAL-083: Summary of Published Historical Safety & Toxicity Data

VAL-083 appears to be a well-tolerated chemotherapeutic agent with definite antitumor activity in

humans. An extensive clinical safety data base exists for VAL-083 in the United States and in China. A

review of the Chinese literature and US Phase I and Phase II US data support the safety profile of VAL-

083.


P a g e | 22


Toxicity in NCI-sponsored Phase I studies of patients with unresectable or metastatic cancer was mainly

hematologic, with thrombocytopenia being more common than leukopenia.27

Additional toxicities noted include nephrotoxicity, fatigue, and alopecia, but these were not reported to be

severe. No cumulative renal, hepatic, central nervous system, cardiac or pulmonary toxicity was

observed. Toxicities in the combination studies were generally more frequent and severe, and more

intense administration (weekly, rather than monthly) also increased toxicities. Any observed

gastrointestinal toxicity included nausea and vomiting and was generally mild to moderate.

The main dose-limiting toxicity related to the administration of VAL-083 observed in the NCI-sponsored

clinical studies overall was myelosuppression, with a higher frequency and severity observed in patients

with significant prior therapies. .

Thrombocytopenia was generally reported as the dose-limiting factor. Recovery of platelet counts to the

normal range occurred spontaneously following the course within a reasonable time frame allowing for

multiple courses of treatment. General leukopenic toxicities could likely be further managed by modern

concomitant medications such as Neupogen™ or growth factors.

Summary of VAL-083 Safety Studies

Ref Dose Schedule Dose Limiting Toxicity

Single-Agent Safety Studies

Espana, 1978 150mg/m2 Single dose tolerated

Eagan, 1976 (n=50) 2-40 mg/m2/d x5 days every 5 weeks Myelosuppression

Hass, 1976 (n=37) 2-31 mg/m2/d x5 or 10 days every 5 weeks Myelosuppression

Vogel, 1976 (n=28) 2-80 mg/m2/d Once per week Myelosuppression

Chinese product insert 25-40 mg/m2/d x5 days every 2 weeks Myelosuppression

Combination Safety Studies

Creagan, 1979 (n=8) VAL-083: 60-70 mg/m2/d

BCNU: 80-90 mg/m2/d

Myelosuppression

Creagan, 1987 (n=9) VAL-083: 60-70 mg/m

2/d

VP-16-213: 60-80 mg/m2/d

CDDP 20 mg/m2/d

4 week cycle:

VAL-083: once per day

VP-16-213 x 3 days

CDDP x 3 day

Myelosuppression

A variety of dose regimens were used with VAL-083 to treat cancer patients with cancer. The most

common regimen was 25-30 mg/m2/day every 5 days, with re-treatment every 2 to 5 weeks. DLT was

myelosuppression with toxic effects noted in reduced white blood cell (WBC) and platelet counts.

Anemia, nausea and vomiting were usually mild to moderate. No renal, hepatic, central nervous system,

cardiac, or pulmonary toxicity was identified.

For example, A dose of 50 mg/m2/day x 5 days every two weeks was used in a study of children with

leukemia, and patients with refractory cancers were treated with a VAL-083 dosing regimen of 50 mg/m2

twice a week for 4 weeks, then twice weekly for 2 weeks and every 6 weeks for maintenance of

refractory cancers.28

According to the Chinese product label, the recommended dosing regimen for the

treatment of solid tumors is 40mg per day over a 5 day course, followed by 2 weeks intermission between

courses.

27 Eagan et al., Journal of the National Cancer Institute. (1976) 28 Finklestein et al., Cancer Treat Rep. (1985)


P a g e | 23


A regimen of 25 mg/m2/day every 5 days, with re-treatment every 5 weeks resulted in nadir (low point of

blood cell counts) of platelets = 88,000/ mm3 (thrombocytopenia) and WBC = 2,100/mm

3 (lymphopenia).

29

A dose of 40mg/m2/day for five days in combination with other chemotherapy resulted in a median platelet

nadir of 31,000/mm3 and WBC nadir of 2,300/mm

3.30

In general, nadir occurred within three weeks and

returned to normal within 7 days.

VAL-083 was also well tolerated in combination with XRT or other alkylating agents. The study by

Espana (1978), patients with malignant glioma were given VAL-083 at a dose of 150 mg/m2 i.v. at 21-day

intervals in conjunction with XRT, and in Eagan 1982, patients received 70 mg/m2 VAL-083 i.v. in

combination with 90 mg/m2 BCNU, with repeat cycles of treatment every 5 – 7 weeks. In both of these

studies, toxicities were not a major concern. No patients were discontinued from drug due to toxicity, and

there were no drug-related deaths.

6.7. VAL-083: DelMar Pharmaceuticals Current Refractory GBM Clinical Trial

In DelMar Pharmaceutical’s current US Phase I/II clinical trial, Dose escalation is being undertaken to

establish a safe, “modernized” dosing regimen for glioblastoma patients who have been pre-treated with

standard XRT + TMZ and have also received or are ineligible for Avastin®. There is currently no available

approved therapy for these patients and their prognosis is poor.

The DelMar “modernized” dosing regimen uses a cycle of treatment on the first three days of every three

weeks. The DelMar dosing regimen is designed to deliver more VAL-083 to the tumor in comparison to

historical NCI-sponsored studies, which employed a dosing regimen of the first five days of every five

weeks.

As noted below, DelMar has achieved doses of VAL-083 that are significantly higher than prior NCI doses

in terms of single-dose, overall cycle exposure, and dose intensity.

DOSING REGIMEN & STUDY

SINGLE DOSE

Acute Regimen (single cycle)

Comparative Cumulative Dose

(@ 35 days)

Dose Density (dose per

week) Status

NCI GBM historical regimen

(Eagan et al.) daily x 5 q 5wks (cycle = 35 days)

25 mg/m2 x5 days = 125 mg/m

2 125 mg/m

2 25mg/m

2/wk

Historical Studies: Myelosuppression

observed

DelMar VAL-083 regimen

daily x 3 q 3wks (cycle = 21 days)

30 mg/m2

x3 days =

90 mg/m2 180 mg/m

2 30mg/m

2/wk No DLT

40 mg/m2 120 mg/m

2 240 mg/m

2 40mg/m

2/wk No DLT

50 mg/m2 150 mg/m

2 300 mg/m

2 50mg/m

2/wk DLT observed

60 mg/m2 180 mg/m

2 360 mg/m

2 60mg/m

2/wk planned

The protocol is designed to determine MTD, with the assumption that early doses are sub-therapeutic;

however, patients are monitored for tumor response by MRI (RANO criteria). One of three GBM patients

in cohort 7 (40mg/m2) and one of three GBM patients in cohort 6 (30 mg/m

2) exhibited stable disease

after one or two cycles of treatment. In earlier cohorts, we reported that two patients exhibited a

response (stable disease or partial response) with a maximum response of 28 cycles (84 weeks) and

improved clinical signs prior to discontinuing due to adverse events unrelated to the study.

29 Eagan et al. JAMA (1979) 30 Eagan et al. Cancer Treat Rep. (1981)


P a g e | 24


No serious adverse events related to study drug or dose limiting toxicity (DLT) were encountered at doses

up to 40mg/m2/day x 3 days. NCI-CTCAE Grade 1 lymphopenia (LLN to >3,000/L) and

thrombocytopenia (platelet counts LLN to >75,000/L) at doses above 20mg/m2/day x 3 days were

observed at doses at doses up to 40mg/m2.

A 50mg/m2 cohort is ongoing:

The first patient completed the required 35 day follow-up period without observation of a DLT.

The second patient in the cohort experienced myelosuppressive DLT as defined by grade four

thrombocytopenia (low platelet counts). The patient's symptoms resolved rapidly and

spontaneously returned to normal without concomitant medication or transfusion. These

observations are consistent with VAL-083-related toxicities and resolution reported in the

scientific literature.

The third patient in the cohort is currently completing the 35-day follow-up period. The patient

experienced grade three thrombocytopenia, which resolved rapidly and spontaneously.

Summary of hematologic-related safety data observed to date in the DelMar clinical trial to date 15-Feb/2015

Cohort Dose &

Hematologic Toxicity Grade

1 Grade

2 Grade

3 Grade

4 Grade

5 Total

1 - 4

up to 10 mg/m2

LYMPHOPENIA 0 0 0 0 0 0

THROMBOCYTOPENIA 0 0 0 0 0 0

5

20 mg/m2



6

30 mg/m2



7

40 mg/m2



8

50 mg/m2 -

Ongoing



If no DLT is observed in the third patient within the 35-day follow-up period, the protocol stipulates that an

additional three patients will be added at the 50mg.m2 dose. If a DLT is observed with any of these

patients, the highest previous dose – 40mg/m2 – will be proposed as the maximum tolerated dose (MTD)

for advancement to registration directed trials. However, if no further DLT is observed at 50mg/m2, dose

escalation to may proceed to 60mg/m2 in accordance with the protocol. However, if significant trends

toward a DLT are observed dose escalation may be stopped and 50mg/m2 proposed the MTD for

advancement to registration directed trials. This decision will be based on data from the 50mg/m2 cohort.

Once MTD is determined, the protocol dictates that an additional 14 patients at that dose to gather more

information about safety and activity. DelMar anticipates requesting a guidance meeting with FDA during

the 14-patient expansion phase of the current trial. The purpose of the meeting will be to discuss the

Phase II/III registration trial design.

The Phase II/III registration trial design is anticipated to involve approximately 100 patients with

radiographic response and overall survival as the primary endpoints. Final trial design will be determined

based on input from DelMar’s clinical advisors and the FDA.


P a g e | 25


6.8. VAL-083: Clinical Pharmacokinetics (PK) and Bio-distribution

The current clinical formulation of VAL-083 is for intravenous use. The drug is orally bioavailable and has

demonstrated clinical activity following oral administration.31

VAL-083 readily enters the CNS and crosses

the BBB.

Historical Human Clinical PK Experience

In humans, intravenously administered doses of 50mg/m2 given as a 1-hour infusion, produced peak

plasma concentrations of 1.9 to 5.6µg/ml.32

Elimination of VAL-083 is biphasic with an alpha half-life of

3.9 minutes and a beta half-life of ~5 hours. Overall, the primary route of elimination is metabolism to a

series of highly polar metabolites, which are excreted in the urine.

Plasma half-life as stated in the published literature is short, about 1-2 hours. The drug appears to reach

steady state rapidly in the plasma. At high doses plasma concentrations and AUC increase only slightly

with dose escalation; for example, the AUC changed only from 32.7±11.2 to 39.4±9.5 when the dose was

raised from 690 to 1050 mg/m2.33

Human Pharmacokinetics: Historical Human Clinical Experience (*=single dose 50mg VAL-083)

Plasma Cerebral Spinal Fluid

t½ Tmax Cmax* AUC* Protein Binding t½ Tmax Cmax AUC Protein Binding

2.05 hr

(1-4hr) 1-2hr 3.6µg/ml 22µg/h-ml 20-30%

20 hr

(3-24) 2 hr

negligible

It has been established that VAL-083 enters the CSF rapidly, peaking at 1-2 hrs and is slowly eliminated,

with a half-life of 20 hrs (vs. 1-2 hrs in plasma). Rapid entry into the CNS is characterized by a

concentration in the CSF of 40-50% of plasma levels at simultaneous time points.34

Published preclinical and clinical research demonstrates that VAL-083 is selective for tumor tissue, with

up to 28-fold higher accumulation in CNS tumor tissue.35

Current Clinical Observations

Pharmacokinetic observations from DelMar Pharmaceuticals’ current clinical study in the United States

are consistent with literature-based plasma PK data. Data from cohorts 1-7 demonstrate dose-dependent

linear systemic exposure with a short plasma 1-2 h terminal half-life; Cmax in cohort 7 (40 mg/m2) ranged

from 1130 to 739 ng/mL (7.7 to 5.1 µM).

These data are well correlated with the PK profile published in the scientific literature (Eagan et al 1982)

as shown in the following figure:

31 DeJageer et al., Eur. J Cancer (1989) 32 Eagan et al., Oncology (1982) 33 Kerpe-Fronius et al., Cancer Chemother Pharmacol (1986) 34Horváth et al., Eur J Cancer Clin Oncol. (1986) 35Eckhardt et al. Cancer Treat Rep. (1977)


P a g e | 26


By extrapolating CNS exposure based on information in the published literature, DelMar has calculated

that observed plasma concentrations obtained to date are predicted to exceed in CNS tissue

concentrations effective against glioma cell lines in vitro.

Dose and Dosing Day of

Each Cycle

Current Trial

Plasma Cmax

(μg/mL)1

Estimated Maximum

Tumor Concentration in

Brain 2,3

IC50 in

GBM Cell

Lines

(μg/g tissue) μM* μM

40mg/m2 Day-1 0.781 0.344 2.36

2.5-5.0 40mg/m2 Day-2 0.781 0.503 3.45

40mg/m2 Day-3 0.781 0.563 3.86

6.9. VAL-083: Manufacturing

VAL-083, which is also known as “Weimutrin” or “Dianhydrodulcitol” in the Chinese market, is approved in

China for the treatment of CML and lung cancer.

VAL-083 is supplied as pure drug product for reconstitution exclusively by Guangxi Wuzhou

Pharmaceutical (Group) Co. Ltd., a wholly owned subsidiary of Zhongheng Group, a publicly listed

company in China (SHG: 600252). VAL-083 is not commercially available outside of China. Guangxi

Wuzhou Pharmaceuticals currently holds the only license from the SFDA for the manufacture of VAL-083

for Injection in China (Approval No. Guoyao Zhunzi H45021133) and is compliant with Ministry of Health

(MoH) Decree No.79 for the manufacture of an injectable pharmaceutical.

DelMar Pharmaceuticals is collaborating with Guangxi Wuzhou Pharmaceuticals to implement FDA-

acceptable cGMP practices into manufacture of the active pharmaceutical ingredient (API) and finished

drug product (DP).


P a g e | 27


For current clinical studies in the United States, DelMar has acquired the finished drug product from the

Chinese manufacturer, for release under Good Manufacturing Practice (“GMP”) in the United States

based on an internally developed analytical methods and expanded specifications.

DelMar has established a collaboration with Guangxi Wuzhou Pharmaceuticals for the supply of VAL-083.

Under the terms of the agreement, the companies are collaborating support activities related to qualifying

Guangxi Wuzhou Pharmaceuticals as a commercial supplier under FDA and EMEA GMP regulations.

Guangxi Wuzhou Pharmaceuticals is funding these activities under DelMar’s supervision. Upon FDA

certification, Guangxi Wuzhou Pharmaceuticals will be the exclusive commercial supplier of VAL-083.

DelMar has also established a back-up supply relationship with a GMP-certified contract manufacturer

based in North America.

6.10. VAL-083: Intellectual Property

VAL-083 has been granted orphan drug status for the treatment of gliomas in the United States and the

European Union, which provides VAL-083 with 7 and 10 years of market exclusivity following approval,

respectively. DelMar Pharmaceuticals intends to seek data and orphan drug protections in other

international jurisdictions where it is available. This strategy extends to new indications in China where

new indications established under a Category 1 or Category 2 SFDA approval obtain a 5 year safety

review period, exclusive of patent protections which may exist on the product.

In addition to Orphan Drug protection, DelMar employs a strategy for obtaining new patent claims to

protect the intellectual property associated with the development of ‘old’ drugs for modern indications has

been validated by companies such as Celgene, Cephalon, Chemgenex and Salmedix. In general, this

strategy includes new patent filings claiming:

The use of the drug in new patient populations, such as those failing modern biologic

therapies which had not yet been invented at the time of the drug’s original study;

Novel label claims, such as modernized dosing administration to improve efficacy and

reduce toxicity;

Improvements to the manufacturing process;

New analytical methods required for product approval under “Current Good

Manufacturing Practice” (cGMP) guidelines;

Identification and control of the chemical composition of the active pharmaceutical

ingredient and the final drug product; and

Composition of matter claims for new chemical entities or analogues to VAL-083 in the

“surrounding” or related chemical space.

To date, three new United States patents and one international patent have been issued for VAL-083

have issued to DelMar Pharmaceuticals and provide patent protection at least through 2030.


P a g e | 28


7. Market Opportunity

GBM is a rapidly progressive and almost universally fatal brain tumor that affects approximately 15,000

new individuals each year in the US,36

with similar incidence globally.

Surgical intervention followed by TMZ and XRT is generally the first course of treatment for newly

diagnosed GBM. Avastin is the current second-line therapy targeted for the approximately 60% of

patients who fail chemo-radiation.

Peak global sales of Temodar in the treatment of GBM were $1.1 billion in 2010, although Temdoar sales

have decreased to $708 million since the drug came off patent in major markets including Europe and the

US during 2013. Yearly, GBM revenue for Avastin is approximately $170 million, mainly from the US

market. Therefore, the global GBM market is approximately $1.3 billion, but this could expand quickly

based on the entrance of innovative new drugs such as immuno-oncology products and VAL-083.

U.S. Market Opportunity in Refractory GBM

Approximately 4,800 (48%) of new GBM patients will fail both Temodar and Avastin in the United States.

No alternative therapy with a demonstrated third-line treatment benefit has been approved for these

patients to date. There is an extremely urgent unmet need for a salvage therapy to address the needs of

refractory patients; however, other innovative therapies such as immuno-oncology products are generally

targeted to newly diagnosed patients. Therefore, VAL-083 has the potential to capture substantial

marketshare in the salvage patient population, which is estimated at approximately 7,000 patients per

year in the United States.

New GBM diagnoses 15,000 Recurrence after surgery 100%Recurrence after chemoradiation 60%Avastin Failure Rate 80%

Salvage patient population 7,200

Temodar is currently reimbursed at $5,600 per month, although it’s worth noting that the drug recently lost

patent protection. New oncology drugs, including Avastin, are priced significantly higher than Temodar.

VAL-083 has the potential to achieve a much higher reimbursement rate than Temodar using a modern

model for oncology pricing and assuming that it demonstrates a compelling benefit for refractory patients.

With estimated treatment duration of 6 months for the nearly 7,000 refractory patients, the total

opportunity for VAL-083 in the third-line setting is an estimated to be between $200 million and 400

million.

36 Ostrom, Q.T. et al., Neuro-Oncology (2014)

Pricing paradigm

Like Temodar $5,000/mo

Like Avastin $10,000/mo

USA Revenue Oppty $216 million/yr

USA Revenue Oppty $432 million/yr


P a g e | 29


Global Opportunity in Newly Diagnosed GBM

VAL-083 has been shown to be a potentiator of XRT in preclinical and clinical studies; to be active

independent of MGMT promoter methylation; and active against CSCs with outcomes comparable or

superior to other alkylating agents in the treatment of GBM.

This represents a compelling profile for VAL-083 as a potential alternative to TMZ in the standard front-

line chemo-radiation + maintenance therapy protocol. A reimbursable MGMT-based prognostic assay for

GBM that could be used as a companion diagnostic to identify patients unlikely to respond to TMZ VAL-

083 is already in common practice.

Peak global sales of Temodar in the treatment of GBM were $1.1 billion in 2010, although Temdoar sales

have decreased to $708 million since the drug came off patent in major markets including Europe and the

US during 2013.

If VAL-083 gains market share in front-line therapy either as an alternative to temozolomide or in

combination with novel immune-oncology agents peak sales could be expected to exceed several billion

annually in the treatment of GBM.

8. DelMar Pharmaceutical’s VAL-083 Development & Commercialization Strategy for GBM

Glioblastoma Multiforme (GBM) is a devastating disease affecting 3 – 5 per 100,000 individuals. Nearly

all patients will experience relapse following first-line treatment. Currently, there are no approved

treatments demonstrating a proven survival benefit for recurrent GBM patients and the 1-year survival

rate is approximately 25% following failure of front-line treatment.

Refractory GBM

DelMar plans to develop VAL-083 initially as single-agent therapy in patients with recurrent GBM who are

resistant to or ineligible for bevacizumab therapy (Avastin) under the auspices of the orphan drug act in

the United States.

The rationale for initially focusing on refractory disease includes opportunity for rapid clinical

advancement through fast-track or breakthrough therapy designation due to unmet medical need; a

relatively small and cost effective open-label registration trial design; ability to market a product with small

sales force; and an attractive reimbursement paradigm.

DelMar initiated a Phase I/II dose-escalation study to establish the MTD for VAL-083 using an optimized

dosing regimen for patients that have experienced relapse following pre-treatment with XRT, TMZ and

Avastin. The dose-escalation portion of the study is currently being undertaken at three centers in the

United States. The purpose of the study is to determine a dose for advancement into Phase II/III

registration-directed clinical trials in the United States.

Based on current progress, it is anticipated that an MTD for advancement into Phase II/III registration-

directed trials will be determined in the first half of 2015. Upon determination of MTD, DelMar will:

Enroll and additional 14-subjects to gather further information about the safety, tolerability

and anti-tumor activity of VAL-083 at the MTD;

Expand the number of clinical sites to accelerate enrollment;

Seek a guidance meeting with FDA to confirm the design for the Phase II/III registration-

directed clinical trial.


P a g e | 30


DelMar anticipates requesting a guidance meeting with FDA during the 14-patient expansion phase of the

current trial. The purpose of the meeting will be to discuss the Phase II/III registration trial design.

The Phase II/III registration trial design is anticipated to involve approximately 100 patients with

radiographic response and overall survival as the primary endpoints. Final trial design will be determined

based on input from DelMar’s clinical advisors and the FDA.

DelMar anticipates significantly expanding the number of sites during the registration trial. DelMar will

use commercially reasonable efforts to include any academic or tertiary medical center that is significantly

involved in the treatment of post-Avastin GBM patients. The company anticipates the trial may

encompass 20-25 centers in the United States and Canada.

The budget for the registration-directed clinical trial is anticipated to be approximately US$85,000 per

patient, including CRO costs and corporate overhead. Therefore the total budget for the Phase II/III

registration-directed trial is expected to approximate US$8.5 million.

Subject to satisfactory enrollment, DelMar anticipates that the Phase II/III registration-directed trial could

be fully enrolled within 12 months of initiation, with approximately six months of follow-up. This potentially

positions NDA filing for late 2016 or early 2017, with commercial launch in the first half of 2017.

timel ine (rev) 2015

MTD Q1 Q2 Q3 Q4 FILE NDA

Find MTD

14 pt Expanion

Begin Reg Tria l

Q1 2017

Refractory GBM patients in the United States and Canada are generally treated at relative small number

of academic medical centers. DelMar anticipates that the primary refractory GBM physician prescriber

base will largely overlap those centers involved in its Phase II/III registration-directed clinical trial. This

will allow DelMar to establish a strong pre-commercial relationship with its potential customer base.

The focused academic medical center customer base could potentially be serviced with a small contract

or in-house sales force. DelMar will seek to retain commercial rights to VAL-083 for the treatment of

refractory GBM at academic medical centers in the context of potential future pharmaceutical

partnerships, which may be consummated for the development of VAL-083.

Front-line GBM

Juxtaposing the promise of historical clinical data in the treatment of GBM, with the modern scientific

profile of VAL-083, DelMar believes that VAL-083 has the potential to replace TMZ as the chemotherapy

of choice in chemo-radiation treatment of newly diagnosed GBM.

The global GBM market is approximately $1.3 billion, but this could expand quickly based on the entrance

of innovative new drugs such as immuno-oncology products and VAL-083. Peak global sales of

Temodar in the treatment of GBM were $1.1 billion in 2010, although Temdoar sales have decreased to

$708 million since the drug came off patent in major markets including Europe and the US during 2013.

Once MTD is established for refractory disease, DelMar plans to leverage its modernized dosing regimen

for development as a potential new therapy for newly diagnosed GBM for patients who are unlikely to

respond to TMZ.


P a g e | 31


An assay for detection of MGMT activity in tumor tissue is commercially available from Sigma Aldrich

(Sigma Product No. MD0100) and other manufacturers. The assay test is certified under CLIA (Clinical

Laboratory Improvement Amendments) and currently used in standard practice as a prognostic indicator

of GBM outcomes, and reimbursed by several insurance carriers. This assay can also be used as a

companion diagnostic to identify patients unlikely to respond to TMZ for purposes of patient selection in

future clinical trials.

DelMar anticipates that a global Phase II/III clinical trial in newly diagnosed GBM patients could be

initiated following a short dose-confirming lead-in trial with XRT + VAL-083. It is anticipated that the trial

would compare outcomes of VAL-083 to TMZ following the standard Stupp regimen (and potentially

including an XRT only arm).

Phase II/III Front Line GBM Trial Design

Based on recent trials and high-level statistical analysis, it is estimated that a Phase II/III registration trial

for front line GBM would require randomization of 500 – 600 patients and an investment of at least $40

million. A Phase II – III adaptive design could potentially be developed to permit step-wise investment to

an early statistical endpoint.

Newly diagnosed GBM is generally treated by community oncologists, which will require a significant

global sales and marketing infrastructure. Based on the costs and infrastructure involved in the

development and commercialization of a front-line GBM therapy, DelMar anticipates seeking partnerships

with global pharmaceutical companies for the development of VAL-083 in newly diagnosed GBM.


P a g e | 32


9. Immunotherapy & GBM: Potential integration with VAL-083

Recently, there have been intensified research efforts studying immunotherapy as an effective adjunct or

alternative to the current treatment paradigm in GBM.

Modest efficacy and variable immunogenicity have been observed in early-stage clinical trials.

Immunotherapy may offer a promising approach to complement and enhance the current chemo-radiation

regimen.

Immunotherapy centers on the principal that the host immune system may destroy tumor cells if immune

effector function is appropriately augmented. There are three basic strategies underlying immunotherapy:

(1) Immune modulating cytokine therapy, (2) passive therapy and (3) active immune therapy including

cancer vaccines.

Cytokine therapy takes advantage of specific immune mediators such as interleukins. While

some success has been achieved in early studies, the immune effects of cytokine therapy are

non-specific often leading to extensive systemic toxicities.37

Clinical results in tumor regression

have been disappointing, which may be due to the multiplicity mechanisms of tumor immune

evasion in the tumor microenvironment. These specific mediators, such as checkpoint

interactions, have themselves become targets of interest for therapeutic intervention.

Immune checkpoint inhibitors are aimed at overcoming a tumor’s mechanism for evading the

immune system through a locally immunosuppressive microenvironment. Immune checkpoint

inhibitors are gaining considerable attention as a strategy for eliminating poorly immunogenic

tumors. It is important to note, however, that the systemic autoimmune toxicities associated with

checkpoint blockade are significant, including severe colitis and pituitary inflammation.

Nevertheless, clinical results in melanoma and other tumors are encouraging and justify

investigation in GBM.

Cancer vaccines have emerged recently in clinical studies with recent advances being achieved

in prostate cancer and advanced melanoma. Dendritic (DC) cell vaccines may be capable of

inducing systemic immunity; however, a significant limitation of this approach is the necessity of

direct physical interaction of DC and tumor antigens, which are protected in the

immunosuppressive tumor microenvironment.38

Therefore a number of techniques to expose

DCs to tumor antigens either ex vivo or in vivo have been developed.

Historically, chemotherapy and immunotherapy have often been regarded as independent or agnostic

treatment modalities; however, recent studies demonstrate the potential benefit of combining these

modalities.

Synergy between cancer immunotherapies, including cancer vaccines, and conventional chemotherapy

have demonstrated potential both in laboratory studies and in early clinical trials demonstrate that

immunotherapy may have potential as a future adjunct to standard of care in multi-modal treatment

paradigms.39

37 Dunn et al., Nat. Immunol ( 2002) 38 Yang et al.,. (2002) 39 Patel et al., Cancers (2014)


P a g e | 33


ICT-107 is a dendritic cell-based vaccine targeting multiple tumor-associated antigens for glioblastoma.

A randomized, double-blind, placebo-controlled phase II study of the safety and efficacy of ICT-107 in

patients with newly diagnosed glioblastoma multiforme following resection and chemo-radiation (with

TMZ) failed to meet its Phase II endpoints; however, retrospective analysis suggests potential benefit in

MGMT methylated patients as an adjuvant to TMZ.

ICT-107 Retrospective Analysis Presented at SNO 2014

Median PFS (AvB) Median OS (AvB)

Methylated (low-MGMT)

Statistically Significant benefit p = 0.004

Analysis ongoing

Unmethylated (high-MGMT)

No Statistical Benefit p = 0.364

No statistical benefit p = 0.223

CDX-110 is an EGFRvIII vaccine that is currently undergoing clinical trials both in newly diagnosed

GBM patients in combination with standard TMZ therapy and in refractory disease.

The variant III mutation of the epidermal growth factor receptor (EGVRvIII) is commonly observed in

human tumors and promotes cell proliferation and inhibits apoptosis. EGVRvIII vaccines therefore

represent a potential alternative or adjunct to standard therapy.

Recent results in the refractory trial demonstrated potential in TMZ refractory patients in combination

with Avastin®; however, patients who were refractory to Avastin® did not benefit from CDX-110. A

Phase III trial in newly diagnosed patients in combination with TMZ is ongoing.

Notably, an effective chemotherapy is a key component of these approaches. Traditional chemo-

radiation has been shown to have synergistic effects when used in combination with immunotherapy

providing for potential benefit in a multi-modal chemo-immunotherapy approach.

Some forms of chemotherapy-induced cell death can be highly immunogenic. Apoptosis in particular may

serve to alter the local tumor microenvironment to disrupt pathways of immune tolerance and suppression

and sensitize tumor cells to immunotherapy.

Upregulating the expression of tumor antigens can augment cross-priming of the tumor-specific t-cell

response, thereby increasing tumor antigen presentation or decreasing the expression of immune

checkpoint molecules.40,41

Likewise, immunotherapies may also be used as pro-inflammatory chemo-sensitizing agents that render

drug-resistant tumors more amenable to standard therapeutic options.42

However, while the benefit of chemo-immunotherapy has been observed, the interaction between

chemotherapy and the immune system is complex and could be antagonistic in some cases Many

standard-dose chemotherapy regimens actually suppress the anti-tumor immune response by directly

decreasing lymphocytes or inhibiting lymphocyte functions. As such, an immunosuppressive

40 Casares, N. et al., J Exp Med. (2005) 41 Emens LA., et al., Curr Opin Mol Ther (2001) 42 Liu et al., Expert Rev Vaccines. (2006)

Surgery

A: TMZ + XRT + ICT107

B: TMZ + XRT + placebo

Randomi-

zation

2

1


P a g e | 34


chemotherapy could hinder immunotherapy response either by inducing lymphopenia or contributing to

lymphocyte dysfunction and truncating immune-based outcomes.

VAL-083 and Immunotherapy

It is important that a chemotherapy regimen does not alter the tumor micro-environment in a way that

inhibits immunotherapy.

Clinical observations with VAL-083 support limited neutropenia or lymphopenia, and, therefore, VAL-083

is unlikely to have a negative impact on immunotherapeutic activity immune response through immune

suppression via neutrophil or t-cells depletion.

Of course, a key component of any chemo-immunotherapy regimen is an active chemotherapy. This

further highlights the need for a novel chemotherapeutic agent that can overcome MGMT-mediated

chemo-resistance in GBM. VAL-083 represents this type of agent.

While a number of immunotherapeutic approaches are currently being investigated for the treatment of

GBM, none have yet to receive regulatory approval.

As one or more of these approaches evolve, DelMar Pharmaceuticals believes that VAL-083 represents

an ideal agent of choice for strategically integrating potential immune-based therapies with chemotherapy

treatment in a multi-modal chemo-immunotherapy regimen.

Such approaches could represent area of safely and effectively harnessing the immune system in the

treatment of GBM and provide much needed improvements in quality of life and survival.


P a g e | 35


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http://www.ncbi.nlm.nih.gov/pubmed/2758560

http://www.researchgate.net/journal/0344-5704_Cancer_Chemotherapy_and_Pharmacology

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