cancer alpha therapy: trials and tribulations...next trial: c595 for muc1 •our preclinical data...

Cancer Alpha Therapy:

Trials and Tribulations

Prof Barry J Allen PhD DSc

Director

Centre for Experimental Radiation

Oncology

St George Cancer Care Centre

How to introduce a new cancer therapy

• Define the problem

• New idea to address the problem

• Preclinical studies in vitro and in nude mice to confirm

the idea

• Translational studies

• Phase 1 clinical trial for dose tolerance

• Phase 2 trial for efficacy at maximum tolerance dose

• $$$$$ from industry for phase 3 trial for comparison

with standard therapy

• Clinical application in cancer centres

Status of cancer therapies

• Surgery is always the first option if possible.

• XBRT* continues to improve with intensity

modulated and conformal targeting with reduced

exposure to normal tissue. [*External Beam Radiotherapy]

• Brachytherapy for prostate is excellent.

• Local control of most cancers is very good; H&N

not so good; GBM very poor.

But patients still die from systemic disease.

Systemic problems

• Few therapies to stop the development of

advanced metastatic cancer from

micrometastases after local treatment of

primary.

• This is the achilles heel of cancer

management.

• Control of micrometastases means

improved prognosis .

Idea!!! Targeted Alpha Therapy

• Bi-213 radioisotope emits alpha radiation.

• Alpha radiation (8.4 MeV) is short range (80

µm) with high Linear Energy Transfer (LET)

and is highly toxic to targeted cells.

• Bi-213 labeled monoclonal antibody or protein

targets antigens expressed by cancer cells.

• Cancer cells and tumour blood vessel cells

killed, tumour regresses.

Why alphas?

Properties alphas betas toxins

Range ( m) 20-80 400-4000 zero*

Lifetime hours days weeks

Energy loss ~100 ~0.3 -

(keV/ m)

* Bystander effect?

Production of alpha emitting

radioisotopes

Actinium-225 : Bismuth-213 Generator

Ac-225 Isotope separation from Th-229,

imported into Australia

Ac-225 (10 d)-> Bi-213 (46 min)

ELEMENTS OF TAT

Radioisotope: Bi-213 (46 min) from Ac-225 (10 d)

Chelators: cDTPA; DTPA-CHX-A”

Targeting: 9.2.27 melanoma, GBM

WM-53 leukaemia

c30.6 colorectal

herceptin breast, ovarian

J591 prostate

C595 bladder, prostate, pancreatic

PAI2 breast, prostate, ovarian

Alpha conjugate: Bi213-chelator-MAb

What have we done?

• In vitro experiments

• In vivo studies

• Intralesional melanoma trial

• Systemic melanoma trial

• Biological dosimetry

Do

0 10 20 300.01

0.10

1.00

10.00

Do

Bi-213

Tb-152

Activity ( Ci)

Log

cel

l su

rviv

al

IN VITRO - MELANOMA

CONCLUSIONS - IN VITRO

1 Stable alpha-conjugates can be formed with mabs

and PAI-2.

2 Alpha-conjugates are highly selective of targeted

cancer cells.

3 In vitro cytotoxicity of alpha-conjugates:

>> beta conjugates,

>> non-specific alpha-conjugates and

>> free alpha isotope.

4 Lethal pathway is by apoptosis.

0 10 20 30 40 500

25

50

75Control

Mouse 2

Mouse 3

Mouse 4

Mouse 5

Post-inoculation period (d)

Tu

mo

ur

size

(m

m2)

In Vivo Melanoma: systemic2mCi/kg at 2 d post-inoculation of cancer cells

micrometastasis model

Intralesional TAT

CONCLUSIONS - IN VIVO

1 Activity tolerances: 8 mCi/kg for intra-peritoneal

injection.

2 Local TAT: complete inhibition of tumourigenesis

for all cancers.

3 Intralesional TAT: 300 Ci gives complete

regression of melanomas.

4 Systemic single dose TAT: all tumours experience

growth delay.

Intralesional TAT phase 1 clinical

trial - 2001

• Starting dose: 150 Ci for 3 patients, monitor

subjects at 2 and 4 weeks; HAMA assay.

• Increase by 300 Ci steps up to 1350 Ci for 15

patients.

• Measure pharmacokinetics with NaI detector over

injection site, kidneys, bladder.

• Derive clearance times in tumour and organs.

• Calculate organ exposures, dose detriment, cancer

risk.

Metastatic Melanoma

Tumour retention of alpha-RIC - Group IV (250uCi)

0.01

0.1

1

0 20 40 60 80 100 120

Time after injection (min)

Fra

cti

on

of

ad

min

iste

red

acti

vit

y

Patient 11

Patient 11 curve f it

Patient 12

Patient 12 curve f it

Patient 13

Patient 13 curve f it

Clearance at injected tumour

Phase 1 Trial of Systemic TAT for

metastatic melanoma - 2003

• IV administration of AIC through cannula.

• Escalation:, injected activities of 1.25, 2.5,

4, 5.5, 7.5, 12.5, 17.5, 23, 25 mCi.

• Cohort of 3 subjects per dose level.

• Monitor renal damage with serum creatinine

(SC) and glomerular filtration rate (GFR).

• 38 subjects treated to 25 mCi.

Adverse Events?

• No complications of any type or level.

• No change in glomerular filtration rate

(GFR) over 12 months.

• No change in serum creatinine (SC)

over 12 months.

Therapeutic Responses

• 10% partial response (ie tumour

regression).

• 40% stable disease.

• 50% no response (progressive disease).

• 10% long term survival (2-5 y).

Systemic TAT for metastatic

melanoma #7

H&E stain negative for melanoma

Lung, liver and sc tumours #18

• 2 chest lesions disappeared

• Jaw lesion regressed

• 3 lung lesions regressed

• Large liver lesions show stable

disease

Baseline #18

8 weeks #18

• TAT is originally designed for

subclinical, micrometastatic disease.

• Half-life too short (46 min) for AIC to

diffuse into solid tumours (24-48 h).

• Range too short (80 microns) for cross

fire.

• TAT cannot regress tumours!

How did this happen????

α

α

α

Tumour anti-vascular alpha therapy

(TAVAT)

• Leaky gaps between endothelial cells in neogenic

tumour capillaries.

• Pericytes and melanoma cells both express the

targeted MCSP antigen.

• Extra-vascular diffusion of AIC to target the MCSP

antigens on contiguous cells.

• Alpha emission kills endothelial cells.

• Neogenic capillary closes down & tumour regresses.

What next?Increase efficacy and reduce toxicity by:

• CHX-A” chelator for improved stability and

reduced dose to kidneys.

• High specific activity (SA~20 mCi/mg ) to reduce

antigen blocking by unlabeled Mab.

• Fractionated dose over 5 days to allow increased

tumour capillary permeability.

• Escalation of activity/FFM to eliminate over or

under dosing to obese or lean patients.

Pros……..

In spite of ANSTO not supporting the project in 1994:

• Gone from test tube to bed side,

• Achieved world class results,

• Good responses w/o adverse events,

• New protocol approved by SGH-HREC,

• Over 50 publications in TAT,

What could go wrong?

Cons: the perfect storm!Funding

• Low NHMRC rating at 40%!!!!!

• NSWCC does not renew funding support.

• Funds left to continue trial this year?

St George Hospital

• SESIAHS cuts salaried research scientists, offers

Voluntary Redundances.

• Clinical trial manager takes VR.

• Scientists terminated for alleged lack of funds.

• Promoted to Displaced Person!

• Site approval for approved clinical trial not

forthcoming.

Conspiracy or Karma?

• TAT is too good to let bureaucracy kill it off.

• Sydney Rotary Clubs: proposal to sponsor a

patient.

• Overseas PhD students enrolled.

• Displaced Persons must do something….

• Survive until next year’s funding round and the

next election.

The cancer dragon has a new

lease on life!!

TAVAT is the lance to target the

heart of the cancer dragon

Next trial: C595 for MUC1

• Our preclinical data and tumour IHC show

that breast, ovarian, prostate and pancreatic

cancers express the MUC1 receptor.

• Phase 1 clinical trial Bi-213-C595 to target

MUC1 expression in breast, ovarian, prostate

and pancreatic cancers.

• Trial design will follow the melanoma trial.

Other Clinical Trials

• MSK, NY: leukaemia – phase 1 with Bi213 TAT

completed; phase 2 chemo+TAT; phase 1 with

Ac225 trial

• Norway: bone pain - phase 1 &2 with Ac223

• Dusseldorf: lymphoma – phase 1 with Bi213

• Geneva: GBM – phase 1 with Bi213

• Duke Univ: GBM – phase 1 with At211 closed.

Hepatocellular Carcinoma (HCC)

• HCC is a major cancer in Asia, but not Australia.

• PhD student from Sun Yat-Sun University.

• HCC tumour blocks for testing MAbs by IHC.

• Best MAbs chelated with Bi-213 for in vitro

testing in HCC cell lines.

• Efficacy of TAT demonstrated in vivo by

inhibiting tumour growth and regressing tumours.

• Dose limiting organ and max tolerance dose

determined in vivo.