Download - Confidential & Proprietary © 2009, Genentech Confidential & Proprietary © 2009, Genentech A PHASE II, DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED STUDY

Confidential & Proprietary© 2009, Genentech


A PHASE II, DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED STUDY EVALUATING THE SAFETY AND EFFICACY OF CARBOPLATIN/PACLITAXEL AND CARBOPLATIN/PACLITAXEL/BEVACIZUMAB WITH AND WITHOUT GDC-0941 IN PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED OR RECURRENT NON-SMALL CELL LUNG CANCER



Study Rationale and Design

Enrollment and Eligibility

Assessment and Biomarker

Dose Modification and Analysis

2



Study Rationale

3



4

Squamous Cell

Adenocarcinoma

PIK3CA PTEN

Amplification Mutation Loss Low (Loss/Low)

30%30% 2%2% 30%30% 50%50%

6%6% 2%2% 4%4% 30%30%



Objectives (squamous)

Primary– To evaluate the efficacy (PFS) of GDC-0941 + carboplatin paclitaxel (Arm A)

versus carboplatin paclitaxel (Arm B) in all patients with squamous NSCLC– To evaluate the efficacy (PFS) of GDC-0941 + carboplatin paclitaxel (Arm A)

versus carboplatin paclitaxel (Arm B) in patients with squamous NSCLC with PIK3CA amplification

Secondary– To assess the clinical activity (ORR, duration of response and OS), of GDC-0941 +

carboplatin paclitaxel (Arm A) versus carboplatin paclitaxel (Arm B) in all patients with squamous NSCLC and in patients with squamous NSCLC with PIK3CA amplification

– To evaluate the safety and tolerability of GDC-0941 when combined with carboplatin paclitaxel in all patients with squamous NSCLC

– To assess specific PK parameters of GDC‑0941 (Cmax and Cmin) and sparse paclitaxel and carboplatin concentrations when administered in combination to patients with squamous or non-squamous NSCLC

– To assess the prevalence of PIK3CA amplification and PTEN-loss/low status in tumor samples from patients with squamous or non-squamous NSCLC

– To assess the prognostic effects of PIK3CA amplification and PTEN-loss/low status on PFS in patients with squamous or non-squamous NSCLC



Objectives (non-squamous)

Primary– To evaluate the efficacy (PFS) of GDC-0941 + carboplatin paclitaxel bevacizumab

(Arm C) versus carboplatin paclitaxel bevacizumab (Arm D) in all patients with non-squamous NSCLC

– To evaluate the efficacy (PFS) of GDC-0941 + carboplatin paclitaxel bevacizumab (Arm C) versus carboplatin paclitaxel bevacizumab (Arm D) in patients with non-squamous NSCLC with PTEN-low status

Secondary– To assess the clinical activity (ORR, duration of response and OS), of GDC-0941 +

carboplatin paclitaxel bevacizumab (Arm C) versus carboplatin paclitaxel bevacizumab (Arm D) in all patients with non-squamous NSCLC and in patients with non-squamous NSCLC with PTEN-low status

– To evaluate the safety and tolerability of GDC-0941 when combined with carboplatin paclitaxel + bevacizumab in all patients with non-squamous NSCLC

– To assess specific PK parameters of GDC‑0941 (Cmax and Cmin) and sparse paclitaxel and carboplatin concentrations when administered in combination to patients with squamous or non-squamous NSCLC

– To assess the prevalence of PIK3CA amplification and PTEN-loss/low status in tumor samples from patients with squamous or non-squamous NSCLC

– To assess the prognostic effects of PIK3CA amplification and PTEN-loss/low status on PFS in patients with squamous or non-squamous NSCLC



Objectives (exploratory)

To explore oncogenic alterations of EGFR, KRAS, LKB1, MET and other potential biomarkers in archival tumor (or new biopsy, if archival tissue is not available), circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and/or tumor DNA in urine:– Prevalence– Value as predictors of response to GDC-0941 + carboplatin paclitaxel with or without

bevacizumab compared with standard of care without GDC-0941

To measure the number of CTCs and levels of cancer-associated proteins in blood, and assess their value as predictors of response to GDC-0941 + carboplatin paclitaxel with or without bevacizumab compared with standard of care without GDC-0941

To explore predictors of response to GDC-0941 + carboplatin paclitaxel with or without bevacizumab compared with standard of care without GDC-0941 based on exploratory analyses using molecular data obtained from tumor tissue by exon resequencing, mRNA and/or miRNA expression profiling and/or DNA copy number profiling

To assess the potential relationship between concentration of GDC-0941, paclitaxel and carboplatin and tumor response and/or safety

To explore the relationship between pharmacogenetic differences in drug‑metabolizing enzymes and transporters and other patient-specific covariates with pharmacokinetics and pharmacodynamics of GDC-0941 when administered in combination with carboplatin paclitaxel with or without bevacizumab



Study DesignStudy Design

8



Untreated advanced NSCLC: stage IV at diagnosis prior radiation or surgery allowed chemotherapy for advanced NSCLC not allowed

Untreated recurrent NSCLC: stage I, II, or III at diagnosis prior radiation or surgery allowed chemotherapy for stage I, II, III allowed: > 12 mo. chemotherapy for recurrent NSCLC not allowed not a candidate for curative-intent treatment

9



10

1L NSCLCMetastaticRecurrent

Squamous

Non-SquamousBev-eligible

Non-SquamousBev-ineligible

R

R

X

Arm A

Arm B

Arm C

Arm D

~150 patients

~150 patients

1 : 1

1 : 1



11

Squamous R

Arm A

Arm B

0941CarboplatinPaclitaxel

0941

PlaceboCarboplatinPaclitaxel

Placebo

Chemotherapyx 4 cycles

Maintenanceto PD

GDC-0941 tablet = 340 mg

Stratification•Performance status•Smoking



12

Non-Squamous R

Arm C

Arm D

0941CarboplatinPaclitaxelBevacizumab

0941Bevacizuma

b

PlaceboCarboplatinPaclitaxelBevacizumab

PlaceboBevacizum

ab


Maintenanceto PD

GDC-0941 tablet = 340 mg

Stratification•Performance status•Smoking



13

R

Arm A/CGDC-0941

Arm B/DPlacebo

GDC-0941C/P ± B


Maintenanceto PD

GDC-0941± B

PlaceboC/P ± B

Placebo± B

PDPD PDPD

• Cross-over is allowed during or after chemotherapy• Patients can cross-over to the GDC-0941 arm ONLY if:

• They have PD; AND • Following unblinding (upon request) they have been on placebo



14

Study drug + Carboplatin/Paclitaxel ± BevacizumabStudy drug + Carboplatin/Paclitaxel ± Bevacizumab

Study drug ± BevacizumabStudy drug ± Bevacizumab

Study drug: 14/21 Study drug: 14/21 daysdays

Study drug: 21/21 daysStudy drug: 21/21 daysStudy drug: 21/21 daysStudy drug: 21/21 days

x 4 Cyclesx 4 Cycles

Cycle 5 to PDCycle 5 to PD

Study drug: GDC-0941 @ 340 mg or PlaceboStudy drug: GDC-0941 @ 340 mg or Placebo

Chemotherapy PhaseChemotherapy Phase

Maintenance PhaseMaintenance Phase

CR, PR, CR, PR, SDSD

Hold: 28 days Hold: 28 days max.max.

Hold: 28 days Hold: 28 days max.max.



Enrollment Process

Inclusion and Exclusion Criteria

15



16

Screening Study treatmentInformed Consent

Archival tissue? Suitable?

Enrollment Process

Labs/ECG: 14 days

CT: 28 days



Review

ArchivalTissue

Tissue Submission

TissueBlock

Slides(5-15)

FreshBiopsy

SitePathologist

EsoterixNo

EsoterixPathologist

Respository

17



Key Inclusion criteria (all Arms)

Signed Informed Consent Form

All patients must consent to the collection, from archival tumor tissue or new biopsy, of freshly cut unstained tumor slides from a formalin-fixed paraffin‑embedded (FFPE) block (10 – 15 preferred, minimum of 5 slides required) for PIK3CA amplification testing and/or PTEN IHC, as well as for other protocol-mandated exploratory assessments.– Availability of archival tissue for biomarker testing must be confirmed by the site prior

to any study-specific screening procedures. – Suitability of archival non-FFPE tissue must be evaluated by the local study

pathologist and discussed with the Genentech Medical Monitor. ECOG Performance Score of 0 or 1 Adequate hematologic and end organ function For female patients of childbearing potential and male patients with partners of

childbearing potential, agreement (by patient and/or partner) to use two effective forms of contraception (e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants)– For females in Arms A and B, continued use for the duration of the study treatment or

6 months after discontinuation of paclitaxel, whichever is longer, is required – For females in Arms C and D, continued use until 6 months after study treatment

discontinuation is required.– For males in Arms A, B, C, and D, continued use until 90 days after study treatment or

6 months after discontinuation of paclitaxel, whichever is longer, is required.



Key Inclusion criteria (all Arms – glucose)

For patients without known type II diabetes, the following is required:– Fasting blood glucose < 135 mg/dL (7.49 mmol/L) and HbA1c < 7.0%

For patients with type II diabetes receiving oral anti-hyperglycemic therapy the following is required:– Fasting blood glucose < 160 mg/dL (8.88 mmol/L) and HbA1c < 8.5– Stable regimen of oral anti-hyperglycemic therapy without the use of

insulin for at least 3 weeks prior to randomization– Fasting blood glucose levels < 160 mg/dL (8.88 mmol/L) and no

hypoglycemia during home monitoring for at least one week prior to randomization



Key Exclusion criteria (all Arms)

NSCLC with documented EGFR mutation or documented fusion gene involving the anaplastic lymphoma kinase (ALK) gene (such as EML4-ALK)

Prior therapy (including chemotherapy, antibody therapy, tyrosine kinase inhibitors, radiotherapy, immunotherapy, hormonal therapy, or investigational therapy) before Day 1 of Cycle 1 for the treatment of advanced (Stage IV) or recurrent NSCLC– Patients who received prior adjuvant chemotherapy or radiotherapy for

NSCLC are not excluded if the time interval from completion of adjuvant therapy until disease progression is 12 months.

– Patients who received prior palliative radiotherapy for metastatic or lobar lesions (not including target lesions) are not excluded (if > 2 weeks prior to Day 1 of Cycle 1).

– Patients who receive hormone-replacement therapy or oral contraceptives are not excluded.

– Patients who received herbal therapy > 2 weeks prior to Day 1 of Cycle 1 are not excluded.




Evidence of tumor invading major blood vessels on imaging– The investigator or the local radiologist must exclude evidence of tumor that

is fully contiguous with, surrounding, or extending into the lumen of a major blood vessel (e.g., pulmonary artery or superior vena cava).

Known CNS disease except for treated brain metastases– Treated brain metastases are defined as having no evidence of progression

or hemorrhage > 2 weeks after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period.

– Stable doses of non-enzyme inducing anti-convulsants are allowed.– Treatment for brain metastases may include whole brain radiotherapy,

radiosurgery (Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician and if > 2 weeks have passed since radiation treatment.

– Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 of Cycle 1 will be excluded.




Type I diabetes

Type II diabetes requiring chronic therapy with insulin

Uncontrolled hypercalcemia, defined as values above the ULN, despite optimal management including bisphosphonate therapy

Chronic use of bisphosphonate therapy for other reasons (e.g., bone metastasis, osteoporosis, etc.) is allowed.

Active inflammatory diseases that require immunosuppressants, including small or large intestine inflammation such as Crohn’s disease or ulcerative colitis

Uncontrolled hypomagnesemia or hypokalemia, defined as values below the LLN despite optimal electrolyte supplementation or management

Grade 2 peripheral neuropathy

Known severe hypersensitivity to taxanes or platinums or any of their excipients (including mannitol and macroglycol ricinoleate)

Inability or unwillingness to swallow pills

Inability to comply with study and follow‑up procedures

Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease)

Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk for treatment complications



Bevacizumab-related Exclusion criteria (Arms C and D)

Histology Histologically or cytologically documented, advanced, mixed nonsmall cell

and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component

Cardiac Inadequately controlled hypertension (defined as systolic blood pressure

150 mmHg and/or diastolic blood pressure 100 mmHg) – Anti-hypertensive therapy to achieve these parameters is allowed

Prior history of hypertensive crisis or hypertensive encephalopathy History of myocardial infarction within 6 months prior to Day 1 of Cycle 1 History of stroke or transient ischemic attacks (TIAs) within 6 months prior

to Day 1 of Cycle 1



Bevacizumab-related Exclusion criteria (Arms C and D)

Bleeding/Vascular-related Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral

arterial thrombosis) within 6 months prior to Day 1 of Cycle 1 History of hemoptysis defined as bright red blood of 1/2 teaspoon within 1 month prior to Day 1 of

Cycle 1 Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic

anticoagulation)

Wound healing Minor surgery, including insertion of an indwelling catheter, within 48 hours prior to Day 1 of Cycle 1 History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months prior to Day

1 of Cycle 1 Patients diagnosed with a tracheo-esophageal fistula Serious, non-healing wound, active ulcer, or untreated bone fracture

Others Proteinuria, as demonstrated by 2.0 g of protein in a 24‑hour collection

– All patients with 2 protein on dipstick urinalysis at baseline must undergo 24‑hour urine collection for protein

Known hypersensitivity to bevacizumab, or any of its excipients, other recombinant, human or humanized antibodies, or Chinese hamster ovary (CHO) cell products



Study Assessments

25



The same imaging modality MUST be used at baseline and throughout the study.

26

Anatomy Preferred Alternative

Chest* CT w/ contrast CT w/o contrast

Abdomen* CT w/ contrast MRI w/ contrast

Brain* MRI w/ contrast CT w/ contrast

Bone (if indicated) MRI w/contrast CT w/ contrast

Other (if indicated) As indicated As indicated

* Required at baseline



New baseline tumor assessment at cross-over

– PD: target lesions ≥20% from nadir

Baseline = last tumor assessment at time of PD

– PD due to new lesion: the new lesion will be added as a target lesion; baseline is the total of all measurable lesions.

Baseline ≠ last tumor assessment at time of PD

27



Study assessments and Cycles

Assessments that are independent of Cycle # /study drug administration

– Tumor assessments (MUST occur every 6 weeks)

– CTCs (at time of tumor assessments)

– CAPs (at time of tumor assessments)

Assessments are largely based on “Cycles”/study drug administration, – Lab assessments

– PK

– Urinalysis

– ECG

28

TAs and Safety assessments may be out of sync, in which case sites must be trained to stay on top of every patients Study Day # and Cycle #



Besides mandatory archival tissue,

• On-study biomarker assessments (to coincide with tumor assessments)

Predose, then every 6 weeks• Circulating tumor cells

• Circulating cancer-associated proteins

At times urine dipstick is required• Urine for tumor DNA (mainly non-squamous arms)

Predose• Circulating tumor DNA

• Optional fresh tumor biopsies

• Optional collection of other previously obtained tumor tissues

• Optional collection of tumor and other tissues obtained during study for non-study reasons

On-study biomarker assessments29

CONFIDENTIAL INFORMATION - DO NOT COPY OR FORWARD



CT scans and ECGs All clinical decision based on local read No real-time central read Central: assess quality and collect scans for future

centralized reads if necessary

30



12

2

8

15FFPEslides

H&E stain (verification)

PIK3CA FISH

PTEN IHC assay

Exploratory assays(Gene expression panel, LKB1, MET)

Blood Circulating Tumor Cell (CTC), ctDNA,Cancer Associated Proteins (CAPs)

Urine tumor DNA

Mutation panel (PIK3CA, EGFR, KRAS)2

Employ assays to maximize information on PI3K pathway status in a given patient

31

.

Urine



Dose Modifications

32



Dose modification – general guidelines

PI decision to hold or discontinue any or all study treatments

General guidance for common toxicities are provided in protocol

Maximum hold for drug-related AEs is 28 consecutive days (some exceptions allowed on a case-by-case basis)

Patients who discontinue part of the regimen due to intolerability may continue on study and receive remaining components of the regimens



Dose modification – general guidelines

Chemotherapy phase (depending on the AE and attribution): – If 0941 held: continue chemo (& bev if applicable)– If chemo held: hold 0941, but continue with bev if held for AE due to

chemo

Bev: Hold/delay OK, no dose reductions allowed– Bev may be on a 4 week cycle ONLY in order to sync up with GDC-0941

administration, tumor assessments etc with drug administration

GDC-941/Placebo – Two dose reductions allowed (260 mg, 200 mg)– D/C study treatment if further reductions needed– re-escalate in maintenance only for reductions that occurred in

chemotherapy phase. If reduction occurs ≥Cycle 5, no re-escalations allowed



Anticipated Adverse Events – GDC-0941

GDC-0941-associated toxicities:– Hematologic

– Rash

– Hyperglycemic

– Pulmonary

– Hepatic

– Gastrointestinal

– Cardiac



Table 2 Dose Reductions for GDC-0941/Placebo

Dose Level GDC-0941/Placebo

0 340

1 260

2 200

Indication for further dose reduction Discontinue treatment



CBC counts obtained 96 hrs prior to Day 1 of each Cycle. ANC ≥1500 mm3 and platelet ≥100,000/mm3 required to proceed. If not:

– ANC (Absolute neutrophil counts – duration dependent): If <1500/mm3 (G2 or higher) – hold C-T and 941/Placebo until counts recover

– If ≥1500/mm3 (G1) within 14 days – C/T may be dose reduced if needed; no dose reduction of GDC-0941 necessary

– If not ≥1500/mm3 (G1) within 14 days – dose reduce to paclitaxel to 150 mg/m2 and carboplatin to AUC 5 and GDC-0941

– Febrile neutropenia (regardless of duration): ANC<1000/mm3, with a single temperature of >38.3°C (101°F) OR a sustained temperature of ≥38°C (100.4°F) Hold C-T and 941/Placebo; consider dose reduction of paclitaxel to 150 mg/m2 and carboplatin to

AUC 5 OR no dose reduction with G-CSF starting Day 2

– Platelet count For Day 1 counts:

– If <100,000/mm3 (G1 or higher), hold C-T and 941/Placebo For nadir counts (from last course)

– If <25,000/mm3 (G4) hold C-T and 941/Placebo; when counts are ≥100,000, dose reduce to paclitaxel to 150 mg/m2 and carboplatin to AUC 5

37

Hematologic toxicities – first episode



For second episode of decreased ANC and/or platelet counts, a second dose reduction of paclitaxel to 100 mg/m2 and carboplatin to AUC 4 is allowed

For second episode of febrile neutropenia, G-CSF treatment should be considered.

38

• Need for a third dose reduction of C-T will mandate discontinuation of chemotherapy – GDC-0941/placebo may be continued after discussion with GNE MM

• Need for a third dose reduction of 941/placebo will mandate discontinuation of study treatment

Hematologic toxicities – second episode



Table 3 Dosing Based on ANC and Febrile Neutropenia

ANC (Day 1 of each cycle) 1500/mm3 1500/mm3

Hold paclitaxel, carboplatin, and

GDC‑0941

Paclitaxel 200 mg/m2

Carboplatin AUC 6.0

Febrile neutropenia (regardless of duration)

Hold paclitaxel, carboplatin, and

GDC‑0941


Carboplatin AUC 5.0or


Carboplatin AUC 6.0with G-CSF starting

on Day 2

ANC absolute neutrophil count; AUC area under the curve; G-CSF granulocyte colony‑stimulating factor.



Table 4 Dosing Based on Platelet Count

Platelet count(Day 1 of each

cycle)

< 100,000/mm3 ≥ 100,000/mm3

Hold paclitaxel, carboplatin, and GDC-

0941


Carboplatin AUC 6

Nadir of last course 25,000/mm3

Hold paclitaxel, carboplatin, and GDC-

0941


Carboplatin AUC 5.0

AUC area under the curve.



Nausea/vomiting – use adequate anti-emetics– For continued G3/4 nausea/vomiting despite anti-emetics, 20% dose

reduction in C-T allowed.

Stomatitis– acute G3 stomatitis: hold; dose reduce C-T after stomatitis has completely

cleared; dose reduce GDC-0941 per protocol

– All other cases: hold C-T and 941/placebo until stomatitis has cleared. If >14 days, discuss with GNE MM about a revised regimen and potential dose reductions. If GDC-0941/placebo was held until C4, treatment may resume (with bev if applicable)

41

Re-escalate C-T as soon as possible

GI toxicities Page 41



AST and total bilirubin must be obtained within 96 hours prior to start of each cycle

42

If T is held, hold C and GDC-0941/placebo. Restart C-T and GDC-0941/placebo when bilirubin is 1.5x ULN

Hepatic toxicities



Asymptomatic bradycardia: no treatment required

Symptomatic arrhythmia: stop the paclitaxel infusion; manage the arrhythmia according to standard practice; discontinue paclitaxel

Chest pain and/or symptomatic hypotension ( 90/60 mmHg or required fluid replacement): stop the paclitaxel infusion; perform an ECG; discontinue paclitaxel; discontinuation of study treatment should be considered.

43

Cardiac toxicities



Neurologic toxicity

•If paclitaxel is held, hold carboplatin and GDC-0941/placebo•If no recovery within 14 days, discontinue paclitaxel •Dose reductions with paclitaxel are permanent•No dose reduction with carboplatin, GDC-0941/placebo

Grade Paclitaxel dose

0 200 mg/m2

1 200 mg/m2

2 Hold paclitaxel, carboplatin and GDC-0941 until patient recovers to Grade 1, then resume

paclitaxel, carboplatin and GDC-0941, with paclitaxel at 160 mg/m2 (a 20% reduction)

3 Hold paclitaxel, carboplatin and GDC-0941 until patient recovers to Grade 1, then resume

paclitaxel, carboplatin and GDC-0941, with paclitaxel at 140 mg/m2 (a 30% reduction)

Table 7



45

GDC-0941 Dose modification guidelines



46

GDC-0941 Dose modification for non-infectious pneumonitis



Anticipated Adverse Events - bevacizumab

Bevacizumab-associated toxicities:– Hypertension

– Proteinuria

– Thromboembolic events (arterial and venous)

– Congestive heart failure

– GI perforations

– Non-GI fistula formation

– Wound healing complications

– Hemorrhage

– Tumor-associated hemorrhage

– Reversible Posterior Leukoencephalopathy Syndrome

– Neutropenia



48

EVENT Hold Bevacizumab Discontinue Bevacizumab

Hypertension - G3 uncontrolled HTNG4 HTN

Hemorrhage

G3 non-pulmonary or non-CNS hemorrhage (see protocol for restart guidelines) - hold all study tx.

G4 non-pulmonary or non-CNS hemorrhage; hold all study tx; see protocol for restart guidelines for remaining study tx.

G1 pulmonary or CNS hemorrhage (see protocol for restart guidelines)

≥G2; hold all study tx; see protocol for restart guidelines for remaining study tx.

Venous thrombolic event G3 or asymptomatic G4 Symptomatic G4

Arterial thromboembolic event - Any gradeCHF - ≥Grade 3; hold all study tx until ≤G2

Proteinuria G2; consider discontinuation for G3 G4GI perforation - Any grade

Fistula - Any grade tracheoesophageal fistulaG4 non-tracheoesophageal fistula

Bowel obstruction - ≥G2; hold all study tx until ≤G1

Wound dehiscence - Any grade; hold all study tx until adequately treated

RPLS - Any grade; hold all study tx until adequately treated

Bevacizumab hold or discontinuation guidelines



Excluded Therapies

49



Excluded therapies

Grapefruit juice or grapefruit supplements

St. John’s Wort or hyperforin

Proton‑pump inhibitors (it is recommended that these agents be replaced with an H2-receptor antagonist when feasible; see below for instructions regarding H2-receptor antagonists)

Any concomitant therapy intended for the treatment of cancer (regulatory approved or experimental), including chemotherapy, radiation therapy, immunotherapy, biologic therapy, herbal therapy, or hormonal therapy.

Quinidine or other anti‑arrhythmic agents. Stable doses of beta-blockers or calcium-channel blockers are permitted.

– As a guide in determining whether a certain medication is known to prolong the QT Interval or induce Torsades de Pointes, the following Internet reference may be used:

http://www.azcert.org/medical-pros/drug-lists/printable-drug-list.cfm



Excluded therapies

Chronic systemic corticosteroid use ( 10 mg of prednisone or an equivalent dose of other anti‑inflammatory corticosteroids) for 7 days or use of other immunosuppressants

Enzyme-inducing anticonvulsants (e.g., phenobarbital, carbamazepine, and phenytoin)

In addition, the following therapies are prohibited as indicated during the treatment period:

H2-receptor antagonists within 10 hours prior to or 2 hours after a GDC‑0941 dose (except on days of paclitaxel administration)

– For H2-receptor antagonist therapy as premedication for paclitaxel, parenteral (IV) ranitidine or famotidine is to be given, and other H2‑receptor antagonists, such as cimetidine, are not allowed.

– For oral H2-receptor antagonist therapy as antiulcer or acid suppressant therapy, ranitidine, famotidine, or nazatidine is to be given, and other H2-receptor antagonists, such as cimetidine, are not allowed. Bedtime dosing regimens are preferred to lessen potential pH effects on GDC‑0491 absorption.

Antacids within 4 hours of a GDC-0941 dose



Excluded therapies

On the basis of in vitro data suggesting that GDC-0941 is partially metabolized by CYP3A4, drugs that are known strong CYP3A4 inducers or inhibitors, such as those listed below, should be avoided. If use of one of these drugs is necessary, the risks and benefits should be discussed with the Genentech Medical Monitor prior to its concomitant use with GDC-0941/placebo:

– Strong CYP3A4/5 inhibitors such as but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandamycin, and voriconazole

– Strong CYP3A4/5 inducers such as but not limited to rifampin, carbamazepine, rifapentine, phenytoin, and phenobarbital

Patients who require use of a CYP3A4/5 inhibitor or inducer that is deemed not permissible by the Genentech Medical Monitor after enrollment will discontinue GDC-0941/placebo but may continue to receive study treatment with the remaining agents at the discretion of the investigator.



Unblinding

Study Endpoints

Interim Analysis

53



54

Cross-Over

Subsequent Therapy

Unblinding

GNEMMGNEMM

Non-Emergency

Emergency

GNEMMGNEMM

SAE

PD



Study Withdrawal

Patients may be withdrawn from the study if they experience any of the following: Disease progression, per investigator assessment Intolerable toxicity due to GDC-0941 Other reasons for patient discontinuation may include, but are not limited to,

the following: Change in patient eligibility Non-compliance Patient decision If the patient becomes pregnant The investigator has the right to discontinue a patient from the study for any

medical condition that the investigator determines may jeopardize the patient’s safety if he or she continues in the study; for reasons of noncompliance (e.g., missed doses, visits); or if the investigator determines it is in the best interest of the patient.

See Sections 4.5.4 and 4.5.5 for assessments that are to be performed for patients who prematurely withdraw from the study during the treatment period.



Events of Special Interest

The following events are events of special interest and will need to be reported to the Sponsor expeditiously (see Section 5.4 for reporting instructions), irrespective of regulatory seriousness criteria:

Grade 4 : proteinuria, hypertension, hyperglycemia Grade 3: Symptomatic hyperglycemia, colitis, rash, Symptomatic CHF (left

ventricular systolic dysfunction Grade 3, should also be graded using the NYHA classification)

Grade 2: pneumonitis, pulmonary hemorrhage, intracranial hemorrhage, spinal cord hemorrhage

Any grade acute coronary syndrome or myocardial infarction Any bleeding events associated with thrombocytopenia that require a

blood transfusion Wound dehiscence requiring medical or surgical intervention Any of the following adverse events of any grade: Arterial thromboembolic event GI perforation



Study treatment discontinuation, study discontinuation, and censoring

57

Tx PD

X-over

Off-Tx

Off-Study(D/LTF)

PD

Tx Off-Tx*

Off-Study(D/LTF)

PD

PFS (C)§ PFS

PFS

OS

OS

crossover phase

on placebo

on 941

*AE, withdrawal of consent, intolerability§censored PFS point if no further scans are available

D/LTF = Death or loss to follow-up



Internal Monitoring Committee Clinical scientist, biostatistician, statistical programmer, clinical

pharmacologist, drug safety officer Independent from PI3K team

Interim Analysis #1: Safety 10 pts in each arm after 3rd tumor assessment (4 cycles)

Interim Analysis #2: Safety and Efficacy 60 events of PD in all Arms Preliminary efficacy analysis

58

Additional safety data analysis per Additional safety data analysis per MM requestMM request

Additional safety data analysis per Additional safety data analysis per MM requestMM request



59



SECTION 4.1.2: INCLUSION CRITERIAFor female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use two effective forms of contraception (e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants)For females in Arms A and B, continued use for the duration of the study treatment or 6 months after discontinuation of paclitaxel, whichever is longer, is required.For females in Arms C and D, continued use until 6 months after study treatment discontinuation is required.For males in Arms A, B, C, and D, continued use until 90 days after study treatment or 6 months after discontinuation of paclitaxel, whichever is longer, is required.

60



SECTION 4.1.3: EXCLUSION CRITERIA

Known CNS disease except for treated brain metastases

Stable doses of non-enzyme inducing anti-convulsants are allowed

Active inflammatory diseases that require immunosuppressants, including small or large intestine inflammation such as Crohn’s disease or ulcerative colitis

Known severe hypersensitivity to taxanes or platinums, or any of their excipients (including mannitol and macroglycol ricinoleate)

61



62



APPENDIX APregnancy testing at every Day 1 of every Cycle for women of childbearing potential, including premenopausal women who have had a tubal ligation

63



64



Genentech guidelines (in accordance with authorship criteria of the International Committee of Medical Journal Editors)

Substantial intellectual contributions to the publication*

Factors that determine order of authors• Number of patients an investigator enrolled• Contribution to study design and execution• Contribution to data analysis and interpretation• Contribution to manuscript writing and revision

Genentech must approve any publication* of the data associated with the molecule and the clinical trial

* Manuscript submitted to a peer-reviewed journal; an abstract, poster, or oral presentation presented at a conference.

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Questions

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