confidential & proprietary © 2009, genentech confidential & proprietary © 2009, genentech...
TRANSCRIPT
Confidential & Proprietary© 2009, Genentech
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
Page 1
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Study Rationale and Design
Enrollment and Eligibility
Assessment and Biomarker
Dose Modification and Analysis
2
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Study Rationale
3
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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%
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 5
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 6
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 7
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Study DesignStudy Design
8
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
12
Non-Squamous R
Arm C
Arm D
0941CarboplatinPaclitaxelBevacizumab
0941Bevacizuma
b
PlaceboCarboplatinPaclitaxelBevacizumab
PlaceboBevacizum
ab
Chemotherapyx 4 cycles
Maintenanceto PD
GDC-0941 tablet = 340 mg
Stratification•Performance status•Smoking
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
13
R
Arm A/CGDC-0941
Arm B/DPlacebo
GDC-0941C/P ± B
Chemotherapyx 4 cycles
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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.
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Enrollment Process
Inclusion and Exclusion Criteria
15
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
16
Screening Study treatmentInformed Consent
Archival tissue? Suitable?
Enrollment Process
Labs/ECG: 14 days
CT: 28 days
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Review
ArchivalTissue
Tissue Submission
TissueBlock
Slides(5-15)
FreshBiopsy
SitePathologist
EsoterixNo
EsoterixPathologist
Respository
17
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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.
Page 18
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 19
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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.
Page 20
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Key Exclusion criteria (all Arms)
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.
Page 21
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Key Exclusion criteria (all Arms)
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
Page 22
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 23
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 24
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Study Assessments
25
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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 #
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Dose Modifications
32
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Dose modification – general guidelines Page 33
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 34
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Anticipated Adverse Events – GDC-0941
GDC-0941-associated toxicities:– Hematologic
– Rash
– Hyperglycemic
– Pulmonary
– Hepatic
– Gastrointestinal
– Cardiac
Page 35
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 36
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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 Page 37
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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 Page 38
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Paclitaxel 150 mg/m2
Carboplatin AUC 5.0or
Paclitaxel 200 mg/m2
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.
Page 39
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Paclitaxel 200 mg/m2
Carboplatin AUC 6
Nadir of last course 25,000/mm3
Hold paclitaxel, carboplatin, and GDC-
0941
Paclitaxel 150 mg/m2
Carboplatin AUC 5.0
AUC area under the curve.
Page 40
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 41GI toxicities Page 41
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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 Page 42
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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 Page 43
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Neurologic toxicity Page 44
•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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
45
GDC-0941 Dose modification guidelines Page 45
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
46
GDC-0941 Dose modification for non-infectious pneumonitis Page 46
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 47
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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 Page 48
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Excluded Therapies
49
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 50
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 51
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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.
Page 52
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Unblinding
Study Endpoints
Interim Analysis
53
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
54
Cross-Over
Subsequent Therapy
Unblinding
GNEMMGNEMM
Non-Emergency
Emergency
GNEMMGNEMM
SAE
PD
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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.
Page 55
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Page 56
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
59
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
62
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
64
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
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.
65
Confidential & Proprietary© 2009, Genentech
Confidential & Proprietary© 2009, Genentech
Questions
66