| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PREVIOUSLY UNTREATED ADVANCED OR RECURRENT NON-SMALL CELL LUNG CANCER |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with previously untreated, advanced or recurrent non-small cell lung cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part I
•To evaluate the efficacy (as measured by PFS) of GDC-0941 340mg+carboplatin+paclitaxel (Arm A) versus carboplatin+paclitaxel (Arm B) in all patients with squamous NSCLC
•To evaluate the efficacy (as measured by PFS) of GDC-0941 340mg+carboplatin+paclitaxel (Arm A) versus carboplatin+paclitaxel (Arm B) in patients with squamous NSCLC with PIK3CA amplification
•To evaluate the efficacy (as measured by PFS) of GDC-0941 340mg+carboplatin+paclitaxel+bevacizumab (Arm C) versus carboplatin+paclitaxel+bevacizumab (Arm D) in all patients with non-squamous NSCLC
•To evaluate the efficacy (as measured by PFS) of GDC-0941 340mg+carboplatin+paclitaxel+bevacizumab (Arm C) versus carboplatin+paclitaxel+bevacizumab (Arm D) in patients with non-squamous NSCLC with PTEN-loss/low status
Part II
•To evaluate the efficacy (as measured by PFS) of GDC-0941 260mg+ carboplatin+paclitaxel+bevacizumab (Arm E) versus carboplatin+paclitaxel+bevacizumab (Arm F) in all patients with non-squamous NSCLC |
|
| E.2.2 | Secondary objectives of the trial |
| Due to the character limit for this field, please refer to protocol section 2.2 for secondary objectives |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For ALL Arms, patients must meet the following criteria to undergo screening procedures:
• Signed Informed Consent Form
• All patients must consent to the collection of an archival formalin-fixed paraffin embedded (FFPE) block or freshly cut unstained tumor slides from archival tumor tissue (10–15 preferred, minimum of 5 slides required) or a newly collected tumor sample 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 central or local study pathologist and discussed with the Genentech Medical Monitor.
Patients with no available archival tissue (or if the sample is difficult to obtain) may undergo a new tumor biopsy to meet eligibility criteria, as long as the patient consents to this and the biopsy can be obtained with minimal risk and discomfort to the patient as determined by the local investigator.
Adequate tumor tissue content of the patient’s archival tumor sample must be confirmed by the site’s pathologist or a third-party vendor prior to randomization of the patient (please see Section 4.5.1.e for details).
For Arms A and B, patients must meet the following criteria to be eligible:
• Histologically documented advanced (Stage IV) or recurrent squamous NSCLC
Diagnoses of squamous NSCLC that are based on cytology alone are not acceptable.
Mixed tumors should be categorized according to the predominant cell type.
For Arms C, D, E & F, patients must meet the following criteria to be eligible:
• Histologically documented advanced (Stage IV) or recurrent non-squamous NSCLC
Diagnoses of non-squamous NSCLC that are based on cytology alone are not acceptable.
Mixed tumors should be categorized according to the predominant cell type.
For ALL Arms, patients must meet the following criteria to be eligible:
• Age ≥ 18 years
• ECO performance status of 0 or 1 (see Appendix E)
• Disease that is measurable per RECIST v1.1 (see Appendix C)
• Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:
Absolute neutrophil count (ANC) ≥ 1500 cells/μL
Without granulocyte colony stimulating factor support within 2 weeks prior to randomization
Platelet count ≥ 100,000/μL
Without transfusion within 2 weeks prior to randomization
Hemoglobin ≥ 9.0 g/dL (90 g/L)
Patients may be transfused to meet this criterion.
Albumin ≥ 3.0 g/dL (30 μmol/L)
Total bilirubin ≤ 1.5 x ULN
AST and ALT ≤ 3.0 x ULN
Serum creatinine ≤ 1.5 x ULN, or creatinine clearance ≥ 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation:
(140-age) x (weight in kg) x (0.85 if female) / 72 x (serum creatinine in mg/dL)
INR ≤ 1.5 and aPTT ≤ 1.5 x ULN, except for patients receiving allowed anti-coagulation therapy
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 1 week prior to randomization
• 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 supplemented with a spermicide, 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, D, E, and F, continued use until 6 months after study treatment discontinuation or paclitaxel discontinuation, whichever is longer, is required.
For males in Arms A, B, C, and D, E and F continued use until 90 days after study treatment discontinuation or 6 months after discontinuation of paclitaxel, whichever is longer, is required. |
|
| E.4 | Principal exclusion criteria |
Exlusion criteria for all arms:
•NSCLC with documented EGFR mutation associated with response to EGFR inhibitors 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 Day1 of Cycle1 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 Day1 of Cycle1)
Patients who receive hormone-replacement therapy or oral contraceptives are not excluded
Patients who received herbal therapy >2 weeks prior to Day1 of Cycle1 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 (eg 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 & 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 Day1 of Cycle1 will be excluded
•Leptomeningeal disease
•Malignancies other than NSCLC successfully treated within 3 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, & carcinoma in situ of any anatomic location treated with curative intent
•Type I diabetes
•Type II diabetes requiring chronic therapy with insulin
•Requirement for supplemental oxygen therapy to perform activities of daily living
•Unstable angina
•Serious cardiac arrhythmia requiring medication during the study
•New York Heart Association Class II or greater congestive heart failure
•History of malabsorption syndrome or other condition that would interfere with enteral absorption
•Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 of Cycle 1, or anticipation of need for major surgical procedure during the course of the study
Placement of vascular access device will not be considered major surgery
•Clinically significant history of liver disease, including cirrhosis, active viral hepatitis and current alcohol abuse
•Known HIV infection
•Active infection requiring IV antibiotics
•Active inflammatory diseases that require immunosuppressants, including small or large intestine inflammation such as Crohn's disease or ulcerative colitis
- Patients currently receiving immunosuppressants (e.g., sulfasalazines) are considered to have active disease and are therefore ineligible.
•Active autoimmune disease that is not controlled by nonsteroidal anti inflammatory drugs
•Need for current chronic corticosteroid therapy (≥10 mg of prednisone per day or an equivalent dose of other anti inflammatory corticosteroids)
Stable use (within 3 months prior to Day 1 of Cycle 1) of inhaled corticosteroids is allowed
•Pregnancy, lactation, or breastfeeding
•Uncontrolled hypercalcemia, defined as values above the ULN, despite optimal management including bisphosphonate therapy
Chronic use of bisphosphonate therapy for other reasons (eg bone metastasis, osteoporosis, etc) is allowed
•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 (eg clinically significant cardiovascular, pulmonary, or metabolic disease)
Refer protocol (section 4.1.3.2) for remaining Exclusion Criteria and (section 4.1.3.2) for Bevacizumab-Specific Exclusion Criteria for Arms C,D,E&F |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
For ALL Arms and all predefined study populations (see Section 3.5), the
primary efficacy outcome measure is:
• PFS, defined as the time from randomization to NSCLC disease progression as assessed by the investigator per RECIST v1.1 (Appendix C) or death from any cause on study (≤ 30 days after the last dose of study treatment) whichever occurs first |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
For ALL Arms and all predefined study populations (see Section 3.5), the secondary efficacy outcome measures are:
• Objective tumor response as assessed by the investigator using RECIST v1.1 (Appendix C); objective responses must be confirmed ≥ 28 days after initial response
• Duration of objective response, defined as the time from first observation of an objective tumor response until first observation of disease progression as assessed by the investigator using RECIST v1.1 (Appendix C)
• OS, defined as the time from randomization until death from any cause |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Italy |
| Netherlands |
| Argentina |
| Australia |
| Brazil |
| Chile |
| Germany |
| Hungary |
| Spain |
| Israel |
| Russian Federation |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| When last patient reaches overal survival (OS) or is lost to follow up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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