A Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GDC-0973 in Combination With GDC-0068 When Administered in Participants With Locally Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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This open-label, multicenter, Phase Ib dose-escalation study will evaluate the safety, tolerability and pharmacokinetics of oral dosing of GDC-0973 and GDC-0068 administered in combination in patients with locally advanced or metastatic solid tumors. Cohorts of patients will receive multiple ascending doses of GDC-0973 and GDC-0068. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.

Official Title
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A Phase Ib, Open-Label, Dose-Escalation Study of the Safety, Tolerability and Pharmacokinetics of GDC-0973 and GDC-0068 in Patients With Locally Advanced or Metastatic Solid Tumors

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Ipatasertib
* Drug: Cobimetinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically documented locally advanced or metastatic solid tumors for which standard therapies either do not exist or have proven ineffective or intolerable Evaluable disease or disease measurable per Response Evaluation Criteria in Solid Tumors (RECIST) Life expectancy >/= 12 weeks Adequate hematologic and end organ function Exclusion Criteria: History of prior significant toxicity from another MEK pathway inhibitor requiring discontinuation of treatment History of prior significant toxicity from another phosphoinositide 3-kinase (PI3K) or Akt pathway or mammalian target of rapamycin (mTOR) inhibitor requiring discontinuation of treatment Anti-cancer therapy within 28 days prior to first dose of study drug, except as stated in protocol History of type I or type II diabetes mellitus requiring insulin Current severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary, or metabolic disease) Clinically significant history of liver disease, current alcohol abuse, or current known active infection with HIV, hepatitis B or hepatitis C virus Active autoimmune disease Pregnant or lactating women Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms History of glaucoma History of retinal vein occlusion

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation stage 1 (Arm A): Cobimetinib and Ipatasertib<br>Participants will receive cobimetinib (GDC-0973) capsules (at a starting dose of 40 mg) and ipatasertib (GDC-0068) capsules (at a starting dose of 200 mg) from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Doses will be increased to identify maximum tolerated dose (MTD) or potential recommended Phase 2 dose (RP2D). Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. | Drug: Ipatasertib<br>* multiple doses<br>* Other names: GDC-0068;Drug: Cobimetinib<br>* multiple doses<br>* Other names: GDC-0973;|
| Experimental: Dose escalation stage 1 (Arm B): Cobimetinib and Ipatasertib<br>Participants will receive cobimetinib (GDC-0973) capsules (at a starting dose of 100 mg) on Days 1, 4, 8, 11, 15, and 18 and ipatasertib (GDC-0068) capsules (at a starting dose of 200 mg) from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Doses will be increased to identify MTD or potential RP2D. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. | Drug: Ipatasertib<br>* multiple doses<br>* Other names: GDC-0068;Drug: Cobimetinib<br>* multiple doses<br>* Other names: GDC-0973;|
| Experimental: Stage 2 (Indication specific dose expansion cohort)<br>Participants will receive cobimetinib (GDC-0973) capsules on Days 1, 4, 8, 11, 15, and 18 and ipatasertib (GDC-0068) capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with phosphatase and tensin homolog (PTEN)-loss triple-negative breast cancer and PTEN-loss endometrial carcinoma. | Drug: Ipatasertib<br>* multiple doses<br>* Other names: GDC-0068;Drug: Cobimetinib<br>* multiple doses<br>* Other names: GDC-0973;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | DLT is defined as 1 of the following toxicities considered by the investigator to be possibly related to study drugs: a) Grade (G) ≥3 febrile neutropenia, b) G ≥4 neutropenia (absolute neutrophil count [ANC] <500/ microliter [μL]) lasting >5 days , c) G ≥4 thrombocytopenia lasting >2 days, d) G ≥4 anemia, e) G ≥3 elevation of total bilirubin or hepatic transaminase or alkaline phosphatase (ALP) lasting >3 days, f) Hepatic transaminases >3 × Upper Limit of Normal (ULN) and an increase in total bilirubin >2 × ULN without any findings of cholestasis and in the absence of other contributory factors, g) G ≥2 visual changes that do not resolve to baseline within 14 days, h) 1 episode of fasting G 4 hyperglycemia or 3 episodes of fasting, i) G 3 hyperglycemia on separate days within 7 days, j) G ≥4 fasting hypercholesterolemia or triglyceridemia for ≥2 weeks, k) G ≥3 nausea, vomiting, or diarrhea despite maximal supportive medications lasting for ≥3 days. | Cycle 1 (28 Days) | 
| Number of DLTs Categorized as Per the Nature | DLT is defined as 1 of the following toxicities considered by the investigator to be possibly related to study drugs: a) G ≥3 febrile neutropenia, b) G ≥4 neutropenia (ANC <500/μL) lasting >5 days , c) G ≥4 thrombocytopenia lasting >2 days, d) G ≥4 anemia, e) G ≥3 elevation of total bilirubin or hepatic transaminase or ALP lasting >3 days, f) Hepatic transaminases >3 × ULN and an increase in total bilirubin >2 × ULN without any findings of cholestasis and in the absence of other contributory factors, g) G ≥2 visual changes that do not resolve to baseline within 14 days, h) 1 episode of fasting G 4 hyperglycemia or 3 episodes of fasting, i) G 3 hyperglycemia on separate days within 7 days, j) G ≥4 fasting hypercholesterolemia or triglyceridemia for ≥2 weeks, k) G ≥3 nausea, vomiting, or diarrhea despite maximal supportive medications lasting for ≥3 days. Hematologic, Hepatic and non-hematologic and non-hepatic DLT categories were to be reported. | Cycle 1 (28 Days) | 
| Maximum Tolerated Doses (MTDs) in Combination of Cobimetinib and Ipatasertib During Dose-Escalation Stage 1 | An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. On the basis of AEs that did not meet protocol-defined DLT criteria (defined in Outcome measure 1) but indicated intolerability of a given dose combination, the combination MTDs were determined (as per investigator) during Stage 1 of the study. | Cycle 1 (28 Days) | 
| Number of Participants With At Least One AE Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version (V) 4.0 | AE was defined in Outcome Measure 3. AEs were graded as per NCI CTCAE V 4.0 as follows: G 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily living (ADL) (instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money and others); G 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL (refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden); G 4: Life-threatening consequences, urgent intervention indicated; G 5: Death related to AE. If a participant had multiple events of different grades, the highest grade that occurred in that participant was counted. | From Baseline up to 30 days after the last dose of study treatment or until initiation of another anticancer treatment whichever occurred first (Up to 33 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Concentration-Time Curve From Time Zero to Last Measurable Concentration After Dose [AUC0-Last] of Ipatasertib and Cobimetinib on Day 1 and Day 15 |  | Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1 | 
| Maximum Plasma Concentration (Cmax) of Ipatasertib and Cobimetinib on Day 1 and Day 15 |  | Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1 | 
| Time Taken to Reach Cmax (Tmax) of Ipatasertib and Cobimetinib on Day 1 and Day 15 |  | Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1 | 
| Last Measurable Concentration (Clast) of Ipatasertib and Cobimetinib on Day 1 and Day 15 |  | Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1 | 
| Number of Participants With Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | RECIST v1.1 (for measurable disease), CR: disappearance of all target lesions, reduction in short axis <10 millimeters in pathological lymph nodes (target and non-target lesions); PR: at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Responses were confirmed by repeat assessments ≥4 weeks after initial documentation. | Screening, Days 21-28 of Cycle 2, Day 25 (± 3 days) of Cycle 4 and every 8 weeks thereafter till study completion (Up to 33 months) | 
| Duration of Objective Response for Participants With Measurable Disease According to RECIST v1.1 | Duration of response, defined as the time from first occurrence of a documented objective response until the time of disease progression, as determined by investigator review of tumor assessments using RECIST 1.1, or death from any cause during the study (i.e., within 30 days after the last dose of study treatment). | Screening, Days 21-28 of Cycle 2, Day 25 (± 3 days) of Cycle 4 and every 8 weeks thereafter till study completion (Up to 33 months) | 
| Progression-Free Survival (PFS) Time for Participants With Measurable Disease According to RECIST v1.1 | PFS is defined as the time from study treatment initiation to the first occurrence of disease progression, as determined by investigator review of tumor assessments using RECIST 1.1, or death from any cause during the study (i.e., within 30 days after the last dose of study treatment). | Screening, Days 21-28 of Cycle 2, Day 25 (± 3 days) of Cycle 4 and every 8 weeks thereafter till study completion (Up to 33 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEK, GDC0973, MEK inhibitor, GDC0068, Akt, Akt inhibitor