A Study of Ipatasertib (GDC-0068) in Combination With Fluoropyrimidine Plus Oxaliplatin in Participants With Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer

Study Overview
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Brief Summary
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This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy of ipatasertib in combination with oxaliplatin, 5-fluorouracil, and leucovorin (modified FOLFOX6 [mFOLFOX6]) chemotherapy in participants with advanced or metastatic gastric or gastroesophageal junction (GEJ) cancer. Participants will be randomized to receive either ipatasertib or placebo orally daily on Days 1 to 7 of each 14-day cycle in combination with mFOLFOX6 on Day 1 of each cycle.

Official Title
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A Randomized, Phase II, Placebo-controlled Study of Ipatasertib (GDC-0068), an Inhibitor to Akt, in Combination With Fluoropyrimidine Plus Oxaliplatin in Patients With Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: 5-Fluorouracil
* Drug: Ipatasertib
* Drug: Leucovorin
* Drug: Oxaliplatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Histologically documented, inoperable locally advanced or metastatic or recurrent gastric/GEJ adenocarcinoma, not amenable to curative therapy Measurable disease, according to RECIST v1.1 Life expectancy greater than or equal to (>/=) 12 weeks Adequate hematologic and organ function Exclusion Criteria: Previous chemotherapy for inoperable locally advanced or metastatic gastric/GEJ adenocarcinoma. Participants may have received prior neoadjuvant or adjuvant chemotherapy and/or radiation treatment for locally advanced gastric/GEJ adenocarcinoma, provided all treatments were completed >/= 6 months prior to randomization. Known human epidermal growth factor receptor 2 (HER2)-positive gastric/GEJ adenocarcinoma Radiation treatment within 28 days of randomization. Participants who have received palliative radiation treatment to peripheral sites (eg, bone metastases) within 28 days of randomization may be enrolled in the study if they have recovered from all acute, reversible effects and with notification of the Medical Monitor. Previous therapy for gastric/GEJ adenocarcinoma with Akt, phosphatidylinositol 3-kinase (PI3K), and/or mammalian target of rapamycin (mTOR) inhibitors Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization or anticipation of need for a major surgical procedure during the course of the study

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ipatasertib + mFOLFOX6<br>Participants will receive oral ipatasertib on Days 1 to 7 of each 14-day cycle in combination with mFOLFOX6, administered on Day 1 of each cycle. | Drug: 5-Fluorouracil<br>* Participants will receive bolus and infusional 5-fluorouracil on Day 1 of each 14-day cycle (as a part of mFOLFOX6 therapy), until disease progression or unacceptable toxicity. The infusion times for infusional 5-fluorouracil may be determined per local and/or institutional standards and product labeling.<br>Drug: Ipatasertib<br>* Participants will receive ipatasertib, 600 milligrams (mg) orally once daily on Days 1 to 7 of each 14-day cycle until disease progression or unacceptable toxicity.<br>Drug: Leucovorin<br>* Participants will receive leucovorin or equivalent substitute orally, on Day 1 of each 14-day cycle (as a part of mFOLFOX6 therapy), until disease progression or unacceptable toxicity.<br>Drug: Oxaliplatin<br>* Participants will receive oxaliplatin via intravenous (IV) infusion on Day 1 of each 14-day cycle (part of mFOLFOX6 therapy). Oxaliplatin will be discontinued after completion of 8 cycles<br>|
| Placebo Comparator: Placebo + mFOLFOX6<br>Participants will receive the placebo equivalent to ipatasertib on Days 1 to 7 of each 14-day cycle in combination with mFOLFOX6, administered on Day 1 of each cycle. | Drug: 5-Fluorouracil<br>* Participants will receive bolus and infusional 5-fluorouracil on Day 1 of each 14-day cycle (as a part of mFOLFOX6 therapy), until disease progression or unacceptable toxicity. The infusion times for infusional 5-fluorouracil may be determined per local and/or institutional standards and product labeling.<br>Drug: Leucovorin<br>* Participants will receive leucovorin or equivalent substitute orally, on Day 1 of each 14-day cycle (as a part of mFOLFOX6 therapy), until disease progression or unacceptable toxicity.<br>Drug: Oxaliplatin<br>* Participants will receive oxaliplatin via intravenous (IV) infusion on Day 1 of each 14-day cycle (part of mFOLFOX6 therapy). Oxaliplatin will be discontinued after completion of 8 cycles<br>Drug: Placebo<br>* Participants will receive matching oral placebo capsules once daily on Days 1 to 7 of each 14-day cycle until disease progression or unacceptable toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) in All Randomized Participants and Participants With PTEN Loss Tumors at Primary Analysis | PFS was defined as the time from randomization to the first occurrence of disease progression (as determined using RECIST Version 1.1 and assessed by the investigator), or death from any cause on study. Progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or progression of non-target lesions. Death on study was defined as death from any cause within 30 days of the last dose of study treatment regimen. Kaplan-Meier estimates were used for evaluation. | Screening, at the end of Cycle 4 (cycle = 14 days) and every fourth cycle thereafter until disease progression or death, whichever occurred first, assessed up to approximately 1.75 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from the date of randomization to the date of death from any cause. Kaplan-Meier estimates were used for evaluation. | Baseline up to end of study (up to approximately 7.5 years) | 
| Objective Response Rate (ORR) | Objective Response Rate was defined as the percentage of participants achieving either a complete response (CR) or a partial response (PR) based on the investigator assessment using RECIST v 1.1. CR: disappearance of all target lesions and all pathological lymph nodes below 10 mm. Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions. | Screening, at the end of Cycle 4 (cycle = 14 days) and every fourth cycle thereafter until disease progression or death, whichever occurred first, up to end of study (up to approximately 7.5 years) | 
| Duration of Objective Tumor Response | Duration of objective tumor response in participants with measurable soft tissue disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST Version 1.1. PD: At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or progression of non-target lesions. | Screening, at the end of Cycle 4 (cycle = 14 days) and every fourth cycle thereafter until disease progression or death, whichever occurred first, up to end of study (up to approximately 7.5 years) | 
| Number of Participants With Adverse Events (AEs) | An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Death on study was defined as death from any cause within 30 days of the last dose of study treatment regimen. | Baseline until end of study (up to approximately 7.5 years) | 
| Serum Concentration of Ipatasertib |  | Day 1 at 1 hour and 4 hours post-dose; Day 5, pre-dose and 2 hours post-dose |