Gastric Cancer
Conditions
Brief summary
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.
Interventions
DRUG5-Fluorouracil
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.
DRUGIpatasertib
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.
DRUGLeucovorin
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.
DRUGOxaliplatin
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
DRUGPlacebo
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.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) in All Randomized Participants and Participants With PTEN Loss Tumors at Primary Analysis | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Baseline up to end of study (up to approximately 7.5 years) | 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. |
| Objective Response Rate (ORR) | 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) | 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. |
| Duration of Objective Tumor Response | 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 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. |
| Number of Participants With Adverse Events (AEs) | Baseline until end of study (up to approximately 7.5 years) | 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. |
| Serum Concentration of Ipatasertib | Day 1 at 1 hour and 4 hours post-dose; Day 5, pre-dose and 2 hours post-dose | — |
Countries
France, Germany, Hong Kong, Italy, Malaysia, Singapore, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 33 centers in 11 countries.
Pre-assignment details
Total 153 participants were randomized in this study, of which 152 participants received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Ipatasertib + mFOLFOX6 Ipatasertib was administered at a dose of 600 milligrams (mg) orally once daily, beginning on Day 1 of Cycle 1 through Day 7 of each 14-day cycle until the participant experienced disease progression or intolerable toxicity. Following ipatasertib administration on Day 1 of each cycle, the participant then received mFOLFOX6 in the following order: oxaliplatin as an 85 milligram per square-meter (mg/m\^2) intravenous (IV) infusion on Day 1 every 14 days with co-administration of leucovorin at 400 mg/m\^2 or equivalent substitute. The participant then received 5-fluorouracil (5-FU) as a 400 mg/m\^2 bolus infusion followed by 5-FU as a 2400 mg/m\^2 continuous IV infusion (or 5-FU as a 1200 mg/m\^2/day continuous IV infusion). Following Cycle 8, oxaliplatin was discontinued. | 71 |
| Placebo + mFOLFOX6 Placebo matched to ipatasertib was administered orally once daily, beginning on Day 1 of Cycle 1 through Day 7 of each 14-day cycle until the participant experienced disease progression or intolerable toxicity. Following placebo administration on Day 1 of each cycle, the participant then received mFOLFOX6 in the following order: oxaliplatin as an 85 mg/m\^2 IV infusion on Day 1 every 14 days with co-administration of leucovorin at 400 mg/m\^2 or equivalent substitute. The participant then received 5-FU as a 400 mg/m\^2 bolus infusion followed by 5-FU as a 2400 mg/m\^2 continuous IV infusion (or 5-FU as a 1200 mg/m\^2/day continuous IV infusion). Following Cycle 8, oxaliplatin was discontinued. | 82 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 57 | 59 |
| Overall Study | Death Prior to Treatment | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 0 |
| Overall Study | Non-compliance | 0 | 1 |
| Overall Study | Study Ended by Sponsor | 7 | 20 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Ipatasertib + mFOLFOX6 | Placebo + mFOLFOX6 | Total |
|---|---|---|---|
| Age, Continuous | 57.6 years STANDARD_DEVIATION 11.4 | 61.4 years STANDARD_DEVIATION 11 | 59.6 years STANDARD_DEVIATION 11.3 |
| Race/Ethnicity, Customized Asian | 43 Participants | 45 Participants | 88 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 67 Participants | 81 Participants | 148 Participants |
| Race/Ethnicity, Customized Not Stated | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 25 Participants | 36 Participants | 61 Participants |
| Sex: Female, Male Female | 19 Participants | 22 Participants | 41 Participants |
| Sex: Female, Male Male | 52 Participants | 60 Participants | 112 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 57 / 70 | 59 / 82 |
| other Total, other adverse events | 70 / 70 | 79 / 82 |
| serious Total, serious adverse events | 39 / 70 | 36 / 82 |
Outcome results
Primary
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.
Time frame: 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
Population: The randomized population was defined as all participants who were randomized in the study. Randomized participants with PTEN loss tumors were also analyzed. For the primary analysis, PTEN loss was defined as the condition Perc Cells Cytoplasmic Stain Int 0 of greater than or equal to 10.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ipatasertib + mFOLFOX6 | Progression-Free Survival (PFS) in All Randomized Participants and Participants With PTEN Loss Tumors at Primary Analysis | All Randomized Participants | 6.57 months |
| Ipatasertib + mFOLFOX6 | Progression-Free Survival (PFS) in All Randomized Participants and Participants With PTEN Loss Tumors at Primary Analysis | Participants With PTEN Loss Tumors | 7.10 months |
| Placebo + mFOLFOX6 | Progression-Free Survival (PFS) in All Randomized Participants and Participants With PTEN Loss Tumors at Primary Analysis | All Randomized Participants | 7.52 months |
| Placebo + mFOLFOX6 | Progression-Free Survival (PFS) in All Randomized Participants and Participants With PTEN Loss Tumors at Primary Analysis | Participants With PTEN Loss Tumors | 7.39 months |
Comparison: All randomized participantsp-value: =0.5690% CI: [0.81, 1.55]Log Rank
Comparison: Participants with PTEN loss tumorsp-value: =0.8690% CI: [0.54, 2.11]Log Rank
Secondary
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.
Time frame: 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)
Population: All randomized participants, randomized participants with PTEN loss tumors and randomized participants who were Akt diagnostic-positive (Akt Dx+) were analyzed. For the final analysis, PTEN loss was defined as the condition Perc Cells Cytoplasmic Stain Int 0 of greater than 10.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ipatasertib + mFOLFOX6 | Duration of Objective Tumor Response | Randomized | 4.63 months |
| Ipatasertib + mFOLFOX6 | Duration of Objective Tumor Response | PTEN Loss Tumor | 4.70 months |
| Ipatasertib + mFOLFOX6 | Duration of Objective Tumor Response | Akt Dx+ | 4.70 months |
| Placebo + mFOLFOX6 | Duration of Objective Tumor Response | PTEN Loss Tumor | 5.98 months |
| Placebo + mFOLFOX6 | Duration of Objective Tumor Response | Randomized | 5.85 months |
| Placebo + mFOLFOX6 | Duration of Objective Tumor Response | Akt Dx+ | 6.80 months |
Comparison: All randomized participantsp-value: =0.597490% CI: [0.76, 1.73]Log Rank
Comparison: Participants with PTEN loss tumorsp-value: =0.538590% CI: [0.28, 1.79]Log Rank
Comparison: Participants who are Akt Dx+p-value: =0.609790% CI: [0.35, 1.75]Log Rank
Secondary
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.
Time frame: Baseline until end of study (up to approximately 7.5 years)
Population: The safety population was defined as all randomized participants who received at least one dose of ipatasertib/placebo or mFOLFOX6, with participants grouped according to the treatment actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ipatasertib + mFOLFOX6 | Number of Participants With Adverse Events (AEs) | 70 Participants |
| Placebo + mFOLFOX6 | Number of Participants With Adverse Events (AEs) | 80 Participants |
Secondary
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.
Time frame: 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)
Population: All randomized participants, randomized participants with PTEN loss tumors and randomized participants who were Akt diagnostic-positive (Akt Dx+) were analyzed. For the final analysis, PTEN loss was defined as the condition Perc Cells Cytoplasmic Stain Int 0 of greater than 10.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ipatasertib + mFOLFOX6 | Objective Response Rate (ORR) | Akt Dx+ | 52.2 percentage of participants |
| Ipatasertib + mFOLFOX6 | Objective Response Rate (ORR) | Randomized | 52.1 percentage of participants |
| Ipatasertib + mFOLFOX6 | Objective Response Rate (ORR) | PTEN Loss Tumors | 50.0 percentage of participants |
| Placebo + mFOLFOX6 | Objective Response Rate (ORR) | Randomized | 57.3 percentage of participants |
| Placebo + mFOLFOX6 | Objective Response Rate (ORR) | PTEN Loss Tumors | 73.3 percentage of participants |
| Placebo + mFOLFOX6 | Objective Response Rate (ORR) | Akt Dx+ | 56.5 percentage of participants |
Comparison: All randomized participantsp-value: =0.520290% CI: [-18.46, 8.06]Cochran-Mantel-Haenszel
Comparison: Participants with PTEN loss tumorsp-value: =0.203590% CI: [-52.24, 5.58]Cochran-Mantel-Haenszel
Comparison: Participants who are Akt Dx+p-value: =0.769790% CI: [-28.48, 19.79]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: Baseline up to end of study (up to approximately 7.5 years)
Population: All randomized participants, randomized participants with PTEN loss tumors and randomized participants who were Akt diagnostic-positive (Akt Dx+) were analyzed. For the final analysis, PTEN loss was defined as the condition Perc Cells Cytoplasmic Stain Int 0 of greater than 10.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ipatasertib + mFOLFOX6 | Overall Survival (OS) | PTEN Loss Tumors | 14.82 months |
| Ipatasertib + mFOLFOX6 | Overall Survival (OS) | Randomized | 11.96 months |
| Ipatasertib + mFOLFOX6 | Overall Survival (OS) | Akt Dx+ | 11.66 months |
| Placebo + mFOLFOX6 | Overall Survival (OS) | Randomized | 15.31 months |
| Placebo + mFOLFOX6 | Overall Survival (OS) | PTEN Loss Tumors | 21.78 months |
| Placebo + mFOLFOX6 | Overall Survival (OS) | Akt Dx+ | 17.22 months |
Comparison: All randomized participantsp-value: =0.023490% CI: [1.12, 2.07]Log Rank
Comparison: Participants with PTEN loss tumorsp-value: =0.286790% CI: [0.75, 3.65]Log Rank
Comparison: Participants who are Akt Dx+p-value: =0.136990% CI: [0.94, 2.93]Log Rank
Secondary
Serum Concentration of Ipatasertib
Time frame: Day 1 at 1 hour and 4 hours post-dose; Day 5, pre-dose and 2 hours post-dose
Population: The pharmacokinetic (PK) population was defined as all participants with evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ipatasertib + mFOLFOX6 | Serum Concentration of Ipatasertib | Day 5: 2 hours post-dose | 557 ng/mL | Standard Deviation 328 |
| Ipatasertib + mFOLFOX6 | Serum Concentration of Ipatasertib | Day 1: 1 hour post-dose | 506 ng/mL | Standard Deviation 550 |
| Ipatasertib + mFOLFOX6 | Serum Concentration of Ipatasertib | Day 1: 4 hours post-dose | 389 ng/mL | Standard Deviation 202 |
| Ipatasertib + mFOLFOX6 | Serum Concentration of Ipatasertib | Day 5: pre-dose | 90.7 ng/mL | Standard Deviation 61 |