Trial Outcomes & Findings for A Study of Ipatasertib (GDC-0068) in Combination With Fluoropyrimidine Plus Oxaliplatin in Participants With Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer (NCT NCT01896531)

Last Updated: 2022-03-02

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

153 participants

Primary outcome timeframe

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

Results posted on

2022-03-02

Participant Flow

The study was conducted at 33 centers in 11 countries.

Total 153 participants were randomized in this study, of which 152 participants received treatment.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	71	82
Overall Study Treated	70	82
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	71	82

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Death	57	59
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
Overall Study Death Prior to Treatment	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ipatasertib + mFOLFOX6 n=71 Participants 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.	Placebo + mFOLFOX6 n=82 Participants 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.	Total n=153 Participants Total of all reporting groups
Age, Continuous	57.6 years STANDARD_DEVIATION 11.4 • n=5 Participants	61.4 years STANDARD_DEVIATION 11.0 • n=7 Participants	59.6 years STANDARD_DEVIATION 11.3 • n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	22 Participants n=7 Participants	41 Participants n=5 Participants
Sex: Female, Male Male	52 Participants n=5 Participants	60 Participants n=7 Participants	112 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	67 Participants n=5 Participants	81 Participants n=7 Participants	148 Participants n=5 Participants
Race/Ethnicity, Customized Not Stated	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Asian	43 Participants n=5 Participants	45 Participants n=7 Participants	88 Participants n=5 Participants
Race/Ethnicity, Customized White	25 Participants n=5 Participants	36 Participants n=7 Participants	61 Participants n=5 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Unknown	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ipatasertib + mFOLFOX6 n=71 Participants 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.	Placebo + mFOLFOX6 n=82 Participants 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.
Progression-Free Survival (PFS) in All Randomized Participants and Participants With PTEN Loss Tumors at Primary Analysis All Randomized Participants	6.57 months Interval 5.72 to 7.52	7.52 months Interval 6.24 to 8.11
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 Interval 5.39 to 9.92	7.39 months Interval 6.51 to 14.69

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Ipatasertib + mFOLFOX6 n=71 Participants 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.	Placebo + mFOLFOX6 n=82 Participants 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.
Overall Survival (OS) Randomized	11.96 months Interval 10.28 to 14.55	15.31 months Interval 13.54 to 16.92
Overall Survival (OS) PTEN Loss Tumors	14.82 months Interval 11.99 to 18.4	21.78 months Interval 14.13 to NA: not estimable due to low number of events
Overall Survival (OS) Akt Dx+	11.66 months Interval 9.92 to 18.4	17.22 months Interval 12.71 to 23.29

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ipatasertib + mFOLFOX6 n=71 Participants 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.	Placebo + mFOLFOX6 n=82 Participants 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.
Objective Response Rate (ORR) Randomized	52.1 percentage of participants Interval 41.74 to 62.35	57.3 percentage of participants Interval 48.02 to 66.59
Objective Response Rate (ORR) PTEN Loss Tumors	50.0 percentage of participants Interval 26.36 to 73.64	73.3 percentage of participants Interval 50.0 to 87.82
Objective Response Rate (ORR) Akt Dx+	52.2 percentage of participants Interval 33.51 to 70.39	56.5 percentage of participants Interval 38.05 to 72.67

SECONDARY outcome

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.

Outcome measures

Outcome measures
Measure	Ipatasertib + mFOLFOX6 n=37 Participants 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.	Placebo + mFOLFOX6 n=47 Participants 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.
Duration of Objective Tumor Response Akt Dx+	4.70 months Interval 3.84 to 14.78	6.80 months Interval 4.86 to 10.71
Duration of Objective Tumor Response Randomized	4.63 months Interval 4.01 to 5.52	5.85 months Interval 4.47 to 6.9
Duration of Objective Tumor Response PTEN Loss Tumor	4.70 months Interval 4.27 to NA: not estimable due to low number of events	5.98 months Interval 4.86 to 10.94

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Ipatasertib + mFOLFOX6 n=70 Participants 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.	Placebo + mFOLFOX6 n=82 Participants 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.
Number of Participants With Adverse Events (AEs)	70 Participants	80 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ipatasertib + mFOLFOX6 n=64 Participants 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.	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.
Serum Concentration of Ipatasertib Day 5: pre-dose	90.7 ng/mL Standard Deviation 61.0	—
Serum Concentration of Ipatasertib Day 5: 2 hours post-dose	557 ng/mL Standard Deviation 328	—
Serum Concentration of Ipatasertib Day 1: 1 hour post-dose	506 ng/mL Standard Deviation 550	—
Serum Concentration of Ipatasertib Day 1: 4 hours post-dose	389 ng/mL Standard Deviation 202	—

Adverse Events

Ipatasertib + mFOLFOX6

Serious events: 39 serious events

Other events: 70 other events

Deaths: 57 deaths

Placebo + mFOLFOX6

Serious events: 36 serious events

Other events: 79 other events

Deaths: 59 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the study but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER