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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT01562275
First received: March 21, 2012
Last updated: February 25, 2016
Last verified: February 2016
Results First Received: February 25, 2016  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Safety Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Neoplasms
Interventions: Drug: Ipatasertib
Drug: Cobimetinib

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Study included two stages. Stage 1: dose escalation cohorts (DEC), consisted of Arm A (concurrent 21 day dosing followed by 7 day dosing holiday) and Arm B (intermittent dosing). Stage 2: indication specific expansion cohorts (PTEN-low endometrial carcinoma and PTEN-low triple-negative breast cancer) treated with recommended phase 2 dose.

Reporting Groups
  Description
DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib Participants received oral 40 milligrams (mg) cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Participants with endometrial carcinoma received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib Participants with triple negative breast cancer received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.

Participant Flow for 2 periods

Period 1:   Stage 1
    DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib     DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib     DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib     DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib     DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib     Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib     Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib  
STARTED     3     7     3     4     4     4     3     7     3     7     3     0     0  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     3     7     3     4     4     4     3     7     3     7     3     0     0  
Adverse Event                 0                 0                 0                 1                 1                 0                 0                 0                 0                 1                 0                 0                 0  
Death                 1                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0  
Non Compliance                 0                 0                 1                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0  
Physician Decision                 0                 0                 0                 0                 1                 0                 1                 0                 1                 0                 0                 0                 0  
Progression of Disease                 2                 6                 2                 1                 2                 4                 1                 7                 2                 5                 3                 0                 0  
Withdrawal by Subject                 0                 1                 0                 2                 0                 0                 1                 0                 0                 1                 0                 0                 0  

Period 2:   Stage 2
    DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib     DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib     DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib     DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib     DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib     Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib     Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib  
STARTED     0     0     0     0     0     0     0     0     0     0     0     14     5  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     0     0     0     0     0     0     0     0     0     0     0     14     5  
Death                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 2                 1  
Progression of Disease                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 12                 4  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All enrolled participants.

Reporting Groups
  Description
DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib Participants received oral 40 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Participants with endometrial carcinoma received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib Participants with triple negative breast cancer received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22−28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
Total Total of all reporting groups

Baseline Measures
    DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib     DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib     DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib     DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib     DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib     DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib     Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib     Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib     Total  
Number of Participants  
[units: participants]
  3     7     3     4     4     4     3     7     3     7     3     14     5     67  
Age  
[units: years]
Mean (Standard Deviation)
  61.0  (3.5)     59.1  (8.7)     58.3  (5.5)     66.8  (16.5)     62.3  (7.0)     51.8  (10.9)     59.0  (9.2)     58.6  (11.9)     61.0  (13.7)     57.6  (10.9)     52.7  (24.9)     62.9  (8.7)     49.0  (10.1)     59.0  (11.0)  
Gender  
[units: participants]
                           
Female     2     4     1     3     3     4     2     3     2     4     1     14     5     48  
Male     1     3     2     1     1     0     1     4     1     3     2     0     0     19  



  Outcome Measures
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1.  Primary:   Number of Participants With Dose Limiting Toxicities (DLTs)   [ Time Frame: Cycle 1 (28 Days) ]

2.  Primary:   Number of DLTs Categorized as Per the Nature   [ Time Frame: Cycle 1 (28 Days) ]

3.  Primary:   Maximum Tolerated Doses (MTDs) in Combination of Cobimetinib and Ipatasertib During Dose-Escalation Stage 1   [ Time Frame: Cycle 1 (28 Days) ]

4.  Primary:   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   [ Time Frame: 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) ]

5.  Secondary:   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   [ Time Frame: Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1 ]

6.  Secondary:   Maximum Plasma Concentration (Cmax) of Ipatasertib and Cobimetinib on Day 1 and Day 15   [ Time Frame: Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1 ]

7.  Secondary:   Time Taken to Reach Cmax (Tmax) of Ipatasertib and Cobimetinib on Day 1 and Day 15   [ Time Frame: Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1 ]

8.  Secondary:   Last Measurable Concentration (Clast) of Ipatasertib and Cobimetinib on Day 1 and Day 15   [ Time Frame: Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1 ]

9.  Secondary:   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)   [ Time Frame: 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) ]

10.  Secondary:   Duration of Objective Response for Participants With Measurable Disease According to RECIST v1.1   [ Time Frame: 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) ]

11.  Secondary:   Progression-Free Survival (PFS) Time for Participants With Measurable Disease According to RECIST v1.1   [ Time Frame: 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) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
As per changes in the planned analysis, PFS and duration of response outcome measures were not analyzed as only few participants experienced a measurable response.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Communications
Organization: Hoffmann-LaRoche
phone: 800-821-8590
e-mail: genentech@druginfo.com



Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT01562275     History of Changes
Other Study ID Numbers: GE28079
2012-003934-18 ( EudraCT Number )
Study First Received: March 21, 2012
Results First Received: February 25, 2016
Last Updated: February 25, 2016
Health Authority: United States: Food and Drug Administration