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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

March 21, 2012
February 25, 2016
April 2012
January 2015   (final data collection date for primary outcome measure)
  • Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (28 Days) ] [ Designated as safety issue: Yes ]
    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.
  • Number of DLTs Categorized as Per the Nature [ Time Frame: Cycle 1 (28 Days) ] [ Designated as safety issue: Yes ]
    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.
  • Maximum Tolerated Doses (MTDs) in Combination of Cobimetinib and Ipatasertib During Dose-Escalation Stage 1 [ Time Frame: Cycle 1 (28 Days) ] [ Designated as safety issue: No ]
    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.
  • 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) ] [ Designated as safety issue: No ]
    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.
  • Incidence of dose-limiting toxicities [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
  • Nature of dose-limiting toxicities [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
  • Estimation of the maximum tolerated dose [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
  • Incidence of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
  • Nature of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
  • Severity of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
  • Incidence of serious adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
  • Nature of serious adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
  • Severity of serious adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01562275 on ClinicalTrials.gov Archive Site
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
    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.
  • 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) ] [ Designated as safety issue: No ]
    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).
  • 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) ] [ Designated as safety issue: No ]
    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).
  • Pharmacokinetic parameters of GDC-0973 and GDC-0068: total exposure [ Time Frame: Days 1, 8, and 15 pre-dose and up to 24 h post-dose for Cycle 1 and Day 1 on Cycles 2 and 3 ] [ Designated as safety issue: No ]
  • Pharmacokinetic parameters of GDC-0973 and GDC-0068: maximum plasma concentration [ Time Frame: Days 1, 8, and 15 pre-dose and up to 24 h post-dose for Cycle 1 and Day 1 on Cycles 2 and 3 ] [ Designated as safety issue: No ]
  • Pharmacokinetic parameters of GDC-0973 and GDC-0068: minimum concentration [ Time Frame: Days 1, 8, and 15 pre-dose and up to 24 h post-dose for Cycle 1 and Day 1 on Cycles 2 and 3 ] [ Designated as safety issue: No ]
  • Objective response for patients with measurable disease according to RECIST criteria [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
  • Duration of objective response for patients with measurable disease according to RECIST criteria [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
  • Progression-free survival for patients with measurable disease according to RECIST criteria [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
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
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
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.
Not Provided
Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Neoplasms
  • Drug: Ipatasertib
    multiple doses
    Other Name: GDC-0068
  • Drug: Cobimetinib
    multiple doses
    Other Name: GDC-0973
  • Experimental: Dose escalation stage 1 (Arm A): Cobimetinib and Ipatasertib
    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.
    Interventions:
    • Drug: Ipatasertib
    • Drug: Cobimetinib
  • Experimental: Dose escalation stage 1 (Arm B): Cobimetinib and Ipatasertib
    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.
    Interventions:
    • Drug: Ipatasertib
    • Drug: Cobimetinib
  • Experimental: Stage 2 (Indication specific dose expansion cohort)
    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.
    Interventions:
    • Drug: Ipatasertib
    • Drug: Cobimetinib
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
67
January 2015
January 2015   (final data collection date for primary outcome measure)

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
Both
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States,   Spain
 
NCT01562275
GE28079, 2012-003934-18
Not Provided
Not Provided
Not Provided
Genentech, Inc.
Genentech, Inc.
Not Provided
Study Director: Clinical Trials Genentech, Inc.
Genentech, Inc.
February 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP