Overview

This trial is active, not recruiting.

Condition lymphoma, solid tumor
Treatments gdc-0575, gemcitabine
Phase phase 1
Targets ChK1, BTK
Sponsor Genentech, Inc.
Start date March 2012
End date June 2017
Trial size 104 participants
Trial identifier NCT01564251, 2011-005602-30, GP28153

Summary

This open-label, multicenter, Phase I, dose-escalation study will evaluate the safety, tolerability, and pharmacokinetics (PK) of GDC-0575 administered alone or in combination with gemcitabine in participants with refractory solid tumors or lymphoma. In Stage 1, cohorts of participants will receive multiple ascending oral doses of GDC-0575 alone or in combination with intravenous gemcitabine. In Stage 2, participants will receive GDC-0575 orally in combination with intravenous gemcitabine at or below the maximum tolerated dose determined in Stage 1. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs, up to approximately 5 years.

United States No locations recruiting
Other countries No locations recruiting

Study Design

Allocation non-randomized
Intervention model parallel assignment
Primary purpose treatment
Masking no masking
Arm
(Experimental)
Participants will receive escalating doses of GDC-0575, administered orally, for 3 consecutive days, starting on Days 1, 8, and 15 of each 21-day cycle.
gdc-0575 RO6845979
Participants will receive GDC-0575 orally at a starting dose of 15 mg.
(Experimental)
Participants will receive gemcitabine 750 milligrams per meter square (mg/m^2) or 1000 mg/m^2, intravenously, on Days 1 and 8 followed by escalating doses of GDC-0575 orally, on Days 2 and 9 of each 21-day cycle.
gdc-0575 RO6845979
Participants will receive GDC-0575 orally at a starting dose of 15 mg.
gemcitabine Gemzar
Participants will receive gemcitabine intravenously at a dose of 1000 mg/m^2 and/or 500 mg/m^2.
(Experimental)
Participants will receive gemcitabine 500 mg/m^2, intravenously, once weekly for approximately 2 consecutive weeks of any 3-week period and escalating doses of GDC-0575 orally approximately 24-hours after each gemcitabine dose.
gdc-0575 RO6845979
Participants will receive GDC-0575 orally at a starting dose of 15 mg.
gemcitabine Gemzar
Participants will receive gemcitabine intravenously at a dose of 1000 mg/m^2 and/or 500 mg/m^2.
(Experimental)
Participants will receive GDC-0575 in combination with gemcitabine intravenously (1000 mg/m^2 and/or 500 mg/m^2), at or below the MTDs for the combination treatments that are determined during Stage 1.
gdc-0575 RO6845979
Participants will receive GDC-0575 orally at a starting dose of 15 mg.
gemcitabine Gemzar
Participants will receive gemcitabine intravenously at a dose of 1000 mg/m^2 and/or 500 mg/m^2.

Primary Outcomes

Measure
Percentage of Participants With Adverse Events (AEs)
time frame: Baseline up to approximately 5 years
Percentage of Participants With Dose-Limiting Toxicities (DLTs)
time frame: Stage 1 Arm 1: Day 1 up to Day 21. Stage 1 Arm 2: Day 1 up to Day 22 or 29
Maximum Tolerated Dose (MTD) of GDC-0575
time frame: Stage 1 Arm 1: Day 1 up to Day 21. Stage 1 Arm 2: Day 1 up to Day 22 or 29
Recommended Phase II Dose of GDC-0575
time frame: Stage 1 Arm 1: Day 1 up to Day 21. Stage 1 Arm 2: Day 1 up to Day 22 or 29
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of GDC-0575
time frame: Stage 1 Arm 1, Cycle 1 of 21 days: predose on Days 1, 2, 3, 8, 15; postdose on Days 1, 2, 3, 4, 5, 8, 15. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose and postdose on Days 2, 9 (detailed timeframe is provided in outcome measure description)
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)
time frame: Stage 1 Arm 1, Cycle 1 of 21 days: predose on Days 1, 2, 3, 8, 15; postdose on Days 1, 2, 3, 4, 5, 8, 15. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose and postdose on Days 2, 9 (detailed timeframe is provided in outcome measure description)
Maximum Observed Plasma Concentration (Cmax) GDC-0575
time frame: Stage 1 Arm 1, Cycle 1 of 21 days: predose on Days 1, 2, 3, 8, 15; postdose on Days 1, 2, 3, 4, 5, 8, 15. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose and postdose on Days 2, 9 (detailed timeframe is provided in outcome measure description)
Minimum Observed Plasma Trough Concentration (Cmin) of GDC-0575
time frame: Stage 1 Arm 1, Cycle 1 of 21 days: predose (5 to 30 minutes) on Days 1, 2, 3, 8, 15; Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose (5 minutes) on Day 2; predose (0.5h) on Day 9
Time to Reach Maximum Observed Plasma Concentration (Tmax) of GDC-0575
time frame: Stage 1 Arm 1, Cycle 1 of 21 days: predose on Days 1, 2, 3, 8, 15; postdose on Days 1, 2, 3, 4, 5, 8, 15. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose and postdose on Days 2, 9 (detailed timeframe is provided in outcome measure description)
Apparent Terminal Half-Life (t1/2) of GDC-0575
time frame: Stage 1 Arm 1, Cycle 1 of 21 days: predose on Days 1, 2, 3, 8, 15; postdose on Days 1, 2, 3, 4, 5, 8, 15. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose and postdose on Days 2, 9 (detailed timeframe is provided in outcome measure description)
Apparent Oral Clearance (CL/F) of GDC-0575
time frame: Stage 1 Arm 1, Cycle 1 of 21 days: predose on Days 1, 2, 3, 8, 15; postdose on Days 1, 2, 3, 4, 5, 8, 15. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose and postdose on Days 2, 9 (detailed timeframe is provided in outcome measure description)
Accumulation Ratio (Rac) of GDC-0575
time frame: Stage 1 Arm 1, Cycle 1 of 21 days: predose on Days 1, 2, 3, 8, 15; postdose on Days 1, 2, 3, 4, 5, 8, 15. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose and postdose on Days 2, 9 (detailed timeframe is provided in outcome measure description)
PK-dose Proportionality as Assessed With Cmax of GDC-0575
time frame: Stage 1 Arm 1, Cycle 1 of 21 days: predose on Days 1, 2, 3, 8, 15; postdose on Days 1, 2, 3, 4, 5, 8, 15. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose and postdose on Days 2, 9 (detailed timeframe is provided in outcome measure description)
PK-dose Proportionality as Assessed With AUC of GDC-0575
time frame: Stage 1 Arm 1, Cycle 1 of 21 days: predose on Days 1, 2, 3, 8, 15; postdose on Days 1, 2, 3, 4, 5, 8, 15. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose and postdose on Days 2, 9 (detailed timeframe is provided in outcome measure description)
Phospho-Cyclin-Dependent Kinase 2 (pCdk2) Levels in Fresh Tumor
time frame: Stage 1 Arm 1: Screening (Day -21 to -1), Cycle 1 Day 4 (Cycle length=21 days). Stage 1 Arm 2a: Screening (Day -21 to -1), Days 3, 10 of Cycle 2. Stage1 Arm2b, Stage 2: Screening (Day -21 to -1), Day 3 of Weeks 4, 5 (Stage1 Arm2b), Weeks 1, 2 (Stage 2)
Phospho-Cyclin-Dependent Kinase 2 (pCdk2) Levels in Skin Tissue
time frame: Stage 1 Arm 1: Screening (Day -21 to -1), Cycle 1 Day 4 (Cycle length=21 days). Stage 1 Arm 2a: Screening (Day -21 to -1), Days 3, 10 of Cycle 2. Stage1 Arm2b, Stage 2: Screening (Day -21 to -1), Day 3 of Weeks 4, 5 (Stage1 Arm2b), Weeks 1, 2 (Stage 2)
Gamma-H2Ax (γ-H2Ax) Levels in Fresh Tumor
time frame: Stage 1 Arm 1: Screening (Day -21 to -1), Cycle 1 Day 4 (Cycle length=21 days). Stage 1 Arm 2a: Screening (Day -21 to -1), Days 3, 10 of Cycle 2. Stage1 Arm2b, Stage 2: Screening (Day -21 to -1), Day 3 of Weeks 4, 5 (Stage1 Arm2b), Weeks 1, 2 (Stage 2)
Gamma-H2Ax (γ-H2Ax) Levels in Skin Tissue
time frame: Stage 1 Arm 1: Screening (Day -21 to -1), Cycle 1 Day 4 (Cycle length=21 days). Stage 1 Arm 2a: Screening (Day -21 to -1), Days 3, 10 of Cycle 2. Stage1 Arm2b, Stage 2: Screening (Day -21 to -1), Day 3 of Weeks 4, 5 (Stage1 Arm2b), Weeks 1, 2 (Stage 2)

Secondary Outcomes

Measure
Percentage of Participants With Objective Response as Determined Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
time frame: Baseline until disease progression or death (up to approximately 5 years)
Progression-Free Survival (PFS) as Determined Using RECIST v1.1
time frame: Baseline until disease progression or death (up to approximately 5 years)
Duration of Objective Response as Determined Using RECIST v1.1
time frame: Baseline until disease progression or death (up to approximately 5 years)

Eligibility Criteria

All participants at least 18 years old.

Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Histologically or cytologically documented, locally advanced or metastatic solid tumors or lymphoma for which standard therapy either does not exist or has proven ineffective or intolerable - Life expectancy greater than or equal to (>=) 12 weeks, in the opinion of the investigator - Adequate hematologic, liver, and renal function - For Stage 2: Participants with human epidermal growth factor receptor 2 (HER2) negative, estrogen-receptor (ER) negative, and progesterone-receptor (PR) negative breast cancer - For Stage 2: Participants with non-mucinous, platinum-resistant ovarian cancer with documented radiographic progression or relapse according to RECIST within 6 months of receiving platinum-based chemotherapy - For Stage 2: Participants with histologically or cytologically confirmed diagnosis of squamous non-small cell lung cancer (NSCLC); mixed histology that is predominantly squamous is acceptable Exclusion Criteria: - History of prior significant toxicity from a same class of agents as GDC-0575 or gemcitabine requiring discontinuation of treatment - All acute toxicities related to prior therapy must have resolved prior to study entry, except for alopecia and mild neuropathy - Current severe, uncontrolled systemic disease (including but not limited to clinically significant cardiovascular, pulmonary, or renal disease or ongoing or active infection) excluding the cancer under study - History of significant cardiac dysfunction - History of malabsorption or other condition that would interfere with enteral absorption - Known human immunodeficiency virus (HIV) infection - Pregnancy, lactation or breastfeeding - Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms - Current use of alpha-adrenergic receptor blockers For Combination Arm only: - Any contraindication to gemcitabine therapy - More than two regimens of cytotoxic chemotherapy for the treatment of locally advanced or metastatic cancer - History of receiving high-dose chemotherapy requiring bone marrow or stem cell support - Irradiation to more than 25% of bone marrow-bearing areas

Additional Information

Official title An Open-label, Phase I, Dose Escalation Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GDC-0575 Administered Alone and in Combination With Gemcitabine in Patients With Refractory Solid Tumors or Lymphoma
Trial information was received from ClinicalTrials.gov and was last updated in April 2017.
Information provided to ClinicalTrials.gov by Genentech, Inc..