Clinical trial NCT01564251: A Study of GDC-0575 Alone and in Combination With Gemcitabine in Participants With Refractory Solid Tumors or Lymphoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphoma, Solid Tumor
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2012-03-27
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: Baseline up to approximately 5 years
measure: Percentage of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: Stage 1 Arm 1: Day 1 up to Day 21. Stage 1 Arm 2: Day 1 up to Day 22 or 29
measure: Maximum Tolerated Dose (MTD) of GDC-0575
timeFrame: Stage 1 Arm 1: Day 1 up to Day 21. Stage 1 Arm 2: Day 1 up to Day 22 or 29
measure: Recommended Phase II Dose of GDC-0575
timeFrame: Stage 1 Arm 1: Day 1 up to Day 21. Stage 1 Arm 2: Day 1 up to Day 22 or 29
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of GDC-0575
timeFrame: 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)
measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)
timeFrame: 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)
measure: Maximum Observed Plasma Concentration (Cmax) GDC-0575
timeFrame: 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)
measure: Minimum Observed Plasma Trough Concentration (Cmin) of GDC-0575
timeFrame: 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
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of GDC-0575
timeFrame: 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)
measure: Apparent Terminal Half-Life (t1/2) of GDC-0575
timeFrame: 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)
measure: Apparent Oral Clearance (CL/F) of GDC-0575
timeFrame: 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)
measure: Accumulation Ratio (Rac) of GDC-0575
timeFrame: 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)
measure: PK-dose Proportionality as Assessed With Cmax of GDC-0575
timeFrame: 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)
measure: PK-dose Proportionality as Assessed With AUC of GDC-0575
timeFrame: 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)
measure: Phospho-Cyclin-Dependent Kinase 2 (pCdk2) Levels in Fresh Tumor
timeFrame: 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)
measure: Phospho-Cyclin-Dependent Kinase 2 (pCdk2) Levels in Skin Tissue
timeFrame: 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)
measure: Gamma-H2Ax (γ-H2Ax) Levels in Fresh Tumor
timeFrame: 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)
measure: Gamma-H2Ax (γ-H2Ax) Levels in Skin Tissue
timeFrame: 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
timeFrame: Baseline until disease progression or death (up to approximately 5 years)
measure: Progression-Free Survival (PFS) as Determined Using RECIST v1.1
timeFrame: Baseline until disease progression or death (up to approximately 5 years)
measure: Duration of Objective Response as Determined Using RECIST v1.1
timeFrame: Baseline until disease progression or death (up to approximately 5 years)
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Nashville
country: United States
facility: The Sarah Cannon Research Inst
state: Tennessee
city: Bordeaux
country: France
facility: Institut Bergonie; Oncologie
city: Villejuif
country: France
facility: Institut Gustave Roussy; Departement Oncologie Medicale
Study officials:
affiliation: Genentech, Inc.
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Italiano A, Infante JR, Shapiro GI, Moore KN, LoRusso PM, Hamilton E, Cousin S, Toulmonde M, Postel-Vinay S, Tolaney S, Blackwood EM, Mahrus S, Peale FV, Lu X, Moein A, Epler J, DuPree K, Tagen M, Murray ER, Schutzman JL, Lauchle JO, Hollebecque A, Soria JC. Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors. Ann Oncol. 2018 May 1;29(5):1304-1311. doi: 10.1093/annonc/mdy076.