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A Study of GDC-0575 Alone and in Combination With Gemcitabine in Participants With Refractory Solid Tumors or Lymphoma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT01564251
First received: March 23, 2012
Last updated: May 18, 2017
Last verified: May 2017
  Purpose
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.

Condition Intervention Phase
Lymphoma, Solid Tumor
Drug: GDC-0575
Drug: Gemcitabine
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Genentech, Inc.:

Primary Outcome Measures:
  • 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) ]
    Stage 1 Arm 1, Cycle 1 of 21 days: predose (5 to 30 minutes) on Days 1, 2, 3, 8, 15; 0.5, 1, 1.5, 2, 4, 6, 8 hours (h) postdose on Days 1, 3; 2, 4h postdose on Days 2, 15; 2h postdose on Day 8; on Days 4, 5. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose (5 minutes), 0.5, 1, 1.5, 2, 4, 6h postdose on Day 2 (additionally at 8h postdose on Day 2 for Arm 2a only); predose (0.5h), 2h postdose on Day 9

  • 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) ]
    Stage 1 Arm 1, Cycle 1 of 21 days: predose (5 to 30 minutes) on Days 1, 2, 3, 8, 15; 0.5, 1, 1.5, 2, 4, 6, 8 h postdose on Days 1, 3; 2, 4h postdose on Days 2, 15; 2h postdose on Day 8; on Days 4, 5. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose (5 minutes), 0.5, 1, 1.5, 2, 4, 6h postdose on Day 2 (additionally at 8h postdose on Day 2 for Arm 2a only) ; predose (0.5h), 2h postdose on Day 9

  • 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) ]
    Stage 1 Arm 1, Cycle 1 of 21 days: predose (5 to 30 minutes) on Days 1, 2, 3, 8, 15; 0.5, 1, 1.5, 2, 4, 6, 8 h postdose on Days 1, 3; 2, 4h postdose on Days 2, 15; 2h postdose on Day 8; on Days 4, 5. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose (5 minutes), 0.5, 1, 1.5, 2, 4, 6h postdose on Day 2 (additionally at 8h postdose on Day 2 for Arm 2a only) ; predose (0.5h), 2h postdose on Day 9

  • 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) ]
    Stage 1 Arm 1, Cycle 1 of 21 days: predose (5 to 30 minutes) on Days 1, 2, 3, 8, 15; 0.5, 1, 1.5, 2, 4, 6, 8 h postdose on Days 1, 3; 2, 4h postdose on Days 2, 15; 2h postdose on Day 8; on Days 4, 5. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose (5 minutes), 0.5, 1, 1.5, 2, 4, 6h postdose on Day 2 (additionally at 8h postdose on Day 2 for Arm 2a only) ; predose (0.5h), 2h postdose on Day 9

  • 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) ]
    Stage 1 Arm 1, Cycle 1 of 21 days: predose (5 to 30 minutes) on Days 1, 2, 3, 8, 15; 0.5, 1, 1.5, 2, 4, 6, 8 h postdose on Days 1, 3; 2, 4h postdose on Days 2, 15; 2h postdose on Day 8; on Days 4, 5. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose (5 minutes), 0.5, 1, 1.5, 2, 4, 6h postdose on Day 2 (additionally at 8h postdose on Day 2 for Arm 2a only) ; predose (0.5h), 2h postdose on Day 9

  • 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) ]
    Stage 1 Arm 1, Cycle 1 of 21 days: predose (5 to 30 minutes) on Days 1, 2, 3, 8, 15; 0.5, 1, 1.5, 2, 4, 6, 8 h postdose on Days 1, 3; 2, 4h postdose on Days 2, 15; 2h postdose on Day 8; on Days 4, 5. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose (5 minutes), 0.5, 1, 1.5, 2, 4, 6h postdose on Day 2 (additionally at 8h postdose on Day 2 for Arm 2a only) ; predose (0.5h), 2h postdose on Day 9

  • 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) ]
    Stage 1 Arm 1, Cycle 1 of 21 days: predose (5 to 30 minutes) on Days 1, 2, 3, 8, 15; 0.5, 1, 1.5, 2, 4, 6, 8 h postdose on Days 1, 3; 2, 4h postdose on Days 2, 15; 2h postdose on Day 8; on Days 4, 5. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose (5 minutes), 0.5, 1, 1.5, 2, 4, 6h postdose on Day 2 (additionally at 8h postdose on Day 2 for Arm 2a only) ; predose (0.5h), 2h postdose on Day 9

  • 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) ]
    Stage 1 Arm 1, Cycle 1 of 21 days: predose (5 to 30 minutes) on Days 1, 2, 3, 8, 15; 0.5, 1, 1.5, 2, 4, 6, 8 h postdose on Days 1, 3; 2, 4h postdose on Days 2, 15; 2h postdose on Day 8; on Days 4, 5. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose (5 minutes), 0.5, 1, 1.5, 2, 4, 6h postdose on Day 2 (additionally at 8h postdose on Day 2 for Arm 2a only) ; predose (0.5h), 2h postdose on Day 9

  • 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) ]
    Stage 1 Arm 1, Cycle 1 of 21 days: predose (5 to 30 minutes) on Days 1, 2, 3, 8, 15; 0.5, 1, 1.5, 2, 4, 6, 8 h postdose on Days 1, 3; 2, 4h postdose on Days 2, 15; 2h postdose on Day 8; on Days 4, 5. Stage 1 Arm 2 and Stage 2, Cycle 1 of 21 days: predose (5 minutes), 0.5, 1, 1.5, 2, 4, 6h postdose on Day 2 (additionally at 8h postdose on Day 2 for Arm 2a only) ; predose (0.5h), 2h postdose on Day 9

  • 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) ]
    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 and 10 of Cycle 2. Stage 1 Arm 2b: Screening (Day -21 to -1), Day 3 of Weeks 4 and 5. Stage 2: Screening (Day -21 to -1), Day 3 of Weeks 1 and 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) ]
    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 and 10 of Cycle 2. Stage 1 Arm 2b: Screening (Day -21 to -1), Day 3 of Weeks 4 and 5. Stage 2: Screening (Day -21 to -1), Day 3 of Weeks 1 and 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) ]
    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 and 10 of Cycle 2. Stage 1 Arm 2b: Screening (Day -21 to -1), Day 3 of Weeks 4 and 5. Stage 2: Screening (Day -21 to -1), Day 3 of Weeks 1 and 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) ]
    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 and 10 of Cycle 2. Stage 1 Arm 2b: Screening (Day -21 to -1), Day 3 of Weeks 4 and 5. Stage 2: Screening (Day -21 to -1), Day 3 of Weeks 1 and 2


Secondary Outcome Measures:
  • 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) ]

Enrollment: 104
Actual Study Start Date: March 31, 2012
Estimated Study Completion Date: June 2, 2017
Estimated Primary Completion Date: June 2, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Stage 1 Arm 1: GDC-0575 Monotherapy
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.
Drug: GDC-0575
Participants will receive GDC-0575 orally at a starting dose of 15 mg.
Other Name: RO6845979
Experimental: Stage 1 Arm 2a: GDC-0575 + Gemcitabine (750 or 1000 mg/m^2)
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.
Drug: GDC-0575
Participants will receive GDC-0575 orally at a starting dose of 15 mg.
Other Name: RO6845979
Drug: Gemcitabine
Participants will receive gemcitabine intravenously at a dose of 1000 mg/m^2 and/or 500 mg/m^2.
Other Name: Gemzar
Experimental: Stage 1 Arm 2b: GDC-0575 plus Gemcitabine (500 mg/m^2)
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.
Drug: GDC-0575
Participants will receive GDC-0575 orally at a starting dose of 15 mg.
Other Name: RO6845979
Drug: Gemcitabine
Participants will receive gemcitabine intravenously at a dose of 1000 mg/m^2 and/or 500 mg/m^2.
Other Name: Gemzar
Experimental: Stage 2: GDC-0575 plus Gemcitabine
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.
Drug: GDC-0575
Participants will receive GDC-0575 orally at a starting dose of 15 mg.
Other Name: RO6845979
Drug: Gemcitabine
Participants will receive gemcitabine intravenously at a dose of 1000 mg/m^2 and/or 500 mg/m^2.
Other Name: Gemzar

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01564251

Locations
United States, Connecticut
Yale Cancer Center
New Haven, Connecticut, United States, 06520
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Oklahoma
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
United States, Tennessee
The Sarah Cannon Research Inst
Nashville, Tennessee, United States, 37203
France
Institut Bergonie; Oncologie
Bordeaux, France, 33076
Institut Gustave Roussy; Departement Oncologie Medicale
Villejuif, France, 94805
Sponsors and Collaborators
Genentech, Inc.
Investigators
Study Director: Clinical Trials Genentech, Inc.
  More Information

Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT01564251     History of Changes
Other Study ID Numbers: GP28153
2011-005602-30 ( EudraCT Number )
Study First Received: March 23, 2012
Last Updated: May 18, 2017

Additional relevant MeSH terms:
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Gemcitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on May 22, 2017