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NCT Number: NCT01564251

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

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.

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Key information

Conditions

Lymphoma, Solid Tumor Hemic and Lymphatic Diseases Immune System Diseases Immunoproliferative Disorders Lymphatic Diseases Lymphoma Lymphoproliferative Disorders Neoplasms Neoplasms by Histologic Type

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Institut Bergonie; Oncologie, Bordeaux, France

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

GDC-0575

Drug

Participants will receive GDC-0575 orally at a starting dose of 15 mg.

Other names: RO6845979

Gemcitabine

Drug

Participants will receive gemcitabine intravenously at a dose of 1000 mg/m^2 and/or 500 mg/m^2.

Other names: Gemzar

Primary outcomes

  1. Percentage of Participants With Adverse Events (AEs)

    Time frame: Baseline up to approximately 5 years

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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 outcomes

  1. 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)

  2. Progression-Free Survival (PFS) as Determined Using RECIST v1.1

    Time frame: Baseline until disease progression or death (up to approximately 5 years)

  3. Duration of Objective Response as Determined Using RECIST v1.1

    Time frame: Baseline until disease progression or death (up to approximately 5 years)

Sponsors and collaborators

Lead sponsor

Genentech, Inc.

Industry

Registry information

Official study 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

Important dates

Study start
2012
Primary completion
2018
Study completion
2018
First posted
Mar 27, 2012
Registry last updated
Feb 25, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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