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

NCT01564251 | Completed Phase 1

• 2 other identifiers: GP281532011-005602-30
• Study Type: interventional
• Target: 104
• Locations: 2 countries
• Sites: 7

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.

Conditions

Lymphoma, Solid Tumor

Outcome Measures

Primary Outcomes (18)

• Percentage of Participants With Adverse Events (AEs)

  Baseline up to approximately 5 years

• Percentage of Participants With Dose-Limiting Toxicities (DLTs)

  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

  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

  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

  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

  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)

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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 (3)

• Percentage of Participants With Objective Response as Determined Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

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

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

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

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

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

Study Arms (4)

Stage 1 Arm 1: GDC-0575 Monotherapy

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.

Drug: GDC-0575

Stage 1 Arm 2a: GDC-0575 + Gemcitabine (750 or 1000 mg/m^2)

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.

Drug: GDC-0575; Drug: Gemcitabine

Stage 1 Arm 2b: GDC-0575 plus Gemcitabine (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.

Drug: GDC-0575; Drug: Gemcitabine

Stage 2: GDC-0575 plus Gemcitabine

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.

Drug: GDC-0575; Drug: Gemcitabine

Interventions

GDC-0575 DRUG

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

Also known as: RO6845979

Stage 1 Arm 1: GDC-0575 Monotherapy; Stage 1 Arm 2a: GDC-0575 + Gemcitabine (750 or 1000 mg/m^2); Stage 1 Arm 2b: GDC-0575 plus Gemcitabine (500 mg/m^2); Stage 2: GDC-0575 plus Gemcitabine

Gemcitabine DRUG

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

Also known as: Gemzar

Stage 1 Arm 2a: GDC-0575 + Gemcitabine (750 or 1000 mg/m^2); Stage 1 Arm 2b: GDC-0575 plus Gemcitabine (500 mg/m^2); Stage 2: GDC-0575 plus Gemcitabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (7)

Yale Cancer Center

New Haven, Connecticut, 06520, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

The Sarah Cannon Research Inst

Nashville, Tennessee, 37203, United States

Location

Institut Bergonie; Oncologie

Bordeaux, 33076, France

Location

Institut Gustave Roussy; Departement Oncologie Medicale

Villejuif, 94805, France

Location

Related Publications (1)

• 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.

  PMID: 29788155 DERIVED

MeSH Terms

Conditions

Lymphoma

Interventions

GDC-0575; Gemcitabine

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Clinical Trials

  Genentech, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 23, 2012
• First Posted: March 27, 2012
• Study Start: March 23, 2012
• Primary Completion: January 11, 2018
• Study Completion: January 11, 2018
• Last Updated: February 25, 2020

Record last verified: 2020-02

Locations

FR (2); US (5)