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Rucaparib and Irinotecan in Cancers With Mutations in DNA Repair

This study is not yet open for participant recruitment.
Verified October 2017 by Pamela Munster, University of California, San Francisco
Sponsor:
ClinicalTrials.gov Identifier:
NCT03318445
First Posted: October 23, 2017
Last Update Posted: October 23, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Clovis Oncology, Inc.
Information provided by (Responsible Party):
Pamela Munster, University of California, San Francisco
  Purpose
This is an open label, non-randomized, dose escalation and expansion Phase Ib trial to evaluate the safety and recommended phase II dose of the combination of irinotecan and rucaparib.

Condition Intervention Phase
Solid Tumor, Unspecified, Adult Drug: Rucaparib Drug: Irinotecan Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Combination Therapy of Rucaparib and Irinotecan in Cancers With Mutations in DNA Repair

Resource links provided by NLM:


Further study details as provided by Pamela Munster, University of California, San Francisco:

Primary Outcome Measures:
  • Overall Response Rate (ORR) [ Time Frame: Over the duration of the study, which is estimated to be approximately 24 months. ]
    ORR is defined as the proportion of patients with either confirmed complete or partial response (as per RECIST version 1.1) as best overall response over the total population.


Secondary Outcome Measures:
  • Response duration [ Time Frame: Over the duration of the study, which is estimated to be approximately 24 months. ]
    • Response duration defined as the time from initial response to the first documented tumor progression.


Estimated Enrollment: 45
Anticipated Study Start Date: November 1, 2017
Estimated Study Completion Date: October 6, 2020
Estimated Primary Completion Date: October 6, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rucaparib and irinotecan

Rucaparib will be taken twice daily by mouth for 7-14 days in 21 or 28 day cycles. Irinotecan will be administered by IV for 90 minutes every 14 days, or every 21 days if not tolerated.

During the dose escalation phase, the maximum tolerated dose for combining Rucaparib and irinotecan will be determined. The dose for rucaparib during dose escalation will range from 300 mg to 600 mg, depending on the progression of study. The dose for irinotecan during dose escalation may range from 40 mg/m2 to 150 mg/m2.

During the dose expansion phase, patients who have received prior PARP inhibitors will be given rucaparib and irinotecan at the maximum tolerated dose levels determined during the dose escalation phase.

Drug: Rucaparib
All participants will take rucaparib by mouth
Other Name: Rubraca
Drug: Irinotecan
Patients in the dose escalation phase, and patients in the dose expansion phase who have received prior PARP inhibitor therapy, will be given irinotecan by in combination with rucaparib.
Other Name: Camptosar
Experimental: Rucaparib only
During the dose expansion phase, patients who have not received prior PARP inhibitor therapy will take 600 mg of rucaparib by mouth daily. Patients who progress on single-agent rucaparib will be given the option to cross-over to the combination treatment arm and receive rucaparib in combination with irinotecan at the maximum tolerated dose levels determined during dose escalation.
Drug: Rucaparib
All participants will take rucaparib by mouth
Other Name: Rubraca

Detailed Description:

In dose escalation, patients will receive irinotecan and rucaparib. Irinotecan will be given once every 2 weeks (or 3 weeks if not tolerated) and rucaparib will be given twice daily for 7-14 days. Each cycle will be 28 days in duration unless we need to switch to the intermediate dosing regimen of every 21 days. Both rucaparib and irinotecan will be escalated.

In dose expansion, patients who have received prior PARP inhibitors will go straight to the combination arm of irinotecan and rucaparib. If patients are PARP inhibitor naïve, they can receive single agent rucaparib until progression. Once patients on single agent rucaparib progress, they can choose to go on the combination treatment arm. Patients will continue on treatment until disease progression or intolerable toxicity.

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for Dose Escalation Cohort:

  1. Men and women, 18 years or older
  2. Understand and voluntarily sign informed consent prior to any study-related assessments or procedures are conducted and are able adhere to the study visit schedule and other protocol requirements.
  3. Solid tumors with one or more of the following DNA repair defects:

    a. BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L (validated from archival tumor tissue or germ line testing from any CLIA approved lab). This testing should occur prior to study consent or enrollment.

  4. Presence of at least one lesion with measurable disease as defined by RECIST 1.1 criteria for response assessment
  5. Advanced solid tumor malignancy without curative options
  6. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1.
  7. Adequate organ function:

    1. Absolute neutrophil count (ANC) ≥ 1.5 X 109/L
    2. Hemoglobin (Hgb) ≥9g/dL; (last transfusion cannot be within 7 days of trial initiation)
    3. Platelets (plt) ≥ 100 x 109/L
    4. AST and ALT ≤2.5 x Upper Limit Normal (ULN), <5x in patients with known liver metastases
    5. Serum total bilirubin ≤ 1.5 x ULN
    6. Creatinine<1.5 x ULN or estimated GFR ≥ 50ml/min by Cockroft-Gault (http://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation/)
  8. The effects of rucaparib on the developing fetus are unknown. Therefore

    a. Given the results of the embryo-fetal development study, in which rucaparib was embryotoxic at all doses administered, females of childbearing potential and their male partners are advised to practice a highly effective method of contraception during treatment with rucaparib and for 1 month following the last dose for females and 4 months following the last dose for males. A woman is considered to be of childbearing potential unless one of the following applies: i. Is considered to be permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.

    ii. Is postmenopausal, defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level consistently in the postmenopausal range (30 mIU/mL or higher) may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy; however, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to confirm a postmenopausal state.

    b. Highly effective contraception is considered to be a method with a < 1% per year failure rate. Recommendations for highly effective contraception while taking rucaparib include: i. Ongoing use of injectable or implantable progesterone ii. Placement of an intrauterine device or intrauterine system iii. Bilateral tubal occlusion iv. Complete (as opposed to periodic) abstinence v. Male sterilization, with appropriate post-vasectomy documentation of absence of sperm in ejaculate

    Additional Inclusion Criteria for Dose Expansion Cohort

  9. Mandatory biopsy on study entry, if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator)
  10. PARPi naïve or prior exposure to PARPi therapy (varies depending on Arm 1 and Arm 2)

    1. Patients in Arm 1 (single agent rucaparib followed by combination upon progression) must be PARPi naïve. Prior irinotecan is allowed
    2. Patients in Arm 2 (combination) must have been treated with and progressed on a PARPi previously. Prior irinotecan is allowed.

Exclusion Criteria for Dose Escalation Cohort:

  1. Any significant medical condition, laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study at clinician's discretion and not otherwise stated below.
  2. Allergic reaction to single-agent rucaparib or irinotecan.
  3. Myelodysplastic features on peripheral blood smear
  4. Prior allergic reaction or known intolerance to irinotecan
  5. Known Gilbert's disease
  6. Poorly controlled or symptomatic CNS metastases or carcinomatous meningitis
  7. Note: Patients with previously treated brain metastases may participate, 2 weeks after gamma knife (or equivalent) or 4 weeks after Whole Brain Radiotherapy (WBRT), provided they are stable (without evidence of progression by imaging and have not been using steroids for at least 7 days prior to study treatment.
  8. Pregnancy and breast feeding
  9. Inability to comply with study procedures or willingness to use adequate birth control

    Additional Exclusion Criteria for Dose Expansion Cohort

  10. PARPi naïve or prior exposure to PARPi therapy

    1. Patients in Arm 1 of the Dose Expansion cohort cannot have prior exposure to PARPi therapy.
    2. Patients in Arm 2 of the Dose Expansion cohort cannot be PARPi naïve.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03318445


Contacts
Contact: Zhang Jenna 415-353-8337 Jenna.Zhang@ucsf.edu

Locations
United States, California
University of California San Francisco Not yet recruiting
San Francisco, California, United States, 94115
Contact: Clinical Trials Office Main Line    877-827-3222    cancertrials@ucsf.edu   
Principal Investigator: Pamela Munster, MD         
Sponsors and Collaborators
Pamela Munster
Clovis Oncology, Inc.
Investigators
Principal Investigator: Pamela Munster, MD University of California, San Francisco
  More Information

Responsible Party: Pamela Munster, Professor, Department of Medicine; Director, Early Phase Clinical Trials Unit, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03318445     History of Changes
Other Study ID Numbers: CC# 169521
First Submitted: October 18, 2017
First Posted: October 23, 2017
Last Update Posted: October 23, 2017
Last Verified: October 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Pamela Munster, University of California, San Francisco:
DNA repair mutation

Additional relevant MeSH terms:
Irinotecan
Camptothecin
Rucaparib
Poly(ADP-ribose) Polymerase Inhibitors
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action