Clinical Trials /

Rucaparib and Irinotecan in Cancers With Mutations in DNA Repair

NCT03318445

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Rucaparib and Irinotecan in Cancers With Mutations in DNA Repair
  • Official Title: Combination Therapy of Rucaparib and Irinotecan in Cancers With Mutations in DNA Repair

Clinical Trial IDs

  • ORG STUDY ID: CC# 169521
  • NCT ID: NCT03318445

Conditions

  • Solid Tumor, Unspecified, Adult

Interventions

DrugSynonymsArms
RucaparibRubracaRucaparib and irinotecan
IrinotecanCamptosarRucaparib and irinotecan

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Rucaparib and irinotecanExperimentalRucaparib 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.
  • Rucaparib
  • Irinotecan
Rucaparib onlyExperimentalDuring 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.
  • Rucaparib

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Over the duration of the study, which is estimated to be approximately 24 months.
Safety Issue:
Description: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

Measure:Response duration
Time Frame:Over the duration of the study, which is estimated to be approximately 24 months.
Safety Issue:
Description:• Response duration defined as the time from initial response to the first documented tumor progression.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pamela Munster

Trial Keywords

  • DNA repair mutation

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