Clinical Trials /

Veliparib and Irinotecan Hydrochloride in Treating Patients With Cancer That Is Metastatic or Cannot Be Removed by Surgery

NCT00576654

Description:

This phase I trial studies the side effects and best dose of veliparib when given together with irinotecan hydrochloride in treating patients with cancer that has spread to other parts of the body or that cannot be removed by surgery. Irinotecan hydrochloride can kill cancer cells by damaging the deoxyribonucleic acid (DNA) that is needed for cancer cell survival and growth. Veliparib may block proteins that repair the damaged DNA and may help irinotecan hydrochloride to kill more tumor cells. Giving irinotecan hydrochloride together with veliparib may kill more cancer cells.

Related Conditions:
  • Breast Carcinoma
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Veliparib and Irinotecan Hydrochloride in Treating Patients With Cancer That Is Metastatic or Cannot Be Removed by Surgery
  • Official Title: A Phase I Dose-Escalation Study of Oral ABT-888 (NSC #737664) Plus Intravenous Irinotecan (CPT-11, NSC#616348) Administered in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2009-01057
  • SECONDARY ID: NCI-2009-01057
  • SECONDARY ID: 1410014852
  • SECONDARY ID: CDR0000579642
  • SECONDARY ID: HIC 1410014852
  • SECONDARY ID: 2007-014
  • SECONDARY ID: HIC1410014852
  • SECONDARY ID: 7977
  • SECONDARY ID: 7977
  • SECONDARY ID: P30CA016359
  • SECONDARY ID: R21CA135572
  • SECONDARY ID: U01CA062487
  • SECONDARY ID: U01CA062490
  • SECONDARY ID: UM1CA186689
  • SECONDARY ID: UM1CA186709
  • NCT ID: NCT00576654

Conditions

  • Advanced Malignant Solid Neoplasm
  • Hodgkin Lymphoma
  • Metastatic Malignant Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • Non-Hodgkin Lymphoma
  • Stage III Breast Cancer AJCC v7
  • Stage III Colon Cancer AJCC v7
  • Stage III Lung Cancer AJCC v7
  • Stage III Ovarian Cancer AJCC v6 and v7
  • Stage III Pancreatic Cancer AJCC v6 and v7
  • Stage IIIA Breast Cancer AJCC v7
  • Stage IIIA Colon Cancer AJCC v7
  • Stage IIIA Ovarian Cancer AJCC v6 and v7
  • Stage IIIB Breast Cancer AJCC v7
  • Stage IIIB Colon Cancer AJCC v7
  • Stage IIIB Ovarian Cancer AJCC v6 and v7
  • Stage IIIC Breast Cancer AJCC v7
  • Stage IIIC Colon Cancer AJCC v7
  • Stage IIIC Ovarian Cancer AJCC v6 and v7
  • Stage IV Breast Cancer AJCC v6 and v7
  • Stage IV Colon Cancer AJCC v7
  • Stage IV Lung Cancer AJCC v7
  • Stage IV Ovarian Cancer AJCC v6 and v7
  • Stage IV Pancreatic Cancer AJCC v6 and v7
  • Stage IVA Colon Cancer AJCC v7
  • Stage IVB Colon Cancer AJCC v7
  • Triple-Negative Breast Carcinoma
  • Unresectable Malignant Neoplasm
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
Irinotecan HydrochlorideCampto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, Irinotecan Hydrochloride Trihydrate, Irinotecan Monohydrochloride Trihydrate, U-101440EDose escalation (irinotecan hydrochloride and veliparib)
VeliparibABT-888, PARP-1 inhibitor ABT-888Dose escalation (irinotecan hydrochloride and veliparib)

Purpose

This phase I trial studies the side effects and best dose of veliparib when given together with irinotecan hydrochloride in treating patients with cancer that has spread to other parts of the body or that cannot be removed by surgery. Irinotecan hydrochloride can kill cancer cells by damaging the deoxyribonucleic acid (DNA) that is needed for cancer cell survival and growth. Veliparib may block proteins that repair the damaged DNA and may help irinotecan hydrochloride to kill more tumor cells. Giving irinotecan hydrochloride together with veliparib may kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the optimal biologic dose (OBD) for poly (adenosine diphosphate [ADP]-ribose)
      polymerase (PARP) inhibition using irinotecan (irinotecan hydrochloride) (once weekly
      intravenously in 2 of 3 weeks), in combination with ABT-888 (veliparib) (twice daily orally
      for 2 of 3 weeks). (ORIGINAL DOSE ESCALATION PORTION) II. To determine the recommended phase
      II dose (RP2D) for irinotecan (once weekly intravenously in 2 of 3 weeks), in combination
      with ABT-888 (twice daily orally for 2 of 3 weeks), determined by evaluating the feasibility,
      safety, dose limiting toxicities and the maximally tolerated dose. (ORIGINAL DOSE ESCALATION
      PORTION) III. To determine the safety profile of irinotecan in combination with ABT-888: the
      incidence of adverse events (AEs) and clinically significant changes in laboratory tests,
      electrocardiograms (ECGs), and vital signs. (ORIGINAL DOSE ESCALATION PORTION) IV. To
      determine the safety profile of irinotecan in combination with ABT-888 at the recommended
      phase II dose: the incidence of adverse events (AEs) and clinically significant changes in
      laboratory tests, ECGs, and vital signs. (ORIGINAL DOSE ESCALATION PORTION) V. To determine
      the recommended phase II dose (RP2D) of each drug for irinotecan (once weekly intravenously
      in 2 of 3 weeks), in combination with ABT-888 (twice daily orally for intermittent dosing
      days 1 to 4 and days 8 to 11 of each cycle), determined by evaluating the feasibility,
      safety, dose limiting toxicities and the maximally tolerated dose (MTD). (DOSE ESCALATION FOR
      INTERMITTENT ABT-888 PORTION) VI. To determine the safety profile of irinotecan in
      combination with ABT-888: the incidence of adverse events (AEs) and clinically significant
      changes in laboratory tests, and vital signs. (DOSE ESCALATION FOR INTERMITTENT ABT-888
      PORTION) VII. To determine the safety profile of irinotecan in combination with ABT-888 at
      the recommended phase II dose: the incidence of adverse events (AEs) and clinically
      significant changes in laboratory tests, and vital signs. (DOSE ESCALATION FOR INTERMITTENT
      ABT-888 PORTION)

      SECONDARY OBJECTIVES:

      I. To determine the pharmacokinetic (PK) profile of ABT-888. II. To determine the PK profile
      of irinotecan (CPT-11) both as a single agent and in combination with ABT-888.

      III. To determine the tumor response as assessed by the Response Evaluation Criteria in Solid
      Tumors (RECIST).

      IV. To determine the tumor response as assessed by the Response Evaluation Criteria in Solid
      Tumors (RECIST). (DOSE ESCALATION FOR INTERMITTENT ABT-888 PORTION) V. To describe response
      rate (RR) in patients. (DOSE ESCALATION FOR INTERMITTENT ABT-888 PORTION)

      TERTIARY OBJECTIVES:

      I. Pharmacodynamic (PD) biomarker response: PARP inhibition in peripheral blood mononuclear
      cells (PBMC) by measurement of PAR levels. (ORIGINAL DOSE ESCALATION PORTION) II. DNA
      damaging effects of irinotecan and the combination of irinotecan with ABT-888: levels of
      gamma H2A histone family, member X (gamma-H2AX) and RAD51 recombinase (Rad51) formation in
      tumor tissue. (ORIGINAL DOSE ESCALATION PORTION) III. Relevance of cytochrome P450 family 2,
      subfamily C, polypeptide 9 (CYP2C9) and 2C19 polymorphisms, uridine 5'-diphosphosphate (UDP)
      glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) polymorphism, and ATP-binding
      cassette, sub-family G (WHITE), member 2 (ABCG2) polymorphism to the pharmacokinetics of
      irinotecan and/or ABT-888. (ORIGINAL DOSE ESCALATION PORTION) IV. To explore whether a
      positive gamma-H2AX response in tumor tissue at 4-6 hours (hrs) is reflected in circulating
      tumor cells (CTCs) between 8-24 hrs but not at 4-6 hrs, as predicted. (EXPANSION PORTION) V.
      To explore whether PARP inhibition increases gamma-H2AX response of CTCs to plasma drug by
      4-6 hrs after CPT-11 administration. (EXPANSION PORTION) VI. To explore whether PARP
      inhibition increases gamma-H2AX response of tumor cells to tissue drug level, as indicated by
      CTCs at 8-24 hrs after CPT-11. (EXPANSION PORTION) VII. To explore when the gamma-H2AX
      response peak in CTCs occurs, indicating a response in tumor. (EXPANSION PORTION) VIII. To
      explore whether there is a tumor switch between gamma-H2AX and excision repair
      cross-complementation group 1 (ERCC1)-mediated repair in the presence of PARP inhibition,
      (i.e., repeat initial PBMC and tumor findings). (EXPANSION PORTION) IX. To perform analysis
      of CTCs at day 15 to help guide alteration in ABT-888 drug administration schedule
      (continuous administration). (EXPANSION PORTION) X. To sequence the genome and transcriptome
      from both normal and tumor tissue from each study patient in the expansion cohort to evaluate
      point mutations, structural changes and copy number events. (EXPANSION PORTION) XI. To
      evaluate the damaging effects of irinotecan and the combination of irinotecan with ABT-888 by
      examining levels of Rad51 formation in tumors. (EXPANSION PORTION) XII. To evaluate the
      percentage of breast cancer stem cells (BCSC) in serial breast tumor biopsies before and
      after irinotecan alone and after 1 cycle of treatment with the combination of irinotecan and
      ABT-888. (EXPANSION PORTION) XIII. To perform molecular profiling of the tumor cell and BCSC
      populations before and after irinotecan alone and after 1 cycle of treatment with the
      combination of irinotecan and ABT-888. (EXPANSION PORTION) XIV. To compare Rad51 foci in
      aldehyde dehydrogenase-positive (ALDH+) stem cell populations to the bulk tumor cells.
      (EXPANSION PORTION) XV. To develop assays to detect trapping of PARP1 and 2 in tumor biopsy
      tissue in response to treatment with irinotecan plus a PARP inhibitor, in this case ABT-888.
      (DOSE ESCALATION FOR INTERMITTENT ABT-888 PORTION) XVI. Additional exploratory assay to be
      named later. (DOSE ESCALATION FOR INTERMITTENT ABT-888 PORTION)

      OUTLINE: This is a dose-escalation study of veliparib. Patients are assigned to 1 of 3
      cohorts.

      DOSE ESCALATION: Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes
      on days 1 and 8 and veliparib orally (PO) twice daily (BID) on days -1 to 14 (days 3-14 of
      course 1 only). Courses repeat every 21 days in the absence of disease progression or
      unacceptable toxicity.

      EXPANSION PORTION: Patients receive irinotecan hydrochloride IV over 90 minutes on days 1 and
      8 and veliparib PO BID on days 1-15 (days 2-15 of course 1 only). Courses repeat every 21
      days in the absence of disease progression or unacceptable toxicity.

      INTERMITTENT DOSE ESCALATION: Patients receive irinotecan hydrochloride IV over 90 minutes on
      days 3 and 10 and veliparib PO BID on days 1 to 4 and 8-11. Courses repeat every 21 days in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Dose escalation (irinotecan hydrochloride and veliparib)ExperimentalPatients receive irinotecan hydrochloride IV over 90 minutes on days 1 and 8 and veliparib PO BID on days -1 to 14 (days 3-14 of course 1 only). Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Irinotecan Hydrochloride
  • Veliparib
Expansion portion (irinotecan hydrochloride and veliparib)ExperimentalPatients receive irinotecan hydrochloride IV over 90 minutes on days 1 and 8 and veliparib PO BID on days 1-15 (days 2-15 of course 1 only). Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Irinotecan Hydrochloride
  • Veliparib
Intermittent dose escalation (irinotecan, ABT-888)ExperimentalPatients receive irinotecan hydrochloride IV over 90 minutes on days 3 and 10 and veliparib PO BID on days 1 to 4 and 8-11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Irinotecan Hydrochloride
  • Veliparib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed diagnosis of malignancy
             that is metastatic or unresectable and for which standard curative or palliative
             measures do not exist or are no longer effective or for whom CPT-11 treatment would be
             a viable therapy regimen; patients with solid hematologic malignancies (Hodgkin's and
             non-Hodgkin's lymphomas) may be included as long as a bone marrow has been performed
             within 6 weeks of treatment

          -  Patients enrolled on the expansion portion of the study will consist of two cohorts:
             those patients who are triple-negative, BRCA-mutant positive and those patients who
             have triple-negative, non-BRCA mutated breast cancer

          -  Patients enrolled on the dose escalation for intermittent ABT-888 portion of the study
             must histologically or cytologically confirmed diagnosis of malignancy that is
             metastatic or unresectable and for which standard curative or palliative measures do
             not exist or are no longer effective or for whom CPT-11 treatment would be a viable
             therapy regimen; patients with solid hematologic malignancies (Hodgkin's and
             non-Hodgkin's lymphomas) may be included as long as a bone marrow has been performed
             within 6 weeks of treatment

          -  Patient must have measurable disease per Response Evaluation Criteria in Solid Tumors
             (RECIST) guidelines

          -  Patients must have tumors determined to be easily accessible for biopsy (e.g.
             pleural-based lesions, peripheral lymph nodes, soft tissue metastases, large liver
             metastases, etc)

          -  Prior chemotherapy is allowed; patients must not have received chemotherapy for 4
             weeks prior to the initiation of study treatment and must have full recovery from any
             acute effects of any prior chemotherapy; patients must not have had nitrosoureas or
             mitomycin C for 6 weeks prior to the initiation of study treatment

          -  Prior radiation therapy is allowed; patients must not have received minimal radiation
             therapy (=< 5% of their total marrow volume) within 3 weeks prior to the initiation of
             study treatment; otherwise, patients must not have received radiation therapy (> 5% of
             their total marrow volume) within 4 weeks prior to the initiation of study treatment;
             patients who have received prior radiation to 50% or more of their total marrow volume
             will be excluded

          -  Prior experimental (non-Food and Drug Administration [FDA] approved) therapies and
             immunotherapies are allowed; patients must not have received these therapies for 4
             weeks prior to the initiation of study treatment and must have full recovery from any
             acute effects of these therapies

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Life expectancy of greater than 12 weeks

          -  Absolute neutrophil count (ANC) >= 1,500/mcL

          -  Platelets (PLT) >= 100,000/mcL

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
             limit of normal (ULN); if liver metastases are present, =< 5 x ULN

          -  Bilirubin =< 1.5 x ULN

          -  Creatinine =< 1.5 x ULN OR calculated or measured creatinine clearance >= 60
             mL/min/1.73 m^2 for patients with creatinine above institutional normal

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for
             the duration of study participation, and for three months following completion of
             study therapy; should a woman become pregnant or suspect she is pregnant while
             participating in this study, she should inform her treating physician immediately

          -  Ability to understand and the willingness to sign a written informed consent document

          -  All patients must provide archival tissue block or paraffin sample from archival
             tissue block (approximately 10 sections) for use in pharmacodynamic correlative
             studies (NOT required for patients enrolled on the dose escalation for intermittent
             ABT-888 portion of the study)

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events due to agents administered more than 4 weeks earlier;
             patients who have been administered ABT-888 as part of a single or limited dosing
             study, such as a phase 0 study, should not necessarily be excluded from participating
             in this study solely because of receiving prior ABT-888

          -  Patients may not have received any other investigational agents within 4 weeks of
             study entry

          -  History of allergic reactions attributed to the following:

               -  Camptothecin derivatives (e.g., topotecan [topotecan hydrochloride], irinotecan,
                  or exatecan [exatecan mesylate])

               -  Any ingredients contained within the liquid irinotecan solution (e.g., sorbitol)
                  or

               -  Any antiemetics or antidiarrheals appropriate for administration with study
                  therapy (e.g., loperamide or dexamethasone)

          -  Patients must not receive any other anti-cancer therapy (cytotoxic, biologic,
             radiation, or hormonal other than for replacement) while on this study except for
             medications that are prescribed for supportive care but may potentially have an
             anti-cancer effect (i.e. megestrol acetate, bisphosphonates); these medications must
             have been started 1 month prior to enrollment on this study; in addition, men
             receiving treatment for prostate cancer will be maintained at castrate levels of
             testosterone by continuation of luteinizing-releasing hormone agonists

          -  Patients with uncontrolled seizures

          -  Patients with known active brain metastases should be excluded from this clinical
             trial; patients with prior treated brain metastases are allowed, providing that they
             were not accompanied by seizures and that a baseline brain magnetic resonance imaging
             (MRI) scan prior to study entry demonstrates no current evidence of brain metastases;
             all patients with central nervous system (CNS) metastases must be stable for > 3
             months after treatment and off steroid treatment prior to study enrollment

          -  Any patient requiring chronic maintenance of white blood cell counts or granulocyte
             counts through the use of growth factor support (e.g. Neulasta, Neupogen)

          -  Any patient requiring cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4)
             isoform-inducing drugs (e.g. phenytoin, phenobarbital, carbamazepine, rifampin,
             rifabutin, ketoconazole, St. John's wort) will be excluded; CYP3A4-inducing drugs
             should be discontinued at least 2 weeks prior to the first cycle of irinotecan

          -  Uncontrolled intercurrent illness including, but not limited to:

               -  Ongoing or active infection

               -  Symptomatic congestive heart failure

               -  Unstable angina pectoris

               -  Cardiac arrhythmia or

               -  Psychiatric illness or social situations that would limit compliance with study
                  requirements

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with ABT-888

          -  Patients who are unable to reliably tolerate and/or receive oral medications
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Optimal biologic dose (OBD)
Time Frame:Up to day 9 of course 1
Safety Issue:
Description:Defined as the dose level at which no greater inhibition of poly(ADP-ribose) (PAR) levels in tumor cells is identified, relative to the next lower dose.

Secondary Outcome Measures

Measure:Incidence of adverse events (AEs), graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time Frame:Up to 30 days
Safety Issue:
Description:Described by point estimates and exact 90% confidence intervals.
Measure:Tumor response
Time Frame:Up to 30 days
Safety Issue:
Description:Evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

January 15, 2021