Veliparib and Topotecan Hydrochloride in Treating Patients With Solid Tumors, Relapsed or Refractory Ovarian Cancer, or Primary Peritoneal Cancer

This study has suspended participant recruitment.
(this study will temporarily close while patients at Dose Level 13 (400 mg ABT-888 twice daily; 3 mg/m2 Topotecan) are assessed per study design.)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01012817
First received: November 11, 2009
Last updated: September 16, 2014
Last verified: August 2014
  Purpose

This phase I/II trial studies the side effects and best dose of veliparib and topotecan hydrochloride and to see how well they work in treating patients with solid tumors, relapsed or refractory ovarian cancer, or primary peritoneal cancer. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as topotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving veliparib with chemotherapy may kill more tumor cells.


Condition Intervention Phase
Recurrent Ovarian Epithelial Cancer
Recurrent Primary Peritoneal Cavity Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Drug: veliparib
Drug: topotecan hydrochloride
Other: pharmacogenomic studies
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of ABT-888, an Inhibitor of Poly (ADP-ribose) Polymerase (PARP), and Topotecan (TPT) in Patients With Solid Tumors (Phase I) and Relapsed or Refractory Ovarian Cancer or Primary Peritoneal Cancer (Phase II) After Prior Platinum Containing First-Line Chemotherapy

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • MTD of topotecan hydrochloride and veliparib, determined according to incidence of dose-limiting toxicity (DLT), graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I) [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
    The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized. The grade 3+ adverse events will also be described and summarized in a similar fashion. Toxicity incidence by BRCA mutation will also be evaluated for the patients enrolled in the expanded Phase I MTD cohort. Frequency distribution, graphical techniques, and other descriptive measures will form the basis of these analyses.

  • Proportion of tumor responses, defined as a CR or PR as assessed using RECIST [ Time Frame: Up to 48 weeks (12 courses) ] [ Designated as safety issue: No ]
    The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner (1987).


Secondary Outcome Measures:
  • Overall survival [ Time Frame: The time from registration to death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier.

  • PFS [ Time Frame: The time from registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    The distribution of PFS will be estimated using the method of Kaplan-Meier.

  • Duration of response [ Time Frame: The date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented, assessed up to 5 years ] [ Designated as safety issue: No ]
  • Time to treatment failure [ Time Frame: The time from the date of registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal, assessed up to 5 years ] [ Designated as safety issue: No ]
  • Adverse events, graded using NCI CTCAE version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.


Estimated Enrollment: 102
Study Start Date: October 2009
Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (veliparib and topotecan hydrochloride)
Patients receive veliparib PO on days 1-3, 8-10, and 15-17 (veliparib is omitted on days 1-3 of course 2) and topotecan hydrochloride IV over 30 minutes on days 2, 9, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: veliparib
Given PO
Other Name: ABT-888
Drug: topotecan hydrochloride
Given IV
Other Names:
  • hycamptamine
  • Hycamtin
  • SKF S-104864-A
  • TOPO
Other: pharmacogenomic studies
Correlative studies
Other Name: Pharmacogenomic Study
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of the combination of ABT-888 (veliparib) and weekly topotecan (topotecan hydrochloride) in adult patients with advanced solid tumors. (Phase I) II. To identify any anti-tumor activity of this treatment combination, as assessed by objective response in patients with advanced solid tumors. (Phase I) III. To assess the confirmed response rate for patients with epithelial ovarian cancer or primary peritoneal carcinoma treated with the combination of ABT-888 and weekly topotecan.

IV. To assess the toxicity of the combination of ABT-888 and weekly topotecan in patients with epithelial ovarian cancer or primary peritoneal carcinoma. (Phase II)

SECONDARY OBJECTIVES:

I. To identify any pharmacokinetic interactions between ABT-888 and topotecan. (Phase I and II) II. Phase I MTD: to provide preliminary view as to difference in response and toxicity based on BRCA mutation status. (Phase I) III. To determine whether topotecan stimulates adenosine diphosphate (ADP)-ribose polymer formation in circulating peripheral blood mononuclear cells. (Phase I) IV. To determine whether ABT-888 inhibits basal or topotecan-stimulated ADP-ribose polymer formation. (Phase I) V. To determine whether topotecan stimulates ADP-ribose polymer formation in circulating tumor cells and whether ABT-888 modulates this. (Phase II) VI. To assess differences in the toxicity and/or efficacy of this regimen based on BRCA 1/2 mutational status. (Phase II) VII. To determine whether pretreatment tumor cell levels of topoisomerase I, poly ADP-ribose polymerase (PARP), BRCA1, BRCA2, XRCC1, tyrosyl-deoxyribonucleic acid (DNA) phosphodiesterase 1 (TDP1), P-glycoprotein or breast cancer resistance protein (BCRP) predict response to this regimen. (Phase II) VIII. To identify, in an exploratory manner, any transcriptional profiles that may predict response to this regimen. (Phase II)

OUTLINE: This is a phase I, dose escalation study of veliparib and topotecan hydrochloride followed by a phase II study.

Patients receive veliparib orally (PO) on days 1-3, 8-10, and 15-17 (veliparib is omitted on days 1-3 of course 2) and topotecan hydrochloride intravenously (IV) over 30 minutes on days 2, 9, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 months (Phase I) or every 3 or 6 months for 5 years (Phase II).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PHASE I: Adult patients with histologically confirmed solid tumor malignancy that is metastatic or unresectable and for which standard curative measures or other therapy definitely capable of extending life expectancy does not exist
  • PHASE II: All patients enrolled in the Phase II portion of this trial must have a history of biopsy-proven ovarian or primary peritoneal cancer at Mayo Clinic, and radiological evidence of recurrence at a previous site of disease, or biopsy confirmation if the site represents a new site of disease; patients must have received =< 2 prior therapeutic regimens and must be either refractory to platinum-based therapy or have relapsed < 1 year after receiving a prior platinum-based regimen
  • Patients must have measurable disease with at least one lesion whose longest diameter can be accurately measured as >= 2.0 cm with conventional techniques or as >= 1.0 cm with spiral computed topography (CT); if spiral CT is used, it must be used for both pre- and post- treatment tumor assessments
  • Absolute neutrophil count >= 1500/mcL
  • Hemoglobin >= 9.0 g/dL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5x the upper limit of normal (ULN)
  • Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) or serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x ULN in the absence of hepatic metastasis; SGPT (ALT) =< 3 x ULN or SGOT (AST) =< 5 x ULN in the presences of hepatic metastasis
  • Creatinine =< 1.5 x ULN
  • International normalized ratio (INR) =< 1.4 unless receiving therapeutic doses of coumadin
  • Partial thromboplastin time (PTT) =< 36 seconds
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1, or 2
  • Ability to provide informed consent
  • Willingness to return to a Mayo Clinic institution for follow up
  • Life expectancy >= 12 weeks
  • Willingness to provide the biologic specimens is required by the protocol; this is part of the mandatory translational research component; these specimens include:

    • PHASE I: peripheral blood for plasma pharmacokinetic analysis and peripheral blood mononuclear cell (PBMC) polymer assessment from 0-24 h after drug administration on days 1 and 2 of cycle 1 as well as day 2 of cycle 2; urine for assessment of ABT-888 renal clearance for 24 h after administration of drugs on days 1 and 2 of cycle 1 as well as day 2 of cycle 2; and a pretreatment peripheral blood sample for possible sequencing of the BRCA1, BRCA2 loci as well as possible pharmacogenomic analysis
    • PHASE II: all of the above samples plus a pretreatment biopsy for biological studies and sequence analysis of the BRCA1 and BRCA2 loci
    • Note: The goals of this study include assessment of the biologic effects on surrogate markers of the agent(s) being tested and are, therefore, contingent upon availability of the biologic specimens
  • Women of childbearing potential only: Negative urine or serum pregnancy test done =< 7 days prior to registration
  • Able to swallow and absorb the medication

Exclusion Criteria:

  • Known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Any of the following prior therapies:

    • Chemotherapy =< 4 weeks prior to registration
    • Mitomycin C/nitrosoureas =< 6 weeks prior to registration
    • Immunotherapy =< 4 weeks prior to registration
    • Biologic therapy =< 4 weeks prior to registration
    • Radiation therapy =< 4 weeks prior to registration
    • Radiation to > 25% of bone marrow
    • Investigational therapy or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) =< 4 weeks prior to registration; subjects with prostate cancer will be permitted to continue hormone therapy
  • Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment
  • New York Heart Association classification III or IV
  • Known central nervous system (CNS) metastases or seizure disorder; patients with known brain metastases that have been successfully treated and stable for >= 6 months without requirement for corticosteroids and without seizure activity will be eligible
  • Any of the following, because this study involves both ABT-888, an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown, and topotecan, an agent that has known genotoxic, mutagenic and teratogenic effects:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
  • Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  • Other active malignancy, except non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer
  • History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • More than 2 prior chemotherapy regimens for the current malignancy; full dose chemotherapy used in conjunction with concurrent radiation therapy will be included as prior therapy; NOTE: Prior hormonal therapy (e.g. leuprolide, aromatase inhibitors, tamoxifen) will be allowed and not included as a prior chemotherapy
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01012817

Locations
United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Investigators
Principal Investigator: Michael Menefee Mayo Clinic
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01012817     History of Changes
Other Study ID Numbers: NCI-2011-00312, NCI-2011-00312, MAYO-MC0861, 09-000742, CDR0000657976, MC0861, 8329, P30CA015083, U01CA069912
Study First Received: November 11, 2009
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neoplasms
Ovarian Neoplasms
Neoplasms, Glandular and Epithelial
Peritoneal Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Neoplasms by Histologic Type
Abdominal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Peritoneal Diseases
Topotecan
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 18, 2014