Veliparib and Topotecan With or Without Carboplatin in Treating Patients With Relapsed or Refractory Acute Leukemia, High-Risk Myelodysplasia, or Aggressive Myeloproliferative Disorders

March 8, 2024 updated by: National Cancer Institute (NCI)

A Phase I Study of ABT-888 in Combination With Topotecan Plus Carboplatin for High-Risk Myeloproliferative Disorders and AML Out of Myeloproliferative Disorders

This phase I trial is studying the side effects and best dose of veliparib when given together with topotecan hydrochloride with or without carboplatin in treating patients with relapsed or refractory acute leukemia, high-risk myelodysplasia, or aggressive myeloproliferative disorders. Veliparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as topotecan hydrochloride and carboplatin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving veliparib together with topotecan hydrochloride and carboplatin may kill more cancer cells.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the feasibility, tolerability, and toxicities of ABT-888 (veliparib) when administered alone and in combination with topotecan hydrochloride with or without carboplatin in patients with relapsed or refractory acute leukemia, high-risk myelodysplasia, or aggressive myeloproliferative disorders.

II. To determine the maximum tolerated dose of ABT-888 when administered with topotecan hydrochloride and carboplatin in these patients.

III. To determine if ABT-888 when administered with topotecan hydrochloride and carboplatin can induce clinical responses in these patients.

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetics of ABT-888 when administered alone and in combination with topotecan hydrochloride with or without carboplatin in these patients.

II. To obtain pharmacodynamic data regarding the ability of ABT-888 to inhibit poly (ADP-ribose) levels in leukemic blasts.

III. To obtain descriptive data regarding the mutational status and/or methylation status of key genes in selected DNA repair pathways (Fanconi complementation groups A-F, Blooms, and ataxia-telangiectasia) in leukemic blasts.

OUTLINE: This is a multicenter, dose-escalation study of veliparib.

Patients receive veliparib orally twice daily on days 1-8, 1-14, or 1-21 and topotecan hydrochloride with or without carboplatin IV continuously over 120 hours on days 3-7. Treatment repeats every 28-63 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection periodically for pharmacokinetic studies.

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

Study Type

Interventional

Enrollment (Actual)

12

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins University/Sidney Kimmel Cancer Center
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic in Rochester

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Pathologically confirmed diagnosis of 1 of aggressive MPD or AML out of MPD

  • Aggressive phase high-risk myeloproliferative disorders (i.e., polycythemia vera, essential thrombocythemia, or Ph-negative chronic myelogenous leukemia) meeting ≥ 1 of the following criteria:

    • Marrow blasts > 5%
    • Peripheral blood blasts plus progranulocytes > 10%
    • New onset or increasing myelofibrosis OR;
  • New onset or > 25% increase in hepatomegaly or splenomegaly
  • New onset constitutional symptoms (i.e., fever, weight loss, splenic pain, or bone pain)
  • Patients who failed primary induction therapy or relapsed after achieving complete remission are eligible
  • No active CNS leukemia; patients with a history of CNS disease must be stable for > 3 months after treatment and off steroid treatment prior to study enrollment

  • Chronic myelomonocytic leukemia meeting either of the following criteria:

    • 5-19% bone marrow blasts (aggressive)
    • At least 20% marrow blasts (transformation)
  • ECOG performance status 0-2
  • No hyperleukocytosis with >= 50,000 blasts/uL
  • AST, ALT, and alkaline phosphatase =< 5 times upper limit of normal
  • Bilirubin =< 2.0 mg/dL
  • Creatinine normal OR creatinine clearance >= 60 mL/min
  • LVEF >= 45% by MUGA or ECHO
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 30 days after completion of study therapy
  • No active disseminated intravascular coagulation
  • No active uncontrolled infection
  • Patients with infection that is under active treatment and controlled with antibiotics are eligible
  • No other life-threatening illness
  • No mental deficits and/or psychiatric history that would preclude giving informed consent or following protocol
  • No prior or current seizure disorder or a history of seizure
  • No more than 3 prior cytotoxic regimens
  • At least 3 weeks since prior cytotoxic chemotherapy
  • At least 2 weeks since prior radiotherapy
  • At least 4 weeks since prior autologous or allogeneic stem cell transplantation
  • No active graft-versus-host disease
  • At least 1 week since prior biologic therapies, including hematopoietic growth factors
  • At least 24 hours since prior hydroxyurea, steroids, imatinib mesylate, arsenic trioxide, interferon, or other noncytotoxic agents for blast count control
  • No prior ABT-888
  • No other concurrent chemotherapy, radiotherapy, or immunotherapy
  • No concurrent antiretroviral therapy for HIV-positive patients
  • No other concurrent investigational or commercial agents or therapies for this cancer

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (veliparib, topotecan hydrochloride, carboplatin)
Patients receive veliparib orally twice daily on days 1-8, 1-14, or 1-21 and topotecan hydrochloride with or without carboplatin IV continuously over 120 hours on days 3-7. Treatment repeats every 28-63 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo
  • JM8
Drug: Topotecan Hydrochloride
Given IV
Other Names:
  • Hycamtin
  • Hycamptamine
  • SKF S-104864-A
  • Topotecan HCl
  • topotecan hydrochloride (oral)
  • Potactasol
  • Evotopin
  • Topotec
Other: Laboratory Biomarker Analysis
Correlative study
Drug: Veliparib
Given orally
Other Names:
  • ABT-888
  • PARP-1 inhibitor ABT-888

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Maximum tolerated dose of veliparib, determined as the highest dose level where 0/3 or 1/6 experience DLT, measured according to NCI-CTCAE 4.0
Time Frame: Up to 63 days
Up to 63 days
Clinical response (CR, CRi, PR)
Time Frame: Up to 3 years
Up to 3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacokinetics and pharmacodynamics of veliparib
Time Frame: Day 1 at pre-treatment, .25, .5, 1, 2, 4, 6, and 8 hours after veliparib and day 4 at pre-veliparib, .25, .5, 1, 2, 4, 6, and 8 hours after the first dose of veliparib
Relevant individual PK parameters will be estimated using non-compartmental PK methods. PK parameters will be compared when administered alone or in combination by a paired student's t-test. Comparison of PK parameters among dose levels will be performed using non-parametric statistical methods for K-independent samples. Associations between exposure parameters (Cmax and AUC) and pharmacodynamic endpoints (cellular PAR levels, mutation and/or altered expression of selected DNA repair genes) will be assessed using the appropriate non-parametric statistical tests.
Day 1 at pre-treatment, .25, .5, 1, 2, 4, 6, and 8 hours after veliparib and day 4 at pre-veliparib, .25, .5, 1, 2, 4, 6, and 8 hours after the first dose of veliparib

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Keith W Pratz, Johns Hopkins University/Sidney Kimmel Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 28, 2007

Primary Completion (Actual)

February 1, 2014

Study Completion (Estimated)

March 7, 2025

Study Registration Dates

First Submitted

December 20, 2007

First Submitted That Met QC Criteria

December 25, 2007

First Posted (Estimated)

January 9, 2008

Study Record Updates

Last Update Posted (Actual)

March 12, 2024

Last Update Submitted That Met QC Criteria

March 8, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2009-00259 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • P30CA006973 (U.S. NIH Grant/Contract)
  • U01CA070095 (U.S. NIH Grant/Contract)
  • UM1CA186691 (U.S. NIH Grant/Contract)
  • U01CA069912 (U.S. NIH Grant/Contract)
  • CDR0000579626
  • J0783 (Other Identifier: Johns Hopkins University/Sidney Kimmel Cancer Center)
  • 7968 (Other Identifier: CTEP)
  • U01CA062491 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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