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

Primary Purpose

Adult Acute Megakaryoblastic Leukemia, Adult Acute Monoblastic Leukemia, Adult Acute Monocytic Leukemia

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Carboplatin
Laboratory Biomarker Analysis
Topotecan Hydrochloride
Veliparib
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Megakaryoblastic Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Mayo Clinic in Rochester

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (veliparib, topotecan hydrochloride, carboplatin)

Arm Description

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.

Outcomes

Primary Outcome Measures

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
Clinical response (CR, CRi, PR)

Secondary Outcome Measures

Pharmacokinetics and pharmacodynamics 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.

Full Information

First Posted
December 20, 2007
Last Updated
September 12, 2023
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00588991
Brief Title
Veliparib and Topotecan With or Without Carboplatin in Treating Patients With Relapsed or Refractory Acute Leukemia, High-Risk Myelodysplasia, or Aggressive Myeloproliferative Disorders
Official Title
A Phase I Study of ABT-888 in Combination With Topotecan Plus Carboplatin for High-Risk Myeloproliferative Disorders and AML Out of Myeloproliferative Disorders
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
November 28, 2007 (Actual)
Primary Completion Date
February 1, 2014 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Acute Megakaryoblastic Leukemia, Adult Acute Monoblastic Leukemia, Adult Acute Monocytic Leukemia, Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With Maturation, Adult Acute Myeloid Leukemia With Minimal Differentiation, Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1, Adult Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-KMT2A, Adult Acute Myeloid Leukemia Without Maturation, Adult Acute Myelomonocytic Leukemia, Adult Erythroleukemia, Adult Pure Erythroid Leukemia, Chronic Myeloid Leukemia, Philadelphia Chromosome Negative, BCR-ABL1 Positive, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndrome, Essential Thrombocythemia, Hematopoietic and Lymphoid Cell Neoplasm, Myelodysplastic Syndrome, Polycythemia Vera, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Secondary Myelodysplastic Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (veliparib, topotecan hydrochloride, carboplatin)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Carboplatin
Other Intervention Name(s)
Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, JM8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative study
Intervention Type
Drug
Intervention Name(s)
Topotecan Hydrochloride
Other Intervention Name(s)
Evotopin, Hycamptamine, Hycamtin, Potactasol, SKF S-104864-A, Topotec, Topotecan HCl, topotecan hydrochloride (oral)
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Veliparib
Other Intervention Name(s)
ABT-888, PARP-1 inhibitor ABT-888
Intervention Description
Given orally
Primary Outcome Measure Information:
Title
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
Title
Clinical response (CR, CRi, PR)
Time Frame
Up to 3 years
Secondary Outcome Measure Information:
Title
Pharmacokinetics and pharmacodynamics of veliparib
Description
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.
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Keith W Pratz
Organizational Affiliation
Johns Hopkins University/Sidney Kimmel Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins University/Sidney Kimmel Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Mayo Clinic in Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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