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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Essential Thrombocythemia, Hematopoietic/Lymphoid Cancer, Philadelphia Chromosome Negative Chronic Myelogenous Leukemia, Polycythemia Vera, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Relapsing Chronic Myelogenous Leukemia, Secondary Myelodysplastic Syndromes

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Trial Information

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


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.


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Time Frame:

Up to 63 days

Safety Issue:

Yes

Principal Investigator

Keith Pratz

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00259

NCT ID:

NCT00588991

Start Date:

November 2007

Completion Date:

Related Keywords:

  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndromes
  • Essential Thrombocythemia
  • Hematopoietic/Lymphoid Cancer
  • Philadelphia Chromosome Negative Chronic Myelogenous Leukemia
  • Polycythemia Vera
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Relapsing Chronic Myelogenous Leukemia
  • Secondary Myelodysplastic Syndromes
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Philadelphia Chromosome
  • Polycythemia
  • Polycythemia Vera
  • Thrombocythemia, Essential
  • Thrombocytosis

Name

Location

Johns Hopkins UniversityBaltimore, Maryland  21205
Mayo ClinicRochester, Minnesota  55905