Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

ABT-888 and Topotecan With or Without Carboplatin in Treating Patients With Relapsed or Refractory Acute Leukemia, High-Risk Myelodysplasia, or Aggressive Myeloproliferative Disorders

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Biomarker/Laboratory analysis, Treatment Active 18 and over NCI JHOC-J0783 J0783, 7968, NCT00588991

Objectives

Primary

1. To determine the feasibility, tolerability, and toxicities of ABT-888 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.
2. To determine the maximum tolerated dose of ABT-888 when administered with topotecan hydrochloride and carboplatin in these patients.
3. To determine if ABT-888 when administered with topotecan hydrochloride and carboplatin can induce clinical responses in these patients.

Secondary

1. To determine the pharmacokinetics of ABT-888 when administered alone and in combination with topotecan hydrochloride with or without carboplatin in these patients.
2. To obtain pharmacodynamic data regarding the ability of ABT-888 to inhibit poly (ADP-ribose) levels in leukemic blasts.
3. 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.

Entry Criteria

Disease Characteristics:

• Pathologically confirmed diagnosis of 1 of the following:
  • Acute myeloid leukemia, acute lymphoblastic leukemia, or high-risk myelodysplastic syndromes that has relapsed at least once or is refractory, including primary induction failure
    • No acute progranulocytic leukemia (M3)
  • 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
    • New onset or > 25% increase in hepatomegaly or splenomegaly
    • New onset constitutional symptoms (i.e., fever, weight loss, splenic pain, or bone pain)
  • Chronic myelomonocytic leukemia meeting either of the following criteria:
    • 5-19% bone marrow blasts (aggressive)
    • At least 20% marrow blasts (transformation)



• Patients who failed primary induction therapy or relapsed after achieving complete remission are eligible



• No active CNS leukemia

Prior/Concurrent Therapy:

• 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

Patient Characteristics:

• ECOG performance status 0-2
• No hyperleukocytosis with ≥ 50,000 blasts/μL
• 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

Expected Enrollment

Outcomes

Feasibility, tolerability, and toxicities of ABT-888 as assessed by NCI-CTCAE v3.0
Maximum tolerated dose of ABT-888
Clinical response

Pharmacokinetics and pharmacodynamics of ABT-888

Outline

This is a multicenter, dose-escalation study of ABT-888.

Patients receive oral ABT-888 twice daily on days 1-8 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.

Trial Contact Information

Trial Lead Organizations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Judith Karp, MD, Protocol chair		Ph: 410-502-7726

U.S.A.
Maryland
	Baltimore
	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
		Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Center at John Hopkins	Ph:  410-955-8804
			Email: jhcccro@jhmi.edu

Registry Information
Official Title		A Phase 1 Study of ABT-888 in Combination with Topotecan plus Carboplatin for Relapsed and Refractory Acute Leukemias and High-Risk Myelodyplasias and Myeloproliferative Disorders
Trial Start Date		2007-11-28
Registered in ClinicalTrials.gov		NCT00588991
Date Submitted to PDQ		2007-11-29
Information Last Verified		2008-02-06
NCI Grant/Contract Number		CA70095, CA06973