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

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

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

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 Summary:

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 toxic
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • Clinical response (CR, CRi, PR) [ Time Frame: Up to 3 years ]
  • 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 ]


Original Primary Outcome:

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


Current Secondary Outcome: 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.


Original Secondary Outcome: Pharmacokinetics and pharmacodynamics of ABT-888

Information By: National Cancer Institute (NCI)

Dates:
Date Received: December 20, 2007
Date Started: November 2007
Date Completion:
Last Updated: May 23, 2017
Last Verified: December 2016