Clinical trial NCT00588991: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-01-09
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
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
timeFrame: Up to 63 days
measure: Clinical response (CR, CRi, PR)
timeFrame: Up to 3 years
Secondary outcomes:
measure: Pharmacokinetics and pharmacodynamics of veliparib
timeFrame: 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
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Johns Hopkins University/Sidney Kimmel Cancer Center
name: Keith W Pratz
role: PRINCIPAL_INVESTIGATOR
References: