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A Phase I Study of the PARP Inhibitor ABT-888 in Combination With Temozolomide in Acute Leukemias


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Accelerated Phase Chronic Myelogenous Leukemia, Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), B-cell Adult Acute Lymphoblastic Leukemia, Blastic Phase Chronic Myelogenous Leukemia, Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, T-cell Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia

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Trial Information

A Phase I Study of the PARP Inhibitor ABT-888 in Combination With Temozolomide in Acute Leukemias


PRIMARY OBJECTIVES:

I. Define the maximum-tolerated dose (MTD) and recommended phase II dose of ABT-888
(veliparib) administered in combination with temozolomide in patients with acute leukemias.

II. Evaluate the feasibility, safety, and toxicity of administering ABT-888 in combination
with temozolomide in patients with acute leukemias.

SECONDARY OBJECTIVES:

I. Document response in acute leukemias. II. Observe the pharmacokinetics of both ABT-888
and temozolomide when administered alone and in combination.

III. Study the pharmacodynamics to determine the levels of poly(ADP-ribose) (PAR) before and
after administration of ABT-888 and temozolomide in patient leukemia blasts, to analyze
methyl-guanine methyl-transferase (MGMT) protein levels in primary leukemia blasts, and to
quantify the induction of γ-H2AX and RAD51 foci in patient leukemia blasts after treatment.

OUTLINE: This is a dose-escalation study of veliparib.

Patients receive oral veliparib once daily on day 1 and twice daily on days 4-12 and oral
temozolomide once daily on days 3-9 of course 1.

Beginning at least 30 days after the start of treatment, patients receive oral veliparib
twice daily on days 1-8 and oral temozolomide once daily on days 1-5. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

Patients achieving complete remission receive 5 more courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.


Inclusion Criteria:



- Histologically or cytologically confirmed diagnosis of one of the following:

- Relapsed or refractory acute myeloid leukemia (AML)

- Patients with acute promyelocytic leukemia [t(15;17)] are eligible provided
they have failed tretinoin, arsenic, and gemtuzumab ozogamicin (patients
should be refractory to all three agents, defined as the absence of durable
hematologic response or relapse with complete remission duration of < 6
months)

- Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL)

- Patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] are
eligible provided that they have failed (intolerance/resistance) ≥ 2
different tyrosine kinase inhibitors (TKIs) or have a mutation associated
with resistance to TKIs (T315I)

- Chronic myelogenous leukemia in accelerated or blastic phase

- Patients failed (resistance/intolerance) ≥ 2 different TKIs or have a
mutation associated with resistance to TKIs (T315I)

- AML arising in the setting of antecedent myelodysplasia or myeloproliferative
disorder

- Therapy-related AML

- Untreated AML in patients meeting the following criteria:

- Adults 60 years of age and older

- Not a candidate for induction chemotherapy due to poor-risk features
including adverse cytogenetics [i.e., complex karyotype (≥ 3 chromosomal
abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11),
t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q) or molecular
markers (FLT3 ITD^+) OR unwilling to receive intensive induction
chemotherapy

- Untreated ALL in patients meeting the following criteria:

- Adults 60 years of age and older

- Not a candidate for induction chemotherapy due to poor-risk features
including adverse cytogenetics [i.e., t[(4;11), t(1;19), hypodiploidy] OR
unwilling to receive intensive induction chemotherapy

- Patients with Ph+ ALL [t(9;22)] are eligible provided that they have failed
(intolerance/resistance) ≥ 2 different TKIs or have a mutation associated
with resistance to TKIs (T315I)

- Received or are ineligible for established curative regimens, including stem cell
transplantation, when applicable

- No hyperleukocytosis with > 30,000 blast/μL

- No active CNS leukemia

- Patients with a history of CNS leukemia must be stable for > 3 months off
treatment and off steroid treatment prior to study entry

- See Disease Characteristics

- ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)

- Total or direct bilirubin ≤ 2 mg/dL

- AST/ALT < 5 times upper limit of normal

- Creatinine ≤ 2 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use adequate contraception before, during, and for 30 days
after completion of study treatment

- Able to swallow pills

- No active, uncontrolled infection

- Patients with infection under active treatment and controlled with antibiotics
are eligible

- No uncontrolled concurrent illness including, but not limited to, any of the
following:

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situations that would limit compliance with study
requirements

- No known HIV-infected patients on combination antiretroviral therapy (except for
zidovudine or stavudine)

- HIV testing will not be performed as part of screening

- HIV patients not on or willing to suspend antiretroviral therapy are eligible
provided that their CD4 cell count is > 250/mm^3

- No uncontrolled, active seizure disorder or a history of seizure

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to veliparib or temozolomide

- See Disease Characteristics

- No prior veliparib or temozolomide

- Any number of prior chemotherapy regimens allowed

- Recovered to ≤ grade 1 from all adverse events (excluding alopecia, acne, and rash)

- Prior allogeneic stem cell transplantation allowed provided patients meet all of the
following criteria:

- At least 60 days since stem cell infusion

- No evidence of graft-vs-host disease

- At least 2 weeks since prior immunosuppressive therapy

- At least 4 weeks since prior autologous stem cell transplantation

- At least 3 weeks since prior cytotoxic chemotherapy (6 weeks since carmustine or
mitomycin C)

- At least 2 weeks since prior radiotherapy

- At least 1 week since prior and no concurrent biologic agents including hematopoietic
growth factors, imatinib, or similar tyrosine kinase inhibitors

- At least 24 hours since prior hydroxyurea, corticosteroids, or leukapheresis for
blast count control

- Concurrent hydroxyurea for patient with rapidly proliferating disease allowed on
treatment days 1 through 12 at the discretion of treating physician

- No other concurrent investigational agents, chemotherapy, radiotherapy, or
immunotherapy

- No other concurrent anticancer therapies or agents

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

MTD of veliparib, determined according to incidence of dose limiting toxicity (DLT), graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Ivana Gojo

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-01457

NCT ID:

NCT01139970

Start Date:

May 2010

Completion Date:

Related Keywords:

  • Accelerated Phase Chronic Myelogenous Leukemia
  • Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • B-cell Adult Acute Lymphoblastic Leukemia
  • Blastic Phase Chronic Myelogenous Leukemia
  • Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Relapsing Chronic Myelogenous Leukemia
  • Secondary Acute Myeloid Leukemia
  • T-cell Adult Acute Lymphoblastic Leukemia
  • Untreated Adult Acute Lymphoblastic Leukemia
  • Untreated Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Blast Crisis
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myeloid, Accelerated Phase
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Myelodysplastic Syndromes
  • Preleukemia
  • Philadelphia Chromosome

Name

Location

Johns Hopkins UniversityBaltimore, Maryland  21205
University of PittsburghPittsburgh, Pennsylvania  15261