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A Phase 1b/2a Study of ABT-888 in Combination With Bendamustine +/- Rituximab in Lymphoma, Multiple Myeloma and Solid Tumors


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
AIDS-related Diffuse Large Cell Lymphoma, AIDS-related Diffuse Mixed Cell Lymphoma, AIDS-related Diffuse Small Cleaved Cell Lymphoma, AIDS-related Immunoblastic Large Cell Lymphoma, AIDS-related Lymphoblastic Lymphoma, AIDS-related Peripheral/Systemic Lymphoma, AIDS-related Small Noncleaved Cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Hepatosplenic T-cell Lymphoma, HIV-associated Hodgkin Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Noncutaneous Extranodal Lymphoma, Peripheral T-cell Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Grade I Lymphomatoid Granulomatosis, Recurrent Grade II Lymphomatoid Granulomatosis, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Refractory Multiple Myeloma, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase 1b/2a Study of ABT-888 in Combination With Bendamustine +/- Rituximab in Lymphoma, Multiple Myeloma and Solid Tumors


PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) of veliparib (ABT-888) in combination with
bendamustine hydrochloride in patients with solid tumors, lymphoma, or multiple myeloma.
(Phase I) II. To establish the safety of ABT-888 in combination with bendamustine
hydrochloride and rituximab in an expansion cohort of patients with non-Hodgkin lymphoma
(NHL). (Phase I) III. To assess the toxicity profile of this regimen in the above patients.
(Phase I) IV. To determine the complete response (CR) rate in patients with indolent NHL or
mantle cell lymphoma (MCL) treated with ABT-888, bendamustine, and rituximab. (Phase II)

SECONDARY OBJECTIVES:

I. To assess response rates and survival parameters of patients treated with ABT-888,
bendamustine hydrochloride, and with or without rituximab. (Phase I) II. To assess
pharmacokinetic parameters of ABT-888 in this regimen. (Phase I) III. To assess
pharmacodynamic endpoints, including PAR levels in tumor samples and gamma-H2AX levels in
peripheral blood mononuclear cells and tumor samples before and after treatment on protocol.
(Phase I and II) IV. To assess progression-free survival, overall survival, and duration of
remission of patients with indolent NHL and MCL treated with ABT-888, bendamustine, and
rituximab. (Phase II)

OUTLINE: This is a dose-escalation, phase I study of veliparib followed by an expansion
cohort and phase II study.

Patients receive veliparib orally twice daily on days 1-7 and bendamustine hydrochloride IV
over 30-60 minutes on days 1-2. Treatment repeats every 28 days for up to 6 courses in the
absence of disease progression or unacceptable toxicity.

Once the maximum-tolerated dose is determined, a cohort of patients receives veliparib and
bendamustine hydrochloride as above and rituximab IV on day 1. Treatment repeats every 28
days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and periodically during study for pharmacokinetic
and pharmacodynamic studies. Bone marrow biopsies and/or core tumor biopsies samples may
also be collected.

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


Inclusion Criteria:



- Patients must have a histologically confirmed solid malignancy, lymphoma, or multiple
myeloma for which standard curative or palliative measures do not exist, are no
longer effective, or for which the patient is not eligible or refuses (Phase I)

- Patients must have a histologically confirmed CD-20 positive B-cell non-Hodgkin
lymphoma for which standard curative or palliative measures do not exist, are no
longer effective, or for which the patient is not eligible or refuses (Phase Ib
cohort expansion)

- Patients must have histologically or cytologically confirmed marginal zone B-cell
lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, or mantle cell
lymphoma, and must have at least one measurable site of disease (phase II)

- For lymphoma and multiple myeloma patients: patients who have relapsed or are
refractory to at least one prior chemotherapeutic regimen or biologic agent; patients
must either be ineligible for or have refused curative options for treatment,
including stem cell transplant, if applicable

- For solid tumor patients: relapsed or refractory to at least one prior
chemotherapeutic regimen or biologic agent; patients must either be ineligible for or
have refused curative options for treatment

- Patients must have had a rest period of at least 2 weeks since prior chemotherapy or
radiation therapy, 6 weeks if the last regimen included BCNU or mitomycin C; there
must be a rest period of at least 3 months if the last therapy was immunotherapy or
radioimmunotherapy (unless the disease has progressed since treatment)

- ECOG performance status 0-1 (Karnofsky >= 60%)

- Life expectancy of greater than 3 months

- ANC ≥ 1,000/mcL

- Platelet count ≥ 100,000/mcL unsupported by transfusion within the prior 2 weeks

- Hemoglobin >= 8.0 g/dL unsupported by transfusion within the prior 2 weeks

- Total bilirubin =< 2x upper normal institutional limits; in patients with Gilbert's
disease or documented liver metastases, total bilirubin up to 3x ULN will be allowed

- AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Prior stem cell transplant allowed provided patient has not relapsed or progressed
within 100 days post transplant

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal, barrier method of birth control, or abstinence) prior to study entry and
for the duration of study participation

- Ability to understand and the willingness to sign a written informed consent document

- Toxicities from prior therapies must have resolved to baseline, or be =< grade 2 and
stable for at least one month

- Patient must be able to swallow pills

- Patients with CNS metastases must be stable after therapy for > 3 months and off
steroid treatment prior to study enrollment

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered to baseline (or are not at stable grade =< 2) from adverse events due to
agents administered more than 2 weeks earlier; patients who have received
immunotherapy or radioimmunotherapy within 3 months, unless disease has progressed
since treatment; patients who have been administered ABT-888 as part of a single or
limited dosing study, such as a phase 0 study, will not be excluded from
participating in this study solely because of receiving prior ABT-888

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ABT-888, bendamustine or mannitol; patients enrolling in the cohort
expansion or phase 2 portions of the study who have been intolerant of repeated doses
of rituximab in the past will be excluded (patients who have had infusion reactions
to their initial dose of rituximab will not be excluded)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because ABT-888 is a PARP inhibitor with
the potential for teratogenic or abortifacient effects; because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of
the mother with ABT-888, breastfeeding should be discontinued if the mother is
treated with ABT-888; teratogenic and nonteratogenic events have been observed in
animal studies following intraperitoneal dosing of bendamustine

- HIV-positive patients on combination antiretroviral therapy are eligible if their HIV
is under adequate control with an antiretroviral regimen that has been stable for >=
4 weeks, as long as the CD4 count is > 300; appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated; due to toxicity
issues, patients on zidovudine or stavudine would not be eligible

- Patients with history of seizure are not eligible

- Patients with uncontrolled CNS metastasis are not eligible

- Patients with unrelated prior malignancies must have undergone potentially curative
therapy for their prior malignancy, have no evidence of that disease for three years,
and be deemed at low risk for recurrence of their prior malignancy by her/his
treating physician; patients with dermal squamous cell carcinoma, basal cell
carcinoma or melanoma in situ that has been completely excised will be eligible
following excision

- Patients with active seizure or a history of seizure

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

MTD of veliparib in combination with bendamustine (phase I)

Outcome Description:

Toxicities will be graded and reported according to criteria listed in CTCAE ver. 4.0.

Outcome Time Frame:

Up to 6 courses

Safety Issue:

Yes

Principal Investigator

John Gerecitano

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02583

NCT ID:

NCT01326702

Start Date:

July 2011

Completion Date:

Related Keywords:

  • AIDS-related Diffuse Large Cell Lymphoma
  • AIDS-related Diffuse Mixed Cell Lymphoma
  • AIDS-related Diffuse Small Cleaved Cell Lymphoma
  • AIDS-related Immunoblastic Large Cell Lymphoma
  • AIDS-related Lymphoblastic Lymphoma
  • AIDS-related Peripheral/Systemic Lymphoma
  • AIDS-related Small Noncleaved Cell Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Angioimmunoblastic T-cell Lymphoma
  • Cutaneous B-cell Non-Hodgkin Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Hepatosplenic T-cell Lymphoma
  • HIV-associated Hodgkin Lymphoma
  • Nodal Marginal Zone B-cell Lymphoma
  • Noncutaneous Extranodal Lymphoma
  • Peripheral T-cell Lymphoma
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Grade I Lymphomatoid Granulomatosis
  • Recurrent Grade II Lymphomatoid Granulomatosis
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Multiple Myeloma
  • Small Intestine Lymphoma
  • Splenic Marginal Zone Lymphoma
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Acquired Immunodeficiency Syndrome
  • HIV Infections
  • Burkitt Lymphoma
  • Hodgkin Disease
  • Immunoblastic Lymphadenopathy
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous
  • Lymphoma, T-Cell, Peripheral
  • Lymphoma, Large-Cell, Anaplastic
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Extranodal NK-T-Cell
  • Neoplasms
  • Lymphoma, Mantle-Cell

Name

Location

Memorial Sloan Kettering Cancer CenterNew York, New York  10021