Veliparib, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed or Refractory Lymphoma, Multiple Myeloma, or Solid Tumors

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and the best dose of veliparib when given together with bendamustine hydrochloride and rituximab and to see how well they work in treating patients with lymphoma, multiple myeloma, or solid tumors that have come back or have not responded to treatment. Veliparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Giving veliparib together with bendamustine hydrochloride and rituximab may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum-tolerated dose (MTD) of ABT-888 (veliparib) in combination with bendamustine (bendamustine hydrochloride) in patients with solid tumors, lymphoma, or multiple myeloma. (Phase Ib) II. To establish the safety of ABT-888 in combination with bendamustine and rituximab in an expansion cohort of patients with non-Hodgkin lymphoma (NHL). (Phase Ib) III. To assess the toxicity profile of this regimen in the above patients. (Phase Ib) IV. To determine the complete response (CR) rate in patients with indolent NHL or mantle cell lymphoma (MCL) treated with ABT-888 + bendamustine + rituximab. (Phase IIa) SECONDARY OBJECTIVES: I. To assess response rates and survival parameters of patients treated with ABT-888 + bendamustine +/- rituximab. (Phase Ib) II. To assess pharmacokinetic parameters of ABT-888 in this regimen. (Phase Ib) III. To assess progression-free survival, overall survival, and duration of remission of patients with indolent NHL and MCL treated with ABT-888 + bendamustine + rituximab. (Phase IIa) OUTLINE: This is a phase I, dose-escalation study of veliparib followed by a phase II study. Patients receive veliparib orally (PO) twice daily (BID) on days 1-7 and bendamustine hydrochloride intravenously (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. After completion of study treatment, patients are followed up for 30 days.

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

Conditions
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Intraocular Lymphoma, Adult B Acute Lymphoblastic Leukemia, Adult Nasal Type Extranodal NK/T-Cell Lymphoma, Adult Solid Neoplasm, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-Cell Lymphoma, Chronic Lymphocytic Leukemia, Cutaneous B-Cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue, Hepatosplenic T-Cell Lymphoma, Lymphomatous Involvement of Non-Cutaneous Extranodal Site, Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma, Nodal Marginal Zone Lymphoma, Recurrent Adult Acute Lymphoblastic Leukemia, 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 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 Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides and Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Hairy Cell Leukemia, Refractory Plasma Cell Myeloma, Small Intestinal Lymphoma, Splenic Marginal Zone Lymphoma, Testicular Lymphoma, Waldenstrom Macroglobulinemia

Intervention / Treatment
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* Drug: Bendamustine Hydrochloride
* Other: Pharmacological Study
* Biological: Rituximab
* Drug: Veliparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1b: 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 1b cohort expansion: patients must have a histologically confirmed cluster of differentiation (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 2a: 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 measureable site of disease 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 3 weeks since prior chemotherapy or radiation therapy, 6 weeks if the last regimen included carmustine (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) Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Life expectancy of greater than 3 months Absolute neutrophil count (ANC) >= 1,000/mcL Platelets >= 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 =< 2 x upper normal institutional limits; in patients with Gilbert's disease or documented liver metastases, total bilirubin up to 3 x upper limits of normal (ULN) will be allowed Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min for patients with creatinine levels above institutional normal Patients with prior stem cell transplant will be eligible as long as they have not relapsed or progressed within 100 days post-transplant and they meet the above inclusion criteria 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; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately 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 central nervous system (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 3 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 3 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; breastfeeding should be discontinued if the mother is treated with ABT-888 Human immunodeficiency virus (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; patients on zidovudine or stavudine would not be eligible Patients with active seizure or a 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, or 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (veliparib, bendamustine hydrochloride, rituximab)<br>Patients receive veliparib PO BID 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. | Drug: Bendamustine Hydrochloride<br>* Given IV<br>* Other names: Treanda;Other: Pharmacological Study<br>* Correlative studies<br>Biological: Rituximab<br>* Given IV<br>* Other names: RTXM83;Drug: Veliparib<br>* Given PO<br>* Other names: PARP-1 inhibitor ABT-888;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Veliparib When Combined With Bendamustine Hydrochloride | Maximum Tolerated Dose (MTD) reflects the highest dose of Veliparib when combined with Bendamustine Hydrochloride that did not cause a DLT. The maximum tolerated dose (MTD) was defined as the highest dose level at which 33% of patients experienced DLT. | 28 days | 
| Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (POD); POD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions. | 2 years | 
| Number of Participants With Adverse Events | Adverse events assessed by NCI CTCAE version 4.0 (Phase Ib) See adverse events section. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) to Study Treatment (Phase IIa) | Summary statistics will be used for CR. Responses will be evaluated by the International Uniform Response Criteria for Multiple Myeloma. | 2 years | 
| Duration of Remission (Phase IIa) |  | From the first documented response to the first documented progression or death, assessed up to 30 days post-treatment | 
| Overall Survival (Phase IIa) | Kaplan-Meier estimates will be calculated and log-rank tests will be employed when certain comparisons are needed. | Up to 30 days post-treatment | 
| Pharmacokinetic Parameters of Veliparib (Phase Ib) | Area Under the Curve from time zero to 12 hours following Veliparib administration | From time zero to 12 hours on day 2 of course 1 | 
| Progression-free Survival Using RECIST Version 1.1 (Phase IIa) | Kaplan-Meier estimates will be calculated and log-rank tests will be employed when certain comparisons are needed. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. | 2 years | 
| Participants With Dose Limiting Toxicities |  | 28 days |