Veliparib, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed or Refractory Lymphoma, Multiple Myeloma, or Solid Tumors
Official Title
A Phase 1b/2a Study of ABT-888 in Combination With Bendamustine +/- Rituximab in Lymphoma, Multiple Myeloma and Solid Tumors
Acronym
Not provided
Organization
National Cancer Institute (NCI)NIH
Status Module
Record Verification Date
Nov 2019
Overall Recruitment Status or Expanded Access Status
Completed
Last Known Status
Not provided
Delayed Posting
Not provided
Why Stopped
Not provided
Expanded Access Info
No
Start Date
Jul 2011
Primary Completion Date
Apr 2015Actual
Completion Date
Apr 2015Actual
First Submitted Date
Mar 30, 2011
First Submission Date that Met QC Criteria
Mar 30, 2011
First Posted Date
Mar 31, 2011Estimated
Results Waived
Not provided
Results First Submitted Date
Sep 18, 2018
Results First Submitted that Met QC Criteria
Nov 22, 2019
Results First Posted Date
Dec 16, 2019Actual
Certification/Extension (aka Delayed Results) First Submitted Date
Not provided
Certification/Extension First Submitted that Passed QC Review
Not provided
Certification/Extension First Posted Date
Not provided
Last Update Submitted Date
Nov 22, 2019
Last Update Posted Date
Dec 16, 2019Actual
Sponsor/Collaborators Module
Responsible Party, by Official Title
Sponsor
Lead Sponsor
National Cancer Institute (NCI)NIH
Collaborators
Not provided
Oversight Module
No data available
No data is available for this block.
Description Module
Brief Summary
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
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.
Conditions Module
Conditions
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
Intraocular 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
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.
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 Outcomes
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)
Other Outcomes
Not provided
Eligibility Module
Eligibility Criteria
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
Soumerai JD, Zelenetz AD, Moskowitz CH, Palomba ML, Hamlin PA Jr, Noy A, Straus DJ, Moskowitz AJ, Younes A, Matasar MJ, Horwitz SM, Portlock CS, Konner JA, Gounder MM, Hyman DM, Voss MH, Fury MG, Gajria D, Carvajal RD, Ho AL, Beumer JH, Kiesel B, Zhang Z, Chen A, Little RF, Jarjies C, Dang TO, France F, Mishra N, Gerecitano JF. The PARP Inhibitor Veliparib Can Be Safely Added to Bendamustine and Rituximab and Has Preliminary Evidence of Activity in B-Cell Lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4119-4126. doi: 10.1158/1078-0432.CCR-16-3068. Epub 2017 Mar 17.
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.
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.
The MTD was established at Dose Level 6 Veliparib 300mg PO BID plus Bendamustine 90 mg/m2
Posted
Number
mg
28 days
ID
Title
Description
OG000
All Study Participants
All Study Participants
Units
Counts
Participants
OG00043
Title
Denominators
Categories
Title
Measurements
OG000300
Primary
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.
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.
Dose Level 7; Bendamustine 90mg/m2, ABT-888 400mg BID Participants treated on Dose Level 7 make up the cohort expansion of VBR in participants with CD20+ B-cell lymphoma.
Posted
Count of Participants
Participants
2 years
ID
Title
Description
OG000
All Study Participants
All Study Participants
Units
Counts
Participants
OG0007
Secondary
Duration of Remission (Phase IIa)
Data were not collected
Posted
From the first documented response to the first documented progression or death, assessed up to 30 days post-treatment
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.
Participants treated on Dose Level 7 make up the cohort expansion of VBR in participants with CD20+ B-cell lymphoma.