Back to resultsStudy of ABT-888 in Combination With Bortezomib and Dexamethasone in Patients With Relapsed Refractory Myeloma
Primary Purpose
Multiple Myeloma
Status
Completed
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
ABT-888/Bortezomib
Sponsored by
About this trial
This is an interventional treatment trial for Multiple Myeloma
Eligibility Criteria
Inclusion Criteria:
- Confirmed diagnosis of multiple myeloma.
- Measurable disease, according to the International Myeloma Working Group criteria.
- ECOG performance status 0, 1 or 2.
- Patients must have received prior treatment for MM and have relapsed or progressed on prior therapy; no limit on number of prior treatment regimens, but prior treatment must be completed 2 weeks prior to registration. Prior exposure to Bortezomib is not an exclusion criteria as long as patients did not progress or relapse while receiving or within 3 months of completing trt with bortezomib
- Prior radiation, completed at least 4 weeks prior to registration, is permitted.
- Adequate marrow reserve, liver and renal function
Exclusion Criteria:
- patients with a history of other malignancies, except: adequately treated nonmelanoma skin cancer, curatively treated in-situ cancer of the cervix, prostate cancer with stable PSA for > 3 years, or other solid tumours curatively treated with no evidence of disease for > 5 years.
- Patients with preexisting grade 2 (or higher) sensory neuropathy or grade 1 sensory neuropathy with neuropathic pain.
- Pregnant or lactating women
- Patients receiving concurrent treatment with other anti-cancer therapy any other investigational agents.
- Active or uncontrolled infections
- Patient with known documented congenital or acquired risk factor for thromboembolic event
- Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive
Sites / Locations
- Tom Baker Cancer Centre
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
ABT-888/Bortezomib
Arm Description
Patients will be on a treatment schedule including twice daily oral dosing for 14 days followed by 1 week rest in combination with standard dosing of Bortezomib and Dexamethasone in a 21 days cycle for a total of 14 cycles.
Outcomes
Primary Outcome Measures
Determine the maximum tolerated dose (MTD) of ABT-888.
Study follows a modified dose escalation scheme with a 3+3 design (3 to 6 patients per dose level or cohort). Only the ABT-888 dose will be escalated with a maximum dose of ABT-888 of 100 mg PO BID. If >1 out 6 patients at any dose level suffer dose limiting toxicity, then dose escalation is stopped, and this dose is declared as MTD. 3 additional patients will be entered at the next lowest dose level. The recommended phase 2 dose is defined as the dose level with ≤ 1 out of 6 patients experiencing DLTs at the highest dose level below the MTD.
Identify the Dose Limiting Toxicities (DLT) of ABT-888
All adverse events, including DLTs, are graded according to the NCI CTCAE, v4.0. A DLT is defined as any grade 3 or higher non-hematologic toxicity, or any grade 4 hematologic toxicity, considered by the investigator to be related to the study drugs and occurring during Days 1-22 of Cycle 1.
Secondary Outcome Measures
Activity Objective - Preliminary assessment of the anti-tumor activity of ABT-888
Response to study drugs is assessed at the end of each cycle according to the International Myeloma Working Group (IMWG) response criteria.
Exploratory Objective - Preliminary assessment of potential biomarkers
Gene expression profiling is performed at baseline and compared between responders versus non-responders in order to identify a "treatment response signature". 2.5 mg of RNA will be extracted from plasma cells sorted from pre-treatment (D1, cycle 1) (n=20) and post-treatment (D11, cycle 1) (n=20) bone marrow aspirates collected from patients treated in the extension cohort. cRNAs will be hybridized onto the U133 Plus 2.0 gene chips and raw data files acquired using Affymetrix Microarray Suite version 5.1 software and analyzed with the Partek Genomics Suite v6.4.
Exploratory Objective - Determine in vivo the effect of ABT-888 on PARP inhibitors.
Poly-ADP-ribose (PAR) levels are measured in sorted CD138+ plasma cells from pre-ABT-888 treatment on day 1 cycle1, as well as post ABT-888 treatment (within 4-6 hours) on days 4 and 11. PAR levels will be measured by standardized ELISA assays (HT PARP in vivo Pharmacodynamic Assay II™, Trevigen).
Determine invivo the effects of Bortezomib on the plasma cells DNA genes expression and function
Gene expression profiling is performed at baseline prior to treatment with bortezomib and on days 4 and 11 post bortezomib treatment. 2.5 mg of RNA will be extracted from plasma cells sorted from bone marrow aspirates collected from patients treated on trial. cRNAs will be hybridized onto the U133 Plus 2.0 gene chips and raw data files acquired using Affymetrix Microarray Suite version 5.1 software and analyzed with the Partek Genomics Suite v6.4.
Full Information
NCT ID
NCT01495351
First Posted
November 16, 2011
Last Updated
September 21, 2017
Sponsor
AHS Cancer Control Alberta
Collaborators
Tom Baker Cancer Centre, Abbott
1. Study Identification
Unique Protocol Identification Number
NCT01495351
Brief Title
Study of ABT-888 in Combination With Bortezomib and Dexamethasone in Patients With Relapsed Refractory Myeloma
Official Title
Phase I Study of ABT-888 in Combination With Bortezomib and Dexamethasone in Patients With Relapsed Refractory Myeloma
Study Type
Interventional
2. Study Status
Record Verification Date
September 2017
Overall Recruitment Status
Completed
Study Start Date
October 2011 (Actual)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
February 10, 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AHS Cancer Control Alberta
Collaborators
Tom Baker Cancer Centre, Abbott
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The combination of PARP inhibitor (ABT-888) with a proteasome inhibitors (bortezomib) have demonstrated significant anti-myeloma effects in preclinical lab and animal studies. The goal of this phase I trial is to evaluate in patients with relapsed or refractory multiple myeloma the safety, toxicity profile and tolerability of ABT-888 (Veliparib) administered on a schedule including twice daily oral dosing for 14 days followed by 1 week rest in combination with standard dosing of Bortezomib.
Detailed Description
This is a dose-finding / dose escalation phase I trial of ABT-888 (Veliparib) in combination with Bortezomib and Dexamethasone in patients with relapsed or refractory multiple myeloma. ABT-888 is given orally (PO) twice daily (every 12 hours) for 14 days in a 21 days cycle.
First dose to be given within 1 hour of Bortezomib on day 1. Planned starting dose is 20 mg PO every 12 hours. Starting dose escalation is planned until an MTD is reached.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
19 (Actual)
8. Arms, Groups, and Interventions
Arm Title
ABT-888/Bortezomib
Arm Type
Experimental
Arm Description
Patients will be on a treatment schedule including twice daily oral dosing for 14 days followed by 1 week rest in combination with standard dosing of Bortezomib and Dexamethasone in a 21 days cycle for a total of 14 cycles.
Intervention Type
Drug
Intervention Name(s)
ABT-888/Bortezomib
Intervention Description
ABT-888 is given orally (PO) twice daily (every 12 hours) for 14 days in a 21 days cycle. First dose to be given within 1 hour of Bortezomib on day 1. Planned starting dose is 20 mg PO every 12 hours. Starting dose escalation is planned until an MTD is reached.
Primary Outcome Measure Information:
Title
Determine the maximum tolerated dose (MTD) of ABT-888.
Description
Study follows a modified dose escalation scheme with a 3+3 design (3 to 6 patients per dose level or cohort). Only the ABT-888 dose will be escalated with a maximum dose of ABT-888 of 100 mg PO BID. If >1 out 6 patients at any dose level suffer dose limiting toxicity, then dose escalation is stopped, and this dose is declared as MTD. 3 additional patients will be entered at the next lowest dose level. The recommended phase 2 dose is defined as the dose level with ≤ 1 out of 6 patients experiencing DLTs at the highest dose level below the MTD.
Time Frame
21 Day Cycle
Title
Identify the Dose Limiting Toxicities (DLT) of ABT-888
Description
All adverse events, including DLTs, are graded according to the NCI CTCAE, v4.0. A DLT is defined as any grade 3 or higher non-hematologic toxicity, or any grade 4 hematologic toxicity, considered by the investigator to be related to the study drugs and occurring during Days 1-22 of Cycle 1.
Time Frame
21 Day Cycle
Secondary Outcome Measure Information:
Title
Activity Objective - Preliminary assessment of the anti-tumor activity of ABT-888
Description
Response to study drugs is assessed at the end of each cycle according to the International Myeloma Working Group (IMWG) response criteria.
Time Frame
21 day cycle
Title
Exploratory Objective - Preliminary assessment of potential biomarkers
Description
Gene expression profiling is performed at baseline and compared between responders versus non-responders in order to identify a "treatment response signature". 2.5 mg of RNA will be extracted from plasma cells sorted from pre-treatment (D1, cycle 1) (n=20) and post-treatment (D11, cycle 1) (n=20) bone marrow aspirates collected from patients treated in the extension cohort. cRNAs will be hybridized onto the U133 Plus 2.0 gene chips and raw data files acquired using Affymetrix Microarray Suite version 5.1 software and analyzed with the Partek Genomics Suite v6.4.
Time Frame
24 months
Title
Exploratory Objective - Determine in vivo the effect of ABT-888 on PARP inhibitors.
Description
Poly-ADP-ribose (PAR) levels are measured in sorted CD138+ plasma cells from pre-ABT-888 treatment on day 1 cycle1, as well as post ABT-888 treatment (within 4-6 hours) on days 4 and 11. PAR levels will be measured by standardized ELISA assays (HT PARP in vivo Pharmacodynamic Assay II™, Trevigen).
Time Frame
24 Months
Title
Determine invivo the effects of Bortezomib on the plasma cells DNA genes expression and function
Description
Gene expression profiling is performed at baseline prior to treatment with bortezomib and on days 4 and 11 post bortezomib treatment. 2.5 mg of RNA will be extracted from plasma cells sorted from bone marrow aspirates collected from patients treated on trial. cRNAs will be hybridized onto the U133 Plus 2.0 gene chips and raw data files acquired using Affymetrix Microarray Suite version 5.1 software and analyzed with the Partek Genomics Suite v6.4.
Time Frame
24 Months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Confirmed diagnosis of multiple myeloma.
Measurable disease, according to the International Myeloma Working Group criteria.
ECOG performance status 0, 1 or 2.
Patients must have received prior treatment for MM and have relapsed or progressed on prior therapy; no limit on number of prior treatment regimens, but prior treatment must be completed 2 weeks prior to registration. Prior exposure to Bortezomib is not an exclusion criteria as long as patients did not progress or relapse while receiving or within 3 months of completing trt with bortezomib
Prior radiation, completed at least 4 weeks prior to registration, is permitted.
Adequate marrow reserve, liver and renal function
Exclusion Criteria:
patients with a history of other malignancies, except: adequately treated nonmelanoma skin cancer, curatively treated in-situ cancer of the cervix, prostate cancer with stable PSA for > 3 years, or other solid tumours curatively treated with no evidence of disease for > 5 years.
Patients with preexisting grade 2 (or higher) sensory neuropathy or grade 1 sensory neuropathy with neuropathic pain.
Pregnant or lactating women
Patients receiving concurrent treatment with other anti-cancer therapy any other investigational agents.
Active or uncontrolled infections
Patient with known documented congenital or acquired risk factor for thromboembolic event
Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nizar J Bahlis, M.D.
Organizational Affiliation
Tom Baker Cancer Centre, University of Calgary
Official's Role
Study Chair
Facility Information:
Facility Name
Tom Baker Cancer Centre
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T2N 4N2
Country
Canada
12. IPD Sharing Statement
Learn more about this trial
Study of ABT-888 in Combination With Bortezomib and Dexamethasone in Patients With Relapsed Refractory Myeloma
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