Phase II Study of Subcutaneous (SC) Bortezomib, Lenalidomide and Dexamethasone for Relapsed and/or Refractory Multiple Myeloma; Followed by SC Bortezomib Maintenance
Background: Bortezomib is a drug approved by the Food and Drug Administration (FDA) to treat patients with multiple myeloma. It is given by intravenous injection. Lenalidomide is a drug that alters the immune system. It may also help suppress tumor growth. It is approved by the FDA to treat some types of blood cancers. Dexamethasone prevents or treats inflammation. It is sometimes used to treat multiple myeloma.
Objectives: The purpose of this study examine how the combination of the study drugs affects myeloma.
- Participants at least 18 years old who have multiple myeloma that has come back, did not respond to treatment, or worsened while being treated.
- Participants who may be pregnant will be tested to ensure that they are not pregnant.
- Participants will be screened with a history and physical examination. Blood work and urine samples will be taken. A series of x-rays of all bones will be done. A bone marrow biopsy will be done.
- Treatment will be monitored with frequent blood tests and imaging studies.
- Treatment will continue as long as the cancer does not grow or spread and no serious side effects develop.
- There will be up to eight 21-day treatment cycles.
- Bortezomib is given by subcutaneous (under the skin) (SC) injection on days 1, 4, 8, and 11 of the cycle.
- Lenalidomide is given by mouth on days 1 14 of the cycle.
- Dexamethasone is given by mouth on days 1, 2, 4, 5, 8, 9, 11, and 12 of the cycle.
- Following cycle eight, if the disease is stable or better, participants will receive bortezomib SC at the dose given at the end of cycle eight.
- Participants will take valacyclovir or acyclovir while taking bortezomib to prevent virus infections.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Study of Subcutaneous (SC) Bortezomib, Lenalidomide and Dexamethasone for Relapsed and/or Refractory Multiple Myeloma; Followed by SC Bortezomib Maintenance|
- Overall Response Rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- Progression-free survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- Duration of response [ Time Frame: 2 years ] [ Designated as safety issue: No ]
|Study Start Date:||July 2012|
|Estimated Study Completion Date:||June 2015|
|Estimated Primary Completion Date:||June 2015 (Final data collection date for primary outcome measure)|
- Multiple myeloma (MM) is an incurable plasma cell neoplasm with a median survival of 3-4 years.
- Increased survival has been achieved with the introduction of the proteasome inhibitor bortezomib and immunomodulatory drugs (IMiDs) such as lenalidomide. Bortezomib and lenalidomide have different but overlapping mechanism of anti-MM activity in preclinical studies.
- Despite the benefits of novel agents, bortezomib and lenalidomide pose clinical challenges. Bortezomib drug toxicity includes neuropathy, GI distress, myelosuppression and herpes zoster reactivation. Together with lenalidomide, the incidence of sensory neuropathy reaches 80%.
- Subcutaneous (SC) Bortezomib was evaluated in a prospective phase I trial for relapsed and/or refractory MM. SC administration was found to be comparable with the established IV route, with no differences in overall systemic availability and pharmacodynamic activity, similar toxicity profiles, and similar response rates.
- Combining SC, rather than IV bortezomib, with lenalidomide and dexamethasone is especially attractive given the potential for less overall neurotoxicity and improved convenience for the patient.
- Also, using bortezomib SC as a maintenance therapy after combination therapy is a novel strategy that has the potential to set the stage for coming oral proteasome inhibitors as potential maintenance strategies in the future.
- Determine response rates, of S.C. bortezomib, lenalidomide, and dexamethasone (VRd) in relapse and/or refractory MM patients
- Assess peripheral blood for immune cell populations in relation to SC bortezomib maintenance
- Evaluate toxicity, including peripheral neuropathy
- Evaluate patterns of change in patient-reported quality of life and symptom distress
- Gauge the feasibility, responsiveness to change and associated effect sizes when using patient-reported outcomes to augment clinician ratings of regimen-related treatment toxicity, including incidence and severity of peripheral neuropathy
- Determine duration of response
- Determine progression free survival
- Patients with histologically confirmed relapsed and/or refractory multiple myeloma
- Age greater than or equal to 18 years
- Without serious co-morbidity that would interfere with receipt of VRd
- If patient has neuropathy, it must be less than or equal to Grade 1 at the time of first dose or within 14 days of enrollment
- Absolute neutrophil count (ANC) greater than equal to 1.0 K/uL, hemoglobin less than or equal to 8 g/dL, and platelet count greater than or equal to 75 K/uL
- Adequate hepatic function, with bilirubin < 1.5 times ULN; AST and ALT < 3.0 times ULN
- Creatinine Clearance greater than or equal to 60 ml/min. CrCl will be calculated by Cockcroft-Gault method. CrCl (calculated) = (140 Age) times Mass (in kilograms) times [0.85 if Female] 72 times Serum Creatinine (in mg/dL). If calculated CrCl based on Cockcroft-Gault method is < 60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must also be greater than or equal to 60 ml/min for the patient to be eligible.
Patient will receive treatment in this single arm study for 8 total cycles (each cycle is 21 days) with the following drugs, dosages and schedule:
Cycle 1-8: 1.0 mg/m(2) SC at a concentration of 2.5 mg/ml to the thighs or abdomen on days 1, 4, 8, 11 of 21 day cycle
Cycle 1: 15 mg oral daily on days 2-14 of 21 day cycle
Cycle 2-8: 15 mg oral daily on days 1-14 of 21 day cycle
Cycle 1: 10 mg oral on days 2,4,5,8,9,11,12 of 21 day cycle
Cycle 2-8: 10 mg oral on days 1,2,4,5,8,9,11,12 of 21 day cycle
- Maintenance therapy
After completion of cycle 8, patients with greater than or equal to stable disease will receive maintenance with bortezomib S.C. at a dose per end of Cycle 8. Maintenance will be given on days 1 and 15 of a 28 day cycle, and will continue until progression or unacceptable toxicity.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01647165
|Principal Investigator:||Carl O Landgren, M.D.||National Cancer Institute (NCI)|