None listed
Conditions
Brief summary
The primary purpose of this study is to determine the efficacy and safety of carfilzomib-thalidomide-dexamethasone (CarTD) therapy for relapsed and/or refractory multiple myeloma (RRMM) patients. Who is it for? You may be eligible to join this study if you are aged over 18 years, have RRMM and have received between one and three lines of therapy previously. Study details The study will recruit participants in Australia and Singapore. All participants will receive 12 x 4-week cycles of CarTD therapy followed by 6 cycles of carfilzomib-dexamethasone only. The first 10 participants recruited in each country will receive a low dose for their first 3 cycles. Depending on the toxicity observed in these participants' first 2 cycles, a higher dose may then be used for their remaining cycles (cycle 4 onwards) and for all cycles in newly recruited participants. Patients will be monitored for myeloma response and safety and tolerability of CarTD therapy using blood samples and by reviewing adverse events that occur as well as for disease progression and survival information for 1 year following the last patients final cycle of treatment. It is hoped that the findings of this trial will provide an evaluation of the efficacy and safety of CarTD therapy in RRMM patients who have relapsed after prior treatment for multiple myeloma.
Interventions
Carfilzomib will be given in the following schedules, on Days 1,2,8,9,15,16 of a 4-week cycle for cycles 1 to 12 then on days 1,2,15,16 in a 4-week cycle during cycles 13-18. For the first 10 patients from each of Australia and Asia, the dose of carfilzomib will be 20/27 per m^2 (i.e. 20mg/m^2 on Cycle 1 Day 1, escalated to 27mg/m^2 from Cycle 1 Day 8). Safety data will be analysed from each of the cohort of 10 patients from Australia and Asia by the respective sponsor’s trial management committ
Carfilzomib will be given in the following schedules, on Days 1,2,8,9,15,16 of a 4-week cycle for cycles 1 to 12 then on days 1,2,15,16 in a 4-week cycle during cycles 13-18. For the first 10 patients from each of Australia and Asia, the dose of carfilzomib will be 20/27 per m^2 (i.e. 20mg/m^2 on Cycle 1 Day 1, escalated to 27mg/m^2 from Cycle 1 Day 8). Safety data will be analysed from each of the cohort of 10 patients from Australia and Asia by the respective sponsor’s trial management committee, after the 10th patient has completed cycle 2 of treatment. Provided no more than 4 of the first 10 patients from each of Australia or Asia, experiencing Grade 4 toxicities as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE v4.03) in the first 2 cycles, the subsequent patients will be started at a higher dose escalation of carfilzomib, 20/56 per m^2 (i.e. 20mg/m^2 on Cycle 1 Day 1, escalated to 56mg/m^2 from Cycle 1 Day 8) in combination with thalidomide and dexamethasone. Enrolment of patient 11 onwards will be halted until safety assessment has been done on the first 10 patients after their completion of 2 cycles of treatment. Safety reviews of the first cohort of 10 patient on carfilzomib dose 20/27mg per m^2 from each of Australia and Asia are to be done separately by the respective sponsor’s trial management committee, and will determine the dose schedule only for the respective patient cohorts. For patients who were initially commenced on carfilzomib 20/27mg per m^2, dose escalation to 56mg/m^2 from Cycle 4 onwards is permitted if the patient has not achieved at least a PR after the second cycle of treatment and provided that the patient has not had grade > or = 3 carfilzomib-related toxicities in the previous cycles. This is allowed prior to and irrespective of the assessment of grade 4 toxicities in the first cohort of 10 patients from each country. As there is evidence that a slower 30-minute infusion is better tolerated, all infusions of carfilzomib will be administered over 30 minutes. Thalidomide will be given at a dose of 100 mg oral tablet daily from cycles 1 to 12. Dexamethasone will be given at a dose of 20 mg oral tablet on Days 1, 8, 9, 15, 16, 22, 23 of a 4-week cycle from cycles 1 to 12, then 20 mg oral tablet on Days 1, 8, 15, 16 of a 4-week cycle from cycles 13-18. For patients aged above 75 years, a lower starting dose of dexamethasone of 12mg will be used and escalated to 20mg at the investigators discretion. A log of administration will be maintained at the hospital.
Sponsors
Australiasian Leukaemia and Lymphoma Group
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female patients, > or =18 years of age 2. Relapsed and/or refractory multiple myeloma at study entry. 3. Patients must have evaluable multiple myeloma with at least one of the following (assessed within 21 days prior to registration): a. Serum M-protein > or = 5 g/L, or b. Urine M-protein > or = 200 mg/24 hour, or In patients without detectable serum or urine M-protein, serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal serum k/l ratio or For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) > or = 7500 mg/L (7.5 g/L). 4. Received at least one, but no more than three prior treatment regimens or lines of therapy for multiple myeloma. (Induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as one line of therapy). 5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2. 6. Adequate hepatic function within 28 days prior to registration with bilirubin < 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times the ULN. 7. Left Ventricular Ejection Fraction (LVEF) > or = 40%. 8. Absolute neutrophil count (ANC) > or = 1000/mm3 (or 1000 cells/microL) within 21 days prior to registration. Screening ANC should be independent of growth factor support for > or = 1 week. 9. Platelet count > or = 50,000 cells/mm^3 (> or = 30,000 cells/mm3 if myeloma involvement in the bone marrow is > 50%) within 21 days prior to registration. Patients should not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count. 10. Calculated or measured creatinine clearance (CrCl) of > or =15 mL/min within 21 days prior to registration. Calculation should be based on the Cockcroft and Gault formula 11. Written informed consent in accordance with federal, local, and institutional guidelines. 12. Female patients of child-bearing potential (FCBP) must have negative serum pregnancy test within 21 days prior to registration and agree to use an effective method of contraception during and for 3 months following last dose of drug. 13. Male patients must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a FCBP.
Exclusion criteria
1. Chemotherapy with approved or investigational anticancer therapeutics within 21 days prior to registration, with the exception of dexamethasone up to 160mg or equivalent every 4 weeks. 2. Previous treatment with carfilzomib. 3. Focal radiation therapy within 7 days prior to registration. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to registration (i.e., prior radiation must have been to less than 30% of the bone marrow). 4. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within four months prior to registration. 5. Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to registration. 6. Known HIV seropositive and/or untreated hepatitis B (patients with hepatitis B surface antigen [HBsAg] and core antibody [HBcAb] are eligible if receiving adequate antiviral therapy directed at hepatitis B). 7. Patients with known cirrhosis. 8. Active malignancy, that is expected to require treatment with chemotherapy within one year, or results in a life expectancy less than one year. 9. Female patients who are pregnant or lactating. 10. Known history of allergy to Captisol (registered trademark) (a cyclodextrin derivative used to solubilise carfilzomib) 11. Patients with hypersensitivity to carfilzomib, velcade, boron, or mannitol. 12. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to registration. 13. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to registration. 14. Any other clinically significant medical disease or psychiatric condition that, in the Investigator’s opinion, may interfere with protocol adherence or a patient’s ability to give informed consent.
Outcome results
None listed