This protocol is a phase I/II multicenter study designed to assess the safety and the efficacy of the proposed combinations as up-front treatment in elderly Multiple Myeloma (MM) patients.
Treatment schedule for 9 cycles of induction: Phase I: In the phase I portion of the study, the following dose levels of carfilzomib will be studied with fixed doses of dexamethasone and cyclophosphamide to define the maximum tolerated dose (MTD): Level-1: 1. Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 36 mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 36 mg/m2 IV once daily on days 1-2, 8-9, 15-16. 2. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15 3. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9, 15-16, 22-23 Level 0: 1. Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 45 mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 45 mg/m2 IV once daily on days 1-2, 8-9, 15-16. 2. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15 3. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9, 15-16, 22-23 Level +1: 1. Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 56 mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 56 mg/m2 IV once daily on days 1-2, 8-9, 15-16. 2. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15 3. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9, 15-16, 22-23 Level +2: 1. Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 36 mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 70 mg/m2 IV once daily on days 1-2, 8-9, 15-16. 2. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15 3. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9, 15-16, 22-23 Patient will be observed at the end of the second cycle of therapy for the assessment of side effects and observation of DLTs. Dose escalation will proceed as follows: * 3 patients will be entered at dose level 0 * If 0/3 patients experience DLT, dose escalation will continue * If 1/3 patients experience DLT, 3 additional patients will be added to this cohort (max 6) * If no further patients experience DLT (1/6) dose escalation will continue * If 2/6 patients experience DLT, the MTD will have been exceeded and the MTD will be the previous dose at which \<2/6 experienced DLT * If 2/3 patients experience a DLT at any given dose, the MTD will have been exceeded and the MTD will be the preceding dose at which \< 2/6 (or 1/3) patients experienced a DLT. Phase II: The dose used to treat patients in the phase II will be the MTD defined in the phase I of the study. Treatment schedule for maintenance until progression or intolerance: Carfilzomib at the MTD defined by phase I study IV once daily on days 1-2, 15-16.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
36
Fondazione EMN Italy Onlus
Torino, Italy
Dose Limiting Toxicity (DLT)
Non-hematologic: * Grade 2 neuropathy with pain * any Grade 3 tox. (excluding nausea, vomiting, diarrhea) * Grade 3 nausea, vomiting, or diarrhea despite maximal antiemetic/antidiarrheal therapy * Grade 4 fatigue lasting for ≥ 7 days * Any non-hematologic tox. requiring a dose reduction within Cycle 1 * Inability to receive Day 1 dose of Cycle 2 due to drug related tox. persisting from Cycle 1 or drug related tox. newly encountered on Day 1 of Cycle 2. Hematologic: * Grade 4 neutropenia (ANC \< 0.5 x 109/L) lasting for ≥ 7 days * Febrile neutropenia (ANC \< 1.0 x 109/L with a fever ≥ 38.3ºC) * Grade 4 thrombocytopenia (platelets \< 25.0 x 109/L) lasting ≥ 7 days despite dose delay * Grade 3-4 thrombocytopenia associated with bleeding * Any hematologic tox. requiring a dose reduction within Cycle 1 * Inability to receive Day 1 dose of Cycle 2 due to drug related tox. persisting from Cycle 1 or drug related tox. newly encountered on Day 1 of Cycle 2.
Time frame: 1 year
Response rate (RR)
Determine the response rate
Time frame: 3 years
Progression-free survival (PFS)
Determine the progression-free survival (PFS)
Time frame: 3 years
Time to progression (TTP)
Determine the time to progression (TTP)
Time frame: 3 years
Duration of response (DOR)
Determine the duration of response (DOR)
Time frame: 3 years
Overall survival (OS)
Determine the overall survival (OS)
Time frame: 3 years
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Time to next therapy (TTNT)
Determine the time to next therapy (TTNT)
Time frame: 3 years
Responses
Determine whether responses obtained with CCyd treatment are associated with a prolongation of PFS, in comparison with non-responding patients
Time frame: 3 years
Response and survival
Determine whether tumor response and outcome may change in subgroups with different prognosis according to current prognostic factors (β2-microglobulin, C-reactive protein (CRP), FISH, gene expression profile)
Time frame: 3 years
Maintenance
Determine the benefit on PFS and OS of maintenance with carfilzomib
Time frame: 3 years
Adverse event
The toxicity is defined as the first occurrence of a grade 4 hematologic drug-related toxicity (grade 4 neutropenia must last longer than 3 days and grade 4 thrombocytopenia must last longer than 7 days in order to be considered a toxicity) excluding anemia. Assessment of adverse events will be performed at the end of third cycle according to the National Cancer Institute Common Terminology Criteria of Adverse Events (CTCAE version 4.0).
Time frame: 1 years