Multiple Myeloma Clinical Trial
Official title:
A Multicenter Open Label Phase 2 Study of Carfilzomib Weekly Plus Melphalan and Prednisone in Untreated Symptomatic Elderly Multiple Myeloma
IFM 2012-03 protocol is a Phase 2 multicenter nonrandomized open in elderly patients with multiple myeloma at diagnosis. Study primary objectives are in the first step to determine Maximum tolerated dose (MTD) of Carfilzomib Weekly based on definition of Dose-limiting toxicities (DLTs) and in the second step to expanded cohort, to determine the VGPR (Very Good Partial Response) + CR (Complete Response) rate of Carfilzomib Weekly at the MTD in combination with Melphalan Prednisone at the end of the 9 induction cycles.
Overall design. This study is a Multicenter, Open-label, Phase 2 study of Carfilzomib Weekly
+MP in Untreated Elderly MM. Eligible patients must have a symptomatic, untreated MM with a
measurable disease. There is a dose escalation part in the study as the MTD remained to be
determined for carfilzomib weekly given for 4 infusions (day 1, 8, 15, 22) on a 35-days
cycle.
This study will thus comprise 2 parts. Step 1. To determine MTD of Carfilzomib Weekly based
on definition of DLTs - (N=6 patients per cohort, maximum 5 cohorts of carfilzomib weekly
+MP) The patients will be included into three cohorts at 36 mg/m², 45 mg/m², 56 mg/m² and
70mg/m² of Carfilzomib Weekly given for 4 infusions (day 1, 8, 15, 22) +MP given on days 1 to
4 of a 35-days cycle. Carfilzomib will be administered at a dose of 36mg/m² for the first
cohort where the 20 mg/m² dose is administered on Day 1 of Cycle 1 only and then 36 mg/m² for
all subsequent doses.
If dose-limiting toxicities (DLTs) occur in fewer or equal than 2 of these patients, the next
cohort of 6 patients (cohort 2) will be opened and patients will receive a dose of 20/45
mg/m². If DLTs occur in fewer or equal than 2 of the patients in cohort 2, the third cohort
of 6 patients will receive a dose of 20/56 mg/m² where the 20 mg/m² dose is administered on
Day 1 of Cycle 1 only and then 56 mg/m² for all subsequent doses. If DLTs occur in fewer or
equal than 2 of the patients in cohort 3, the fourth and five cohort of 6 patients will
receive a dose of 20/70 mg/m² where the 20 mg/m² dose is administered on Day 1 of Cycle 1
only and then 70 mg/m² for all subsequent doses.
If at any time during cycle 1 of a dose cohort, > 2 subjects experience a drug-related DLT,
the MTD will have been exceeded, additional enrolment within the cohort will cease, and dose
escalation will stop. The MTD will be defined as the dose level below which DLT is observed
in > 33% (i.e. > 2 of 6) subjects in a cohort.
The following are defined as DLTs:
- Any hematologic toxicity of grade 4 intensity or preventing administration of 2 or more
of the 4 carfilzomib doses of the first treatment cycle
- Grade ≥ 3 febrile neutropenia
- Grade ≥ 3 gastrointestinal toxicities
- Any other grade ≥ 3 nonhematologic toxicity considered related to CMP by the principal
investigator.
- Grade ≥ 3 peripheral neuropathy persisting for more than 3 weeks after discontinuation
of study drugs.
Exceptions are:
1. grade 4 thrombocytopenia without bleeding lasting ≤ 7 days or
2. grade 4 neutropenia lasting ≤ 7 days
3. grade ≥ 3 nausea/ vomiting if the patient had not received adequate antiemetic
prophylaxis Adverse events (AEs) will be graded according to National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI CTCAE, version 4.0). MTD
determination will be based on occurrence of DLTs during the first induction treatment
cycle only.
Step 2. Expanded Cohort (N=50 patients; Carfilzomib weekly at the MTD +MP only) After
identification of the MTD, it is planned for the dose cohort to be expanded to include up to
a total of 50 patients treated at the MTD of carfilzomib weekly for the step 2 of the study.
A full treatment course is the same as for step 1, see "dosing regimen".
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