Trial of Carfilzomib Plus Melphalan and Prednisone in Elderly Untreated Patients With Multiple Myeloma (CARMYSAP)
Status:
Completed
Trial end date:
2014-02-01
Target enrollment:
Participant gender:
Summary
Phase I/II trial of Carfilzomib plus melphalan and prednisone in elderly untreated patients
with multiple myeloma. Nine: University Hospital of Nantes, University Hospital of Nancy,
University Hospital of Lille, University Hospital of Tours, department Hospital of La Roche
Sur Yon, University Hospital of Reims, University Hospital of Clermont-Ferrand, University
Hospital of Toulouse, University Hospital of Dijon Newly diagnosed symptomatic Multiple
Myeloma > 65 years. Treatment comprises an initial phase consisting of nine 6-week cycles of
Carfilzomib on Days 1, 2, 8, 9, 22, 23, 29, 30 (carfilzomib is administered at 20 mg/m2 on
Days 1 and 2 of the first cycle and 20, 27, 36 or 45 mg/m2 thereafter) followed by a 12 day
rest period (42-day cycle), in combination with oral Melphalan 9 mg/m² and oral prednisone
60mg/m², both on days 1 to 4.
Phase I: Identification of Maximum Tolerated Dose (MTD)
Carfilzomib will be administered at a dose of 20mg/m² for all doses to the first cohort of 6
patients. If dose-limiting toxicities (DLTs) occurred in fewer than 2 of these patients, the
next cohort of 6 patients (cohort 2) will receive a dose of 20/27 mg/m² where the 20 mg/m²
dose is administered on Day 1 and 2 of Cycle 1 only and then 27 mg/m² for all subsequent
doses. If DLTs occurred in fewer than 2 of the patients in cohort 2, the third cohort of 6
patients will receive a dose of 20/36 mg/m² where the 20 mg/m² dose is administered on Day 1
and 2 of Cycle 1 only and then 36 mg/m² for all subsequent doses. If DLTs occurred in fewer
than 3 of the patients in cohort 3 the fourth cohort of 6 patients will receive a dose of
20/45 mg/m² where the 20 mg/m² dose is administered on Day 1 and 2 of Cycle 1 only and then
45 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
enrollment 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 8 carfilzomib doses of the first treatment cycle except a) grade 4
thrombocytopenia without bleeding lasting ≤ 7 days or b) grade 4 neutropenia lasting ≤ 7
days
- Grade ≥ 3 febrile neutropenia
- Grade ≥ 3 gastrointestinal toxicities (except for grade ≥ 3 nausea/ vomiting if the
patient had not received adequate antiemetic prophylaxis)
- 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.
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.
Phase II: Expanded Cohort. After identification of the MTD, it is planned for the dose cohort
to be expanded to include up to a total of 20 patients treated at the MTD for the phase II
part of the study. A full treatment course is the same as for phase I: nine 6-week cycles of
CMP.
PRIMARY ENDPOINT Phase I: MTD of combination Phase II: Overall response rate [(ORR),
consisting of complete response (CR), very good partial response (VGPR), and partial response
(PR) SECONDARY ENDPOINTS Safety and tolerability of CMP Clinical benefit response [(CBR = ORR
+ minimal response (MR)], Progression-free survival (PFS), Duration of response Overall
survival (OS). Safety data analysis will be conducted on all subjects receiving at least one
dose of study treatment. Analyses will consist of data summaries for reported AEs. The number
and percentage of subjects experiencing one or more AEs will be summarized by dose,
relationship to study drugs, and severity. AEs will be coded using MedDRA terminology.
Disease Response Analyses: Overall response rate (ORR = CR + VGPR + PR) to treatment will be
measured using the International Myeloma Working Group (IMWG) criteria. Clinical benefit
response (CBR = ORR + MR) will be determined using minimal response (at least 6 weeks
duration) as defined by the European Group for Blood and Marrow Transplant (EBMT). The
distribution of subjects by response category will be made overall and by dose cohort.
Time-to-event endpoints will be evaluated with the use of the Kaplan-Meier method and plots
will be provided. Analysis of time-to-event outcomes will be performed for the overall
sample.