Trial of Carfilzomib Plus Melphalan and Prednisone in Elderly Untreated Patients With Multiple Myeloma (CARMYSAP)

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.

Conditions

• Myeloma

Interventions

DRUG

Carfilzomib

There are 9 cycle of 20mg/m²,Intravenous for J1, J2, J8, J9, J22, J23, J29 and 30 days with 12 days rest (42 day cycle) for the first cohort; or 20mg/m²,Intravenous for J1, J2, and 27 mg/m² for J8, J9, J22, J23, J29 and 30 days with 12 days rest (42 day cycle) for the second cohort for the last, third cohort 20mg/m²,Intravenous for J1, J2, and 36 mg/m² for J8, J9, J22, J23, J29 and 30 days with 12 days rest (42 day cycle)and the fourth cohort 20mg/m²,Intravenous for J1, J2, and 45 mg/m² for J8, J9, J22, J23, J29 and 30 days with 12 days rest (42 day cycle). .

DRUG

Melphalan

from 9 cycle: 9 mg/m²/day PO from day 1-4

DRUG

Prednisone

from 9 cycle: 60 mg/m²/day PO from day 1-4

Sponsors & Collaborators

• Nantes University Hospital

  lead OTHER

Principal Investigators

• Philippe Moreau · Nantes University Hospital

• Carine Chaleteix · University Hospital, Clermont-Ferrand

• Denis Caillot · CH DIJON

• Thierry FACON · CHRU - Hôpital Claude Huriez Lille

• Cyril Hulin · Hôpital de Brabois Nancy

• Brigitte Kolb · Hôpital R. Debré Reims

• Hervé Maisonneuve · CHD La Roche sur Yon

• Michel Attal · CHRU - Hôpital Purpan Toulouse

• Benboubker · CHRU - Hôpital Bretonneau Tours

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

65 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2010-10-31

Primary Completion

2014-02-28

Completion

2014-02-28

Countries

• France

Study Locations