IFM2012-03: Study of Carfilzomib Weekly Plus Melphalan and Prednisone in Untreated Symptomatic Elderly Multiple Myeloma

Sponsor

University Hospital, Lille (Other)

Overall Status

Unknown status

CT.gov ID

NCT02302495

Collaborator

Amgen (Industry)

Enrollment

Locations

Arm

Anticipated Duration (Months)

2.4

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Carfilzomib	Phase 2

Detailed Description

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:

grade 4 thrombocytopenia without bleeding lasting ≤ 7 days or
grade 4 neutropenia lasting ≤ 7 days
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".

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Multicenter Open Label Phase 2 Study of Carfilzomib Weekly Plus Melphalan and Prednisone in Untreated Symptomatic Elderly Multiple Myeloma

Actual Study Start Date :

Jan 1, 2014

Anticipated Primary Completion Date :

Jul 1, 2021

Anticipated Study Completion Date :

Jul 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Other: Carfilzomib weekly+Melphalan+Prednisone one arm, two steps and two parts.In the first step of the study: 5 cohorts of 6 patients with Carfilzomib weekly administrated at different dose regimen will be opened one after the other to determine Maximum tolerated dose of Carfilzomib based on definition of Dose-limiting toxicities.In the second step of the study:expanded Cohort, 50 patients received Carfilzomib at the MTD. In Part 1. Induction.Nine 5 weeks cycles of weekly CMP are plannedCarfilzomib. 36, 45, 56 or 70 mg/m² on days 1, 8, 15, 22 IV route . Patients will start the first cycle day 1 with 20mg/m². In combination with oral Melphalan 0.25mg/kg/j and oral prednisone 60mg/m², both on days 1 to 4.Part 2. Maintenance.Carfilzomib. 36 mg/m² weekly, every two weeks IV route for 1 year.	Drug: Carfilzomib DOSING REGIMEN. The regimen will have 2 parts: Part 1. Induction. Nine 5 weeks cycles (35-days each) of weekly Carfilzomib Melphalan Prednisone are planned Carfilzomib. 36, 45, 56 or 70 mg/m² on days 1, 8, 15, 22 IV route followed by a 13-day rest period per 35-days cycle. Patients will start the first cycle day 1 with 20mg/m². In combination with oral Melphalan 0.25mg/kg/j and oral prednisone 60mg/m², both on days 1 to 4. Part 2. Maintenance. Carfilzomib. 36 mg/m² weekly, every two weeks IV route for 1 year. Melphalan and Prednisone is not pursued at this phase of the study. Other Names: Melphalan Prednisone

Arm

Intervention/Treatment

Other: Carfilzomib weekly+Melphalan+Prednisone

one arm, two steps and two parts.In the first step of the study: 5 cohorts of 6 patients with Carfilzomib weekly administrated at different dose regimen will be opened one after the other to determine Maximum tolerated dose of Carfilzomib based on definition of Dose-limiting toxicities.In the second step of the study:expanded Cohort, 50 patients received Carfilzomib at the MTD. In Part 1. Induction.Nine 5 weeks cycles of weekly CMP are plannedCarfilzomib. 36, 45, 56 or 70 mg/m² on days 1, 8, 15, 22 IV route . Patients will start the first cycle day 1 with 20mg/m². In combination with oral Melphalan 0.25mg/kg/j and oral prednisone 60mg/m², both on days 1 to 4.Part 2. Maintenance.Carfilzomib. 36 mg/m² weekly, every two weeks IV route for 1 year.

Drug: Carfilzomib

DOSING REGIMEN. The regimen will have 2 parts: Part 1. Induction. Nine 5 weeks cycles (35-days each) of weekly Carfilzomib Melphalan Prednisone are planned Carfilzomib. 36, 45, 56 or 70 mg/m² on days 1, 8, 15, 22 IV route followed by a 13-day rest period per 35-days cycle. Patients will start the first cycle day 1 with 20mg/m². In combination with oral Melphalan 0.25mg/kg/j and oral prednisone 60mg/m², both on days 1 to 4. Part 2. Maintenance. Carfilzomib. 36 mg/m² weekly, every two weeks IV route for 1 year. Melphalan and Prednisone is not pursued at this phase of the study.

Other Names:

Melphalan

Prednisone

Outcome Measures

Primary Outcome Measures

Dose Maximum Tolerate of Carfilzomib Weekly [35 days]
If dose-limiting toxicities occur in fewer than 3 of these patients per cohort, the next cohort of 6 patients (cohort 2,3 and 4) will be open. If at any time during cycle 1 of a dose cohort, > 2 subjects experience a drug-related dose-limiting toxicities, the Maximum Tolerate Dosing will have been exceeded, additional enrolment within the cohort will cease, and dose escalation will stop. The Maximum Tolerate Dosing will be defined as the dose level below which dose-limiting toxicities is observed in >33% subjects in a cohort.

Secondary Outcome Measures

number of patients who reach Very Good Partial Response and Complete [315 days]
Expanded cohort, the primary endpoint is the Very Good Partial Response and Complete Response rate of Carfilzomib Weekly at the Maximum Tolerate Dosing and melphalan prednisone at the end of the 9 induction cycles using International Myeloma Working Group response criteria.

Eligibility Criteria

Criteria

Ages Eligible for Study:

65 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

able to understand and voluntarily sign an informed consent form
able to adhere to the study visit schedule and other protocol requirements.
age ≥ 65 years.
life expectancy > 6 months.Patients must have Symptomatic Measurable previously Untreated MM
have measurable disease as defined by the following: quantifiable monoclonal M-component value in the serum and/or urine
eastern Cooperative Oncology Group performance status score ≤2
dequate bone marrow function, documented within 72 hours and without transfusion 5 days prior to the first intake of investigational product no growth factor support Adequate organ function
subjects affiliated with an appropriate social security system.
male subjects must:Understand the potential teratogenic,and genotoxic risk of Melphalan if engaged in sexual activity with a pregnant female or a female of childbearing potential.
understand the potential genotoxic risk of Carfilzomib if engaged in sexual activity with a pregnant female or a female of childbearing potential.
practice complete abstinence or understand the need and agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential throughout the entire duration of study treatment, during dose interruptions and until at least 3 months after the end of treatment discontinuation of CMP, even if he has undergone a successful vasectomy.
if pregnancy or a positive pregnancy test does occur in the partner of a male study patient during study participation, the investigator must be notified immediately.
agree not to donate semen or sperm during study drug therapy and until at least 3 months after the end of treatment discontinuation of CMP.

Exclusion Criteria:

any other uncontrolled medical condition or comorbidity that might interfere with subject's participation.
known positive for HIV or active infectious hepatitis, type B or C.
patient with terminal renal failure that require dialysis and clearance creatinine < 30 ml/min.
prior history of malignancies, other than multiple myeloma, unless the patients has been free of the disease for ≥ 5 years.
prior local irradiation within two weeks before first dose
evidence of central nervous system (CNS) involvement.
unable to take corticotherapy at study entry
any ongoing adverse event or medical history > grade 2 severity
persons protected by a legal regime (guardianship, trusteeship).Alkeran's (Melphalan) contraindication: Hypersensitivity to Melphalan or to any other constituents.
patients with heart failure class 3 and 4 according to the NYHA criteria, or patients with past history of myocardial infarction within the last 6 months or no controlled cardiac conduction abnormalities.
patients with a left ventricular ejection fraction under or equal to 45 % (LVEF ≤ 45%)

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Centre Hospitalier H. Duffaut	Avignon	France	84902
2	Centre Hospitalier de la côte basque	Bayonne	France	64109
3	Hôpital Jean Minjoz	Besançon	France	25030
4	Institut Bergonie	Bordeaux	France	33076
5	Polyclinique Bordeaux Nord Aquitaine	Bordeaux	France	33300
6	Centre Hospitalier William Morey	Chalon-sur-Saône	France	71100
7	Centre Hospitalier de Chambery	Chambery	France	73011
8	Hôpital St Antoine Béclére	Clamart	France	92140
9	CH Louis Pasteur	Colmar	France	68024
10	CH Francilien	Corbeil - Essonnes	France	91106
11	CHU Henri Mondor	Creteil	France	94010
12	Hématologie Clinique, CHU, Hôpital d'Enfants	Dijon	France	21000
13	Centre hospitalier départemental La Roche sur Yon	La Roche sur Yon	France	85025
14	Centre Jean Bernard	Le Mans	France	72000
15	Hôpital St Vincent de Paul - GH-ICL	Lille	France	59020
16	Chru Lille	Lille	France	59037
17	CHU de Limoges	Limoges	France	87000
18	Hématologie, Institut Paoli Calmette	Marseille	France	13273
19	CH Meaux	Meaux	France	77104
20	Hôpital Notre Dame de Bon Secours	Metz	France	57038
21	Hopital J Monod	Montivilliers	France	76290
22	Hôpital E Muller	Mulhouse	France	68100
23	CHRU, Hôtel Dieu	Nantes	France	44035
24	Centre de NICE 2/ Hôpital Archet	Nice	France	06202
25	CHU Nimes CAREMEAU	Nimes	France	30029
26	Hôpital St Antoine	Paris	France	75571
27	Groupe hospitalier Pitié Salpétrière	Paris	France	75651
28	Hôpital Haut-Leveque	PESSAC cedex	France	33604
29	Centre Hospitalier Lyon Sud -1	Pierre Benite	France	69495
30	Unité de Recherche Clinique - CH Perigueux	Périgueux	France	24019
31	Hématologie Clinique, Hôpital Robert Debré, CHU Reims	Reims	France	51092
32	Hématologie, IUCT oncopole	Toulouse	France	31059
33	CHRU, Hôpitaux de Brabois	Vandœuvre-lès-Nancy	France	54511