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

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ClinicalTrials.gov Identifier: NCT02302495
Recruitment Status : Active, not recruiting
First Posted : November 27, 2014
Last Update Posted : February 19, 2018
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
University Hospital, Lille

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:

  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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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
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 : January 2014
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : July 2021


Arm Intervention/treatment
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




Primary Outcome Measures :
  1. Dose Maximum Tolerate of Carfilzomib Weekly [ Time Frame: 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 :
  1. number of patients who reach Very Good Partial Response and Complete [ Time Frame: 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.



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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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%)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02302495


Locations
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France
Centre Hospitalier H. Duffaut
Avignon, France, 84902
Centre Hospitalier de la côte basque
Bayonne, France, 64109
Hôpital Jean Minjoz
Besançon, France, 25030
Institut Bergonie
Bordeaux, France, 33076
Polyclinique Bordeaux Nord Aquitaine
Bordeaux, France, 33300
Centre Hospitalier William Morey
Chalons-sur-Saone, France, 71100
Centre Hospitalier de Chambery
Chambery, France, 73011
Hôpital St Antoine Béclére
Clamart, France, 92140
CH Louis Pasteur
Colmar, France, 68024
CH Francilien
Corbeil - Essonnes, France, 91106
CHU Henri Mondor
Creteil, France, 94010
Hématologie Clinique, CHU, Hôpital d'Enfants
Dijon, France, 21000
Centre hospitalier départemental La Roche sur Yon
La Roche sur Yon, France, 85025
Centre Jean Bernard
Le Mans, France, 72000
Hôpital St Vincent de Paul - GH-ICL
Lille, France, 59020
Chru Lille
Lille, France, 59037
CHU de Limoges
Limoges, France, 87000
Hématologie, Institut Paoli Calmette
Marseille, France, 13273
CH Meaux
Meaux, France, 77104
Hôpital Notre Dame de Bon Secours
Metz, France, 57038
Hopital J Monod
Montivilliers, France, 76290
Hôpital E Muller
Mulhouse, France, 68100
CHRU, Hôtel Dieu
Nantes, France, 44035
Centre de NICE 2/ Hôpital Archet
Nice, France, 06202
CHU Nimes CAREMEAU
Nimes, France, 30029
Hôpital St Antoine
Paris, France, 75571
Groupe hospitalier Pitié Salpétrière
Paris, France, 75651
Hôpital Haut-Leveque
PESSAC cedex, France, 33604
Centre Hospitalier Lyon Sud -1
Pierre Benite, France, 69495
Unité de Recherche Clinique - CH Perigueux
Périgueux, France, 24019
Hématologie Clinique, Hôpital Robert Debré, CHU Reims
Reims, France, 51092
Hématologie, IUCT oncopole
Toulouse, France, 31059
CHRU, Hôpitaux de Brabois
Vandoeuvre, France, 54511
Sponsors and Collaborators
University Hospital, Lille
Amgen
Investigators
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Study Chair: Leleu Xavier, MD, PhD University Hospital

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Responsible Party: University Hospital, Lille
ClinicalTrials.gov Identifier: NCT02302495     History of Changes
Other Study ID Numbers: 2012_32
2012-004490-10 ( EudraCT Number )
First Posted: November 27, 2014    Key Record Dates
Last Update Posted: February 19, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by University Hospital, Lille:
Carfilzomib weekly
and Melphalan and Prednisone

Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Prednisone
Melphalan
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors