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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified April 2012 by Nantes University Hospital.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
Nantes University Hospital
ClinicalTrials.gov Identifier:
NCT01279694
First received: January 18, 2011
Last updated: April 26, 2012
Last verified: April 2012
  Purpose

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.


Condition Intervention Phase
Myeloma
Drug: Carfilzomib
Drug: Melphalan
Drug: Prednisone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Carfilzomib Plus Melphalan and Prednisone in Elderly Untreated Patients With Multiple Myeloma.

Resource links provided by NLM:


Further study details as provided by Nantes University Hospital:

Primary Outcome Measures:
  • Phase I: determination of MTD by evaluation of hematological and non hematological toxicity [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Safety of CMP Clinical benefit response [(CBR = ORR + minimal response (MR)], Progression-free survival (PFS), Duration of response Overall survival (OS). [ Designated as safety issue: Yes ]
  • Tolerability of CMP Clinical benefit response [(CBR = ORR + minimal response (MR)], Progression-free survival (PFS), Duration of response Overall survival (OS). [ Designated as safety issue: No ]

Estimated Enrollment: 68
Study Start Date: October 2010
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Intervention Details:
    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
    Other Name: alkéran
    Drug: Prednisone
    from 9 cycle: 60 mg/m²/day PO from day 1-4
Detailed Description:

The primary objectives of this phase I/II study are to identify the most appropriate dose of Carfilzomib in combination with a standard MP treatment regimen (phase I) and to evaluate the efficacy of Carfilzomib plus MP (CMP) in terms of overall response rate [(ORR), consisting of complete response (CR), very good partial response (VGPR), and partial response (PR) (phase II)]. Phase I/II single arm open label

  Eligibility

Ages Eligible for Study:   65 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Karnofsky performance status (KPS) of at least 60%
  • Life expectancy of more than 3 months.
  • Must understand and voluntarily sign an informed consent form
  • Age >65 years at the time of signing consent
  • Previously untreated, symptomatic multiple myeloma as defined by the 2 criteria below:○ MM diagnostic criteria (all 3 required):· Monoclonal plasma cells in the bone marrow ≥10% and/or presence of a biopsy-proven plasmacytoma· Monoclonal protein present in the serum and/or urine· Myeloma-related organ dysfunction (at least 1 of the following) [C] Calcium elevation in the blood (serum calcium >10.5 mg/L or upper limit of normal)[R] Renal insufficiency (serum creatinine > 2 mg/dL)[A] Anemia (hemoglobin <10 g/dL or 2 g < normal)[B] Lytic bone lesions or osteoporosisAND have measurable disease by protein electrophoresis analyses as defined by one or more of the following:· IgG multiple myeloma: Serum monoclonal paraprotein (M protein) level by SPEP ³ 0.5 g/dL or urine M-protein level ³ 200 mg/24 hours· IgA multiple myeloma: Serum M-protein level ³ 0.5 mg/dL or urine M-protein level ³ 200 mg/24 hours· IgM multiple myeloma (IgM M-protein plus lytic bone disease documented by skeletal survey plain films): Serum M-protein level ≥ 1.0 g/dL or urine M-protein level ≥ 200 mg/24 hours· IgD multiple myeloma: Serum M-protein level ³ 0.05 g/dL or urine M-protein level ³ 200 mg/24 hours Light chain multiple myeloma: Patients with serum free light chain disease in whom the involved light chain measures ≥ 10 mg/dL
  • ECOG performance status of 0, 1, or 2
  • Able to adhere to the study visit schedule and other protocol requirements
  • Affiliation number to National Health Care System

Exclusion Criteria:

  • Patients are ineligible if they meet any of the following criteria: 1 Previous treatment with antimyeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid [i.e., less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 28 days (4 weeks) of consent]).
  • Any serious medical condition that places the patient at an unacceptable risk if he or she participates in this study.
  • Female of childbearing potential
  • Any of the following laboratory abnormalities:· Absolute neutrophil count (ANC) < 1,000 cells/mL (1.0 × 109/L) · Platelet count < 50,000 cells/mL (50 × 109/L) for patients in whom < 50% of bone marrow nucleated cells are plasma cells; but platelet count <30,000 cells/mL for patients in whom ³ 50% of bone marrow nucleated cells are plasma cells · Serum SGPT/ALT > 3.0 × upper limit of normal (ULN); Bilirubin >2 × ULN [ALT more specific to liver]· Creatinine clearance ≤ 30 mL/min (Cockcroft-Gault calculation)5 Prior history of malignancies, other than multiple myeloma, unless the subject has been free of the disease for ³ 3 years. Exceptions include the following:o Basal cell carcinoma of the skin Squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast6 Incidental histological finding of prostate cancer (TNM stage of T1a or T1b) Peripheral neuropathy of > grade 2 severity.
  • Known HIV positivity or active infectious hepatitis, type A, B, or C.
  • Myocardial infarction within 3 months of enrollment, unstable angina within 2 months or New York Heart Association class III or IV heart failure.
  • Oral or IV fluid hydration contraindicated
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01279694

Contacts
Contact: Philippe Moreau philippe.moreau@chu-nantes.fr

Locations
France
CHU de Nantes Recruiting
Nantes, France, 44000
Contact: Philippe Moreau, Profesor       philippe.moreau@chu-nantes.fr   
Sponsors and Collaborators
Nantes University Hospital
Investigators
Principal Investigator: Philippe Moreau CHU Nantes
Principal Investigator: Carine Chaleteix University Hospital, Clermont-Ferrand
Principal Investigator: Denis Caillot CH DIJON
Principal Investigator: Thierry FACON CHRU - Hôpital Claude Huriez Lille
Principal Investigator: Cyril Hulin Hôpital de Brabois Nancy
Principal Investigator: Brigitte Kolb Hôpital R. Debré Reims
Principal Investigator: Hervé Maisonneuve CHD La Roche Sur Yon
Principal Investigator: Michel Attal CHRU - Hôpital Purpan Toulouse
Principal Investigator: Benboubker CHRU - Hôpital Bretonneau Tours
  More Information

No publications provided

Responsible Party: Pr Philippe Moreau, CHU de Nantes
ClinicalTrials.gov Identifier: NCT01279694     History of Changes
Other Study ID Numbers: 10/3-D
Study First Received: January 18, 2011
Last Updated: April 26, 2012
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Nantes University Hospital:
newly-diagnosed multiple myeloma.

Additional relevant MeSH terms:
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
Melphalan
Prednisone
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal

ClinicalTrials.gov processed this record on July 29, 2014