Study of Weekly Carfilzomib, Cyclophosphamide and Dexamethasone In Newly Diagnosed Multiple Myeloma Patients (wCCyd)

Sponsor
European Myeloma Network (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT01857115
Collaborator
Fondazione EMN Italy Onlus (Other)
63
Enrollment
1
Location
1
Arm
116
Anticipated Duration (Months)
0.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This protocol is a phase I/II multicenter study designed to assess the safety and the efficacy of the proposed combinations as up-front treatment in elderly Multiple Myeloma (MM) patients.

Condition or DiseaseIntervention/TreatmentPhase
Phase 1/Phase 2

Detailed Description

TREATMENT PERIOD Patients will start the induction treatment with wCCyd, as soon as the screening visits of the pre-treatment period have been terminated.

Each cycle will be repeated every 28 days for a total of 9 courses.

Treatment schedule for 9 cycles of induction:
Phase I:

In the phase I part of the study, the following dose levels of carfilzomib will be studied with constant doses of dexamethasone and cyclophosphamide to define the maximum tolerated dose (MTD):

Level -1

  1. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15.

  2. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9,15-16, 22-23.

  3. Carfilzomib given 20 mg/m2 IV once daily on Day 1 of Cycle 1 only followed by 36 mg/m2 on days 8, 15 of Cycle 1, then for all subsequent doses 36 mg/m2 IV once daily on days 1, 8, 15, followed by 14-day rest period (day 16 through 28).

Level 0 (starting dose)

  1. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15.

  2. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9,15-16, 22-23.

  3. Carfilzomib given 20 mg/m2 IV once daily on Day 1 of Cycle 1 only followed by 45 mg/m2 on days 8, 15 of Cycle 1, then for all subsequent doses 45 mg/m2 IV once daily on days 1, 8, 15, followed by 14-day rest period (day 16 through 28).

Level +1

  1. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15.

  2. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9,15-16, 22-23.

  3. Carfilzomib given 20 mg/m2 IV once daily on Day 1 of Cycle 1 only followed by 56 mg/m2 on days 8, 15 of Cycle 1, then for all subsequent doses 56 mg/m2 IV once daily on days 1, 8, 15, followed by 14-day rest period (day 16 through 28).

Level +2

  1. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15.

  2. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9,15-16, 22-23.

  3. Carfilzomib given 20 mg/m2 IV once daily on Day 1 of Cycle 1 only followed by 70 mg/m2 on days 8, 15 of Cycle 1, then for all subsequent doses 70 mg/m2 IV once daily on days 1, 8, 15, followed by 14-day rest period (day 16 through 28).

Patients will be observed during the first cycle of therapy for the assessment of side effects and observation of DLTs. Dose escalation will proceed as follows:

  • 3 patients will be entered at dose level 0.

  • If 0/3 patients experience DLT, dose escalation will continue.

  • If 1/3 patients experience DLT, 3 additional patients will be added to this cohort (max 6).

  • If no further patients experience DLT (1/6) dose escalation will continue.

  • If 2/6 patients experience DLT, the MTD will have been exceeded and the MTD will be the previous dose at which < 2/6 experienced DLT.

  • If 2/3 patients experience a DLT at any given dose, the MTD will have been exceeded and the MTD will be the preceding dose at which < 2/6 (or 1/3) patients experienced a DLT.

Phase II:

The dose used to treat patients in the phase II will be the MTD defined in the phase I of the study.

MAINTENANCE PERIOD At the end of the induction phase, patients will start the maintenance phase with Carfilzomib at the MTD defined by the phase I study IV once daily on days 1, 8, 15 until progression or intolerance.

Treatment schedule for maintenance until progression or intolerance:

Carfilzomib at the MTD defined by phase I study IV once daily on days 1, 8, 15.

Study Design

Study Type:
Interventional
Actual Enrollment :
63 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A MULTICENTER, OPEN LABEL STUDY OF WEEKLY CARFILZOMIB, CYCLOPHOSPHAMIDE AND DEXAMETHASONE (wCCyd) IN NEWLY DIAGNOSED MULTIPLE MYELOMA (MM) PATIENTS
Actual Study Start Date :
Apr 1, 2013
Actual Primary Completion Date :
Nov 1, 2013
Anticipated Study Completion Date :
Dec 1, 2022

Arms and Interventions

ArmIntervention/Treatment
Experimental: CCyd

Treatment schedule for 9 cycles of induction: Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9,15-16, 22-23. Carfilzomib given 20 mg/m2 IV once daily on Day 1 of Cycle 1 only followed by 36/45/56/70 mg/m2 on days 8, 15 of Cycle 1, then for all subsequent doses 70 mg/m2 IV once daily on days 1, 8, 15, followed by 14-day rest period (day 16 through 28). Treatment schedule for maintenance until progression or intolerance: Carfilzomib at the MTD defined by phase I study IV once daily on days 1, 8, 15.

Drug: Carfilzomib
Other Names:
  • Krypolis
  • Drug: Cyclophosphamide
    Other Names:
  • Endoxan
  • Drug: Dexamethasone
    Other Names:
  • Decadron
  • Outcome Measures

    Primary Outcome Measures

    1. Identification of Dose-limiting toxicity (DLT) [1 year]

      Non-hematologic: Grade2 neuropathy with pain any Grade 3 toxicity (excluding nausea, vomiting, diarrhea) Grade3 nausea, vomiting, or diarrhea despite maximal antiemetic/antidiarrheal therapy Grade4 fatigue lasting for ≥7days Any non-hematologic toxicity requiring a dose reduction within Cycle1 Inability to receive Day 1 dose of Cycle2 due to drug related toxicity persisting from Cycle1 or drug related toxicity newly encountered on Day1 of Cycle2. Hematologic: Grade 4 neutropenia (ANC<0.5x109/L) lasting for ≥7days Febrile neutropenia (ANC<1.0x109/L with a fever ≥38.3ºC) Grade 4 thrombocytopenia (platelets<25.0x109/L) lasting ≥7 days despite dose delay Grade 3-4 thrombocytopenia associated with bleeding Any hematologic toxicity requiring a dose reduction within Cycle1 Inability to receive Day1 dose of Cycle2 due to drug related toxicity persisting from Cycle1 or drug related toxicity newly encountered on Day1 of Cycle2.

    2. Partial Response (PR) [1 year]

      The primary efficacy endpoints will be assessed by considering partial response (PR) following the proposed regimen, at the end of third cycle.

    Secondary Outcome Measures

    1. Response rate (RR) [3 years]

      Determine the response rate

    2. Progression free-survival (PFS) [3 years]

      Determine progression free-survival

    3. Time to progression (TTP) [3 years]

      Determine the time to progression

    4. Duration of response (DOR) [3 years]

      Determine the duration of response

    5. Overall survival (OS) [3 years]

      Determine the overall survival

    6. Time to next therapy (TTNT) [3 years]

      Determine the time to next therapy

    7. Responses [3 years]

      Determine whether responses obtained with wCCyd treatment are associated with a prolongation of PFS, in comparison with non-responding patients

    8. Response and survival [3 years]

      Determine whether tumor response and survival might significantly change in particular subgroups of patients defined on prognostic factors (β2-microglobulin, C-reactive protein (CRP), FISH, gene expression profile)

    9. Maintenance [3 years]

      Determine the benefit on PFS and OS of maintenance with Carfilzomib Determine the benefit on tumor load of maintenance with Carfilzomib

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    65 Years to 99 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    Disease-related

    1. Patient is a newly diagnosed MM patient.

    2. Patient is age ≥ 65 year of age or who are ineligible for autologous stem cell transplantation.

    3. Patient has measurable disease, defined as follows: any quantifiable serum monoclonal protein value (generally, but not necessarily, ≥ 0.5 g/dL of M-protein) and, where applicable, urine light-chain excretion of > 200 mg/24 hours. For patients with oligo- or non-secretory MM, it is required that they have measurable plasmacytoma > 2 cm as determined by clinical examination or applicable radiographs (i.e. MRI, CT-Scan) or an abnormal free light chain ratio (n.v.: 0.26-1.65). We anticipate that less than 10% of patients admitted to this study will be oligo- or non-secretory MM with free light chains only in order to maximize interpretation of benefit results.

    Demographic:
    1. Age ≥ 18 years.

    2. Life expectancy ≥ 3 months.

    3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Appendix F).

    Laboratory:
    1. Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 14 days prior to randomization.

    2. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to randomization.

    3. Corrected serum calcium ≤ 14 mg/dL (3.5 mmol/L).

    4. Alanine transaminase (ALT): ≤ 3 x the ULN.

    5. Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to randomization (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines).

    6. Platelet count ≥ 50 × 109/L (≥ 30 × 109/L if myeloma involvement in the bone marrow is

    50%) within 14 days prior to randomization.

    1. Creatinine clearance (CrCl) ≥ 15 mL/minute within 7 days prior to randomization, either measured or calculated using a standard formula (eg, Cockcroft and Gault).
    Ethical/Other:
    1. Written informed consent in accordance with federal, local, and institutional guidelines.

    2. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception.

    3. Male subjects must agree to practice contraception.

    Exclusion Criteria:
    Disease-related:
    1. Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid; ≤ to the equivalent of dexamethasone 40 mg/day for 4 days)

    2. Patient with relapsed or refractory multiple myeloma.

    3. Patients with non-secretory MM unless serum free light chains are present and the ratio is abnormal.

    Concurrent Conditions:
    1. Pregnant or lactating females (Appendix I).

    2. Major surgery within 21 days prior to randomization.

    3. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization.

    4. Known human immunodeficiency virus infection.

    5. Active hepatitis B or C infection.

    6. Unstable angina or myocardial infarction within 4 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker.

    7. Uncontrolled hypertension, uncontrolled congestive heart failure (CHF) or uncontrolled diabetes within 14 days prior to randomization.

    8. Non-hematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas.

    9. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to randomization.

    10. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).

    11. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment.

    12. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization.

    13. Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Fondazione EMN Italy OnlusTorinoItaly10126

    Sponsors and Collaborators

    • European Myeloma Network
    • Fondazione EMN Italy Onlus

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    European Myeloma Network
    ClinicalTrials.gov Identifier:
    NCT01857115
    Other Study ID Numbers:
    • IST-CAR-561
    First Posted:
    May 20, 2013
    Last Update Posted:
    Mar 25, 2022
    Last Verified:
    Mar 1, 2022
    Keywords provided by European Myeloma Network
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Mar 25, 2022