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

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ClinicalTrials.gov Identifier: NCT01857115
Recruitment Status : Active, not recruiting
First Posted : May 20, 2013
Last Update Posted : August 2, 2018
Sponsor:
Collaborator:
Fondazione Neoplasie Sangue Onlus
Information provided by (Responsible Party):
Stichting Hemato-Oncologie voor Volwassenen Nederland

Tracking Information
First Submitted Date  ICMJE April 17, 2013
First Posted Date  ICMJE May 20, 2013
Last Update Posted Date August 2, 2018
Actual Study Start Date  ICMJE April 2013
Actual Primary Completion Date November 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 17, 2013)
  • Identification of Dose-limiting toxicity (DLT) [ Time Frame: 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.
  • Partial Response (PR) [ Time Frame: 1 year ]
    The primary efficacy endpoints will be assessed by considering partial response (PR) following the proposed regimen, at the end of third cycle.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01857115 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 17, 2013)
  • Response rate (RR) [ Time Frame: 3 years ]
    Determine the response rate
  • Progression free-survival (PFS) [ Time Frame: 3 years ]
    Determine progression free-survival
  • Time to progression (TTP) [ Time Frame: 3 years ]
    Determine the time to progression
  • Duration of response (DOR) [ Time Frame: 3 years ]
    Determine the duration of response
  • Overall survival (OS) [ Time Frame: 3 years ]
    Determine the overall survival
  • Time to next therapy (TTNT) [ Time Frame: 3 years ]
    Determine the time to next therapy
  • Responses [ Time Frame: 3 years ]
    Determine whether responses obtained with wCCyd treatment are associated with a prolongation of PFS, in comparison with non-responding patients
  • Response and survival [ Time Frame: 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)
  • Maintenance [ Time Frame: 3 years ]
    • Determine the benefit on PFS and OS of maintenance with Carfilzomib
    • Determine the benefit on tumor load of maintenance with Carfilzomib
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Weekly Carfilzomib, Cyclophosphamide and Dexamethasone In Newly Diagnosed Multiple Myeloma Patients (wCCyd)
Official Title  ICMJE A MULTICENTER, OPEN LABEL STUDY OF WEEKLY CARFILZOMIB, CYCLOPHOSPHAMIDE AND DEXAMETHASONE (wCCyd) IN NEWLY DIAGNOSED MULTIPLE MYELOMA (MM) PATIENTS
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma
Intervention  ICMJE
  • Drug: Carfilzomib
    Other Name: Krypolis
  • Drug: Cyclophosphamide
    Other Name: Endoxan
  • Drug: Dexamethasone
    Other Name: Decadron
Study Arms  ICMJE Experimental: CCyd

Treatment schedule for 9 cycles of induction:

  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 36/45/56/70 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.

Interventions:
  • Drug: Carfilzomib
  • Drug: Cyclophosphamide
  • Drug: Dexamethasone
Publications * Bringhen S, Mina R, Petrucci MT, Gaidano G, Ballanti S, Musto P, Offidani M, Spada S, Benevolo G, Ponticelli E, Galieni P, Cavo M, Caravita di Toritto T, Di Raimondo F, Montefusco V, Palumbo A, Boccadoro M, Larocca A. Once-weekly versus twice-weekly carfilzomib in patients with newly diagnosed multiple myeloma: a pooled analysis of two phase 1/2 studies. Haematologica. 2019 Feb 7. pii: haematol.2018.208272. doi: 10.3324/haematol.2018.208272. [Epub ahead of print]

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 9, 2016)
63
Original Estimated Enrollment  ICMJE
 (submitted: May 17, 2013)
71
Estimated Study Completion Date  ICMJE April 2019
Actual Primary Completion Date November 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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:

  4. Age ≥ 18 years.
  5. Life expectancy ≥ 3 months.
  6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Appendix F).

    Laboratory:

  7. 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.
  8. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to randomization.
  9. Corrected serum calcium ≤ 14 mg/dL (3.5 mmol/L).
  10. Alanine transaminase (ALT): ≤ 3 x the ULN.
  11. 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).
  12. Platelet count ≥ 50 × 109/L (≥ 30 × 109/L if myeloma involvement in the bone marrow is > 50%) within 14 days prior to randomization.
  13. 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:

  14. Written informed consent in accordance with federal, local, and institutional guidelines.
  15. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception.
  16. 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:

  4. Pregnant or lactating females (Appendix I).
  5. Major surgery within 21 days prior to randomization.
  6. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization.
  7. Known human immunodeficiency virus infection.
  8. Active hepatitis B or C infection.
  9. 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.
  10. Uncontrolled hypertension, uncontrolled congestive heart failure (CHF) or uncontrolled diabetes within 14 days prior to randomization.
  11. 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.
  12. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to randomization.
  13. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
  14. 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.
  15. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization.
  16. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 65 Years to 99 Years   (Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01857115
Other Study ID Numbers  ICMJE IST-CAR-561
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Stichting Hemato-Oncologie voor Volwassenen Nederland
Study Sponsor  ICMJE Stichting Hemato-Oncologie voor Volwassenen Nederland
Collaborators  ICMJE Fondazione Neoplasie Sangue Onlus
Investigators  ICMJE Not Provided
PRS Account Stichting Hemato-Oncologie voor Volwassenen Nederland
Verification Date August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP