Evaluation of the Safety and the Efficacy of Carfilzomib Combined With Cyclophosphamide and Dexamethasone (CCyd) or Lenalidomide and Dex (CRd) Followed by ASCT or 12 Cycles of Carf Combined With Dex and Len for Patients Eligible for ASCT With Newly Diagnosed Multiple Myeloma. (FORTE)

• ClinicalTrials.gov Identifier: NCT02203643
• Recruitment Status: Active, not recruiting
• First Posted: July 30, 2014
• Last Update Posted: November 30, 2023
• Sponsor: Mario Boccadoro
• Information provided by (Responsible Party): Mario Boccadoro, University of Turin, Italy

Tracking Information

• First Submitted Date: June 30, 2014
• First Posted Date: July 30, 2014
• Last Update Posted Date: November 30, 2023
• Study Start Date: February 2015
• Actual Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 28, 2014)

Efficacy in term of at least Very Good Partial Response (VGPR) [ Time Frame: Up to 2 years ]

The efficacy, in term of at least VGPR, of the combination of carfilzomib, dexamethasone with cyclophosphamide or lenalidomide after 4 cycles of induction treatment in newly diagnosed MM patients eligible for ASCT.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 28, 2014)

• sCR rate [ Time Frame: up to 1 year ]
  the stringent complete response (sCR) rate in the 3 arms after complete primary therapy (induction, ASCT and consolidation for the transplant arms and after 12 cycles in the long treatment arm) in an explorative manner.
• Safety as incidence of grade 3/4 adverse events [ Time Frame: Up to 3 years ]
  the safety in the 3 induction/consolidation arms and in the 2 maintenance arms.
• Survival [ Time Frame: Up to 5 years ]
  the survival in the 3 induction/consolidation arms and in the 2 maintenance arms.
• Correlation between tumor response and outcome with baseline prognostic factors. [ Time Frame: up to 5 years ]
• Minimal Residual Disease (MRD) [ Time Frame: up to 5 years ]
  Minimal Residual Disease
• Survival after relapse [ Time Frame: up to 7 years ]
  the survival after relapse

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of the Safety and the Efficacy of Carfilzomib Combined With Cyclophosphamide and Dexamethasone (CCyd) or Lenalidomide and Dex (CRd) Followed by ASCT or 12 Cycles of Carf Combined With Dex and Len for Patients Eligible for ASCT With Newly Diagnosed Multiple Myeloma.
• Official Title: A MULTICENTER, RANDOMIZED, OPEN LABEL PHASE II STUDY OF CARFILZOMIB, CYCLOPHOSPHAMIDE AND DEXAMETHASONE (CCyd) as Pre Transplant INDUCTION and Post Transplant Consolidation or CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE (CRd) as Pre Transplant INDUCTION and Post Transplant Consolidation or Continuous Treatment With CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE (12 Cycles) Without Transplant, All Followed by MAINTENANCE With LENALIDOMIDE (R) Versus LENALIDOMIDE AND CARFILZOMIB (CR) IN NEWLY DIAGNOSED MULTIPLE MYELOMA (MM) PATIENTS ELEGIBLE FOR AUTOLOGOUS TRANSPLANT

Brief Summary

This study will evaluate the safety and the efficacy of carfilzomib combined with cyclophosphamide and dexamethasone (CCyd) or lenalidomide and dexamethasone (CRd) followed by autologous transplantation ASCT or 12 cycles of carfilzomib combined with dexamethasone and lenalidomide for patients eligible for ASCT with newly diagnosed multiple myeloma. As a secondary endpoint this study will evaluate the best maintenance treatment between lenalidomide and lenalidomide combined with carfilzomib.

Four hundred seventy-seven patients, males and females aged > 18 years, enrolled in several sites, will take part in this study.

The duration of the study is approximately 5 years.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: MULTIPLE MYELOMA (MM)

Intervention

• Drug: Carfilzomib
• Drug: Cyclophosphamide
• Drug: Lenalidomide
  Other Name: Revlimid
• Drug: Dexamethasone

Study Arms

• Experimental: CCyd

  Carfilzomib Cyclophosphamide and Dexamethasone administered for 4 28-day cycles. This treatment will be followed by autologous stem cell transplantation (ASCT). Carfilzomib Cyclophosphamide and Dexamethasone administered for 4 28-day cycles, as consolidation treatment.

  After the end of consolidation all patients will be randomized to receive:

  Lenalidomide or Lenalidomide and Carfilzomib until any sign of progression or intolerance.

  Interventions:

  • Drug: Carfilzomib
  • Drug: Cyclophosphamide
  • Drug: Dexamethasone
• Experimental: CRd

  Carfilzomib Lenalidomide and Dexamethasone administered for 4 28-day cycles. This treatment will be followed by autologous stem cell transplantation (ASCT). Carfilzomib Cyclophosphamide and Dexamethasone administered for 4 28-day cycles, as consolidation treatment.

  After the end of consolidation all patients will be randomized to receive:

  Lenalidomide or Lenalidomide and Carfilzomib until any sign of progression or intolerance.

  Interventions:

  • Drug: Carfilzomib
  • Drug: Lenalidomide
  • Drug: Dexamethasone
• Experimental: CRd long treatment

  Carfilzomib Lenalidomide and Dexamethasone administered for 4 28-day cycles. Stem cells collection will be performed. Carfilzomib Lenalidomide and Dexamethasone administered for 8 28-day cycles.

  After that all patients will be randomized to receive:

  Lenalidomide or Lenalidomide and Carfilzomib until any sign of progression or intolerance.

  Interventions:

  • Drug: Carfilzomib
  • Drug: Lenalidomide
  • Drug: Dexamethasone

Publications *

• Bertamini L, Oliva S, Rota-Scalabrini D, Paris L, More S, Corradini P, Ledda A, Gentile M, De Sabbata G, Pietrantuono G, Pascarella A, Tosi P, Curci P, Gilestro M, Capra A, Galieni P, Pisani F, Annibali O, Monaco F, Liberati AM, Palmieri S, Luppi M, Zambello R, Fazio F, Belotti A, Tacchetti P, Musto P, Boccadoro M, Gay F. High Levels of Circulating Tumor Plasma Cells as a Key Hallmark of Aggressive Disease in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2022 Sep 20;40(27):3120-3131. doi: 10.1200/JCO.21.01393. Epub 2022 Jun 6.
• Gay F, Musto P, Rota-Scalabrini D, Bertamini L, Belotti A, Galli M, Offidani M, Zamagni E, Ledda A, Grasso M, Ballanti S, Spadano A, Cea M, Patriarca F, D'Agostino M, Capra A, Giuliani N, de Fabritiis P, Aquino S, Palmas A, Gamberi B, Zambello R, Petrucci MT, Corradini P, Cavo M, Boccadoro M. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial. Lancet Oncol. 2021 Dec;22(12):1705-1720. doi: 10.1016/S1470-2045(21)00535-0. Epub 2021 Nov 11.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 28, 2014): 477
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 2033
• Actual Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Age ≥ 18 years Newly diagnosed MM based on standard CRAB criteria (see appendix B). Patient < 65 years eligible for ASCT. Patient has measurable disease according to IMWG (International Myeloma Working Group) criteria.

Patient has given voluntary written informed consent. Patient agrees to use acceptable methods for contraception. Patient has a Karnofsky performance status ≥ 60%

Pretreatment clinical laboratory values within 30 days of enrolment:

Platelet count ≥50 x 109/L (≥30 x 109 /L if myeloma involvement in the bone marrow is > 50%) Absolute neutrophil count (ANC) ≥ 1 x 109/L without the use of growth factors Corrected serum calcium ≤14 mg/dL (3.5 mmol/L) Alanine transaminase (ALT): ≤ 3 x the Upper Limit Normal (ULN) Total bilirubin: ≤ 2 x the ULN Calculated or measured creatinine clearance: ≥ 30 mL/minute. LVEF≥40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available Life expectancy ≥ 3 months

Exclusion Criteria:

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) Patients with non-secretory MM unless serum free-light chains are present and the ratio is abnormal or a plasmocytoma with minimum largest diameters of > 2 cm Patients ineligible for autologous transplantation Pregnant or lactating females

Presence of:

Clinical active infectious hepatitis type A, B, C or HIV Acute active infection requiring antibiotics or infiltrative pulmonary disease Myocardial infarction or unstable angina ≤ 4 months or other clinically significant heart disease Peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 4.0 Known history of allergy to Captisol ® (a cyclodextrin derivative used to solubilize carfilzomib) Contraindication to any of the required drugs or supportive treatments Invasive malignancy within the past 3 years Serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the enrolment or place the subject at unacceptable risk.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT02203643
• Other Study ID Numbers: UNITO-MM-01 / FORTE
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Mario Boccadoro, University of Turin, Italy
• Original Responsible Party: Guido Tarone, University of Turin, Italy, MD
• Current Study Sponsor: Mario Boccadoro
• Original Study Sponsor: Guido Tarone
• Collaborators: Not Provided

Investigators

• Principal Investigator: Antonio Palumbo, MD; University of Turin, Italy

• PRS Account: University of Turin, Italy
• Verification Date: November 2023