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Study of Carfilzomib, Daratumumab and Dexamethasone for Patients With Relapsed and/or Refractory Multiple Myeloma. (CANDOR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03158688
Recruitment Status : Active, not recruiting
First Posted : May 18, 2017
Results First Posted : September 11, 2020
Last Update Posted : September 11, 2020
Sponsor:
Information provided by (Responsible Party):
Amgen

Brief Summary:
Compare carfizomib, dexamethasone, and daratumumab (KdD) to Carfilzomib and dexamethasone (Kd) in terms of progression free survival (PFS) in participants with multiple myeloma who have relapsed after 1 to 3 prior therapies.

Condition or disease Intervention/treatment Phase
Relapsed Multiple Myeloma Refractory Multiple Myeloma Drug: Dexamethasone Drug: Daratumumab Drug: Carfilzomib Phase 3

Detailed Description:

This is a phase 3 multicenter, open-label, randomized study in participants with relapsed or refractory multiple myeloma (RRMM) who have received 1 to 3 prior therapies.

Participants receive the treatment determined by randomization for a maximum of 4 years or until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or death (whichever occurs first). No crossover between the treatment arms is allowed.

This was an open-label study. However, the assessment of response and disease progression for the primary analysis was determined by an Independent Review Committee (IRC) in a blinded manner. Sensitivity analyses of response and disease progression were determined centrally by the sponsor using a validated computer algorithm (Onyx Response Computational Assessment [ORCA]) in a blinded manner.

Following progression or discontinuation of study drug(s), participants have 2 follow-up visits (30 days [+ 3] and 8 weeks [± 7 days] after last dose of all study drug[s]) and then remain in long-term follow-up (LTFU) where data on survival status and subsequent antimyeloma therapy is gathered every 12 weeks ± 2 weeks.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 466 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open-label, Phase 3 Study Comparing Carfilzomib, Dexamethasone, and Daratumumab to Carfilzomib and Dexamethasone for the Treatment of Patients With Relapsed or Refractory Multiple Myeloma
Actual Study Start Date : June 13, 2017
Actual Primary Completion Date : July 14, 2019
Estimated Study Completion Date : July 21, 2022


Arm Intervention/treatment
Active Comparator: Kd - Carfilzomib and Dexamethasone

Carfilzomib was administered intravenously (IV) at 20 mg/m^2 in Cycle 1: days 1 and 2; at 56 mg/m^2 in Cycle 1: days 8, 9, 15 and 16. The 56 mg/m^2 dosage was continued in Cycles 2+ on days 1, 2, 8, 9, 15 and 16.

Dexamethasone was taken by IV infusion at 20 mg on Cycle 1, days 1 and 2 (in Cycles 2+, days 1 and 2 could be either oral or IV) and either orally or by IV infusion on days 8, 9, 15 and 16 and at 40 mg on day 22 of all 28-day cycles.

Drug: Dexamethasone
Commercially available oral and IV formulas were obtained by investigative sites. Amgen supplied IV or PO dexa for some countries (Poland, Hungry, Romania, Bulgaria, Korea). Dosage modification rules applied based on participant age (participants > 75 years were given lower doses), dexa-related toxicities, and discontinuation of carfilzomib.

Drug: Carfilzomib

Carfilzomib for infusion was supplied as a lyophilized, sterile product in single-use vials. The lyophilized product was reconstituted with preservative-free sterile water for injection, the reconstituted solution contained carfilzomib 2 mg/mL. IV injections lasted approximately 30 minutes.

Dose could be modified based on a >=20% change in body weight or toxicity.

Other Name: KYPROLIS®

Experimental: KdD - Carfilzomib, Dexamethasone and Daratumumab

Carfilzomib was administered intravenously (IV) at 20 mg/m^2 in Cycle 1: days 1 and 2; at 56 mg/m^2 in Cycle 1: days 8, 9, 15 and 16. The 56 mg/m^2 dosage was continued in Cycles 2+ on days 1, 2, 8, 9, 15 and 16.

Dexamethasone was taken by IV infusion at 20 mg on Cycle 1, days 1 and 2 (in Cycles 2+, days 1 and 2 could be either oral or IV) and either orally or by IV infusion on days 8, 9, 15 and 16 and at 40 mg on day 22 of all 28-day cycles. The administration of dexamethasone was given on carfilzomib and/or daratumumab IV infusion days.

Daratumumab was administered by IV at 8 mg/kg on Cycle 1: days 1 and 2; at 16 mg/kg on Cycle 1: days 8, 15 and 22, and Cycle 2: days 1, 8, 15, and 22. The 16 mg/kg dosage was continued on Cycles 3-6: days 1 and 15. The 16 mg/kg was further continued on Cycles 7+: day 1 only.

Drug: Dexamethasone
Commercially available oral and IV formulas were obtained by investigative sites. Amgen supplied IV or PO dexa for some countries (Poland, Hungry, Romania, Bulgaria, Korea). Dosage modification rules applied based on participant age (participants > 75 years were given lower doses), dexa-related toxicities, and discontinuation of carfilzomib.

Drug: Daratumumab
Daratumumab was supplied as a concentrated solution for infusion in single-use vials.
Other Name: DARZALEX®

Drug: Carfilzomib

Carfilzomib for infusion was supplied as a lyophilized, sterile product in single-use vials. The lyophilized product was reconstituted with preservative-free sterile water for injection, the reconstituted solution contained carfilzomib 2 mg/mL. IV injections lasted approximately 30 minutes.

Dose could be modified based on a >=20% change in body weight or toxicity.

Other Name: KYPROLIS®




Primary Outcome Measures :
  1. Progression-free Survival (PFS) as Assessed by the Independent Review Committee (Data Cut-off Date 14 July 2019) [ Time Frame: From randomization until the data cut-off date of 14 July 2019; as of the data cut-off date, a median of 40.29 weeks of treatment (any study drug) in the Kd group and 70.14 weeks of treatment (any study drug) in the KdD group. ]
    Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Participants were evaluated for disease response and progression according to the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) as assessed by an Independent Review Committee (IRC).


Secondary Outcome Measures :
  1. Overall Response (OR) as Assessed by the Independent Review Committee (Data Cut-off Date 14 July 2019) [ Time Frame: From randomization until the data cut-off date of 14 July 2019; as of the data cut-off date, a median of 40.29 weeks of treatment (any study drug) in the Kd group and 70.14 weeks of treatment (any study drug) in the KdD group. ]

    Overall response rate was defined as the percentage of participants in each treatment group who achieve partial response (PR) or better per the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) as their best response.

    Complete Response (CR): No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow.

    Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-component with urine M-component <100 mg/24 hours.

    Partial Response (PR): ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to < 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.

    95% CIs for proportions were estimated using the Clopper-Pearson method.


  2. Minimal Residual Disease Negative Complete Response Rate (MRD[-]CR) at 12 Months as Assessed by the Independent Review Committee (Data Cut-off Date 14 July 2019) [ Time Frame: 12 Months (8- to 13-month window) ]
    MRD[-]CR at 12 months was defined as achievement of CR per International Myeloma Working Group-Uniform Response Criteria and MRD[-] status as assessed by next-generation sequencing (NGS) at the 12 months landmark (8 to 13 month window).

  3. Overall Survival [ Time Frame: At approximately 230 OS events or 58 months after the first participant is enrolled, whichever occurs earlier. ]
    Overall survival was defined as the time from randomization until death from any cause.

  4. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Data Cut-off Date 14 July 2019) [ Time Frame: From Day 1 until the data cut-off date of 14 July 2019; as of the data cut-off date, a median of 40.29 weeks of treatment (any study drug) in the Kd group and 70.14 weeks of treatment (any study drug) in the KdD group. ]

    Treatment-emergent adverse events are defined as any adverse event with an onset after the administration of the first dose of any study treatment and within the end of study or 30 days of the last dose of any study treatment, whichever occurs earlier.

    The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, where where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal.

    Treatment-related adverse events are adverse events considered related to at least one investigational product by the investigator, including those with unknown relationship.


  5. Kaplan-Meier Estimate for Duration of Response (DOR) (Data Cut-off Date 14 July 2019) [ Time Frame: Day 1 until the data cut-off date of 14 July 2019; as of the data cut-off date, a median of 40.29 weeks of treatment (any study drug) in the Kd group and 70.14 weeks of treatment (any study drug) in the KdD group. ]

    Duration of response (DOR) was defined as the time (in months) from first evidence of partial response (PR) or better per IMWG-URC to the earlier of disease progression or death due to any cause for participants with a best response of PR or better. For those who are alive and have not experienced disease progression at the time of data cutoff for analysis, duration of response was right-censored.

    Medians were estimated using the Kaplan-Meier method. 95% CIs for medians were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.


  6. Kaplan-Meier Estimate for Time to Next Treatment (TTNT) (Data Cut-off Date 14 July 2019) [ Time Frame: From randomization until the data cut-off date of 14 July 2019; as of the data cut-off date, a median of 40.29 weeks of treatment (any study drug) in the Kd group and 70.14 weeks of treatment (any study drug) in the KdD group. ]

    Time to next treatment was defined as the time (in months) from randomization to the initiation of subsequent non-protocol anti-cancer treatment for multiple myeloma. Time to next treatment for participants who do not start the subsequent treatment for multiple myeloma was censored at the date when the participant's information was last available.

    Medians of TTNT duration were estimated using the Kaplan-Meier method. 95% CIs for medians were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.


  7. Kaplan-Meier Estimates for Time to Progression (TTP) as Assessed by the Independent Review Committee (Data Cut-off Date 14 July 2019) [ Time Frame: From randomization until the data cut-off date of 14 July 2019; as of the data cut-off date, a median of 40.29 weeks of treatment (any study drug) in the Kd group and 70.14 weeks of treatment (any study drug) in the KdD group ]
    Time to progression was defined as the time (in months) from randomization to documented disease progression. Participants who did not have documented disease progression were censored at the date when data was last available.

  8. Time to Progression (TTP): Percentage of Participants Who Had Not Had Disease Progression as Assessed by the Independent Review Committee at Months 3, 6, 12, and 18 (Data Cut-off Date 14 July 2019) [ Time Frame: Randomization to Months 3, 6, 12, and 18 ]

    Time to progression was defined as the time (in months) from randomization to documented disease progression. This outcome reports TTP as the percentage of participants who were event free (that is, they had not had disease progression) at the specified time frames. Independent Review Committee assessment for this outcome measure was not planned after the primary analysis.

    95% CIs for event-free rates were estimated using the method by Kalbfleisch and Prentice (1980) with log-log transformation.


  9. Time to Overall Response as Assessed by the Independent Review Committee (Data Cut-off Date 14 July 2019) [ Time Frame: From randomization until the data cut-off date of 14 July 2019; the maximum time to response was 14 months ]
    Time to overall response was defined as the time from randomization to the earliest date a response of partial response (PR) or better as per IMWG-URC is first achieved and subsequently confirmed for participants with a best response of PR or better.

  10. Percentage of Participants Who Achieved and Maintained a Minimal Residual Disease Negative Complete Response (MRD[-]CR) for 12 Months or More (Data Cut-off Date 14 July 2019) [ Time Frame: Month 8 to 25 months (maximum time as of data cut-off) ]

    A measure of the persistence of the CR (includes strict CR) per International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) and MRD[-] status as assessed by next-generation sequencing (NGS) for 12 months or more after achieving MRD[-]CR status.

    95% confidence intervals (CIs) for proportions were estimated using the Clopper-Pearson method.


  11. Time to Complete Response (CR) as Assessed by the Independent Review Committee (Data Cut-off Date 14 July 2019) [ Time Frame: From randomization until the data cut-off date of 14 July 2019; the maximum time to CR was 16 months. ]
    Time to complete response was defined as the time from randomization to the earliest date a response of strict complete response (sCR) or complete response (CR) per IMWG-URC is first achieved and subsequently confirmed.

  12. Percentage of Participants Who Achieved Minimal Residual Disease Negative (MRD[-]) Status as Assessed by Next Generation Sequencing at 12 Months [ Time Frame: 12 Months (8- to 13-month window) ]

    MRD[-] at 12-month was defined as achievement of MRD[-] status as assessed by next-generation sequencing (NGS) at the 12 months landmark (from 8 months to 13 months window).

    95% confidence intervals (CIs) for proportions were estimated using the Clopper-Pearson method.


  13. Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores For Baseline Up to the First Follow-Up Visit After the Last Dose (Data Cut-off Date 14 July 2019) [ Time Frame: Baseline (Day 1 pre-dose) up to Week 102 (maximum treatment by cut-off) ]

    Health-related quality of life was assessed with the use of the European Organization for Research and Treatment of Cancer Quality of Life Core Module (QLQ-C30) questionnaire, a validated instrument in multiple myeloma patients. Scores range from 0 to 100, with higher scores indicating better health related quality of life.

    QLQ-C30 questionnaire was administered prior to dosing every 28 ± 7 days starting from cycle 1 day 1 through first follow-up visit (30 days [+3] after last dose of all study drugs). (data cut-off date 14 July 2019)




Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Criteria 1 Relapsed or progressive multiple myeloma after last treatment
  • Criteria 2 Males or females ≥ 18 years of age
  • Criteria 3 Measurable disease with at least 1 of the following assessed within 21 days prior to randomization:
  • IgG multiple myeloma: serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL,
  • IgA, IgD, IgE multiple myeloma: serum M-protein level ≥ 0.5 g/dL,
  • urine M-protein ≥ 200 mg/24 hours,
  • in subjects without measurable serum or urine M- protein, serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio
  • Criteria 4 Received at least 1 but not more than 3 prior lines of therapy for multiple myeloma (induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as 1 line of therapy
  • Criteria 5 Prior therapy with carfilzomib is allowed as long as the patient had at least a partial response (PR) to most recent therapy with carfilzomib, was not removed due to toxicity, did not relapse within 60 days from discontinuation of carfilzomib, and will have at least a 6-month carfilzomib treatment-free interval from last dose received until first study treatment. (Patients may receive maintenance therapy with drugs that are not proteasome inhibitors or CD38 antibodies during this 6-month carfilzomib treatment free interval)
  • Criteria 6 Prior therapy with anti-CD38 antibodies is allowed as long as the patient had at least a PR to most recent therapy with CD38 antibody, was not removed due to toxicity, did not relapse within 60 days from intensive treatment (at least every other week) of CD38 antibody therapy, and will have at least a 6 month CD38 antibody treatment-free interval from last dose received until first study treatment
  • Other inclusion criteria may apply

Exclusion Criteria:

  • Criteria 1 Waldenström macroglobulinemia
  • Criteria 2 Multiple myeloma of IgM subtype
  • Criteria 3 POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  • Criteria 4 Plasma cell leukemia (> 2.0 * 10^9/L circulating plasma cells by standard differential)
  • Criteria 5 Myelodysplastic syndrome
  • Criteria 6 Known moderate or severe persistent asthma within the past 2 years
  • Criteria 7 Known chronic obstructive pulmonary disease (COPD) with a FEV1 < 50% of predicted normal
  • Criteria 8 Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, clinically significant electrocardiogram (ECG) abnormalities, screening ECG with corrected QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction within 4 months prior to randomization
  • Other exclusion criteria may apply

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): NCT03158688


Locations
Show Show 115 study locations
Sponsors and Collaborators
Amgen
Investigators
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Study Director: MD Amgen
  Study Documents (Full-Text)

Documents provided by Amgen:
Study Protocol  [PDF] May 17, 2019
Statistical Analysis Plan  [PDF] July 15, 2019

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT03158688    
Other Study ID Numbers: 20160275
2016-003554-33 ( EudraCT Number )
First Posted: May 18, 2017    Key Record Dates
Results First Posted: September 11, 2020
Last Update Posted: September 11, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
URL: https://www.amgen.com/datasharing

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Amgen:
Carfilzomib
Dexamethasone
Daratumumab
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
Dexamethasone
Daratumumab
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents