Clinical Trials /

Study of Daratumumab Combined With Carfilzomib, Lenalidomide and Dexamethasone for Newly Diagnosed Multiple Myeloma

NCT04113018

Description:

This study is being done because, despite major advances in therapy, MM is still considered an incurable disease. The purpose of this study is to determine the efficacy (how well it works) of the study treatment that combines the following drugs: daratumumab, carfilzomib, lenalidomide, dexamethasone in subjects who have a recent diagnosis of multiple myeloma (MM). Normal plasma (blood) cells are found in the bone marrow and are an important part of the immune system. MM is a cancer formed by malignant (cancerous) plasma cells. Daratumumab, one of the study drugs, is a man-made protein that works with your immune system by attaching itself to the cancerous cells. Once daratumumab attaches itself to these cells, it gets your body's immune system to attack and destroy the MM cells. Daratumumab has shown to be effective in subjects with MM when combined with medicines like bortezomib, or lenalidomide + dexamethasone.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Daratumumab Combined With Carfilzomib, Lenalidomide and Dexamethasone for Newly Diagnosed Multiple Myeloma
  • Official Title: LCI-HEM-MYE-KRdD-001: Phase II Study of Daratumumab Combined With Carfilzomib, Lenalidomide and Dexamethasone in Newly Diagnosed Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: LCI-HEM-MYE-KRDD-001
  • SECONDARY ID: 00037709
  • NCT ID: NCT04113018

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
Carfilzomib, lenalidomide, dexamethasone (KRd) + Daratumumab1

Purpose

This study is being done because, despite major advances in therapy, MM is still considered an incurable disease. The purpose of this study is to determine the efficacy (how well it works) of the study treatment that combines the following drugs: daratumumab, carfilzomib, lenalidomide, dexamethasone in subjects who have a recent diagnosis of multiple myeloma (MM). Normal plasma (blood) cells are found in the bone marrow and are an important part of the immune system. MM is a cancer formed by malignant (cancerous) plasma cells. Daratumumab, one of the study drugs, is a man-made protein that works with your immune system by attaching itself to the cancerous cells. Once daratumumab attaches itself to these cells, it gets your body's immune system to attack and destroy the MM cells. Daratumumab has shown to be effective in subjects with MM when combined with medicines like bortezomib, or lenalidomide + dexamethasone.

Detailed Description

      This single arm, two-stage, open-label Phase II study is designed with the primary objective
      of evaluating the efficacy of induction therapy comprised of 8 cycles of carfilzomib,
      lenalidomide, dexamethasone and daratumumab (KRd+daratumumab) in terms of complete response
      or better (CR) in subjects with NDMM, and comparing to relevant historical controls. Post
      induction, all subjects will undergo disease evaluation, including assessment of minimal
      residual disease (MRD). Post-induction disease evaluation will be followed by an MRD-based
      treatment algorithm. This trial will allow us to gather preliminary data on use of MRD status
      to direct post-induction therapy.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalInduction: Carfilzomib, lenalidomide, dexamethasone (KRd) + Daratumumab
  • Carfilzomib, lenalidomide, dexamethasone (KRd) + Daratumumab

Eligibility Criteria

        Inclusion Criteria:

        Subject must meet all of the following applicable inclusion criteria to participate in this
        study:

          1. Written informed consent and HIPAA authorization for release of personal health
             information signed by the subject or his/her legally authorized representative. NOTE:
             HIPAA authorization may be included in the informed consent or obtained separately.

          2. Age ≥ 18 years at the time of consent.

          3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 (see Appendix A,
             Section 18.1) within 28 days prior to day 1 of treatment.

          4. Confirmation of newly diagnosed multiple myeloma (NDMM) as per the IMWG 2014 criteria
             (see Appendix D, Section 18.4). Newly diagnosed MM patients who may have deferred
             transplant are also allowed.

          5. Measurable disease present at baseline assessments. Baseline disease assessments are
             defined as disease assessments collected within 28 days of initiation of the first
             pre-study induction cycle (subjects who received prior therapy) or within 28 days
             prior to day 1 of study treatment (subjects with no prior therapy). Measurable disease
             is defined as:

               1. Serum M-protein ≥ 1 g/dL (> 0.5 g/dL for IgA or IgM) OR

               2. Urine M-protein ≥ 200 mg/24 h OR

               3. Involved free light chain (FLC) level ≥ 10 mg/dL provided serum FLC ratio is
                  abnormal

          6. No more than one prior cycle of systemic therapy (completed within 6 weeks of consent)
             for MM (to accommodate subjects who needed emergent therapy at diagnosis); any prior
             radiotherapy must be completed at least 14 days prior to day 1 of treatment. Subject
             must have recovered from treatment-induced toxicities to ≤ grade 1 or baseline.
             Subject who received prior therapy must have had either PET/CT and/or Whole Body
             (WB)-MRI prior to initiation of therapy.

          7. Demonstrate adequate organ function within 1 week of day 1 of treatment as defined in
             the table below:

             Hematological:

               -  White Blood Cell (WBC) : ≥ 2,000/mm3

               -  Absolute Neutrophil Count (ANC) : ≥ 1,000/mm3 without growth factors within 1
                  week of day 1 of treatment

               -  Hemoglobin (Hgb) : ≥ 8 g/dL

               -  Platelet count : ≥ 70,000/mm3 if bone marrow plasmacytosis of <50%; otherwise ≥
                  50,000/mm3

             Renal:

             Serum creatinine OR Creatinine clearance : ≤ 1.5 × upper limit of normal (ULN) OR

             ≥ 30 mL/min as measured by a 24-hour urine collection or estimated by the Cockcroft -
             Gault formula ( See formula in Appendix B, Section 18.2 )

             Hepatic:

               -  Bilirubin : ≤ 2 × ULN; < 3.0 for subjects with Gilbert's Syndrome

               -  Aspartate aminotransferase (AST) : ≤ 2.5× ULN

               -  Alanine aminotransferase (ALT) : ≤ 2.5 × ULN

          8. Adequate cardiac function as defined by ≥ 45% Left Ventricular Ejection Fraction
             (LVEF) by ECHO or MUGA within 28 days prior to day 1 of treatment.

          9. Females of childbearing potential (FCBP) must have a negative serum pregnancy test
             (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to day
             1 of treatment, and be willing to undergo serial serum or urine pregnancy testing.
             NOTE: Females are considered of child bearing potential unless they are surgically
             sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral
             oophorectomy) or are postmenopausal (at least 12 consecutive months with no menses
             without an alternative medical cause).

         10. FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a
             failure rate of <1% per year when used consistently and correctly) plus a second
             contraceptive method (considered acceptable [failure rate of >1% per year] or highly
             effective) from the time of informed consent until 3 months after the last protocol
             prescribed therapy (which also includes FCBP on carfilzomib) has been discontinued.
             NOTE: estrogens may further increase the risk of thrombosis (beyond that associated
             with lenalidomide) and their use should be based on a benefit-risk decision. For the
             highly effective contraceptive method, a method with low user dependency is preferable
             but not required (see tables, adapted from:
             http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2
             014_09_HMA_CTFG_Contraception.pdf)

             Highly Effective Birth Control Methods:

               -  combined (estrogen and progestogen containing) hormonal contraception associated
                  with inhibition of ovulation

                    -  oral

                    -  intravaginal

                    -  transdermal

               -  progestogen-only hormonal contraception associated with inhibition of ovulation

                    -  oral

                    -  injectable

                    -  implantable (Contraception method considered to have low user dependency)

               -  intrauterine devide (IUD) (Contraception method considered to have low user
                  dependency)

               -  intrauterine hormone-releasing system (IUS) (Contraception method considered to
                  have low user dependency)

               -  vasectomised partner (Contraception method considered to have low user
                  dependency) Vasectomised partner is a highly effective birth control method
                  provided that partner is the sole sexual partner of the FCBP trial participant

               -  sexual abstinence (Sexual abstinence is considered a highly effective method only
                  if defined as refraining from heterosexual intercourse during the entire period
                  of risk associated with the study treatments)

             Acceptable Birth Control Methods:

               -  Progestogen-only oral hormonal contraception, where inhibition of ovulation is
                  not the primary mode of action

               -  Male or female condom with or without spermicide (A combination of male condom
                  with either cap, diaphragm or sponge with spermicide (double barrier methods) are
                  also considered acceptable, but not highly effective, birth control methods.

         11. Male subjects (even those who have had a vasectomy) who are sexually active with a
             FCBP must be willing to use latex or synthetic condoms from initiation of study
             treatment until 3 months after the last protocol prescribed therapy has been
             discontinued. They must also refrain from donating sperm for at least 90 days after
             the last dose of carfilzomib. The FCBP partner should also consider contraception
             recommendations (see inclusion #10).

         12. As determined by the enrolling physician, ability of the subject to understand and
             comply with study procedures for the entire length of the study.

        Exclusion Criteria:

        Subjects meeting any of the criteria below may not participate in the study:

          1. Any infection requiring systemic therapy (i.e. involving IV antibiotics) (NOTE: at
             discretion of investigator, subjects with uncomplicated urinary tract infections may
             be eligible).

          2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
             mother is being treated on study, and any female subject must agree not to donate eggs
             during the study and for 3 months after the last protocol prescribed therapy has been
             discontinued).

          3. Has a known additional malignancy that is active and/or progressive requiring
             treatment; exceptions include basal cell or squamous cell skin cancer, in situ
             cervical or bladder cancer, carcinoma of the prostate with a current PSA value of <0.5
             ng/mL or other cancer for which the subject has completed treatment, been disease-free
             for at least five years, and is considered by Sponsor-Investigator to be at <30% risk
             of relapse, or on hormonal therapy for a history of either prostate cancer or breast
             cancer, provided that there has been no evidence of disease progression during the
             previous three years.

          4. Non-secretory MM.

          5. Active involvement of the central nervous system by MM.

          6. Prior cardiovascular cerebrovascular accident with persistent neurological deficit.

          7. Has chronic obstructive pulmonary disease with a forced expiratory volume in 1 second
             (FEV1) < 50% of predicted normal. FEV1 is required for subjects suspected of having
             chronic obstructive pulmonary disease and are not eligible if FEV1 is < 50% of
             predicted normal.

          8. Has had moderate or severe persistent asthma within the past 2 years from enrollment
             and/or has currently uncontrolled asthma of any classification.

          9. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly,
             endocrinopathy, monoclonal protein, and skin changes).

         10. Had major surgery within 2 weeks prior to day 1 of treatment.

         11. Treatment with any investigational drug within 4 weeks prior to day 1 of treatment.

         12. Uncontrolled clinically significant illness including, but not limited to,
             uncontrolled hypertension (as per the most updated Joint National Committee for the
             Management of Hypertension definitions), symptomatic congestive heart failure (as per
             New York Heart Association [NYHA] class III or IV [see Appendix C, Section 18.3],
             uncontrolled angina pectoris, myocardial infarction within the past 6 months from
             consent, known or suspected amyloidosis, uncontrolled cardiac arrhythmia, psychiatric
             illness/social situations that would limit compliance with study requirements as
             determined by the investigator, or any other condition (including laboratory
             abnormalities) that would, in the opinion of the investigator, place the subject at
             unacceptable risk if he/she were to participate in the study.

         13. Known allergies, hypersensitivity or intolerance to monoclonal antibodies or human
             proteins, daratumumab or its excipients or known sensitivity to mammalian-derived
             products, carfilzomib or its excipients, lenalidomide or its excipients, or
             dexamethasone or its excipients.

         14. Is seropositive for hepatitis B (defined by a positive test for hepatitis B surface
             antigen [HBsAg]). Subjects with resolved infection (i.e. subjects who are HBsAg
             negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or
             antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time
             polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels.
             Subjects who are PCR positive will be excluded. Exception: subjects with serologic
             findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic
             marker) and a known history of prior HBV vaccination do not need to be tested for HBV
             DNA by PCR.

         15. Is seropositive for hepatitis C (except in the setting of a sustained virologic
             response [SVR], defined as aviremia at least 12 weeks after completion of antiviral
             therapy).

         16. Is known to be seropositive for human immunodeficiency virus.

         17. Transplant ineligible subjects > 70 years old only: Defined frail, per IMWG criteria
             of 'frailty' [32]. Frailty assessment does not need to be performed unless the subject
             is transplant ineligible and > 70 years old.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Response
Time Frame:From enrollment to best response; assessed for approximately 5 years
Safety Issue:
Description:(CR)- Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:From date of treatment start to date of progression or death; assessed for approximately 5 years
Safety Issue:
Description:PFS is defined as duration of time from enrollment to the study to time of progression or death.
Measure:Overall Survival (OS)
Time Frame:From date of enrollment to date of death; assessed for approximately 5 years
Safety Issue:
Description:OS is defined as the duration from enrollment to the study (treatment start date) to the date of death from any cause. Subjects who are alive or lost to follow-up at the time of the analysis will be censored at the last known date they were alive.
Measure:Time to Next Treatment (TTNT)
Time Frame:assessed for approximately 5 years
Safety Issue:
Description:Time to next treatment (TTNT) will be calculated from the time of treatment start until the start of the first subsequent anti-cancer therapy after all protocol directed therapy is completed. For surviving subjects who do not receive subsequent therapy, TTNT will be censored at the last contact date. For subjects who die before beginning subsequent anti-cancer therapy, TTNT will be censored at the date of death.
Measure:Duration of Response (DoR)
Time Frame:assessed for approximately 5 years
Safety Issue:
Description:Duration of response (DoR) will be calculated for each subject achieving a PR or better and will be calculated from the time of the first assessment that identified response until disease progression or death
Measure:Time to Disease Progression (TTP)
Time Frame:From date of start of treatment to date of disease progression; assessed for approximately 5 years
Safety Issue:
Description:Time to disease progression (TTP) will be calculated in the same fashion as described for PFS with the exception that for subjects who die for causes other than disease progression, TTP will be censored at the date of the other cause mortality.
Measure:Overall Response (OR)
Time Frame:From enrollment to best response while on treatment (subjects on induction treatment for approximately 32 weeks)
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Saad Z. Usmani, MD

Last Updated

December 17, 2019