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

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ClinicalTrials.gov Identifier: NCT04113018
Recruitment Status : Not yet recruiting
First Posted : October 2, 2019
Last Update Posted : November 20, 2019
Sponsor:
Collaborators:
Amgen
Celgene
Janssen, LP
Information provided by (Responsible Party):
Saad Z. Usmani, MD, Atrium Health

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Carfilzomib, lenalidomide, dexamethasone (KRd) + Daratumumab Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: LCI-HEM-MYE-KRdD-001: Phase II Study of Daratumumab Combined With Carfilzomib, Lenalidomide and Dexamethasone in Newly Diagnosed Multiple Myeloma
Estimated Study Start Date : November 2019
Estimated Primary Completion Date : October 2026
Estimated Study Completion Date : October 2026


Arm Intervention/treatment
Experimental: 1
Induction: Carfilzomib, lenalidomide, dexamethasone (KRd) + Daratumumab
Drug: Carfilzomib, lenalidomide, dexamethasone (KRd) + Daratumumab
Experimental




Primary Outcome Measures :
  1. Complete Response [ Time Frame: From enrollment to best response; assessed for approximately 5 years ]
    (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 :
  1. Progression Free Survival (PFS) [ Time Frame: From date of treatment start to date of progression or death; assessed for approximately 5 years ]
    PFS is defined as duration of time from enrollment to the study to time of progression or death.

  2. Overall Survival (OS) [ Time Frame: From date of enrollment to date of death; assessed for approximately 5 years ]
    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.

  3. Time to Next Treatment (TTNT) [ Time Frame: assessed for approximately 5 years ]
    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.

  4. Duration of Response (DoR) [ Time Frame: assessed for approximately 5 years ]
    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

  5. Time to Disease Progression (TTP) [ Time Frame: From date of start of treatment to date of disease progression; assessed for approximately 5 years ]
    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.

  6. Overall Response (OR) [ Time Frame: From enrollment to best response while on treatment (subjects on induction treatment for approximately 32 weeks) ]


Information from the National Library of Medicine

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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:

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/2014_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.

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): NCT04113018


Contacts
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Contact: Danielle Harris 980-442-2033 danielle.harris@atriumhealth.org

Locations
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United States, North Carolina
Levine Cancer Institute Not yet recruiting
Charlotte, North Carolina, United States, 28204
Sponsors and Collaborators
Saad Z. Usmani, MD
Amgen
Celgene
Janssen, LP
Investigators
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Principal Investigator: Saad Usmani, MD Atrium Health

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Responsible Party: Saad Z. Usmani, MD, Director, Clinical Research in Hematologic Malignancies; Division Chief, Plasma Cell Disorders, Atrium Health
ClinicalTrials.gov Identifier: NCT04113018     History of Changes
Other Study ID Numbers: LCI-HEM-MYE-KRDD-001
00037709 ( Other Identifier: Advarra IRB )
First Posted: October 2, 2019    Key Record Dates
Last Update Posted: November 20, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Multiple Myeloma
Daratumumab
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
Dexamethasone acetate
Lenalidomide
BB 1101
Antibodies, Monoclonal
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