LCI-HEM-MYE-KRdD-001: Phase II Study of Daratumumab Combined With Carfilzomib, Lenalidomide and Dexamethasone in Newly Diagnosed Multiple Myeloma
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.
‣ Subject must meet all of the following applicable inclusion criteria to participate in this study:
• 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.
• Age ≥ 18 years at the time of consent.
• 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.
• 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.
• 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:
∙ Serum M-protein ≥ 1 g/dL (\> 0.5 g/dL for IgA or IgM) OR
‣ Urine M-protein ≥ 200 mg/24 h OR
‣ Involved free light chain (FLC) level ≥ 10 mg/dL provided serum FLC ratio is abnormal
• 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.
• 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 with Creatinine clearance : ≤ 1.5 × upper limit of normal (ULN) with creatinine clearance
• ≥ 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
• 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.
• 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).
⁃ 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.
⁃ 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 and at least 90 days from the last dose of daratumumab. The FCBP partner should also consider contraception recommendations (see inclusion #10).
⁃ As determined by the enrolling physician, ability of the subject to understand and comply with study procedures for the entire length of the study.