Carfilzomib in Combination With Daratumumab, Lenalidomide and Dexamethasone in Transplant-ineligible NDMM Patients

NCT04065789 | Completed Phase 2

• 2 other identifiers: 0101-17-TLVMOH_2018-01-18_001958
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 14

Brief Summary

Patients with newly diagnosed multiple myeloma (NDMM) who failed to achieve at least a minimal response (MR) after 2 cycles or a partial response (PR), after 4 cycles of a bortezomib-containing therapy, or progress on therapy during first 4 cycles (response defined by international Myeloma Working Group \[IMWG\] criteria), will be treated with a quadruple regimen comprised of: Daratumumab 16 mg/Kg weekly during cycles 1-2, q14 days during cycles 3-6, thereafter monthly (1st dose cycle 1 may be split over 2 days); Once-weekly intravenous (IV) administration of Carfilzomib on days 1, 8, 15, of cycle numbers 1-9 and Days 1 and 15 only of cycle numbers 10-18, at a dose of 20 mg/m2 on day 1 of cycle 1; at dose of 56 mg/m2 on all subsequent once weekly dosing days, alongside concomitant treatment with twice-weekly IV or oral dexamethasone 20mg administered on Days 1-2, 8-9, 15-16, and 22-23 of a 28-day cycle, for cycles 1-2 followed by weekly 20 mg dexamethasone on subsequent cycles; and oral Lenalidomide 25 mg, administered on days 1-21 of a 28-day cycle. On treatment days that require both Carfilzomib and Daratumumab infusions, Carfilzomib will be administrated prior to Daratumumab administration. All patients will undergo frailty assessment based on IMWG recommendations, and will be classified as fit, intermediate-fit and frail. Frail patients will receive Lenalidomide dose adjustment to 15 mg (throughout the study, from cycle 1 and on), and dexamethasone at 10 mg x 2/week cycles 1-2 followed by 10 mg/week for subsequent cycles. The quadruple regimen will be administered for 18 cycles, followed by long-term follow-up in which patients will receive standard of care treatment with Lenalidomide/dexamethasone (Rd) treatment, unless disease progression, the physician decides otherwise, the patient suffers from unacceptable toxicity, withdraws consent, or dies (whichever occurs first).

Conditions

Myeloma Multiple; Myeloma, Plasma-Cell; Myeloma-Multiple; Plasma Cell Myeloma

Keywords

multiple myeloma (MM); Myeloma; NDMM; RRMM

Outcome Measures

Primary Outcomes (1)

• Proportion of patients who experience any AE incidence, grade > 2 drug-elicited toxicities, peripheral neuropathy events (Grade 2 or higher).

  Determined by adverse events, vital signs and clinical laboratory parameters in relation to study intervention.

  from screening through month 20

Secondary Outcomes (10)

• PFS

  From treatment initiation to the earlier of disease progression or death due to any cause. Up to 2 years from last patient enrollment

• OS

  From treatment initiation to date of death (whatever the cause). Up to 2 years from last patient enrollment

• Overall response rate (ORR)

  From Screening and up to 2 years from last patient enrollment

• Duration of response (DOR)

  From initiation of treatment and up to 2 years from last patient enrollment

• Time to progression (TTP)

  From initiation of treatment and up to 2 years from last patient enrollment

Other Outcomes (1)

• exploratory genomic profiling

  From Screening and up to 2 years from last patient enrollment

Study Arms (1)

Carfilzomib,Daratumumab,revlimid and dexamethasone

EXPERIMENTAL

Carfilzomib, Daratumumab, Lenalidomide, Dexamethasone

Drug: Carfilzomib; Drug: Daratumumab; Drug: Lenalidomide; Drug: Dexamethasone

Interventions

Carfilzomib DRUG

Carfilzomib on Days 1, 8, 15, of cycle numbers 1-9 and Days 1 and 15 only of cycle numbers 10-18, at a dose of 20 mg/m2 on day 1 of cycle 1; at dose of 56 mg/m2 on all subsequent once weekly dosing days. The quadruple regimen treatment will be administered for 18 cycles.

Also known as: Kyprolis

Carfilzomib,Daratumumab,revlimid and dexamethasone

Daratumumab DRUG

Daratumumab : 16 mg/Kg weekly for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks thereafter. The quadruple regimen treatment will be administered for 18 cycles.

Also known as: Darzalex

Carfilzomib,Daratumumab,revlimid and dexamethasone

Lenalidomide DRUG

Lenalidomide (25 mg), administered on days 1-21 of 28-day cycle.In frail patients, Lenalidomide dose will be reduced according to 15 mg . The quadruple regimen treatment will be administered for 18 cycles.

Also known as: Revlimid

Carfilzomib,Daratumumab,revlimid and dexamethasone

Dexamethasone DRUG

Patients will be treated with IV or oral dexamethasone (20 mg for fit and INT-FIT, 10 mg for frail), administered on Days 1-2, 8-9, 15-16, and 22-23 of each 28-day cycle for cycles 1-2 followed by weekly 20 mg dexamethasone on subsequent cycles; In frail patients, dexamethasone will be reduced to 10 mg . The quadruple regimen treatment will be administered for 18 cycles.

Carfilzomib,Daratumumab,revlimid and dexamethasone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosed with multiple myeloma and started induction therapy within 6 months prior to study entry
• Received bortezomib-based induction therapy, with corticosteroids, with or without alkylators
• Determined by investigator to be transplant-ineligible
• Failed to achieve a minimal response (MR) after 2 cycles or a partial response (PR), after 4 cycles of a bortezomib-containing therapy, or progress on therapy during first 4 cycles (response defined by international Myeloma Working Group \[IMWG\] criteria)
• Measurable disease at time of enrolment including:
• Serum M-protein ≥ 0.5 g/dL, or
• Urine M-protein ≥ 200 mg/24 hour, or
• Serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa/lambda ratio, or
• In patients with immunoglobulin A (IgA) type MM, whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA), qIgA ≥ 750 mg/dL (0.75 g/dL)
• Male/female, ≥ 18 years of age
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2
• Adequate hepatic function within 28 days prior to treatment initiation, with bilirubin \< 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 times the ULN
• Left ventricular ejection fraction ≥ 40%
• Absolute neutrophil count (ANC) ≥ 1500/mm3 within 28 days prior to enrollment, and reconfirmed within 7 days prior to first dose. Screening ANC should be independent of growth factor support for ≥ 1 week.
• Hemoglobin ≥ 8.0 g/dL within 28 days prior to treatment initiation, and reconfirmed within 7 days prior to first dose. Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed, however most recent RBC transfusion may not have been done within 7 days of obtaining Screening hemoglobin.

You may not qualify if:

• Prior therapy with any immunomodulatory drug (IMiD) or with Carfilzomib
• Any unresolved Grade 2 or higher toxicity from bortezomib based induction treatment
• Multiple myeloma of immunoglobulin M (IgM) subtype
• POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome
• Plasma cell leukemia or circulating plasma cells ≥ 2 × 10e9/L
• Waldenström macroglobulinemia
• Patients with known amyloidosis
• Focal radiation therapy within 7 days prior to treatment initiation; radiation therapy to an extended field, involving a significant volume of bone marrow, within 21 days prior to enrollment (i.e., prior radiation must have been to less than 30% of the bone marrow)
• Major surgery (excluding kyphoplasty) within 28 days prior to treatment initiation
• Active congestive heart failure (New York Heart Association \[NYHA\] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention; myocardial infarction within 4 months prior to treatment initiation
• Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to treatment initiation
• Known human immunodeficiency virus (HIV) seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B surface antigen \[SAg\] and core antibody receiving and responding to antiviral therapy directed at hepatitis B; these patients are allowed).
• Patients with known cirrhosis
• Second malignancy within the past 3 years except:
• A. Adequately treated basal cell or squamous cell skin cancer B. Carcinoma in situ of the cervix C. Prostate cancer Gleason score ≤ 6 with stable prostate-specific antigen (PSA) over 12 months D. Breast carcinoma in situ with full surgical resection E. Treated medullary or papillary thyroid cancer

Sponsors & Collaborators

• Tel-Aviv Sourasky Medical Center: lead

Study Sites (14)

Haemek Medical Center

Afula, Israel

Location

Barzilai Medical Center

Ashkelon, Israel

Location

Soroka Medical Center

Beersheba, Israel

Location

Bnai-Zion Medical Center

Haifa, Israel

Location

Carmel Medical center

Haifa, Israel

Location

Rambam medical Center

Haifa, Israel

Location

Hadassah Ein-Karem Medical Center

Jerusalem, Israel

Location

Shaare Zedek medical Center

Jerusalem, Israel

Location

Meir Medical Center

Kfar Saba, Israel

Location

Rabin Medical Center

Petah Tikva, Israel

Location

Kaplan Medical center

Rehovot, Israel

Location

Ziv Medical Center

Safed, Israel

Location

Hematology Department Sourasky Medical Center

Tel Aviv, 6423906, Israel

Location

Assuta Medical Center

Tel Aviv, Israel

Location

Related Publications (1)

• Cohen YC, Zada M, Wang SY, Bornstein C, David E, Moshe A, Li B, Shlomi-Loubaton S, Gatt ME, Gur C, Lavi N, Ganzel C, Luttwak E, Chubar E, Rouvio O, Vaxman I, Pasvolsky O, Ballan M, Tadmor T, Nemets A, Jarchowcky-Dolberg O, Shvetz O, Laiba M, Shpilberg O, Dally N, Avivi I, Weiner A, Amit I. Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing. Nat Med. 2021 Mar;27(3):491-503. doi: 10.1038/s41591-021-01232-w. Epub 2021 Feb 22.

  PMID: 33619369 DERIVED

MeSH Terms

Conditions

Multiple Myeloma; Neoplasms, Plasma Cell

Interventions

carfilzomib; daratumumab; Lenalidomide; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Yael Cohen, MD

  Tel-Aviv Sourasky Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 31, 2019
• First Posted: August 22, 2019
• Study Start: May 2, 2018
• Primary Completion: August 27, 2021
• Study Completion: November 12, 2021
• Last Updated: January 27, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

IL (14)