Carfilzomib Thalidomide and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

NCT03140943 | Unknown Phase 2

• 1 other identifier: AMN002
• Study Type: interventional
• Target: 100
• Locations: 4 countries
• Sites: 4

Brief Summary

All patients with multiple myeloma (MM) are destined to relapse even with the best available approved agents. Median OS from diagnosis in the current era is reported at 5.4 years. Given that myeloma remains an incurable disease, future improved OS is therefore reliant on the expansion of salvage options for patients with RRMM. Carfilzomib (formerly PR-171) is a tetrapeptide epoxyketone-based irreversible inhibitor of the 20S proteasome. This second-generation proteasome inhibitor (PI) is structurally and mechanistically different to the dipeptide boronic acid PI, bortezomib. Compared to bortezomib, carfilzomib showed less off-target activity that may account for the reduced myelosuppression and reduced neuropathy that is observed compared to bortezomib. As monotherapy, carfilzomib has demonstrated robust and durable activity in heavily pre-treated patients with RRMM in phase I and II trials The idea of combining a PI and an immunomodulatory drug (IMiD) such as thalidomide or lenalidomide is attractive in MM due to the efficacy previously demonstrated with combination bortezomib, thalidomide and dexamethasone. Such efficacy obviates the need for chemotherapy that is known to induce genetic instability and in turn gives rise to secondary cancers. In combination with lenalidomide (25mg), Niesvizky and colleagues have demonstrated a maximum planned dose (MPD) of carfilzomib as 20/27 mg/m2 with promising safety and efficacy. Combination carfilzomib and thalidomide, as opposed to lenalidomide, is practically a more affordable regimen that will be more applicable to the Asia-Pacific region.

Conditions

Relapsed and/or Refractory Multiple Myeloma

Keywords

carfilzomib

Outcome Measures

Primary Outcomes (1)

• Progression free survival (PFS)

  To assess the progression free survival (PFS) in patients with RRMM who have had 1 to 3 prior lines of therapies, treated with combination carfilzomib, thalidomide and dexamethasone (CaTD)

  5 years or until disease progression

Secondary Outcomes (6)

• Overall survival (OS)

  5 years

• Overall Rate of Response (ORR)

  anytime from commencement of treatment to the end of study baseline until disease progression, unmanageable adverse event or death, whichever occurs first, approximately up to 3 years

• Duration of response (DOR)

  5 years

• Time to progression (TTP)

  5 years

• Number of Participants affected by Adverse Events

  Baseline up to 4 Weeks after the last dose of study drug administration

Study Arms (1)

Carfilzomib, Thalidomide and Dexamethasone

EXPERIMENTAL

Drug: Carfilzomib, Thalidomide and Dexamethasone

Interventions

Carfilzomib, Thalidomide and Dexamethasone DRUG

Carfilzomib will be given on days 1,2,8,9,15,16 in a 4-week (28 day) cycle during induction cycles 1-12, followed by days 1,2,15,16 in a 4-week cycle during maintenance cycles 13-18 (section 4.0) Dexamethasone, 40mg po will be given on days 1,8,15, 22 in a 4-week cycle during induction cycles 1-12, followed by days 1,15, in a 4-week cycle during maintenance cycles 13-18. Thalidomide, 100mg po will be given daily during induction cycles 1-12 only.

Carfilzomib, Thalidomide and Dexamethasone

Eligibility Criteria

• Age: 21 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female patients, ≥18 years of age
• Relapsed and/or refractory multiple myeloma at study entry.
• Patients must have evaluable multiple myeloma with at least one of the following (assessed within 21 days prior to registration):
• Serum M-protein ≥ 5 g/L, or
• Urine M-protein ≥ 200 mg/24 hour, or In patients without detectable serum or urine M-protein, serum free light chain (SFLC) \> 100 mg/L (involved light chain) and an abnormal serum k/l ratio or For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 7500 mg/L (7.5 g/L).
• Received one, but no more than three prior treatment regimens or lines of therapy for multiple myeloma. (Induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as one line of therapy).
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.
• Adequate hepatic function within 28 days prior to registration with bilirubin \< 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 times the ULN.
• LVEF ≥ 40%.
• Absolute neutrophil count (ANC) ≥ 1000/mm3 (or 1000 cells/L) within 21 days prior to registration. Screening ANC should be independent of growth factor support for ≥ 1 week.
• Platelet count ≥ 50,000 cells/mm3 (≥ 30,000 cells/mm3 if myeloma involvement in the bone marrow is \> 50%) within 21 days prior to registration. Patients should not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count.
• Calculated or measured creatinine clearance (CrCl) of ≥ 15 mL/min within 21 days prior to registration. Calculation should be based on the Cockcroft and Gault formula (Appendix 3)
• Written informed consent in accordance with federal, local, and institutional guidelines.
• Female patients of child-bearing potential (FCBP) must have negative serum pregnancy test within 21 days prior to registration and agree to use an effective method of contraception during and for 3 months following last dose of drug.
• Male patients must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a FCBP.

You may not qualify if:

• Chemotherapy with approved or investigational anticancer therapeutics within 21 days prior to registration, with the exception of dexamethasone up to 160mg or equivalent every 4 weeks.
• Previous treatment with carfilzomib.
• Focal radiation therapy within 7 days prior to registration. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to registration (i.e., prior radiation must have been to less than 30% of the bone marrow).
• 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 four months prior to registration.
• Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to registration.
• Known HIV seropositive and/or untreated hepatitis B (patients with hepatitis B surface antigen \[HBsAg\] and core antibody \[HBcAb\] are eligible if receiving adequate antiviral therapy directed at hepatitis B).
• Patients with known cirrhosis.
• Active malignancy, that is expected to require treatment with chemotherapy within one year, or results in a life expectancy less than one year.
• Female patients who are pregnant or lactating.
• Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
• Patients with hypersensitivity to carfilzomib, velcade, boron, or mannitol.
• Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to registration.
• Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to registration.
• Any other clinically significant medical disease or psychiatric condition that, in the Investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent.

Sponsors & Collaborators

• National University Hospital, Singapore: lead
• The Australasian Leukaemia & Lymphoma Group (ALLG): collaborator
• International Myeloma Foundation: collaborator
• Celgene: collaborator

Study Sites (4)

Queen Mary Hospital

Hong Kong, Hong Kong

NOT YET RECRUITING

National University Hospital

Singapore, Singapore

RECRUITING

Unknown Facility

South Korea, South Korea

NOT YET RECRUITING

National Taiwan University

Taipei, Taiwan

NOT YET RECRUITING

Related Publications (1)

• Ninkovic S, Harrison SJ, Lee JJ, Murphy N, Lee JH, Estell J, Chen VM, Horvath N, Kim K, Eek R, Augustson B, Bang SM, Huang SY, Rajagopal R, Szabo F, Engeler D, Butcher BE, Mollee P, Durie B, Chng WJ, Quach H. Carfilzomib, thalidomide, and dexamethasone are safe and effective in relapsed and/or refractory multiple myeloma: final report of the single-arm, multicenter, phase II ALLG MM018/AMN002 study. Haematologica. 2024 Jul 1;109(7):2229-2238. doi: 10.3324/haematol.2023.284238.

  PMID: 38235519 DERIVED

MeSH Terms

Interventions

carfilzomib; Thalidomide; Dexamethasone

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

• Wee Joo Chng

  National University Hospital, Singapore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Wee Joo Chng

CONTACT

6779 5555; mdccwj@nus.edu.sg

Adeline Lin

CONTACT

adeline_hf_lin@nuhs.edu.sg

Study Design

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

Model Details: All patients will continue treatment for 18 cycles (12 induction cycles, 6 maintenance cycles) unless development of adverse events that require early cessation of treatment. Patients will be followed up for progression and survival until 1 year following the completion of the last patient's final cycle of induction therapy.

Study Record Dates

• First Submitted: April 13, 2017
• First Posted: May 4, 2017
• Study Start: September 13, 2017
• Primary Completion: June 1, 2019
• Study Completion: June 1, 2022
• Last Updated: November 6, 2017

Record last verified: 2017-02

Locations

HK (1); KR (1); SG (1); TW (1)