Efficacy and Safety of Carfilzomib in Combination With Ibrutinib vs Ibrutinib in Waldenström's Macroglobulinemia

NCT04263480 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: CZAR-1
• Study Type: interventional
• Target: 99
• Locations: 3 countries
• Sites: 20

Brief Summary

In Waldenström macroglobulinemia (WM) chemotherapy induces only low CR/VGPR (Complete Remission/ Very Good Partial Response) rates and responses of short duration compared to other indolent lymphomas. Thus, innovative approaches are needed which combine excellent activity and tolerability in WM. Chemotherapy-free approaches are highly attractive for this patient group. Based on its high activity in WM and its low toxicity, Ibrutinib was approved for the treatment of WM by the European Medicines Agency (EMA). However, also Ibrutinib fails to induce CRs and the VGPR rate is 16% in relapsed patients. In addition, activity of Ibrutinib depends on the genotype: compared to MYD88mut/CXCR4WT patients Ibrutinib single agent therapy induces substantially lower response rates in patients with the MYD88mut/CXCR4mut or the MYD88WT/CXCR4WT genotype (major response (at least PR) in 91.7 % compared to 61.9 and 0 %, respectively). Phase II data have indicated that the proteasome inhibitor Carfilzomib is able to overcome the inferior prognosis of Ibrutinib in MYD88mut/CXCR4mut and MYD88WT/CXCR4WT patients, as response rates were high for all genotypes in a phase II study combining Carfilzomib with Rituximab and Dexamethasone. Based on this the investigators hypothesize that addition of Carfilzomib to Ibrutinib will increase the VGPR/CR rate compared to Ibrutinib alone in patients with WM, in particular in patients carrying the CXCR4 mutation. In addition, the investigators hypothesize, that the combination Carfilzomib and Ibrutinib will be also highly active in MYD88 wildtype patients and that this combination will be at least as efficient in treatment naïve patients as in relapsed/refractory patients.

Conditions

Waldenstrom Macroglobulinemia

Keywords

MYD88 mutation; CXCR4 mutation; Carfilzomib; Ibrutinib; Hematology; Oncology

Outcome Measures

Primary Outcomes (1)

• CR/VGPR

  Primary endpoint is the rate of CR or VGPR 12 months after the start of treatment using the response criteria updated at the Sixth IWWM (CR/VGPR).

  12 months

Secondary Outcomes (11)

• Response rate

  12/ 24 months

• Best response

  12 months

• Time to best response

  12 months

• Time to first response

  12 months

• Time to treatment failure (TTF)

  7 years

Study Arms (2)

Arm A: Carfilzomib + Ibrutinib

EXPERIMENTAL

Patients will be treated with Ibrutinib until evidence of progressive disease or no longer tolerated. Patients will receive in addition Carfilzomib for two years.

Drug: Carfilzomib + Ibrutinib

Arm B: Ibrutinib

ACTIVE COMPARATOR

Patients will be treated with Ibrutinib until evidence of progressive disease or no longer tolerated.

Drug: Ibrutinib

Interventions

Carfilzomib + Ibrutinib DRUG

Carfilzomib: Cycle 1, day 1: 20 mg/m² i.v. Cycle 1, day 8, day 15: 70 mg/m² i.v. Cycle 2 - 12, day 1, day 8, day 15: 70 mg/m² i.v. Cycle 13 - 24, day 1, day 15: 70 mg/m² i.v. Ibrutinib: 420 mg p.o daily until disease progression or non-tolerable toxicities

Arm A: Carfilzomib + Ibrutinib

Ibrutinib DRUG

Ibrutinib: 420 mg p.o daily until disease progression or non-tolerable toxicities

Arm B: Ibrutinib

Eligibility Criteria

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

You may qualify if:

• Proven clinicopathological diagnosis of WM as defined by consensus panel one of the Second International Workshop on WM. Histopathology has to occur before randomization within the last 4 months. In addition, pathological specimens have to be sent to the pathological reference center prior to randomization for the determination of the mutational status of MYD88 and CYCR4. Immunophenotyping will be performed in each center and saved locally. The positivity for CD20 can be assumed from any previous bone marrow immunohistochemistry or flow cytometry analysis performed up to 4 months prior to enrollment. Flow cytometry of bone marrow and blood cells will include at least one double staining and assess the disease specific expressions.
• De novo and relapsed/refractory WM independent of the genotype.
• Determination of mutational status of MYD88 and CXCR4.
• Patients must have at least one of the following criteria to initiate treatment as partly defined by "Consensus Panel Two" recommendations from the Second International Workshop on Waldenström Macroglobulinemia:
• Recurrent fever, night sweats, weight loss, fatigue (at least one of them).
• Hyperviscosity.
• Lympadenopathy which is either symptomatic or bulky (≥ 5 cm in maximum diameter).
• Symptomatic hepatomegaly and/or splenomegaly.
• Symptomatic organomegaly and/or organ or tissue infiltration.
• Peripheral neuropathy due to WM.
• Symptomatic cryoglobulinemia.
• Cold agglutinin anemia.
• IgM related immune hemolytic anemia and/or thrombocytopenia.
• Nephropathy related to WM.
• Amyloidosis related to WM.

You may not qualify if:

• The presence of any of the following will exclude a subject from enrolment:
• Previous treatments with following substances:
• Prior exposure to Ibrutinib or other BTK inhibitors.
• Prior exposure to Carfilzomib. Prior exposure to other proteasome inhibitors is allowed if the patients were not refractory, that is, had a remission (at least minor response) duration of ≥ 6 months. Prior plasmapheresis and short-term administration of corticosteroids ≤ 6 weeks administered at a dose equivalent to ≤ 20 mg/day of prednisone is also allowed.
• Serious medical or psychiatric illness (especially undergoing treatment) likely to interfere with participation in this clinical study.
• Active HIV, HBV or HCV infection.
• Central Nervous System involvement by lymphoma.
• History of a non-lymphoid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for ≥ 1 year prior to randomization, other Stage 1 or 2 cancer treated with a curative intent and currently in complete remission, for ≥ 3 years.
• Uncontrolled illness including, but not limited to:
• Uncontrolled diabetes mellitus (as indicated by metabolic derangements and / or severe diabetes mellitus related uncontrolled organ complications).
• Chronic symptomatic congestive heart failure (Class NYHA III or IV) or LVEF \< 40%.
• Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months prior to randomization.
• Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia.
• Known pericardial disease.
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.

Sponsors & Collaborators

• Christian Buske: lead
• Amgen: collaborator
• Janssen, LP: collaborator

Study Sites (20)

Uniklinikum Salzburg

Salzburg, 5020, Austria

Location

Medizinische Universität Wien

Vienna, 1090, Austria

Location

Vivantes Klinikum am Urban

Berlin, 10967, Germany

Location

Ev. Diakoniekrankenhaus

Bremen, 28239, Germany

Location

Kath. St.-Johannes-Gesellschaft Dortmund gGmbH

Dortmund, 44137, Germany

Location

Gemeinschaftspraxis Mohm / Prange-Krex

Dresden, 01307, Germany

Location

OncoResearch Lerchenfeld GmbH

Hamburg, 22081, Germany

Location

MediProject Onkologisches Ambulanzzentrum Hannover

Hanover, 30171, Germany

Location

Praxis für Hämatologie und Onkologie, onkologische Tagesklinik-VK&K Studien GbR

Landshut, 84036, Germany

Location

Praxis Dr. Vehling-Kaiser

Landshut, 84130, Germany

Location

Rotkreuzklinikum München

Munich, 80634, Germany

Location

Hämatologie/Onkologie München Pasing MVZ GmbH

Munich, 81241, Germany

Location

Kliniken Ostalb, Staufenklinikum Schw. Gmuend

Mutlangen, 72557, Germany

Location

Friedrich-Ebert-Krankenhaus

Neumünster, 24534, Germany

Location

Bruederkrankenhaus St. Josef

Paderborn, 33098, Germany

Location

Universitätsmedizin Rostock

Rostock, 18055, Germany

Location

Klinikum Mutterhaus Mitte Trier gGmbh Studienzentrum

Trier, 54290, Germany

Location

University Hospital Ulm

Ulm, 89081, Germany

Location

Hämatologisch-Onkologische Schwerpunktpraxis Drs. Schöttker & Pretscher

Würzburg, 97080, Germany

Location

Alexandra Hospital

Athens, 11528, Greece

Location

MeSH Terms

Conditions

Waldenstrom Macroglobulinemia; Neoplasms

Interventions

carfilzomib; ibrutinib

Condition Hierarchy (Ancestors)

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

Study Officials

• Christian Buske, MD

  University of Ulm

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr. med.

Study Record Dates

• First Submitted: February 7, 2020
• First Posted: February 10, 2020
• Study Start: August 18, 2021
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2028
• Last Updated: April 4, 2025

Record last verified: 2025-04

Locations

DE (17); AU (2); GR (1)