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Waldenstrom Macroglobulinemia

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Ibrutinib

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

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

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

Carfilzomib + Ibrutinib

Ibrutinib:

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

Jana Berthold

Richard Greil, MD

Philipp Staber, MD

Christian Scholz, MD

Ralf Ulrich Trappe, MD

Ralf Georg Meyer, MD

Gabriele Prange-Krex, MD

Volkmar Böhme, MD

Michael Gärtner, MD

Ursula Vehling-Kaiser, MD

Alexander Hoellein, MD

Matthias Zingerle, MD

Holgar Hebart, MD

Stefan Mahlmann, MD

Tobias Gaska, MD

Sebastian Böttcher, MD

Rolf Mahlberg, MD

Christian Buske, MD

Björn Schöttker, MD

Meletios A. Dimopoulos, MD

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.

In Waldenström macroglobulinemia (WM) conventional chemotherapy induces only low Complete Remission (CR) rates and responses of short duration compared to other indolent lymphomas. Thus, innovative approaches are needed which combine excellent activity and tolerability in patients with WM, who are mostly of advanced age. Today, chemotherapy in combination with the anti-CD20 antibody Rituximab is still the backbone of treatment in patients with WM and is recommended as first line in national and international treatment guidelines.With the approval of Ibrutinib by the EMA 2015 for patients with relapsed WM or for patients not eligible for chemotherapy with treatment naïve WM treatment landscape has changed in this lymphoma subtype and there is an urgent need to evaluate to which extent chemotherapy-free approaches add clinical benefit to the patient. Based on its high activity in WM and its low toxicity, Ibrutinib was approved for the treatment of WM by the EMA. However, also Ibrutinib fails to induce CRs and the VGPR (Very Good Partial Response) rate is 16% in relapsed patients. In addition, activity of Ibrutinib depends on the genotype with inferior response rates in MYD88mut/CXCR4mut patients and in patients with unmutated MYD88 and CXCR4 compared to MYD88mut/CXCR4WT patients (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.

The study is an international, phase II, multicenter, open label and randomized trial comparing Carfilzomib in combination with Ibrutinib (treatment Arm A) versus Ibrutinib (treatment arm B) in male or female patients aged ≥ 18 years of de novo and relapsed/refractory WM in need of treatment.

The phase II study will consist of an open labeled, stratified 1:1 randomization between Arm A and Arm B. Stratification factors are MYD88 and CXCR4 status (positive vs. negative) and number of prior lines (0 vs. ≥ 1 treatment lines). A stratified central block randomization will be used.

The primary objective of the trial is to test the efficacy and toxicity of Carfilzomib and Ibrutinib in patients with treatment naïve or relapsed WM.

The aim of this study is to investigate the rate of CR or VGPR 12 months after the start of treatment using the response criteria updated at the Sixth IWWM (CR/VGPR).

99 patients at approximately 25 investigator sites will be recruited. Patients will be followed up after end of treatment. Patients will receive Ibrutinib in both treatment arms until progression, non-tolerated toxicity or until the study duration has reached its maximum of 7 years after the first patient was included into the trial. Follow-up (5 years or until disease progression for patients who discontinue treatment due to toxicity) or survival follow-up (for patients with progression disease) will be performed until the study duration has reached its maximum of 7 years after the first patient was included into the trial.

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

Efficacy and Safety of Carfilzomib in Combination With Ibrutinib vs Ibrutinib Alone in Waldenström's Macroglobulinemia (CZAR-1)

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).

The response rates (CR, VGPR, PR, MR) and overall response rate (CR, VGPR, PR, MR) are evaluated 12 and 24 months after the start of treatment.

Best response (at least achieving a MR) is determined in the time interval from the start of induction therapy to end of follow-up.

Time to best response is defined as the time from the start of induction to best response the patient achieves (CR, VGPR, PR, MR).

Time to first response is defined as the time from the start of induction to first response (MR, PR, VGPR or CR).

TTF is defined as the time of start of induction treatment to discontinuation of therapy for any reason including death from any cause, progression, toxicity or add-on of new anti-cancer therapy. Patients alive without progression and relapse will be censored at the latest tumor assessment date.

Remission duration will be calculated in patients with response (CR, VGPR, PR, MR) from the date of response to the date of progression, relapse or death from any cause. Patients alive without progression and relapse will be censored at the latest tumor assessment date.

PFS will be calculated from the date of start of treatment to the following events: the date of progression (as defined in Appendix A) and the date of death if it occurred earlier. Patients alive without progression and relapse will be censored at the latest tumor assessment date.

Cause specific survival is defined as the period from the start of induction treatment to death from lymphoma or lymphoma related cause; death unrelated to WM is considered as a competing event.

Overall survival is defined as the period from the start of induction treatment to death from any cause. Patients who have not died until the time of the analysis will be censored at their last contact date.

Number of adverse events and comparison of adverse event rate in both treatment arms.

Changes in quality of life will be assessed by the FACT-Lym questionnaire and compared in both treatment arms.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Efficacy and Safety of Carfilzomib in Combination With Ibrutinib vs Ibrutinib in Waldenström's Macroglobulinemia	NCT04263480	Waldenstrom Mac...	Carfilzomib + I... Ibrutinib	18 Years -	University of Ulm
Efficacy and Safety of Carfilzomib in Combination With Ibrutinib vs Ibrutinib in Waldenström's Macroglobulinemia	NCT04263480	Waldenstrom Mac...	Carfilzomib + I... Ibrutinib	18 Years -	University of Ulm

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