Clinical Trials /

Efficacy of Carfilzomib in Combination With Ibrutinib in Waldenström's Macroglobulinemia

NCT04263480

Description:

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.

Related Conditions:
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Efficacy of Carfilzomib in Combination With Ibrutinib in Waldenström's Macroglobulinemia
  • Official Title: Efficacy of Carfilzomib in Combination With Ibrutinib in Waldenström's Macroglobulinemia (CZAR-1)

Clinical Trial IDs

  • ORG STUDY ID: CZAR-1
  • NCT ID: NCT04263480

Conditions

  • Waldenstrom Macroglobulinemia

Interventions

DrugSynonymsArms
Carfilzomib + IbrutinibArm A: Carfilzomib + Ibrutinib
IbrutinibArm B: Ibrutinib

Purpose

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.

Detailed Description

      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 III, 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 III 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).

      184 patients at approximately 60 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 10 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 10 years after the first patient was included into the trial.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: Carfilzomib + IbrutinibExperimentalPatients will be treated with Ibrutinib until evidence of progressive disease or no longer tolerated. Patients will receive in addition Carfilzomib for two years.
  • Carfilzomib + Ibrutinib
Arm B: IbrutinibActive ComparatorPatients will be treated with Ibrutinib until evidence of progressive disease or no longer tolerated.
  • Ibrutinib

Eligibility Criteria

        Inclusion Criteria:

        Each patient must meet all of the following inclusion criteria to be enrolled in this
        study:

          -  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
             national 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 expression of the following antigens: surface
             immunoglobulin, CD19, CD20, CD5, CD10, CD38 and CD23. Patients are eligible if tumor
             cells express the following antigens: CD19, CD20, CD38 and if they are negative for
             CD5, CD10 and CD23 expression. Patients with tumor cells positive for CD5 and/or CD23
             and morphologically similar to WM cells may be included after ruling out other
             low-grade B-cell malignancies.

          -  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.

               -  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.

               -  Hemoglobin ≤ 10 g/dL (patients should not have received red blood cells
                  transfusions for at least 7 days prior to obtaining the screening haemoglobin).

               -  Platelet count < 100 x 109/L (caused by BM infiltration of the lymphoma).

               -  Serum monoclonal protein > 5 g/dL, even with no overt clinical symptoms.

               -  IgM serum concentration ≥ 5g/dl.

               -  and other WM associated relevant symptoms.

          -  World Health Organization (WHO)/ECOG performance status 0 to 2.

          -  Left ventricular ejection fraction ≥ 40% as assessed by transthoracic echocardiogram
             (TTE).

          -  Other criteria

               -  Age ≥ than 18 years (male and female).

               -  Life expectancy > 3 months.

               -  Baseline platelet count ≥ 50 x 109/L, absolute neutrophil count ≥ 0.75 x 109/L.
                  (if not due to BM infiltration by the lymphoma).

               -  Meet the following pre-treatment laboratory criteria at the Screening visit
                  conducted within 30 days prior to randomization:

          -  ASAT (SGPOT): < 3.0 times the ULN.

          -  ALAT (SGPT): < 3.0 times the ULN.

          -  Total Bilirubin: < 1.5 times the ULN, unless clearly related to the disease (except if
             due to Gilbert's syndrome).

          -  Serum creatinine: ≤ 2 mg/dl.

          -  Women of childbearing potential (WOCBP) must agree to use a highly effective method of
             birth control for the duration of the therapy up to 6 months after end of therapy. A
             highly effective method of birth control is defined as those which result in a low
             failure rate (i.e. less than 1% per year) when used consistently and correctly such as
             combined (estrogen and progestogen containing) hormonal contraception associated with
             inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal
             contraception associated with inhibition of ovulation (oral, injectable or
             implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS),
             bilateral tubal occlusion, vasectomized partner or sexual abstinence. A postmenopausal
             state is defined as no menses for 12 months without an alternative medical cause.
             Contraception and pregnancy testing are required according the CTFG recommendations.

          -  Men must agree not to father a child for the duration of therapy and 6 months after
             (use of a condom) and must agree to advice a female partner to use a highly effective
             method of birth control. Males must refrain from sperm donation for at least 6 months
             after the last dose of treatment.

          -  Voluntary written informed consent in the native language of the patient before
             performance of any study-related procedure not part of normal medical care, with the
             understanding that consent may be withdrawn by the subject at any time without
             prejudice to future medical care.

        Exclusion Criteria:

        The presence of any of the following will exclude a subject from enrolment:

          -  Previous treatments with following substances are not allowed including into the
             trial:

               -  Prior exposure to Ibrutinib or BTK inhibitors

               -  Prior exposure to Carfilzomib. Prior exposure to other proteasome inhibitors are
                  allowed if the patients were not refractory, that is had a remission duration of
                  ≥ 6 months. Prior Plasmapheresis and short-term administration of corticosteroids
                  ≤ 6 weeks administered at a dose equivalent to ≤ 20 mg/day prednisone is also
                  allowed.

          -  Serious medical or psychiatric illness (especially undergoing treatment) likely to
             interfere with participation in this clinical study.

          -  Uncontrolled bacterial, viral or fungal infection.

          -  Active HIV, HBV or HCV infection.

          -  Known interstitial lung disease.

          -  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 study enrolment visit,
             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).

               -  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.

          -  Primary amyloidosis.

          -  Recent major surgery within 30 days prior to randomization.

          -  Chemotherapy with approved or investigational anticancer therapeutic within 21 days
             prior to randomization.

          -  Focal radiation therapy within 7 days prior to randomization. Radiation therapy to an
             extended field involving a significant volume of bone marrow within 21 days prior to
             randomization (i.e. prior radiation must have been to less than 30% of the bone
             marrow).

          -  Contraindication to any of the required concomitant drugs or supportive treatments,
             including hypersensitivity to antiviral drugs.

          -  Infiltrative pulmonary disease, known pulmonary hypertension.

          -  Active infection within 14 days prior to randomization requiring systemic antibiotics,
             antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents.
             Such infection must be fully resolved prior to initiating study treatment.

          -  Pleural effusions requiring thoracentesis within 14 days prior to randomization.

          -  Ascites requiring paracentesis within 14 days prior to randomization.

          -  Uncontrolled hypertension, defined as an average systolic blood pressure > 159 mmHg or
             diastolic > 99 mmHg despite optimal treatment (measured following European Society of
             Hypertension/European Society of Cardiology [ESH/ESC] 2013 guidelines.

          -  History of stroke or intracranial hemorrhage within 6 months prior to randomization

          -  Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in
             1 second (FEV1) < 50% of predicted normal.

          -  Known severe persistent asthma within the past 2 years (see also
             https://www.nhlbi.nih.gov/files/docs/guidelines/asthsumm.pdf), or currently has
             uncontrolled asthma of any classification or at time of screening has an FEV1 of < 50%
             of predicted normal.

          -  Known cirrhosis.

          -  Autologous stem cell transplant less than 90 days prior to randomization.

          -  Allogeneic stem cell transplant less than 100 days prior to randomization.

          -  Vaccination with live attenuated vaccines within 30 days prior to randomization.

          -  History or evidence of any other clinically significant disorder, condition or disease
             (with the exception of those outlined above) that, in the opinion of the investigator
             or sponsor, if consulted, would pose a risk to subject safely or interfere with the
             study evaluation, procedures or completion.

          -  Women who are pregnant as well as women who are breast-feeding and do not consent to
             discontinue breast-feeding.

          -  Participation in another interventional clinical trial within 30 days before
             randomization in this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:CR/VGPR
Time Frame:12 months
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Response rate
Time Frame:12/ 24 months
Safety Issue:
Description: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.
Measure:Best response
Time Frame:12 months
Safety Issue:
Description:Best response (at least achieving a MR) is determined in the time interval from the start of induction therapy to end of follow-up.
Measure:Time to best response
Time Frame:12 months
Safety Issue:
Description:Time to best response is defined as the time from the start of induction to best response the patient achieves (CR, VGPR, PR, MR).
Measure:Time to first response
Time Frame:12 months
Safety Issue:
Description:Time to first response is defined as the time from the start of induction to first response (MR, PR, VGPR or CR).
Measure:Time to treatment failure (TTF)
Time Frame:10 years
Safety Issue:
Description: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.
Measure:Remission duration (RD)
Time Frame:10 years
Safety Issue:
Description: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.
Measure:Progression Free Survival (PFS)
Time Frame:10 years
Safety Issue:
Description: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.
Measure:Cause specific survival (CSS)
Time Frame:10 years
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:10 years
Safety Issue:
Description: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.
Measure:Safety
Time Frame:10 years
Safety Issue:
Description:Safety including treatment associated adverse events.
Measure:Quality of Life
Time Frame:10 years
Safety Issue:
Description:Quality of Life will be assessed by the FACT-Lym questionnaire.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Christian Buske

Trial Keywords

  • MYD88 mutation
  • CXCR4 mutation
  • Carfilzomib
  • Ibrutinib
  • Hematology
  • Oncology

Last Updated

February 10, 2020