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 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.
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
