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JOURNAL ONKOLOGIE – STUDIE
CZAR-1

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

Rekrutierend

NCT-Nummer:
NCT04263480

Studienbeginn:
Februar 2021

Letztes Update:
24.03.2023

Wirkstoff:
Carfilzomib + Ibrutinib, Ibrutinib

Indikation (Clinical Trials):
Waldenstrom Macroglobulinemia

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Christian Buske

Collaborator:
Amgen, Janssen, LP,

Studienleiter

Christian Buske, MD
Study Chair
University of Ulm

Kontakt

Studienlocations
(3 von 20)

Alle anzeigen

Studien-Informationen

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 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.

Ein-/Ausschlusskriterien

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

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.

- 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:

- 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.

- Cardiac amyloidosis.

- Recent major surgery within 30 days prior to randomization.

- Known cirrhosis (meeting child-pugh stage C).

- Approved or investigational anticancer treatment within 21 days prior to

randomization.

- Glucocorticoid therapy within 14 days prior to randomization that exceeds a cumulative

dose of 160 mg of Dexamethasone or equivalent dose of other corticosteroids.

- 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.

- Hypersensitivity to the active substances or to any of the excipients of the

investigational medicinal products.

- 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 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 according European Society of

Hypertension/European Society of Cardiology [ESH / ESC] 2013 guidelines[65].

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

- Known interstitial lung disease.

- Infiltrative pulmonary disease, known pulmonary hypertension.

- 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.

- Autologous or allogeneic stem cell transplant less than 100 days prior to

randomization.

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

- Patients who require strong or moderate inducers or inhibitors for cytochrome P450,

family 3 or subfamily A (CYP3A).

- Patients who have an uncontrolled bleeding disorder or require an anticoagulant (e.g.

warfarin or other vitamin K antagonists; novel oral anticoagulants (NOACs) are

allowed) at time of screening.

- 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 patient safely or interfere with the

study evaluation, procedures or completion.

- Patient is a woman who is pregnant or breastfeeding (and do not consent to discontinue

breast-feeding) or planning to become pregnant while enrolled in this study or within

6 months after the last study treatment.

- Vulnerable patients, e.g. patients who are incapable of giving informed consent

(severe dementia or psychosis, patients kept in detention).

- Participation in another interventional clinical study within 30 days before

randomization in this study.

Studien-Rationale

Primary outcome:

1. CR/VGPR (Time Frame - 12 months):
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:

1. Response rate (Time Frame - 12/ 24 months):
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.

2. Best response (Time Frame - 12 months):
Best response (at least achieving a MR) is determined in the time interval from the start of induction therapy to end of follow-up.

3. Time to best response (Time Frame - 12 months):
Time to best response is defined as the time from the start of induction to best response the patient achieves (CR, VGPR, PR, MR).

4. Time to first response (Time Frame - 12 months):
Time to first response is defined as the time from the start of induction to first response (MR, PR, VGPR or CR).

5. Time to treatment failure (TTF) (Time Frame - 7 years):
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.

6. Remission duration (RD) (Time Frame - 7 years):
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.

7. Progression Free Survival (PFS) (Time Frame - 7 years):
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.

8. Cause specific survival (CSS) (Time Frame - 7 years):
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.

9. Overall survival (OS) (Time Frame - 7 years):
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.

10. Rate of Adverse Events (safety) (Time Frame - 7 years):
Number of adverse events and comparison of adverse event rate in both treatment arms.

11. Changes in Quality of Life (Time Frame - 7 years):
Changes in quality of life will be assessed by the FACT-Lym questionnaire and compared in both treatment arms.

Studien-Arme

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

Geprüfte Regime

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

Quelle: ClinicalTrials.gov


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