Efficacy and safety of Carfilzomib in combination with Ibrutinib vs. Ibrutinib alone in Waldenström’s Macroglobulinemia (CZAR-1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Ulm AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Neoplasms [C04]

Trial duration

28 Jan 2021 → ongoing

Decision date (initial)

2024-10-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Janssen Pharmaceutical NV · Amgen Inc.

External identifiers

EU CT number

2024-511929-60-00

EudraCT number

2018-003526-88

ClinicalTrials.gov

NCT04263480

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

explore the efficacy of Carfilzomib in combination with Ibrutinib compared to Ibrutinib alone in patients with treatment naïve or relapsed WM

Secondary objectives 6

1. to evaluate the anti-lymphoma activity of Carfilzomib / Ibrutinib compared to Ibrutinib alone in patients with treatment naïve or relapsed WM assessing response rates
2. evaluate the anti-lymphoma activity of Carfilzomib / Ibrutinib compared to Ibrutinib alone in patients with treatment naïve or relapsed WM assessing time to treatment failure
3. evaluate the anti-lymphoma activity of Carfilzomib / Ibrutinib compared to Ibrutinib alone in patients with treatment naïve or relapsed WM assessing remission duration
4. evaluate the anti-lymphoma activity of Carfilzomib / Ibrutinib compared to Ibrutinib alone in patients with treatment naïve or relapsed WM assessing cause specific survival
5. evaluate the anti-lymphoma activity of Carfilzomib / Ibrutinib compared to Ibrutinib alone in patients with treatment naïve or relapsed WM assessing overall survival
6. assess the safety and quality of live

Conditions and MedDRA coding

Waldenström’s Macroglobulinemia

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Proven clinicopathological diagnosis of WM as defined by consensus panel one of the Second International Workshop on WM (IWWM)[66]
2. De novo or relapsed / refractory WM independent of the genotype
3. Patients must have at least one of the following criteria to start study treatment as partly defined by consensus panel criteria from the Seventh IWWM[5
4. World Health Organization (WHO) / ECOG performance status ≤ 2.
5. Left ventricular ejection fraction ≥ 40% as assessed by transthoracic echocardiogram (TTE).
6. Age ≥ 18 years (male and female). and Life expectancy > 3 months in the opinion of the investigator.
7. adequate laboratory values
8. Women of childbearing potential (WCBP), i.e. fertile, following menarche and until becoming postmenopausal 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 with Carfilzomib or Ibrutinib
9. Men must agree not to father a child for the duration of therapy and 6 months after and must agree to advice their female partner to use a highly effective method (use of a condom) of birth control. Males must refrain from sperm donation for the duration of treatment and at least 6 months after the last dose of Carfilzomib or Ibrutinib
10. Each patient must sign an informed consent form in a fluent language of the patient indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.

Exclusion criteria 29

1. Previous treatments with following substances: o Prior exposure to Ibrutinib or other BTK inhibitors. o 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.
2. Serious medical or psychiatric illness (especially undergoing treatment) likely to interfere with participation in this clinical study.
3. Active HIV, HBV or HCV infection
4. Central Nervous System involvement by lymphoma.
5. 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
6. Uncontrolled illnesses including, but not limited to: o Uncontrolled diabetes mellitus (as indicated by metabolic derangements and / or severe diabetes mellitus related uncontrolled organ complications). o Chronic symptomatic congestive heart failure (Class NYHA III or IV) or LVEF < 40%. o Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months prior to randomization. o Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia. o Known pericardial disease. o 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. o Cardiac amyloidosis.
7. Recent major surgery within 30 days prior to randomization.
8. Known cirrhosis (meeting child-pugh stage C).
9. Approved or investigational anticancer treatment within 21 days prior to randomization.
10. Glucocorticoid therapy within 14 days prior to randomization that exceeds a cumulative dose of 160 mg of Dexamethasone or equivalent dose of other corticosteroids.
11. 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
12. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs.
13. Hypersensitivity to the active substances or to any of the excipients of the investigational medicinal products.
14. 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.
15. Ascites requiring paracentesis within 14 days prior to randomization
16. 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
17. History of stroke or intracranial hemorrhage within 6 months prior to randomization.
18. Known interstitial lung disease.
19. Infiltrative pulmonary disease, known pulmonary hypertension.
20. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal
21. Known severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification or at time of screening has an FEV1 of < 50% of predicted normal
22. Autologous or allogeneic stem cell transplant less than 100 days prior to randomization.
23. Vaccination with live attenuated vaccines within 30 days prior to randomization.
24. Patients who require strong or moderate inducers or inhibitors for cytochrome P450, family 3 or subfamily A (CYP3A).
25. 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.
26. 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 safety or interfere with the study evaluation, procedures or completion.
27. 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.
28. Vulnerable patients, e.g. patients who are incapable of giving informed consent (severe dementia or psychosis, patients kept in detention).
29. Participation in another interventional clinical study within 30 days before randomization in this study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Complete Remission (CR) or Very Good Partial Remission (VGPR) 12 months from randomization using the modified response criteria updated at the Sixth IWWM[1] (CR/VGPR).

Secondary endpoints 12

1. Response rate (CR, VGPR, PR, MR) and ORR (CR, VGPR, PR) 12 months
2. Response rate (CR, VGPR, PR, MR) and ORR (CR, VGPR, PR) 24 monthsResponse rate (CR, VGPR, PR, MR) and ORR (CR, VGPR, PR) 24 months
3. Best response
4. Time to best response
5. Time to first response
6. Time to treatment failure
7. Remission Duration
8. Progression free survival
9. Cause specific survival
10. Overall survival
11. Safety
12. Quality of life

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Ulm AöR

Sponsor organisation

Universitaetsklinikum Ulm AöR

Address

Albert-Einstein-Allee 29, Eselsberg Eselsberg

City

Ulm

Postcode

89081

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Ulm AöR

Contact name

Prof. Dr. med Christian Buske

Public contact point

Organisation

Universitaetsklinikum Ulm AöR

Contact name

Prof. Dr. med Christian Buske

Third parties 5

Locations

3 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 26 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications