Overview

Daratumumab Plus Ibrutinib in Patients With Waldenstrӧm's Macroglobulinemia

Status:
Recruiting
Trial end date:
2024-10-01
Target enrollment:
0
Participant gender:
All
Summary
This study evaluates the safety and efficacy of daratumumab in combination with ibrutinib in patients with Waldenstrӧm's macroglobulinemia (WM). The study will evaluate this combination in two cohorts. Cohort A will comprise of ibrutinib naïve WM patients. Patients in this cohort may be treatment naïve or relapsed but who remain ibrutinib naïve. Cohort B will comprise of patients who are currently receiving ibrutinib but whose response to treatment has plateaued. In this cohort, daratumumab will be added on to ibrutinib in an attempt to deepen response.
Phase:
Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Weill Medical College of Cornell University
Collaborators:
Janssen Scientific Affairs, LLC
Mayo Clinic
Treatments:
Antibodies, Monoclonal
Daratumumab
Criteria
Inclusion Criteria:

- Subjects must have a diagnosis of WM and meet the requirements for active therapy as
defined by the 2nd International Workshop on Waldenstrom's Macroglobulinemia

- Age ≥18 years of age

- Ibrutinib naïve or previously treated patients currently on ibrutinib with a plateau
in disease response are eligible to participate.

1. Ibrutinib naïve subjects may be either treatment naïve or previously treated but
ibrutinib naïve to enter cohort A.

2. Subjects entering cohort B must have a plateau response on ibrutinib defined as ≥
6 months of ibrutinib treatment with 2 IgM measurements at least 2 months apart
with ≤ 15% change from the previous measurement. Subjects with IgM level < 0.7
g/dL will be eligible if their IgM level increases < 0.15 g/dL over two
subsequent IgM measurements as defined above.

- Subjects must have measurable disease defined by a serum IgM level ≥0.5g/dL

- Eastern Cooperative Oncology Group performance status of 0-2

- Hematology values must be within the following limits:

1. Absolute neutrophil count (ANC) ≥ 1000/mm3 independent of growth factor support
for 7 days of study entry if cytopenias are due to marrow involvement.

2. Platelets ≥ 50,000/mm3 independent of transfusion support within 7 days of study
entry. TPO mimetics are not allowed to meet eligibility criteria.

3. Hemoglobin ≥ 8g/dL, independent of transfusion support within 7 days of study
entry

- Biochemical values within the following limits:

d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper
limit of normal (ULN)

e. Total bilirubin ≤ 2 x ULN unless bilirubin rise is due to Gilbert's syndrome or of
non-hepatic origin

f. Creatinine clearance (CLcr) > 25 ml/min

- Women of childbearing potential and men who are sexually active must be practicing a
highly effective method of birth control during and after the study consistent with
local regulations regarding the use of birth control methods for subjects
participating in clinical trials. Men must agree to not donate sperm during and after
the study. For females, these restrictions apply for 1 month after the last dose of
study drug. For males, these restrictions apply for 3 months after the last dose of
study drug.

- Women of childbearing potential must have a negative serum (beta-human chorionic
gonadotropin (beta-hCG) or urine beta hCG pregnancy test at Screening. Women who are
pregnant or breastfeeding are ineligible for this study.

- Subjects must be able to sign (or their legally-acceptable representatives must sign)
an informed consent indicating that they understand the rational of the study and can
participate in all study procedures.

Exclusion Criteria:

- Subject does not have a recorded IgM level recorded within 3 months prior to ibrutinib
initiation.

- Subject meeting definition of disease progression while on ibrutinib. Subjects with
IgM levels < 0.7gdL are given special consideration. Please see inclusion criteria for
2b.

- Subjects in cohort B experiencing ongoing non hematologic toxicities attributable to
ibrutinib > Grade 1 will be excluded from study entry.

- Major surgery or a wound that has not fully healed within 4 weeks of enrollment.

- Evidence of disease transformation at time of enrollment.

- Waldenstrom's complicated by amyloidosis

- Known central nervous system lymphoma.

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

- Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg,
phenprocoumon).

- Requires chronic treatment with strong CYP3A inhibitors. Subjects that required strong
CYP3A inhibitors but completed a course of treatment can be considered for enrollment
after a washout period of 14 days prior to study drug administration.

- Requires strong CYP3A inducers. Subjects that required strong CYP3A inducers but
completed a course of treatment can be considered for enrollment after a washout
period of 14 days prior to study drug administration.

- Patients with history of Chronic Obstructive Pulmonary Disease or Reactive Airway
disease must have PFTs with FEV1 calculated. Patients with a FEV1 ≤ 50% of predicted
normal will be excluded.

- Clinically significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by
the New York Heart Association Functional Classification.

- Vaccinated with live, attenuated vaccines within 4 weeks of randomization.

- Seropositive for human immunodeficiency virus (HIV).

- Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg
negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or
antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time
polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels.
Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic
findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic
marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV
DNA by PCR.

- Seropositive for hepatitis C (except in the setting of a sustained virologic response
[SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).

- Any life-threatening illness, medical condition, or organ system dysfunction which, in
the investigator's opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue
risk.

- Active malignancy not treated with curative intent within 2 years of study entry.
Nonmelanotic skin cancers and cervical carcinoma in situ are excluded from this
criteria.