Daratumumab Plus Ibrutinib in Patients With Waldenstrӧm's Macroglobulinemia

NCT03679624 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: 1708018494
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Waldenstrom Macroglobulinemia; Waldenstrom's Disease; Waldenström; Hypergammaglobulinemia; Waldenstrom's Macroglobulinemia Recurrent; Waldenstrom's Macroglobulinemia of Lymph Nodes; Waldenstrom's Macroglobulinaemia, Without Mention of Remission; Waldenstrom's Macroglobulinemia Refractory

Keywords

treatment naive; relapsed; frontline; refractory; daratumumab; ibrutinib

Outcome Measures

Primary Outcomes (1)

• Safety of Combination Treatment With Ibrutinib and Daratumumab as Measured by the Number of Patients That Experience 1 or More Adverse Event

  Number of patients that experience 1 or more adverse event

  3 months

Secondary Outcomes (6)

• Major Response Rate in Cohort A

  5 years

• Deepening of Response Rate in Cohort B After Daratumumab Addition

  5 years

• Duration of Response

  5 years

• Time to Progression

  5 years

• Progression Free Survival

  3 months

Study Arms (2)

Cohort A - Ibrutinib naive

EXPERIMENTAL

Cohort A will consist of subjects who are ibrutinib naïve and appropriate for ibrutinib based treatment. Treatment naïve subjects will be eligible to enroll in this cohort. All subjects in this cohort will receive ibrutinib plus daratumumab

Drug: Ibrutinib; Drug: Daratumumab

Cohort B - Ibrutinib response plateau

EXPERIMENTAL

Cohort B will consist of subjects who have had at least 6 months of exposure to single agent ibrutinib and who have demonstrated an IgM response plateau defined by two IgM measurements, at least 8 weeks apart that have changed \<15% from the previous mark. All subjects in this cohort will receive ibrutinib plus daratumumab

Drug: Ibrutinib; Drug: Daratumumab

Interventions

Ibrutinib DRUG

Ibrutinib, 420mg orally, once daily

Also known as: IMBRUVICA

Cohort A - Ibrutinib naive; Cohort B - Ibrutinib response plateau

Daratumumab DRUG

Daratumumab, 16 mg/kg intravenously, weekly for 8 weeks, bi weekly for 16 weeks, then monthly for up to 19 months.

Also known as: DARZALEX

Cohort A - Ibrutinib naive; Cohort B - Ibrutinib response plateau

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Ibrutinib naïve subjects may be either treatment naïve or previously treated but ibrutinib naïve to enter cohort A.
• 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:
• Absolute neutrophil count (ANC) ≥ 1000/mm3 independent of growth factor support for 7 days of study entry if cytopenias are due to marrow involvement.
• Platelets ≥ 50,000/mm3 independent of transfusion support within 7 days of study entry. TPO mimetics are not allowed to meet eligibility criteria.
• 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

You may not qualify if:

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

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead
• Janssen Scientific Affairs, LLC: collaborator
• Mayo Clinic: collaborator

Study Sites (1)

Weill Cornell Medicine

New York, New York, 10065, United States

Location

Related Links

• WCM Joint Clinical Trials Office

MeSH Terms

Conditions

Waldenstrom Macroglobulinemia; Hypergammaglobulinemia; Recurrence

Interventions

ibrutinib; daratumumab

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Disease Attributes; Pathologic Processes

Results Point of Contact

• Title: Dr. John Allan, Associate Professor of Medicine
• Organization: Weill Cornell Medicine

joa9069@med.cornell.edu

2127463481

Study Officials

• John N. Allan, M.D.

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2018
• First Posted: September 20, 2018
• Study Start: July 30, 2020
• Primary Completion: September 15, 2020
• Study Completion: October 13, 2020
• Last Updated: October 23, 2023
• Results First Posted: October 23, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)