A Study of Ulocuplumab And Ibrutinib in Symptomatic Patients With Mutated CXCR4 Waldenstrom's Macroglobulinemia

Study Overview
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Brief Summary
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This research study is studying Ulocuplumab combined with ibrutinib as a possible treatment for symptomatic Waldenstrom's Macroglobulinemia (WM).

Detailed Description
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This is a Phase I/II clinical trial. A Phase I clinical trial tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. Investigational means that the drug is being studied. The FDA (the U.S. Food and Drug Administration) has not approved Ulocuplumab as a treatment for any disease. Ulocuplumab is a type of protein called an antibody that attacks CXCR4, a protein that is found on B-cells like WM. The FDA (the U.S. Food and Drug Administration) has Ibrutinib as a treatment option for this disease. Ibrutinib has been under investigation in research studies in participants with recurrent B-cell lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and prolymphocytic leukemia, and WM. In a study of ibrutinib in relapsed/refractory WM patients, response rates were high and the treatment was well tolerated. In that study participants who had a CXCR4 mutation had a lower response rate to ibrutinib than those without a mutation. In this research study, the investigators are evaluating the safety of ulocuplumab in combination with ibrutinib participants with symptomatic WM who have a CXCR4 mutation. The investigators are also evaluating how well the ulocuplumab works in combination with ibrutinib

Official Title
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A Phase 1/2 Study of Ulocuplumab And Ibrutinib in Symptomatic Patients With Mutated CXCR4 Waldenstrom's Macroglobulinemia

Conditions
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Waldenstrom's Macroglobulinemia

Intervention / Treatment
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* Drug: Ulocuplumab
* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinicopathological diagnosis of Waldenstrom's Macroglobulinemia and meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenstrom's macroglobulinemia (Kyle et al, 2003) or have high risk disease with an serum IgM level of 6,000 mg or higher (Gustine et al, 2016). MYD88 and CXCR4 mutated disease (determined by Treon laboratory or molecular diagnostics laboratory). Measurable disease, defined as presence of serum immunoglobulin M (IgM) with a minimum IgM level of >2 times the upper limit of normal of each institution is required. Age ≥ 18 years ECOG performance status < or = 2 (see Appendix A.). To establish eligibility, participants must have adequate organ and marrow function as defined below: Absolute neutrophil count ≥ 1,000/uL Platelets ≥ 75,000/uL Hemoglobin ≥ 8 g/dL Total bilirubin ≤ 1.5 mg/dL or < 2 mg/dL if attributable to hepatic infiltration by neoplastic disease or Gilbert's syndrome AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal Creatinine ≤ 2 mg/dL Not on any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin. Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or have or will have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 28 days after discontinuation from the study. Men must agree to use a latex condom during sexual contact with a FCBP even if the participants have had a successful vasectomy. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test at screening. Able to adhere to the study visit schedule and other protocol requirements. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Any serious medical condition, laboratory abnormality, uncontrolled intercurrent illness, or psychiatric illness/social condition that would prevent study participation. Concurrent use of any other anti-cancer agents or treatments or any other investigational agents. Treatment with strong CYP3A4/5 and/or CYP2D6 inhibitors Prior exposure to ibrutinib or ulocuplumab With the exception of low-dose aspirin, subjects enrolled in this study should not take concomitant medications that durably inhibit platelet function including marine oil tablets. For such medications a wash-out period of ≥ 7 days is required prior to starting treatment. Agents which inhibit platelet function transiently or inhibit coagulation by other mechanisms are restricted (e.g. use with caution). Medications that directly and durably inhibit platelet function include aspirin containing combinations, clopidogrel, dipyridamole, tirofiban, epoprostenol, eptifibatide, cilostazol, abciximab, ticlopidine, cilostazol. Participants should not take drugs that directly and durably inhibit coagulation with the exception of warfarin (coumadin) and heparin including low-molecular-weight heparin (LMWH), including enoxaparin, tinzaparin, etc. Any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Known CNS lymphoma. New York Heart Association classification III or IV heart failure. Known history of Human Immunodeficiency Virus (HIV), active infection with Hepatitis B Virus (HBV), and/or Hepatitis C Virus (HCV). Lactating or pregnant women. Grade > 2 toxicity (other than alopecia) continuing from prior anti-cancer therapy. Inability to swallow capsules History of non-compliance to medical regimens.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibrutinib + Ulocuplumab<br>Ibrutinib administered orally once daily Ulocuplumab administered intravenously 2-4 times per cycle for Cycles 1-6 | Drug: Ulocuplumab<br>* Ulocuplumab is a type of protein called an antibody that attacks CXCR4<br>* Other names: BMS-936564;Drug: Ibrutinib<br>* Ibrutinib small-molecule inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity<br>* Other names: Imbruvica;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Ulocuplumab | Determine the maximum dose or maximum tolerated dose from the Phase I dose escalation based on the number of dose limiting toxicities in each cohort. | 1 year | 
| Major Response Rate | Major Response Rate= Partial response (>50% reduction in serum IgM from baseline) + Very Good Partial Response (>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly) | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Minor Response | Time in months to >25%-50% reduction in serum IgM from baseline | 2 years | 
| Time to Major Response | Time in months to >50-90% reduction in serum IgM from baseline | 2 years | 
| Time to Progression | Time in months until >25% increase in serum IgM from nadir | 2 years | 
| Overall Response Rate | Overall Response Rate= Minor response (>25%-50% reduction in serum IgM from baseline) + Partial Response (>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly). | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Waldenstrom's Macroglobulinemia