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

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

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

Study Overview

• Status: Terminated
• Conditions: Waldenstrom's Macroglobulinemia
• Intervention / Treatment: Drug: Ulocuplumab; Drug: Ibrutinib

Detailed Description

This was planned to be 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 study was halted early and did not open the Phase II portion.

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

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 Dose level 1: Ibrutinib + Ulocuplumab 400mg Cycle 1 and 800mg Cycles 2-6; Ibrutinib administered orally once daily for 48 cycles; Ulocuplumab administered intravenously at 400mg for Cycle 1 on Days 1, 8, 15, and 22. Ulocuplumab administered IV at 800mg for Cycles 2-6 on Days 1 and 15.	Drug: Ulocuplumab; Ulocuplumab is a type of protein called an antibody that attacks CXCR4; Other Names: BMS-936564; Drug: Ibrutinib; Ibrutinib small-molecule inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity; Other Names: Imbruvica
Experimental: Phase 1 Dose level 2: Ibrutinib + Ulocuplumab 800mg Cycle 1 and 1200mg Cycles 2-6; Ibrutinib administered orally once daily for 48 cycles; Ulocuplumab administered intravenously at 800mg for Cycle 1 on Days 1, 8, 15, and 22. Ulocuplumab administered IV at 1200mg for Cycles 2-6 on Days 1 and 15.	Drug: Ulocuplumab; Ulocuplumab is a type of protein called an antibody that attacks CXCR4; Other Names: BMS-936564; Drug: Ibrutinib; Ibrutinib small-molecule inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity; Other Names: Imbruvica
Experimental: Phase 1 Dose level 3: Ibrutinib + Ulocuplumab 800mg Cycle 1 and 1600mg Cycles 2-6; Ibrutinib administered orally once daily for 48 cycles; Ulocuplumab administered intravenously at 800mg for Cycle 1 on Days 1, 8, 15, and 22. Ulocuplumab administered IV at 1600mg for Cycles 2-6 on Days 1 and 15.	Drug: Ulocuplumab; Ulocuplumab is a type of protein called an antibody that attacks CXCR4; Other Names: BMS-936564; Drug: Ibrutinib; Ibrutinib small-molecule inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity; Other Names: Imbruvica

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) of Ulocuplumab	MTD was determined by testing increasing doses up to 1600mg of ulocuplumab on dose escalation levels 1 to 3 with 3 to 7 participants each. MTD reflects the highest dose of ulocuplumab that did not cause a Dose-Limiting Toxicity (DLT) in >33% of participants. DLTs were defined as any Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE 4.0) grade 4 or 5 hematologic toxicities (anemia, neutropenia, or thrombocytopenia) and grade 3 or above non-hematologic toxicities. Exceptions were allowed for toxicities attributed to underlying disease, grade 3 infection, and easily reversible asymptomatic laboratory abnormalities, and nausea, vomiting, or diarrhea controlled by medications.	Up to 8 weeks for each dose level

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	Response evaluated at each cycle day 1, starting at Cycle 2 Day 1 through Cycle 48
Time to Major Response	Time in months to >50-90% reduction in serum IgM from baseline	Response evaluated at each cycle day 1, starting at Cycle 2 Day 1 through Cycle 48
Progression Free Survival (PFS)	Time in months until >25% increase in serum IgM from nadir	Response and progression status evaluated at each cycle day 1, starting at Cycle 2 Day 1 through Cycle 48, and every 12 weeks during follow-up for up to 2 years after end of treatment

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Steven P. Treon, MD, PhD, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• Kipps TJ. Mining the Microenvironment for Therapeutic Targets in Chronic Lymphocytic Leukemia. Cancer J. 2021 Jul-Aug 01;27(4):306-313. doi: 10.1097/PPO.0000000000000536.
• Treon SP, Meid K, Hunter ZR, Flynn CA, Sarosiek SR, Leventoff CR, White TP, Cao Y, Roccaro AM, Sacco A, Demos MG, Guerrera ML, Kofides A, Liu X, Xu L, Patterson CJ, Munshi M, Tsakmaklis N, Yang G, Ghobrial IM, Branagan AR, Castillo JJ. Phase 1 study of ibrutinib and the CXCR4 antagonist ulocuplumab in CXCR4-mutated Waldenstrom macroglobulinemia. Blood. 2021 Oct 28;138(17):1535-1539. doi: 10.1182/blood.2021012953.

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2017
• Primary Completion (Actual): December 31, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: June 29, 2017
• First Submitted That Met QC Criteria: July 20, 2017
• First Posted (Actual): July 21, 2017

Study Record Updates

• Last Update Posted (Actual): May 3, 2024
• Last Update Submitted That Met QC Criteria: November 26, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Waldenstrom's Macroglobulinemia
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Waldenstrom Macroglobulinemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Ibrutinib
• Other Study ID Numbers: 17-235

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No