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

NCT ID: NCT03225716

Last Updated: 2024-05-03

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-20
• Study Completion Date: 2022-12-31

Brief Summary

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

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

Conditions

Waldenstrom's Macroglobulinemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Ulocuplumab

Intervention Type: DRUG

Ulocuplumab is a type of protein called an antibody that attacks CXCR4

Ibrutinib

Intervention Type: DRUG

Ibrutinib small-molecule inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity

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.

Group Type: EXPERIMENTAL

Ulocuplumab

Intervention Type: DRUG

Ulocuplumab is a type of protein called an antibody that attacks CXCR4

Ibrutinib

Intervention Type: DRUG

Ibrutinib small-molecule inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity

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.

Group Type: EXPERIMENTAL

Ulocuplumab

Intervention Type: DRUG

Ulocuplumab is a type of protein called an antibody that attacks CXCR4

Ibrutinib

Intervention Type: DRUG

Ibrutinib small-molecule inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity

Interventions

Ulocuplumab

Ulocuplumab is a type of protein called an antibody that attacks CXCR4

Intervention Type: DRUG

Ibrutinib

Ibrutinib small-molecule inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity

Intervention Type: DRUG

Other Intervention Names

BMS-936564; Imbruvica

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

Dana-Farber Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Steven Treon, MD, PhD

MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Steven P. Treon, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 34398557 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34289017 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

17-235

Identifier Type: -

Identifier Source: org_study_id