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

NCT03225716 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: 17-235
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Waldenstrom's Macroglobulinemia

Keywords

Waldenstrom's Macroglobulinemia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Time to Minor Response

  Response evaluated at each cycle day 1, starting at Cycle 2 Day 1 through Cycle 48

• Time to Major Response

  Response evaluated at each cycle day 1, starting at Cycle 2 Day 1 through Cycle 48

• Progression Free Survival (PFS)

  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

Study Arms (3)

Phase 1 Dose level 1: Ibrutinib + Ulocuplumab 400mg Cycle 1 and 800mg Cycles 2-6

EXPERIMENTAL

* 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; Drug: Ibrutinib

Phase 1 Dose level 2: Ibrutinib + Ulocuplumab 800mg Cycle 1 and 1200mg Cycles 2-6

EXPERIMENTAL

* 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; Drug: Ibrutinib

Phase 1 Dose level 3: Ibrutinib + Ulocuplumab 800mg Cycle 1 and 1600mg Cycles 2-6

EXPERIMENTAL

* 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; Drug: Ibrutinib

Interventions

Ulocuplumab DRUG

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

Also known as: BMS-936564

Phase 1 Dose level 1: Ibrutinib + Ulocuplumab 400mg Cycle 1 and 800mg Cycles 2-6; Phase 1 Dose level 2: Ibrutinib + Ulocuplumab 800mg Cycle 1 and 1200mg Cycles 2-6; Phase 1 Dose level 3: Ibrutinib + Ulocuplumab 800mg Cycle 1 and 1600mg Cycles 2-6

Ibrutinib DRUG

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

Also known as: Imbruvica

Phase 1 Dose level 1: Ibrutinib + Ulocuplumab 400mg Cycle 1 and 800mg Cycles 2-6; Phase 1 Dose level 2: Ibrutinib + Ulocuplumab 800mg Cycle 1 and 1200mg Cycles 2-6; Phase 1 Dose level 3: Ibrutinib + Ulocuplumab 800mg Cycle 1 and 1600mg Cycles 2-6

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (2)

• 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.

  PMID: 34398557 DERIVED

• 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.

  PMID: 34289017 DERIVED

MeSH Terms

Conditions

Waldenstrom Macroglobulinemia

Interventions

ulocuplumab; ibrutinib

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

Results Point of Contact

• Title: Steven Treon
• Organization: DFCI

steven_treon@dfci.harvard.edu

617-632-2681

Study Officials

• Steven P. Treon, MD, PhD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: June 29, 2017
• First Posted: July 21, 2017
• Study Start: October 20, 2017
• Primary Completion: December 31, 2022
• Study Completion: December 31, 2022
• Last Updated: May 3, 2024
• Results First Posted: May 3, 2024

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)