Clinical trial NCT03225716: A Study of Ulocuplumab And Ibrutinib in Symptomatic Patients With Mutated CXCR4 Waldenstrom's Macroglobulinemia
Official title: A Phase 1/2 Study of Ulocuplumab And Ibrutinib in Symptomatic Patients With Mutated CXCR4 Waldenstrom's Macroglobulinemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Waldenstrom's Macroglobulinemia
Keywords: Waldenstrom's Macroglobulinemia
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2017-07-21
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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

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.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) of Ulocuplumab
timeFrame: Up to 8 weeks for each dose level
Secondary outcomes:
measure: Time to Minor Response
timeFrame: Response evaluated at each cycle day 1, starting at Cycle 2 Day 1 through Cycle 48
measure: Time to Major Response
timeFrame: Response evaluated at each cycle day 1, starting at Cycle 2 Day 1 through Cycle 48
measure: Progression Free Survival (PFS)
timeFrame: 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
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Steven P. Treon, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.