Waldenstrom's Macroglobulinemia
Conditions
Keywords
Waldenstrom's Macroglobulinemia
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
Interventions
DRUGUlocuplumab
Ulocuplumab is a type of protein called an antibody that attacks CXCR4
DRUGIbrutinib
Ibrutinib small-molecule inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity
Sponsors
Bristol-Myers Squibb
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Ulocuplumab | Up to 8 weeks for each dose level | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Minor Response | Response evaluated at each cycle day 1, starting at Cycle 2 Day 1 through Cycle 48 | Time in months to \>25%-50% reduction in serum IgM from baseline |
| Time to Major Response | Response evaluated at each cycle day 1, starting at Cycle 2 Day 1 through Cycle 48 | Time in months to \>50-90% reduction in serum IgM from baseline |
| 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 | Time in months until \>25% increase in serum IgM from nadir |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 7 |
| Phase 1 Dose Level 2: Ibrutinib + Ulocuplumab 800 mg 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. | 3 |
| 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. | 3 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 |
| Overall Study | Lack of Efficacy | 1 | 0 | 0 |
| Overall Study | Study early termination by Sponsor | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 0 |
Baseline characteristics
| Characteristic | Phase 1 Dose Level 1: Ibrutinib + Ulocuplumab 400mg Cycle 1 and 800mg Cycles 2-6 | Phase 1 Dose Level 2: Ibrutinib + Ulocuplumab 800 mg Cycle 1 and 1200mg Cycles 2-6 | Phase 1 Dose Level 3: Ibrutinib + Ulocuplumab 800mg Cycle 1 and 1600mg Cycles 2-6 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 2 Participants | 3 Participants | 11 Participants |
| Age, Continuous | 60 years | 63 years | 54 years | 61 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 3 Participants | 3 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 3 Participants | 3 Participants | 13 Participants |
| Region of Enrollment United States | 7 Participants | 3 Participants | 3 Participants | 13 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 5 Participants | 1 Participants | 1 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 7 / 7 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 3 / 7 | 1 / 3 | 1 / 3 |
Outcome results
Primary
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.
Time frame: Up to 8 weeks for each dose level
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Maximum Tolerated Dose (MTD) of Ulocuplumab | 1600 milligram |
Secondary
Progression Free Survival (PFS)
Time in months until \>25% increase in serum IgM from nadir
Time frame: 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
Population: Of the 13 participants enrolled, only 1 participant confirmed disease progression during the study period. Median PFS was not reached. The median follow-up time before participants follow-up was terminated for each participant is reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Progression Free Survival (PFS) | 20 months |
| Phase 1 Dose Level 2: Ibrutinib + Ulocuplumab 800 mg Cycle 1 and 1200mg Cycles 2-6 | Progression Free Survival (PFS) | 43 months |
| Phase 1 Dose Level 3: Ibrutinib + Ulocuplumab 800mg Cycle 1 and 1600mg Cycles 2-6 | Progression Free Survival (PFS) | 37 months |
Secondary
Time to Major Response
Time in months to \>50-90% reduction in serum IgM from baseline
Time frame: Response evaluated at each cycle day 1, starting at Cycle 2 Day 1 through Cycle 48
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Time to Major Response | 3 months |
| Phase 1 Dose Level 2: Ibrutinib + Ulocuplumab 800 mg Cycle 1 and 1200mg Cycles 2-6 | Time to Major Response | 1 months |
| Phase 1 Dose Level 3: Ibrutinib + Ulocuplumab 800mg Cycle 1 and 1600mg Cycles 2-6 | Time to Major Response | 1 months |
Secondary
Time to Minor Response
Time in months to \>25%-50% reduction in serum IgM from baseline
Time frame: Response evaluated at each cycle day 1, starting at Cycle 2 Day 1 through Cycle 48
Population: All participants who received at least 1 dose of Ulocuplumab, either at 400mg for cycle 1 and 800mg for cycle 2+, 800mg for cycle 1 and 1200mg for cycle 2+, or 800mg for cycle 1 and 1600mg for cycle 2+
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Time to Minor Response | 1 months |
| Phase 1 Dose Level 2: Ibrutinib + Ulocuplumab 800 mg Cycle 1 and 1200mg Cycles 2-6 | Time to Minor Response | 1 months |
| Phase 1 Dose Level 3: Ibrutinib + Ulocuplumab 800mg Cycle 1 and 1600mg Cycles 2-6 | Time to Minor Response | 1 months |