Waldenstrom Macroglobulinemia
Conditions
Keywords
Waldenstrom Macroglobulinemia, WM
Brief summary
This research study is studying a targeted therapy as a possible treatment for relapsed or refractory Waldenstrom's Macroglobulinemia (WM). This study is using the study intervention ABT-199.
Detailed description
This research study is a Phase II clinical trial. ABT-199 is a pill that blocks BCL-2, a protein that is important for the survival of WM cells. The purpose of this research study is to evaluate how well the study drug works and the safety of ABT-199 as a single agent in participants with WM that has come back or has shown no response to previous treatment. The FDA (the U.S. Food and Drug Administration) has not approved ABT-199 as a treatment for any disease.
Interventions
DRUGABT199
Oral BCL-2 antagonist
Sponsors
AbbVie
Dana-Farber Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
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 (Owen 2003; Kyle 2003). * 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. * Have received at least one prior therapy for WM. * Age ≥ 18 years. * ECOG performance status \<2 (see Appendix A). * Participants must have normal organ and marrow function (growth factors cannot be given prophylactically to establish eligibility) as defined below: * Absolute neutrophil count \> 1,000/mm3 * Platelets \> 50,000/mm3 * Hemoglobin \> 8 g/dL * Total bilirubin ≤ 1.5 mg/dL or \< 2 mg/dL if attributable to hepatic infiltration by neoplastic disease * AST (SGOT) and ALT (SGPT) \< 2.5X the institutional upper limit of normal * Creatinine clearance ≥50 ml/min * 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 they have had a successful vasectomy. FCBP must be referred to a qualified provider of contraceptive methods if needed. * 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 the participant from signing the informed consent form. * Concurrent use of any other anti-cancer agents or treatments or any other study agents. * Prior exposure to ABT-199 or BCL2 inhibitors. * Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, ECG finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the patient, including symptomatic hyperviscosity; alter the absorption, distribution, metabolism or excretion of ABT-199; or impair the assessment of study results. * Grade \> 2 toxicity (other than alopecia) continuing from prior anti-cancer therapy. * Known CNS lymphoma. * Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening. * New York Heart Association classification III or IV heart failure. * Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. * Known history of Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), and/or Hepatitis C Virus (HCV) infection. * Lactating or pregnant women. * Inability to swallow tablets. * History of non-compliance to medical regimens. * Unwilling or unable to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | 2 years | Overall Response Rate= Minor response (\>25%-50% reduction in serum IgM from baseline) + Partial Response (\>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (\>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Complete Response | 2 years | A complete response is defined as having resolution of WM related symptoms, normalization of serum IgM levels with complete disappearance of IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly. |
| Number of Participants With Very Good Partial Response | 2 years | Very Good Partial Response (VGPR): is defined as ≥90% reduction in serum IgM levels, or normalization of serum IgM levels. |
| Number of Participants With Partial Response | 2 years | Partial response (PR) is defined as achieving a ≥50% reduction in serum IgM levels. |
| Number of Participants With Minor Response | 2 years | Minor Response (MR): A minor response (MR) is defined 25-49% reduction in serum IgM levels. |
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | 2 years | Number of participants who experienced an adverse event while on ABT-199 |
| Progression Free Survival | 4 years | Amount of time following ABT-199 administration until \>25% increase in serum IgM |
| Overall Response Rate Among CXCR4 Mutated Participants | 2 years | Overall Response Rate for participants who tested positive for a CXCR4 mutation= Minor response (\>25%-50% reduction in serum IgM from baseline) + Partial Response (\>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (\>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly). |
| Overall Response Rate Among Participants Without CXCR4 Mutations | 2 years | Overall Response Rate in participants who tested negative for a CXCR4 mutation= Minor response (\>25%-50% reduction in serum IgM from baseline) + Partial Response (\>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (\>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly). |
| Number of Participants With Stable Disease | 2 years | Stable disease is defined as having \<25% increase in serum IgM levels and \<25% reduction in serum IgM levels |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ABT199 ABT199 will be administered daily, with 28 consecutive days defined as a treatment cycle for a maximum for 26 cycles
ABT199: Oral BCL-2 antagonist | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Disease Progression | 6 |
| Overall Study | IgM Myeloma diagnosis | 1 |
| Overall Study | Inability to Swallow pills | 1 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Medical insurance coverage | 1 |
| Overall Study | Non-compliance | 1 |
Baseline characteristics
| Characteristic | ABT199 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 19 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Age, Continuous | 66 years |
| CXCR4 Mutation | 17 Participants |
| MYD88 Mutation | 32 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Region of Enrollment United States | 33 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 33 |
| other Total, other adverse events | 33 / 33 |
| serious Total, serious adverse events | 13 / 33 |
Outcome results
Primary
Overall Response Rate
Overall Response Rate= Minor response (\>25%-50% reduction in serum IgM from baseline) + Partial Response (\>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (\>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly).
Time frame: 2 years
Population: 1 participant was censored from the response analysis after it was determined that he had IgM Myeloma rather than Waldenstrom's macroglobulinemia.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ABT199 | Overall Response Rate | 26 Participants |
Secondary
Number of Participants With Complete Response
A complete response is defined as having resolution of WM related symptoms, normalization of serum IgM levels with complete disappearance of IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly.
Time frame: 2 years
Population: 1 participant was censored from the response analysis after it was determined that he had IgM Myeloma rather than Waldenstrom's macroglobulinemia.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ABT199 | Number of Participants With Complete Response | 0 Participants |
Secondary
Number of Participants With Minor Response
Minor Response (MR): A minor response (MR) is defined 25-49% reduction in serum IgM levels.
Time frame: 2 years
Population: 1 participant was censored from the response analysis after it was determined that he had IgM Myeloma rather than Waldenstrom's macroglobulinemia.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ABT199 | Number of Participants With Minor Response | 1 Participants |
Secondary
Number of Participants With Partial Response
Partial response (PR) is defined as achieving a ≥50% reduction in serum IgM levels.
Time frame: 2 years
Population: 1 participant was censored from the response analysis after it was determined that he had IgM Myeloma rather than Waldenstrom's macroglobulinemia.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ABT199 | Number of Participants With Partial Response | 19 Participants |
Secondary
Number of Participants With Stable Disease
Stable disease is defined as having \<25% increase in serum IgM levels and \<25% reduction in serum IgM levels
Time frame: 2 years
Population: 1 participant was censored from the response analysis after it was determined that he had IgM Myeloma rather than Waldenstrom's macroglobulinemia.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ABT199 | Number of Participants With Stable Disease | 2 Participants |
Secondary
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
Number of participants who experienced an adverse event while on ABT-199
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ABT199 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | 33 Participants |
Secondary
Number of Participants With Very Good Partial Response
Very Good Partial Response (VGPR): is defined as ≥90% reduction in serum IgM levels, or normalization of serum IgM levels.
Time frame: 2 years
Population: 1 participant was censored from the response analysis after it was determined that he had IgM Myeloma rather than Waldenstrom's macroglobulinemia.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ABT199 | Number of Participants With Very Good Partial Response | 6 Participants |
Secondary
Overall Response Rate Among CXCR4 Mutated Participants
Overall Response Rate for participants who tested positive for a CXCR4 mutation= Minor response (\>25%-50% reduction in serum IgM from baseline) + Partial Response (\>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (\>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly).
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ABT199 | Overall Response Rate Among CXCR4 Mutated Participants | 14 Participants |
Secondary
Overall Response Rate Among Participants Without CXCR4 Mutations
Overall Response Rate in participants who tested negative for a CXCR4 mutation= Minor response (\>25%-50% reduction in serum IgM from baseline) + Partial Response (\>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (\>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly).
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ABT199 | Overall Response Rate Among Participants Without CXCR4 Mutations | 13 Participants |
Secondary
Progression Free Survival
Amount of time following ABT-199 administration until \>25% increase in serum IgM
Time frame: 4 years
Population: 1 participant was censored from the response analysis after it was determined that he had IgM Myeloma rather than Waldenstrom's macroglobulinemia.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT199 | Progression Free Survival | 31.5 months |