Study of ABT-199 (GDC-199) In Patients With Relapsed Or Refractory Waldenström Macroglobulinemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II Study of ABT-199 (GDC-199) In Patients With Relapsed Or Refractory Waldenström Macroglobulinemia

Conditions
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Waldenstrom Macroglobulinemia

Intervention / Treatment
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* Drug: ABT199


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABT199<br>ABT199 will be administered daily, with 28 consecutive days defined as a treatment cycle for a maximum for 26 cycles | Drug: ABT199<br>* Oral BCL-2 antagonist<br>* Other names: Venetoclax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 2 years | 
| 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. | 2 years | 
| 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. | 2 years | 
| Number of Participants With Partial Response | Partial response (PR) is defined as achieving a ≥50% reduction in serum IgM levels. | 2 years | 
| Number of Participants With Minor Response | Minor Response (MR): A minor response (MR) is defined 25-49% reduction in serum IgM levels. | 2 years | 
| 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 | 2 years | 
| Progression Free Survival | Amount of time following ABT-199 administration until >25% increase in serum IgM | 4 years | 
| 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). | 2 years | 
| 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). | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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WM, Waldenstrom Macroglobulinemia