Dasatinib In Waldenström Macroglobulinemia

Phase 1

Terminated

Conditions: Waldenstrom Macroglobulinemia
DASATINIB

Interventions: Drug: Dasatinib

Registration Number: NCT04115059

Lead Sponsor: Jorge J. Castillo, MD

Brief Summary: This is Phase I pilot, single center study designed to explore the safety of Dasatinib in symptomatic Waldenström Macroglobulinemia participants who are progressing on ibrutinib therapy with BTK Cys481 or PLCG2 mutations

Detailed Description: This research study is a Pilot Study, which is the first time investigators are examining this drug in patients with Waldenström Macroglobulinemia who have progressed on ibrutinib.

Patients who fulfill eligibility criteria will be entered into the trial to receive Dasatinib

After the screening procedures confirm participation in the research study:

The participant will be given a study drug-dosing calendar for each treatment cycle. In this research study, the investigators are planning to give Dasatinib, which is a targeted therapy intended to treat cancer by binding to the target protein called BTK.

* BTK is believed to be an important target for treatment of patients with specific gene mutations. Some patients who have disease progression after taking ibrutinib have these gene mutations.

* Making treatment decisions based on genetic testing is investigational, and the FDA has not approved this genetic testing.

The U.S. Food and Drug Administration (FDA) has not approved Dasatinib for Waldenström Macroglobulinemia but it has been approved for other uses.

Dasatinib is produced by Bristol-Myers Squibb.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 3

Inclusion Criteria

Participants must meet the following criteria on screening examination to be eligible to participate. Screening evaluations including consent, physical exam, and laboratory assessments will be done within 30 days prior to Cycle 1 Day 1. Bone marrow biopsy & aspirate, and CT C/A/P will be done within 90 days prior to Cycle 1 Day 1.
Clinicopathological diagnosis of Waldenstrom's Macroglobulinemia
Known tumor expression of mutated MYD88 performed by a CLIA certified laboratory.
Participants must have a BTKCys481 and/or PLCγ2 mutation. Genomic alterations must be confirmed via sequencing performed at NeoGenomics Laboratories
At least one previous therapy, with ibrutinib as the most recent treatment. Participants may remain on ibrutinib therapy during screening. A 1 day washout before starting dasatinib is required.
Documented disease progression on last regimen (ibrutinib) per the Sixth International Workshop on WM. One or more of the following:
25% increase in serum IgM level with at least 500 mg/dL absolute increase from nadir with re-confirmation
Progression of clinically significant disease related symptoms
Symptomatic disease meeting criteria for treatment using consensus panel criteria from the Second International Workshop on WM [26]. One or more of the following:
- Constitutional symptoms
- Progressive or symptomatic lymphadenopathy or splenomegaly
- Hemoglobin <10 g/dL
- Platelet count <100 k/uL
- Symptomatic peripheral neuropathy
- Systemic amyloidosis
- Renal insufficiency
- Symptomatic cryoglobulinemia
Age 18 years or older
Measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum serum IgM level of > 2 times the upper limit normal.
ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
Women of childbearing potential: 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. FCBP must be referred to a qualified provider of contraceptive methods if needed.
Men must agree to use a latex condom during sexual contact with a female of childbearing potential (FCBP) even if they have had a successful vasectomy.
Participants must have normal organ and marrow function as defined below:
- Absolute neutrophil count ≥500/ uL (Growth factor not permitted)
- Platelets ≥50,000/ uL (Platelet transfusion not permitted)
- Hemoglobin ≥ 7 g/dL (RBC transfusion permitted)
- Total bilirubin ≤ 2 mg/dL
- Potassium ≥ LLN
- Magnesium ≥ LLN
- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
- Estimated GFR ≥ 30 ml/min
Able to swallow pills.
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

Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study:
Lactating or pregnant women.
Participants who are receiving any other investigational agents.
Prior therapy with BCR-ABL inhibitors.
Known CNS lymphoma.
Symptomatic hyperviscosity requiring urgent therapy.
Human Immunodeficiency Virus (HIV), active infection with Hepatitis B Virus (HBV), and/or Hepatitis C Virus (HCV).
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, pleural or pericardial effusion, unstable angina pectoris, cardiac arrhythmia, QT Prolongation, or psychiatric illness/social situations that would limit compliance with study requirements.
Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)
History clinically significant ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes
Known history of alcohol or drug abuse
On any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin.
History of non-compliance to medical regimens.
Treatment with strong CYP3A4/5 inhibitors or inducers
Participants who are taking St. Johns Wort. Must discontinue at least 5 days before starting dasatinib.
Treatment with H2 Antagonists and proton pump inhibitors

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dasatinib	Dasatinib	-- After the screening procedures confirm participation in the research study: The participant will be given a study drug-dosing calendar for each treatment cycle. Dasatinib: Oral Study Drug(s): * Each study treatment cycle lasts 4 weeks during which time you will be taking the study drug one time per day. * This will continue for up to 24 cycles.

Primary Outcome Measures

Name	Time	Method
Number of Participants With at Least One Treatment-Emergent Adverse Event	2 years	Count of participants who experience a treatment-emergent adverse event

Secondary Outcome Measures

Name	Time	Method
Partial Response Rate	2 years	Percentage of patients with partial response (PR) to therapy. (PR is 50-89% reduction in serum IgM from baseline)
Minimal Response Rate	2 years	Percentage of patients with Minor Responses to therapy. (MR is 25-49% reduction in serum IgM from baseline)
Overall Response Rate	2 years	Percentage of patients with an Overall Response. 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 to Next Therapy (TTNT)	From first dose through initiation of new therapy, up to 2 years from baseline	The amount of time between starting study treatment and initiating a new therapy
Very Good Partial Response Rate	2 years	Percentage of patients with very good partial response (VGPR) to therapy. (VGPR is \>90% reduction in serum IgM from baseline)
Stable Disease Rate	2 years	Percentage of patients with Stable disease to therapy. (SD is \<25% reduction in serum IgM from baseline).
Complete Response Rate	2 years	Percentage of patients with Complete Response (CR). Complete Response requires resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, and resolution of any adenopathy or splenomegaly.
Progressive Disease Rate	From first dose through disease progression, up to 2 years from baseline	Percentage of patients with who experienced disease progression on study. PD is \>25% increase in serum IgM from baseline with an absolute increase of at least 500 mg/dL, or progression of clinically significant disease related symptoms. Death from any cause or initiation of a new anti-neoplastic therapy will also be considered a progression event. An increase of 1 cm in any axis for adenopathy, or 2 cm in the craniocaudal axis of the spleen will be considered evidence of progression of extramedullary disease. Development of Bing Neel syndrome, or other extramedullary disease manifestations, as well as disease transformation will be considered as progressive events.
Progression Free Survival	From first dose through disease progression, up to 2 years from baseline	The amount of time between starting treatment and experiencing disease progression. PD is \>25% increase in serum IgM from baseline with an absolute increase of at least 500 mg/dL, or progression of clinically significant disease related symptoms. Death from any cause or initiation of a new anti-neoplastic therapy will also be considered a progression event. An increase of 1 cm in any axis for adenopathy, or 2 cm in the craniocaudal axis of the spleen will be considered evidence of progression of extramedullary disease. Development of Bing Neel syndrome, or other extramedullary disease manifestations, as well as disease transformation will be considered as progressive events.
Overall Survival	From first dose through death, up to 2 years from baseline	The number of participants who are still alive at the end of follow-up. Participants were observed for up to 2 years after discontinuing study therapy for survival status.