Clinical trial NCT04115059: Dasatinib In Waldenström Macroglobulinemia
Official title: Dasatinib in Patients With Waldenström Macroglobulinemia (WM) Progressing on Ibrutinib
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Waldenstrom Macroglobulinemia
DASATINIB
Keywords: Waldenstrom Macroglobulinemia
DASATINIB
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2019-10-03
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With at Least One Treatment-Emergent Adverse Event
timeFrame: 2 years
Secondary outcomes:
measure: Overall Response Rate
timeFrame: 2 years
measure: Complete Response Rate
timeFrame: 2 years
measure: Very Good Partial Response Rate
timeFrame: 2 years
measure: Partial Response Rate
timeFrame: 2 years
measure: Minimal Response Rate
timeFrame: 2 years
measure: Stable Disease Rate
timeFrame: 2 years
measure: Progressive Disease Rate
timeFrame: From first dose through disease progression, up to 2 years from baseline
measure: Progression Free Survival
timeFrame: From first dose through disease progression, up to 2 years from baseline
measure: Time to Next Therapy (TTNT)
timeFrame: From first dose through initiation of new therapy, up to 2 years from baseline
measure: Overall Survival
timeFrame: From first dose through death, up to 2 years from baseline
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Jorge Castillo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Castillo JJ, Sarosiek S, Flynn CA, Leventoff C, Little M, White T, Meid K, Treon SP. A pilot study on dasatinib in patients with Waldenstrom macroglobulinemia progressing on ibrutinib. EJHaem. 2022 Jun 7;3(3):927-929. doi: 10.1002/jha2.493. eCollection 2022 Aug.