Dasatinib In Waldenström Macroglobulinemia

Dasatinib in Patients With Waldenström Macroglobulinemia (WM) Progressing on Ibrutinib

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

Study Overview

• Status: Terminated
• Conditions: Waldenstrom Macroglobulinemia; DASATINIB
• Intervention / Treatment: Drug: Dasatinib

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jorge Castillo, MD; Phone Number: (617) 632-4218; Email: jorgej_castillo@dfci.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Dasatinib; Oral, daily, dosing per protocol, once a day for cycle; Other Names: Sprycel

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	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).	2 years
Complete Response Rate	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.	2 years
Very Good Partial Response Rate	Percentage of patients with very good partial response (VGPR) to therapy. (VGPR is >90% reduction in serum IgM from baseline)	2 years
Partial Response Rate	Percentage of patients with partial response (PR) to therapy. (PR is 50-89% reduction in serum IgM from baseline)	2 years
Minimal Response Rate	Percentage of patients with Minor Responses to therapy. (MR is 25-49% reduction in serum IgM from baseline)	2 years
Stable Disease Rate	Percentage of patients with Stable disease to therapy. (SD is <25% reduction in serum IgM from baseline).	2 years
Progressive Disease Rate	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.	From first dose through disease progression, up to 2 years from baseline
Progression Free Survival	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.	From first dose through disease progression, up to 2 years from baseline
Time to Next Therapy (TTNT)	The amount of time between starting study treatment and initiating a new therapy	From first dose through initiation of new therapy, up to 2 years from baseline
Overall Survival	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.	From first dose through death, up to 2 years from baseline

Collaborators and Investigators

• Sponsor: Jorge J. Castillo, MD
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Jorge Castillo, MD, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2019
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: October 2, 2019
• First Submitted That Met QC Criteria: October 2, 2019
• First Posted (Actual): October 3, 2019

Study Record Updates

• Last Update Posted (Actual): March 21, 2024
• Last Update Submitted That Met QC Criteria: September 12, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Waldenstrom Macroglobulinemia; DASATINIB
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Waldenstrom Macroglobulinemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Dasatinib
• Other Study ID Numbers: 19-305

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No