Dasatinib In Waldenström Macroglobulinemia

• ClinicalTrials.gov Identifier: NCT04115059
• Recruitment Status: Recruiting
• First Posted: October 3, 2019
• Last Update Posted: March 24, 2022
• Sponsor: Jorge J. Castillo, MD
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Jorge J. Castillo, MD, Dana-Farber Cancer Institute

Study Description

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

Condition or disease	Intervention/treatment	Phase
Waldenstrom Macroglobulinemia; DASATINIB	Drug: Dasatinib	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Dasatinib in Patients With Waldenström Macroglobulinemia (WM) Progressing on Ibrutinib
• Actual Study Start Date: November 4, 2019
• Actual Primary Completion Date: March 1, 2022
• Estimated Study Completion Date: March 1, 2024

Arms and Interventions

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 Name: Sprycel

Outcome Measures

Primary Outcome Measures :

1. To evaluate the toxicity profile of dasatinib in WM patients who progressed on ibrutinib with BTK or PLCG2 mutations. [ Time Frame: 2 years ]
   Number and type of toxicities experienced by patients related to dasatinib.

Secondary Outcome Measures :

1. Overall Response Rate [ Time Frame: 2 years ]
   Proportion of patients with MR, PR, VGPR, or CR to therapy.
2. Complete Response Rate [ Time Frame: 2 years ]
   Proportion of patients with CR
3. Very good partial response rate [ Time Frame: 2 years ]
   Proportion of patients with VGPR to therapy. (VGPR is >90% reduction in serum IgM from baseline)
4. Partial Response Rate [ Time Frame: 2 years ]
   Proportion of patients with PR to therapy. (PR is 50-89% reduction in serum IgM from baseline)
5. Minimal Response Rate [ Time Frame: 2 years ]
   Proportion of patients with Minor Responses to therapy. (MR is 25-49% reduction in serum IgM from baseline)
6. Stable Disease Rate [ Time Frame: 2 years ]
   Proportion of patients with Stable disease to therapy. (SD is <25% reduction in serum IgM from baseline).
7. Progressive Disease Rate [ Time Frame: 2 years ]
   Proportion of patients with a best response of PD to therapy. (PD is >25% increase in serum IgM from baseline).
8. Progression Free Survival [ Time Frame: 2 years ]
   Kaplan Meier methodology
9. Time to Next Therapy (TTNT) [ Time Frame: 2 years ]
   Kaplan Meier
10. Overall Survival [ Time Frame: 2 years ]
    Kaplan Meier

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Jorge Castillo, MD; (617) 632-4218; jorgej_castillo@dfci.harvard.edu

Locations

United States, Massachusetts

Dana Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Jorge J Castillo, MD 617-632-6045 Jorgej_castillo@dfci.harvard.edu

Principal Investigator: Jorge J Castillo, MD

Sponsors and Collaborators

Jorge J. Castillo, MD

Bristol-Myers Squibb

Investigators

• Principal Investigator: Jorge Castillo, MD; Dana-Farber Cancer Institute

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Jorge J. Castillo, MD, Sponsor Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT04115059
• Other Study ID Numbers: 19-305
• First Posted: October 3, 2019
• Last Update Posted: March 24, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jorge J. Castillo, MD, Dana-Farber Cancer Institute:

Waldenstrom Macroglobulinemia; DASATINIB

Additional relevant MeSH terms:

Waldenstrom Macroglobulinemia; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Dasatinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action