Pirtobrutinib and Venetoclax in Waldenström Macroglobulinemia

NCT05734495 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 22-611
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 2

Brief Summary

This study is being done to examine the safety and effectiveness of pirtobrutinib combined with venetoclax as a possible treatment for participants with Waldenström Macroglobulinemia (WM). The names of the study drugs involved in this study are:

• Pirtobrutinib (a Noncovalent Bruton Tyrosine Kinase (BTK) inhibitor)
• Venetoclax (a BCL2 inhibitor)

Conditions

Waldenstrom Macroglobulinemia

Keywords

Waldenstrom Macroglobulinemia; Lymphoplasmacytic lymphoma

Outcome Measures

Primary Outcomes (1)

• Very Good Partial Response (VGPR) or Better Response Rate

  VGPR or better response rate is defined as proportion of participants experienced VGPR or complete response (CR) based on modified 6th International Workshop on WM \[IWWM\] criteria (NCCN 2014).

  up to 2 years

Secondary Outcomes (11)

• Best Response

  up to 2 years

• Median Progression-Free Survival (PFS)

  up to 4 years

• Median Time to Next Treatment (TTNT)

  Up to 6 years

• Median Duration of Response (DOR)

  up to 4 years

• Median Overall Survival (OS)

  Up to 6 years

Study Arms (1)

PIRTOBRUTINIB + VENETOCLAX

EXPERIMENTAL

Participants will receive: * Standard of care bone marrow aspirate \& biopsy within 90 days of Cycle 1 Day 1. * Computed Tomography (CT) scan of chest, pelvis \& abdomen within 90 days of Cycle 1 Day 1. * Electrocardiogram at screening. * Cycle 1 * Electrocardiogram. * Day 1-28: Predetermined dose of Pirtobrutinib 1x daily. * Cycle 2 -Day 1-28: Predetermined dose Pirtobrutinib \& Venetoclax 1x daily. Tumor lysis syndrome (TLS) prophylaxis, predetermined dose Allopurinol at least 72 hrs prior to 1st administration of Venetoclax and dose escalation at Day 8 \& Day 15. * Cycles 3-24 * Day 1-28: Predetermined dose of Pirtobrutinib \& Venetoclax 1x daily. * Electrocardiogram: Cycles 3, 6, 9,12,15,18,21,24 * CT scan of chest, pelvis \& abdomen: Cycles 7, 13, End of Treatment if extramedullary disease at baseline unresolved in previous CT scan * Standard of care bone marrow aspirate and biopsy: Cycles 7, 13, End of Treatment * Follow up every 12 wks for 4 yrs.

Drug: Pirtobrutinib; Drug: Venetoclax

Interventions

Pirtobrutinib DRUG

Noncovalent Bruton Tyrosine Kinase (BTK) inhibitor, tablet taken orally.

Also known as: LY3527727, LOXO-305

PIRTOBRUTINIB + VENETOCLAX

Venetoclax DRUG

Small-molecule B-cell lymphoma-2 (Bcl-2) family inhibitor, tablet taken orally.

Also known as: ABT-199, A-1195425.0, GDC-0199, RO5537382, Venclexta, and Venclyxto.

PIRTOBRUTINIB + VENETOCLAX

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 Waldenström Macroglobulinemia, including MYD88 Wild-Type.
• At least 1 prior line of treatment.
• Prior covalent BTK inhibitor is allowed even if prior progression documented on this agent.
• Prior venetoclax is allowed unless participant had documented progression while on this agent.
• Symptomatic disease meeting criteria for treatment using consensus panel criteria from the Second International Workshop on WM. At least one of the following:
• Constitutional Symptoms
• Recurrent fever
• Night sweats
• Fatigue
• Weight loss
• Progressive or symptomatic lymphadenopathy or splenomegaly
• Hemoglobin ≤ 10 g/dL
• Platelet count ≤ 100 k/uL
• Hyperviscosity syndrome

You may not qualify if:

• Prior exposure to non-covalent BTK inhibitors
• Participants who experienced a major bleeding event or grade \> 3 arrhythmia on prior treatment with a BTK inhibitor. NOTE: Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g. retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome).
• Participants who are receiving any other investigational agents.
• Female participants who are pregnant, breastfeeding, or planning to become pregnant or breastfeed while enrolled in this study or within 6 months of last dose of study drug.
• Participants with known CNS lymphoma.
• Participants with known history of Human Immunodeficiency Virus (HIV) and known active cytomegalovirus (CMV) infection.
• Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
• Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (antiHBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before enrollment. Patients who are hepatitis B PCR positive will be excluded.
• Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before enrollment. Patients who are hepatitis C RNA positive will be excluded.
• Concurrent administration of warfarin.
• Concurrent administration of moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or strong p-glycoprotein (P-gp) inhibitors
• Concurrent systemic immunosuppressant therapy. System steroids at doses \<20mg prednisone per day are permitted.
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
• Active uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the Investigator and the Sponsor makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required.
• Major surgery within 4 weeks of first dose of study drug.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Eli Lilly and Company: collaborator

Study Sites (2)

Beth Israel Deaconness Medical

Boston, Massachusetts, 02215, United States

RECRUITING

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

MeSH Terms

Conditions

Waldenstrom Macroglobulinemia; Lymphoma, B-Cell, Marginal Zone

Interventions

pirtobrutinib; venetoclax

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma

Study Officials

• Jorge Castillo, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jorge Castillo, MD

CONTACT

617-632-6045; jorgej_castillo@dfci.harvard.edu

Kirsten Meid

CONTACT

617-632-6045; kirsten_meid@dfci.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 6, 2023
• First Posted: February 21, 2023
• Study Start: May 2, 2023
• Primary Completion (Estimated): January 25, 2029
• Study Completion (Estimated): January 25, 2033
• Last Updated: May 11, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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

Locations

US (2)