Pirtobrutinib and Venetoclax in Waldenström Macroglobulinemia

NCT ID: NCT05734495

Last Updated: 2025-05-11

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-05-02
• Study Completion Date: 2033-01-25

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)

Detailed Description

This is a single-arm, open-label, Phase II study to evaluate the safety and efficacy of venetoclax combined with pirtobrutinib (VEN-P) in participants with symptomatic Waldenström Macroglobulinemia (WM) with previously treated disease. Pirtobrutinib blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps cells live and grow. Venetoclax blocks BCL-2, a protein essential for WM cells' survival.

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

The FDA has not approved venetoclax for Waldenström Macroglobulinemia (WM), but it has been approved for other uses.

The FDA has not approved the combination of pirtobrutinib and venetoclax as a treatment for any disease.

Study procedures include screening for eligibility, treatment visits, CT scans, blood tests, and bone marrow aspirates and biopsies.

Participants will receive study treatment for up to 2 years and will be followed for up to 4 years or until they start a new therapy.

It is expected that about 42 people will take part in this research study.

Eli Lilly supports this research study by providing study drug pirtobrutinib and funding.

Conditions

Waldenstrom Macroglobulinemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

PIRTOBRUTINIB + VENETOCLAX

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.

Group Type: EXPERIMENTAL

Pirtobrutinib

Intervention Type: DRUG

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

Venetoclax

Intervention Type: DRUG

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

Interventions

Pirtobrutinib

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

Intervention Type: DRUG

Venetoclax

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

Intervention Type: DRUG

Other Intervention Names

LY3527727, LOXO-305; ABT-199, A-1195425.0, GDC-0199, RO5537382, Venclexta, and Venclyxto.

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 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
• 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 6 months 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 1) while participating in the study; and 2) for at least 6 months after discontinuation from the study.
• Participants must have normal organ and marrow function as defined below:

• Absolute neutrophil count ≥750/ uL the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis
• Platelets ≥50,000/ uL not requiring transfusion support; the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis
• Hemoglobin ≥ 8 g/dL not requiring transfusion support or growth factors; the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis or hemolysis
• Total bilirubin ≤ 1.5 X ULN, or ≤3 x ULN with documented liver involvement, hemolysis, or Gilbert's Disease
• AST(SGOT)/ALT(SGPT) ≤3 × institutional upper limit of normal, or ≤5 X ULN with documented liver involvement
• Creatinine clearance ≥ 30 ml/min using Cockcroft/Gault formula
• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• 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

• 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.
• Malabsorption syndrome or other condition that precludes enteral route of administration.
• Participants with known history of alcohol or drug abuse.
• Participants with inability to swallow pills and inability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of the study participation
• Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) where new therapy introduced or concomitant therapy escalated within the 4 weeks prior to study enrollment is required to maintain adequate blood counts.
• Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec on at least 2/3 consecutive electrocardiograms (ECGs), and mean QTcF > 470 msec on all 3 ECGs, during Screening. QTcF is calculated using Fridericia's Formula (QTcF): QTcF=QT/(RR0.33).

• Correction of suspected drug-induced QTcF prolongation can be attempted at the Investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
• Correction for underlying bundle branch block (BBB) allowed. Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
• Significant cardiovascular disease defined as:

• Unstable angina, or
• History of myocardial infarction within 6 months prior to planned start of pirtobrutinib, or
• Previously documented left ventricular ejection fraction (LVEF) by any method of ≤ 45% in the 12 months prior to planned start of pirtobrutinib; assessment of LVEF via echocardiogram or multigated acquisition (MUGA) scan during Screening should be performed in selected patients as medically indicated, or
• Any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or
• Uncontrolled or symptomatic arrhythmias
• Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, EKG finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism or excretion of the study drug; or impair the assessment of study results
• Participants with a known hypersensitivity to any of the excipients of pirtobrutinib or venetoclax
• Participants with a history of non-compliance to medical regimens.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eli Lilly and Company

INDUSTRY

Sponsor Role: collaborator

Dana-Farber Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Jorge J. Castillo, MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jorge Castillo, MD

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

Beth Israel Deaconness Medical

Boston, Massachusetts, United States

Site Status: RECRUITING

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Jorge Castillo, MD

Role: CONTACT

jorgej_castillo@dfci.harvard.edu

617-632-6045

Kirsten Meid

Role: CONTACT

kirsten_meid@dfci.harvard.edu

617-632-6045

Facility Contacts

Gottfried von Keudell, MD

Role: primary

gkeudell@bidmc.harvard.edu

Jorge J Castillo, MD

Role: primary

jorgej_castillo@dfci.harvard.edu

617-632-6045

Other Identifiers

22-611

Identifier Type: -

Identifier Source: org_study_id