RECRUITING

Pirtobrutinib and Venetoclax in Waldenström Macroglobulinemia

Conditions

Waldenstrom Macroglobulinemia Lymphoplasmacytic lymphoma

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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)

Official Title

A Phase II Study Evaluating Venetoclax and Pirtobrutinib in Previously Treated Waldenström Macroglobulinemia

Quick Facts

Study Start:2023-05-02

Study Completion:2033-01-25

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT05734495

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
* 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: * 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.	* 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.

Inclusion Criteria

Exclusion Criteria

* 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:
* 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.

* 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.

Contacts and Locations

Study Contact

Jorge Castillo, MD

CONTACT

617-632-6045

jorgej_castillo@dfci.harvard.edu

Kirsten Meid

CONTACT

617-632-6045

kirsten_meid@dfci.harvard.edu

Principal Investigator

Jorge Castillo, MD

PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Study Locations (Sites)

Beth Israel Deaconness Medical

Boston, Massachusetts, 02215

United States

Dana Farber Cancer Institute

Boston, Massachusetts, 02215

United States

Collaborators and Investigators

Sponsor: Dana-Farber Cancer Institute

Jorge Castillo, MD, PRINCIPAL_INVESTIGATOR, Dana-Farber Cancer Institute

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2023-05-02

Study Completion Date2033-01-25

Study Record Updates

Study Start Date2023-05-02

Study Completion Date2033-01-25

Terms related to this study

Keywords Provided by Researchers

Waldenstrom Macroglobulinemia
Lymphoplasmacytic lymphoma

Additional Relevant MeSH Terms

Waldenstrom Macroglobulinemia