Overview
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)
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.
Eligibility
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.