Pirtobrutinib With Rituximab for the Treatment of Newly Diagnosed Marginal Zone Lymphoma

Marginal Zone Lymphoma Clinical Trial

Official title:

A Phase II Study of Pirtobrutinib in Combination With Rituximab in Newly Diagnosed Marginal Zone Lymphoma: A Risk Adapted Approach

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06390956
• Other study ID #: OSU-23307
• Secondary ID: NCI-2024-03049
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: May 1, 2024
• Est. completion date: December 31, 2025

Study information

• Verified date: April 2024
• Source: Ohio State University Comprehensive Cancer Center
• Contact: The Ohio State Comprehensive Cancer Center
• Phone: 800-293-5066
• Email: OSUCCCClinicaltrials[@]osumc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial tests how well pirtobrutinib in combination with rituximab works in treating patients with marginal zone lymphoma (MZL). Pirtobrutinib is a BTK inhibitor. It works by blocking the action of the protein that signals tumor cells to multiply. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving pirtobrutinib in combination with rituximab may be an effective treatment for MZL.

Description:

PRIMARY OBJECTIVE:

I. To assess the efficacy of the combination of pirtobrutinib and rituximab based on overall response rate (ORR) at the end of cycle (C) 6.

SECONDARY OBJECTIVES:

I. Complete response (CR) rate at end of C6. II. Duration of response (DOR). III. Median and 2-year progression-free survival (PFS). IV. Median and 2-year overall survival (OS).

EXPLORATORY OBJECTIVES:

I. To determine the rate of undetectable minimal residual disease (uMRD) at end of C6 and C12.

II. To characterize BTK and PLCG2 gene mutations, concurrently activated oncogenic pathways and the pharmacodynamic response to treatment from peripheral, bone marrow and/or tumor/lymph node biopsies before and during treatment and after disease progression (PD), in select patients.

OUTLINE:

Patients receive pirtobrutinib orally (PO) once daily (QD) on days 1-28 and rituximab intravenously (IV) on day 1 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After 6 cycles, patients with a CR receive pirtobrutinib for an additional 6 cycles and patients with partial response (PR) or stable disease (SD) receive pirtobrutinib and rituximab for an additional 6 cycles. Patients who then achieve a CR after cycle 12 may continue pirtobrutinib for an additional 6 cycles. Patients with a PR or SD after cycle 12 may continue pirtobrutinib until PD. Patients also undergo blood sample collection, computed tomography (CT) or positron emission tomography (PET)/CT and PET throughout the study. Patients may also undergo tissue biopsy at screening and relapse.

After completion of study treatment, patients are followed up at 30 days, every 3 months up to disease progression or next anticancer treatment then every 6 months.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 23
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age = 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

• Histologically documented marginal zone lymphoma, including splenic, nodal, and extranodal sub-types at the enrolling institution

• No prior systemic therapy for MZL except for the following:

• Prior antibiotic therapy for helicobacter (H.) pylori, chlamydophila (C.) psittaci, and borrelia (B.) burgdorferi

• Prior antiviral therapy for hepatitis C virus (HCV)

• Note: Subjects are eligible if they had a prior splenectomy or other local surgical treatment or local radiation therapy without systemic therapy and now require their first ever systemic therapy. In the event of the receipt of radiation therapy, the minimum wash out period is 14 days

• Patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma must be H. pylori negative or have failed a trial of H. pylori eradication

• Patients with localized MALT lymphoma must be ineligible for, have refused or failed radiation therapy (washout period of 14 days)

• Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio [INR] not greater than 1.5 x upper limit of normal [ULN])

• Life expectancy of > 3 months, in the opinion of the investigator

• Willingness of women of reproductive potential and their partners to observe highly effective birth control methods for the duration of treatment and for 1 month following the last dose of pirtobrutinib and 12 months following the last rituximab infusion

• Patients must have an indication for treatment

• Absolute neutrophil count (ANC) = 750 cells/mm^3 ( = 0.75 x 10^9/L) independent of granulocyte colony-stimulating factor [G-CSF] support, unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case ANC of 500 cells/mm^3 (0.5 x 10^9/L) is permissible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow

• Platelet count = 50,000 cells/mm^3 (= 50 x 10^9/L) independent of transfusion support unless there is documented bone marrow involvement in which case platelet count of 30,000 cells/mm^3 (0.3 x 10^9/L) is permissible. Patients must be responsive to transfusion support if given for thrombocytopenia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow

• The platelet count threshold in the current study (= 50,000 cells/mm^3 or = 50 x 10^9/L) is lower than normal threshold (= 75,000 cells/mm^3 or = 75 x 10^9/L) as the majority of MZL patients have lower than normal platelets due to splenomegaly and or autoimmune phenomena (which are related to the underlying lymphoma) and hence the lower than normal platelet count threshold for study entry

• Hemoglobin of = 8 g/dL (= 80 g/L) independent of transfusion support unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case hemoglobin of 7 g/dL (70 g/L) is permissible. Patients must be responsive to transfusion support if given for anemia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow

• Total bilirubin = 1.5 x upper limit of normal (ULN) or = 3 x ULN with document liver involvement and/or Gilbert's disease transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) = 3 x ULN or = 5 x ULN with documented liver involvement

• Calculated creatinine clearance = 30 mL/min according to Cockcroft/Gault Formula

• Ability to swallow oral tablets

• Patients or their legal representatives must be able to read, understand, and provide informed consent to participate in the trial

• Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol

Exclusion Criteria:

• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug

• Major surgery within 4 weeks prior to enrollment

• History of bleeding diathesis

• History of stroke or intracranial hemorrhage within 6 months of enrollment

• Significant cardiovascular disease defined as:

• Unstable angina or acute coronary syndrome within the past 2 months prior to study enrollment

• History of myocardial infarction within 3 months prior to study enrollment or

• Documented left ventricular ejection fraction (LVEF) by any method of = 40% in the 12 months prior to study enrollment

• Grade 3 New York Heart Association (NYHA) functional classification system of heart failure, uncontrolled or symptomatic arrhythmias

• Patients with central nervous system (CNS) involvement

• Prolongation of the QT interval corrected for heart rate (Fridericia's Correction Formula [QTcF]) > 470 msec. QTcF is calculated using Fridericia's Formula (QTcF):

• 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

• Patients who have tested positive for human immunodeficiency virus (HIV) are excluded due to potential drug-drug interactions between anti-retroviral medications and pirtobrutinib and risk of opportunistic infections with both HIV and irreversible BTK inhibitors

• 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 (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before enrollment. Patients who are HBV deoxyribonucleic acid (DNA) PCR positive will be excluded. Patients with positive anti-HBc and negative HBV DNA should be on prophylactic nucleo(t)side analogue therapy to prevent reactivation with serial HBV DNA PCR monitoring

• 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

• Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible

• Evidence of other clinically significant uncontrolled condition(s) including but not limited to, 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 medical monitor may pose a risk for patient participation. Screening for chronic conditions is not required

• Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts

• Active second malignancy unless in remission and with life expectancy > 2 years

• Pregnancy or plan to become pregnant during the study or within 1 month of the last dose of pirtobrutinib or 12 months following the last rituximab infusion

• Lactation or plan to breastfeed during the study or within 1 week of the last dose of pirtobrutinib or 6 months following the last rituximab infusion

• Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist

• Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment

• Have a known hypersensitivity to any of the excipients of Pirtobrutinib

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell, Marginal Zone
• Marginal Zone Lymphoma

Intervention

Procedure:
• Biopsy
Undergo tissue biopsy
• Biospecimen Collection
Undergo blood sample collection
• Computed Tomography
Undergo CT or PET/CT

Drug:
• Pirtobrutinib
Given PO

Procedure:
• Positron Emission Tomography
Undergo PET/CT and PET

Biological:
• Rituximab
Given IV

Locations

Country	Name	City	State
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Narendranath Epperla	Eli Lilly and Company

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall response rate (ORR)	ORR will be assessed based on revised International Working Group (IWG) criteria for non-Hodgkin lymphoma (NHL) using consistent imaging. The ORR will be reported as a percentage, with 90% binomial exact confidence interval.	At the completion of cycle 6 (each cycle is 28 days)
Secondary	Complete response (CR) rate	CR rate will be reported as a percentage, with the 95% binomial exact confidence interval.	At the completion of cycle 6 (each cycle is 28 days)
Secondary	Duration of response (DOR)	DOR will be assessed using Kaplan Meier methods. Median DOR and 95% confidence intervals will be reported.	At time of response to death or progression up to 2 years
Secondary	Progression free survival (PFS)	PFS will be analyzed using Kaplan Meier methods. Median PFS will be reported if reached, along with the corresponding 95% confidence intervals. PFS probabilities and 95% confidence intervals will also be reported at a landmark of 2 years after treatment initiation.	At initiation of treatment to progression or death up to 2 years
Secondary	Overall survival (OS)	OS will be analyzed using Kaplan Meier methods. Median OS will be reported if reached, along with the corresponding 95% confidence intervals. OS probabilities and 95% confidence intervals will also be reported at a landmark of 2 years after treatment initiation.	At initiation of treatment to death up to 2 years
Secondary	Incidence of adverse events (AEs)	AEs will be graded according to the Common Terminology Criteria for Adverse Events version 5.0. Toxicity and AE data will be reported both overall and by attribution of AEs in relation to study treatment.	Up to 30 days after last dose of study drug

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