MRD Guided De-intensification of Bendamustine/Rituximab for Indolent Non-Hodgkin Lymphoma

HM-225: Measurable Residual Disease (MRD) Guided De-intensification of Bendamustine/Rituximab (BR) for Indolent Non-Hodgkin Lymphoma

This is a phase II pilot, single arm, open label study designed to assess the efficacy, safety, and feasibility of MRD adapted duration of BR for untreated or R/R iNHL.

Study Overview

• Status: Not yet recruiting
• Conditions: Lymphoma; Indolent Non-hodgkin Lymphoma
• Intervention / Treatment: Drug: Bendamustine; Drug: Rituximab

Detailed Description

This is a phase II pilot, single arm, open label study designed to assess the efficacy, safety, and feasibility of MRD adapted duration of BR for untreated or R/R iNHL.

All patients with untreated or R/R (not previously treated with Bendamustine) iNHL (Follicular Lymphoma (Grade 1-3a2), Marginal Zone Lymphoma, Lymphoplasmacytic Lymphoma) are candidates for this trial. Patients requiring treatment per treating physician's discretion are eligible for the trial.

Patients who recently started on and received two cycles of Bendamustine at 90 mg/m2 dose with Ritxumab 375 mg/m2 are also eligible for this trial. For these patients, C2D1 BR should be no more than 14 days prior to the time of study enrollment (i.e. enrollment no later than C2D14). Patients who have received two cycles of 90mg/m2 Bendamustine dose with Rituximab 375 mg/m2 can enter the study and initiate cycle 3 once pre-screening and screening procedures have been completed.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Abigail O'Keefe; Phone Number: 215-728-2451; Email: abigail.o'keefe@fccc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Patients must have pathologically confirmed:

• indolent Non-Hodgkin Lymphoma, consistent with one of the below diagnoses:
• Follicular Lymphoma (Grade 1-3a)
• Marginal Zone Lymphoma
• Lymphoplasmacytic Lymphoma

Patient may be treatment naïve or relapsed/refractory without having received prior Bendamustine or patients recently started on Bendamustine 90 mg/m2 with Rituximab 375 mg/m2 are eligible if C2D1 BR is no more than 14 days prior to enrollment and they otherwise meet eligibility criteria

• Age > 18 years
• ECOG performance status 0-2

Patients must have normal organ and marrow function as defined below:

• Absolute Neutrophil Count >1000mm3 and Hemoglobin >8 g/dL (unless due to bone marrow involvement by lymphoma)
• Total bilirubin > 1.5x upper limit of normal (patients with Gilbert's syndrome can have total bilirubin up to 3x upper normal limit)
• Aspartate aminotransferase/ alanine aminotransferase (serum glutamic-oxaloacetic transaminase/ serum glutamic-pyruvic transaminase) < 5 times institutional normal limits
• Creatinine clearance > 30 Ml/min

Exclusion Criteria:

• Radiation or systemic treatment for lymphoma within the past 28 days prior to cycle 1 day 1 of BR.
• Patients with pathologically confirmed transformed lymphoma, including diffuse large B cell lymphoma or other high grade lymphomas
• Patients on active treatment for second malignancy with the exception of endocrine therapy for non-metastatic breast cancer, hormone therapy for prostate cancer, or local treatment for non-melanoma skin cancer.
• Pregnant or breast-feeding. Refer to section 5.4 for further detail.
• Failure to identify a dominant clonal sequence with ClonoSEQ from pre-treatment specimen or inadequate tissue for testing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Single Arm; This is a phase II pilot, single arm, open label study designed to assess the efficacy, safety, and feasibility of Measurable Residual Disease (MRD) adapted duration of BR for untreated or R/R iNHL (indolent non-hodgkin lymphoma). All patients will receive Bendamustine 90 mg/m2 IV on Days 1-2 and Rituximab 375 mg/m2 IV(BR) on Day 1 of each cycle. Each cycle will last 28 days. On day 1 of each cycle, patients will receive Rituximab before Bendamustine, and CBC (complete blood count), CMP (comprehensive metabolic panel) will be obtained to capture any hematologic toxicities as well as clonoSEQ testing to determine MRD status. After completing Cycle 3, imaging results (with confirmatory biopsy if applicable) and the clonoSEQ MRD testing results obtained from ctDNA (blood collection) will determine whether patients will receive Cycles 5 and 6 of Bendamustine and Rituximab (BR).

Drug: Bendamustine; Bendamustine will be administered as 10 minute IV infusion at 90 mg/m2 (drug dose calculation is based on treatment day weight) on days 1 and 2 for 4-6 cycles (number of cycles determined per treatment design). Subjects will be dosed every 28 days. Ondansetron 16 mg IV is given as premedication per institutional guidelines. Dose modifications will be determined based on renal and hepatic function. Subjects should be carefully monitored for infusion reactions during Bendamustine administration. If an acute infusion reaction is noted, subjects should be managed according to institutional guidelines. Doses of Bendamustine may be interrupted, delayed, or discontinued depending on how well the subject tolerates the treatment based on physician discretion.; Other Names: cytostasan; belrapzo; treanda; vivimusta; Drug: Rituximab; Rituximab will be administered as an IV infusion at 375 mg/m2 (longer for the first dose) (drug dose calculation is based of treatment day weight) on day 1 for 4-6 cycles (number of cycles determined per treatment design). Infusion rate will be determined as per institutional standards. Subjects will be dosed every 28 days. Diphenhydramine 50 mg IV and acetaminophen 650 mg are required to be given to the subjects within 30 minutes prior to Rituximab dose. There are no dose modifications recommended with Rituximab. If an acute infusion reaction is noted, subjects should be managed according to institutional guidelines. Doses of Rituximab may be interrupted, delayed, or discontinued depending on how well the subject tolerates the treatment.; Other Names: Rituxan; Ruxience; Truxima; Azulfidine; riabni

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS Evaluation	To evaluate the 2-year progression free survival (PFS) for patients treated with Bendamustine and Rituximab (BR) with measurable residual disease directed (MRD) duration of therapy.	2 years
Statistical PFS	The proportion (p) of patients who are progression-free and are alive at 2 years from the initiation of treatment using Lugano Criteria.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary Outcome Measure	Assess additional clinical outcomes including overall survival (OS),	2 years
Measurable Residual Disease Evaluation	To determine the rate of MRD (minimal residual disease) negativity at end of treatment and at 2 years post-treatment	2 years
Adverse Event assessment	Assess adverse effects of treatment	2 years
Overall Survival Assessment	OS, defined as time from initiation of study treatment until death, or the end of follow-up, whichever occurs first. Patients who are still alive at the end of follow-up will be considered censored.	2 years
Measurable Residual Disease Negativity	To evaluate MRD negativity rate at the end of treatment and at 2 years post-treatment.	2 years
Rate of 3+ adverse events	The rate of grade 3+ adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0.The rate of grade 3+ adverse events as assessed by CTCAE v5.0.	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Outcome Measures	Assess and compare measurable residual disease (MRD) sensitivity of both circulating tumor DNA (ctDNA) and circulating tumor cells (CTC), both being obtained at baseline, after each cycle, and during follow up	2 years
Measurable Residual Disease (MRD)	Assess MRD level, both ctDNA and circulating tumor cell (CTC) testing, after each cycle of Bendamustine and Rituximab (BR) and correlate with Progression Free Survival (PFS)	2 years
Progression Free Survival (PFS) for Measurable Residual Disease (MRD)	To evaluate PFS for patients with low level detectable MRD (10^-4 to 10^-6) after 3 cycles of Bendamustine and Rituximab	2 years
Measurable Residual Disease (MRD) to guide indolent lymphoma treatment evaluation	Evaluate feasibility of using MRD to guide treatment for indolent lymphoma	2 years
Measurable Residual Disease (MRD) failure rate	Determine MRD test baseline failure rate from ctDNA and Circulating Tumor Cell (CTC) testing	2 years
Infection occruance	Assess occurrence of infection of any grade	2 years
Secondary malignancy occurrence	Assess occurrence of secondary malignancy	2 years
Ntural Killer and T cell reconstitution	Assess the rate of NK (natural kiler) cell and T cell subset reconstitution after Bendamustine and Rituximab; distinguish if there is difference between shorter/longer treatment regimens	2 years
Quality Life Assessment	Assess differences in quality of life based on Functional Assessment of Cancer Therapy (FACT-Lym) questionnaire between patients who received varying lengths of treatment.	2 years
Baseline Proliferative Rate	Correlation of baseline proliferative rate	2 years

Collaborators and Investigators

• Sponsor: Fox Chase Cancer Center
• Collaborators: Adaptive Biotechnologies
• Investigators: Principal Investigator: Marcus Messmer, Fox Chase Cancer Center

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2025
• Primary Completion (Estimated): September 29, 2027
• Study Completion (Estimated): March 30, 2028

Study Registration Dates

• First Submitted: August 9, 2024
• First Submitted That Met QC Criteria: August 13, 2024
• First Posted (Actual): August 16, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 3, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Antineoplastic Agents, Immunological; Anti-Infective Agents; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Antirheumatic Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Alkylating; Alkylating Agents; Bendamustine Hydrochloride; Rituximab; Sulfasalazine
• Other Study ID Numbers: 24-1014, HM-225

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No