A Phase II Study Using Rituximab Plus Venetoclax in the Front Line Treatment of Marginal Zone Lymphoma

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04416451

Collaborator

AbbVie (Industry)

Enrollment

Locations

Arm

24.9

Anticipated Duration (Months)

5.9

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will help researchers understand how effective the combination of venetoclax and rituximab is in treating MZL in people who have not received a previous treatment for their cancer.

Condition or Disease	Intervention/Treatment	Phase
Marginal Zone Lymphoma	Drug: Rituximab Drug: Venetoclax	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

47 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

This is a single-arm, phase II study.This is a single-arm, phase II study.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II Study Using Rituximab Plus Venetoclax in the Front Line Treatment of Marginal Zone Lymphoma

Actual Study Start Date :

May 4, 2021

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rituximab and Venetoclax Patients will be treated with an Induction phase of rituximab 375 mg/m2 weekly for 4 weeks. Patients will undergo restaging imaging after the last of 4 weekly rituximab doses and before beginning venetoclax. Based on post-rituximab restaging studies, patients will be risk-stratified for risk of Tumor Lysis Syndrome (TLS) and treated in the appropriate setting with TLS prophylaxis per institutional TLS guide lines starting at week 5. Oral venetoclax will follow a ramp-up dosing schedule and will be taken daily after 4 weeks of rituximab therapy. Following the 4-week ramped-up phase of venetoclax, patients will begin their target dose of venetoclax and continue for a maximum of 24 months. In addition, patients will receive rituximab 375 mg/m2 starting on day 1 of the maintenance phase and repeated once every 3 months for 12 months. Venetoclax may be continued after this period if patient has not achieved a complete remission	Drug: Rituximab Induction:Rituximab will be administered per institutional guidelines once per week for 4 weeks at a dose of 375 mg/m^2. Maintenance: In addition, patients will receive rituximab 375 mg/m2 starting on day 1 of the maintenance phase and repeated once every 3 months for 12 months (for a total of 4 infusions). On days when venetoclax and rituximab will both be administered, patients will take venetoclax prior to administration of rituximab. Drug: Venetoclax Induction: Starting one week after the last induction dose of rituximab (approximately week 5), venetoclax will be administered orally at a flat dose of 100 mg daily and escalating each week to a target dose of 800 mg daily on the following schedule: Week 1: 100 mg Week 2: 200 mg Week 3: 400 mg Week 4: 800 mg Maintenance: Following the 4-week induction phase ramp-up of venetoclax, patients will begin their target dose of 800 mg venetoclax daily and continue this dose during the 24- month maintenance treatment phase. On days when venetoclax and rituximab will both be administered, patients will take venetoclax prior to administration of rituximab.

Arm

Intervention/Treatment

Experimental: Rituximab and Venetoclax

Patients will be treated with an Induction phase of rituximab 375 mg/m2 weekly for 4 weeks. Patients will undergo restaging imaging after the last of 4 weekly rituximab doses and before beginning venetoclax. Based on post-rituximab restaging studies, patients will be risk-stratified for risk of Tumor Lysis Syndrome (TLS) and treated in the appropriate setting with TLS prophylaxis per institutional TLS guide lines starting at week 5. Oral venetoclax will follow a ramp-up dosing schedule and will be taken daily after 4 weeks of rituximab therapy. Following the 4-week ramped-up phase of venetoclax, patients will begin their target dose of venetoclax and continue for a maximum of 24 months. In addition, patients will receive rituximab 375 mg/m2 starting on day 1 of the maintenance phase and repeated once every 3 months for 12 months. Venetoclax may be continued after this period if patient has not achieved a complete remission

Drug: Rituximab

Induction:Rituximab will be administered per institutional guidelines once per week for 4 weeks at a dose of 375 mg/m^2. Maintenance: In addition, patients will receive rituximab 375 mg/m2 starting on day 1 of the maintenance phase and repeated once every 3 months for 12 months (for a total of 4 infusions). On days when venetoclax and rituximab will both be administered, patients will take venetoclax prior to administration of rituximab.

Drug: Venetoclax

Induction: Starting one week after the last induction dose of rituximab (approximately week 5), venetoclax will be administered orally at a flat dose of 100 mg daily and escalating each week to a target dose of 800 mg daily on the following schedule: Week 1: 100 mg Week 2: 200 mg Week 3: 400 mg Week 4: 800 mg Maintenance: Following the 4-week induction phase ramp-up of venetoclax, patients will begin their target dose of 800 mg venetoclax daily and continue this dose during the 24- month maintenance treatment phase. On days when venetoclax and rituximab will both be administered, patients will take venetoclax prior to administration of rituximab.

Outcome Measures

Primary Outcome Measures

complete response rate (CRR) [2 years]
Will be evaluated in this study using the RECIL criteria.

Secondary Outcome Measures

overall response rates (ORR) [2 years]
Overall response rate (ORR) will be measured as the number of patients that achieve a PR or CR per RECIL criteria.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age greater than or equal to 18 years
Histologically confirmed Marginal Zone Lymphoma
Patients must have measurable disease as defined by at least one lymph node ≥1.5 cm or spleen >13 cm.

°Patients with intestinal MALT lymphoma must have disease that is detectable by EGD or colonoscopy with biopsy

Patients with gastric MALT lymphoma must be h. pylori negative

°Patients who are h. pylori positive are allowed if they have failed a trial of h.pylori eradication

Patients with gastric MALT lymphoma who are h. pylori negative or who have relapsed/refractory disease after h. pylori eradication must be ineligible for, have refused or failed gastric radiation therapy
ECOG performance status ≤ 1
Life expectancy of greater than 2 years
Patients must have normal organ function as defined below:
Platelet count ≥ 50,000 cells/mm^3
Hemoglobin ≥ 8.0 g/dL
Absolute neutrophil count ≥ 1000 cells/mcL. If there is documented bone marrow involvement, ANC must be >/= 500 cells/mcL
Total bilirubin < 1.5 x upper normal institutional limits. In patients with Gilbert's disease or documented liver involvement, total bilirubin up to 3x ULN will be allowed
AST(SGOT)/ALT(SGPT) <3 x institutional upper limit of normal unless elevation is caused by liver involvement with MZL
AST(SGOT)/ALT(SGPT) <3 x institutional upper limit of normal unless elevation is caused by liver involvement with MZL

°OR Creatinine clearance >60 mL/min for patients with creatinine levels above institutional normal (by Cockcroft-Gault estimate or 12-24h creatinine clearance measurements).

Ability to understand and the willingness to sign a written informed consent document.
Able to swallow pills
HIV-positive patients on combination antiretroviral therapy are eligible if their HIV is under adequate control with an antiretroviral regimen that has been stable for > 4 weeks, as long as the CD4 count is > 300. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
Patients with Hepatitis B surface antibody serum positivity due to prior immunization, as well as those with Hepatitis B core antibody positivity with negative PCR on antiviral therapy will be eligible.

Exclusion Criteria:

Patients who have had prior systemic therapy, including rituximab
Patients who have had prior radiation therapy, with the following exception:

°Palliative radiotherapy RT is allowed but must be completed at least 1 week prior to treatment on this study, and prior baseline imaging studies or biopsies. Patients must meet criteria for measurable/assessable disease as outlined above after completion of RT

Prior treatment with ibrutinib or other BTK inhibitor
Patients with h. pylori-associated gastric MALT or stage I/II MZL will be excluded unless they are deemed to be unfit for radiation therapy with curative intent.
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

°Patients with Hep B core ab positivity are allowed provided Hep B PCR is undetectable

Lactating or pregnant women
Participants unwilling to adhere to institutional guidelines for highly effective contraception for 12 months after the last dose of rituximab
Patients who received moderate or strong CYP3A inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 7 days prior to the first dose of venetoclax.
Patients who received moderate or strong CYP3A inducers (such as rifampin, carbamazepine, phenytoin, St. John's Wort) within 7 days prior to the first dose of venetoclax.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Cancer Center (Data collection only)	Duarte	California	United States	91010
2	Memoral Sloan Kettering Basking Ridge (All Protocol Activities)	Basking Ridge	New Jersey	United States	07920
3	Memoral Sloan Kettering Monmouth (All protocol activities)	Middletown	New Jersey	United States	07748
4	Memorial Sloan Kettering Bergen (All protocol Activities)	Montvale	New Jersey	United States	07645
5	Memorial Sloan Kettering Commack (All Protocol Activities)	Commack	New York	United States	11725
6	Memorial Sloan Kettering Westchester (All Protocol Activities)	Harrison	New York	United States	10604
7	Memorial Sloan Kettering Cancer Center (All Protocol Activities)	New York	New York	United States	10065
8	Memorial Sloan Kettering Rockville Centre (All Protocol Activities)	Rockville Centre	New York	United States	11570