Bendamustine, Mitoxantrone, and Rituximab (BMR) for Patients With Untreated High Risk Follicular Lymphoma

Study Overview
=================
Brief Summary
-----------------
The goal of this clinical research study is to learn if the combination of bendamustine hydrochloride, mitoxantrone, and rituximab can help to control follicular lymphoma. The safety of this drug combination will also be studied.

Detailed Description
-----------------
The Study Drugs: Bendamustine is designed to damage and destroy the DNA (genetic material) of cancer cells. Mitoxantrone is designed to stop cancer cells from making DNA, which may stop the cells from making more cells. Rituximab is designed to attach to lymphoma cells, which may cause them to die. Study Drug Administration: If you are found to be eligible to take part in this study, you will receive the study drugs in 28-day cycles. On Days 1 and 2 of each cycle, you will receive bendamustine through a needle in a vein over 30-60 minutes. On Day 1 of each cycle, you will receive rituximab by vein over several hours, depending on how well you tolerate it. Usually, the first dose of rituximab is given over 6-8 hours. If you tolerate the first dose well, you will receive the next doses over 4 hours. On Day 2 of each cycle, you will receive mitoxantrone by vein over 15 minutes. Study Visits: At every study visit (Days 1, 8, 15, and 22 of each cycle), your vital signs will be measured. You will be asked if you have experienced any side effects and to list any drugs you may be taking. The measurement of vital signs on Days 8, 15, and 22 of each cycle may be done by your personal doctor, and the results can be sent in to the study staff. On Day 1 of each cycle, the following tests and procedures will be performed: You will have a physical exam, including measurement of your weight. Blood (about 1-2 teaspoons) will be drawn for routine tests. You will have a performance status evaluation. On Days 8, 15, and 22 of each cycles, blood (about 1 teaspoon) will be drawn for routine tests. These tests may be performed by your personal doctor, and the results can be sent in to the study staff. At the end of Cycle 3, you will have a positron emission tomography (PET) scan and/or CT scan to check the status of the disease. If your bone marrow showed lymphoma at the beginning of the study, you will have an additional bone marrow aspiration and biopsy if the disease goes away while you are on study. This will be to check the status of the disease. If at any time the doctor thinks it is necessary, you will have extra blood and urine collected for routine tests. Length of Study Participation: You may receive up to 6 cycles (about 6 months) of study treatment. If the disease gets worse or intolerable side effects occur, you will be taken off study treatment early. End-of-Study Visit: At 30-40 days after your last dose of study drugs, you will have an end-of-study visit. At this visit, the following tests and procedures will be performed: You will have a physical exam, including measurement of your vital signs and weight. You will have a performance status evaluation. Blood (about 1-2 teaspoons) will be drawn for routine tests. You will have CT and PET scans to check the status of the disease. You will be asked if you have experienced any side effects and to list any drugs you may be taking. Long-Term Follow-Up: Every 3 months for 2 years after your study treatment ends, you will have follow-up visits. If after 2 years your body shows no signs of cancer, you will have follow-up visits every 6 months after that. These follow-up tests are considered routine care. The following tests and procedures will be performed at these visits: You will have a performance status evaluation. Blood (about 1-2 teaspoons) will be drawn for routine tests. You will be asked how you are doing and whether you are receiving any new treatments for the disease. You will have CT and PET scans to check the status of the disease. The study doctor will check the results of any other scans and tests you may have for routine care. The study doctor will also check the results of physical exams you may have. This is an investigational study. All 3 study drugs are commercially available. Rituximab is FDA approved to treat follicular lymphoma. Mitoxantrone is FDA approved for use in combination for certain types of leukemia. Bendamustine is FDA approved to treat chronic lymphocytic leukemia. The combination of rituximab, mitoxantrone, and bendamustine is not FDA approved to treat follicular lymphoma. At this time, it is only being used in research. Up to 37 patients will take part in this study. All will be enrolled at M. D. Anderson.

Official Title
-----------------
A Phase II Study of Bendamustine, Mitoxantrone, and Rituximab (BMR) for Patients With Untreated High Risk Follicular Lymphoma

Conditions
-----------------
Follicular Lymphoma

Intervention / Treatment
-----------------
* Drug: Bendamustine
* Drug: Mitoxantrone
* Drug: Rituximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age >18 years at the time of signing the informed consent form. Able to adhere to the study visit schedule and other protocol requirements. Untreated grade 1, 2, or 3a follicular non-Hodgkin's lymphoma. At least one measurable lesion according to the International Working Group Criteria for Response, of greater that 1.5cm. Eastern Cooperative Oncology Group (ECOG) performance status of < 2 at study entry. Laboratory test results within these ranges: Absolute neutrophil count >/=1.5 x 10^9/L; Platelet count >/=100 x 10^9/L; Serum creatinine </= 2.0 mg/dL; Total bilirubin </= 1.5 mg/dL; AST (SGOT) and ALT (SGPT) </= 2 x upper limit of normal (ULN) or </= 5 x ULN if hepatic metastases are present. Disease free of prior malignancies for at least 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or breast. Have a high risk FLIPI score, as defined by a FLIPI score >/= 3. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 milli-International unit (mIU)/mL within 10 to 14 days prior to study entry. An ejection fraction of >/= 50% as documented by a cardiac function study. Exclusion Criteria: Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. Pregnant or breast feeding females. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Use of any prior chemotherapy for follicular lymphoma. Known hypersensitivity to Bendamustine, mitoxantrone, or mannitol. A history of congestive heart failure. Any prior use of bendamustine or mitoxantrone. Concurrent use of other anti-cancer agents or experimental treatments. Known positive for HIV or infectious hepatitis type B or C. Creatinine clearance less than 40 ml/min. A known history of hepatic insufficiency (patients with a history of fulminate hepatic failure, hepatic encephalopathy, cirrhosis, and autoimmune hepatitis). Any history of grade 3b follicular lymphoma.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bendamustine + Mitoxantrone + Rituximab<br>Bendamustine starting dose 90 mg/m^2 intravenously (IV) over 30-60 minutes on Days 1 and 2 of each 8-day cycle. Mitoxantrone 10 mg/m^2 IV over 15 minutes on Day 2 of each cycle. Rituximab 375 mg/m^2 IV over several hours on Day 1 of each cycle. | Drug: Bendamustine<br>* Starting dose 90 mg/m^2 by vein over 30-60 minutes on Days 1 and 2 of each cycle.<br>* Other names: Treanda;Drug: Mitoxantrone<br>* 10 mg/m^2 by vein over 15 minutes on Day 2 of each cycle.<br>* Other names: Novantrone;Drug: Rituximab<br>* 375 mg/m^2 by vein over several hours on Day 1 of each cycle.<br>* Other names: Rituxan;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate of the Combination of BMR (Bendamustine + Mitoxantrone + Rituximab) | To evaluate the complete response rate of the combination of BMR in previously untreated follicular non-Hodgkin's lymphoma. CR defined by International Working Group Criteria for Response for Non-Hodgkin's Lymphoma as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Adverse Events | To evaluate the toxicity and safety of BMR in participants with untreated follicular lymphoma. | 3 months | 
| Time to Progression (TTP) for Participants Treated With BMR (Bendamustine, Mitoxantrone, and Rituximab) | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 5 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Novantrone, Lymphoma, Non-Hodgkin's Lymphoma, Untreated High Risk Follicular Lymphoma, Bendamustine hydrochloride, Bendamustine HCI, Bendamustine, CEP-18083, SDX-105, Treanda, Mitoxantrone, Rituximab, Rituxan