Rituximab and Combination Chemotherapy in Treating Patients With Previously Untreated Mantle Cell Lymphoma

Phase II Study of Rituximab in Combination With Methotrexate, Doxorubicin, Cyclophosphamide, Leucovorin, Vincristine, Ifosfamide, Etoposide, Cytarabine and Mesna (R-MACLO/IVAM) in Patients With Previously Untreated Mantle Cell Lymphoma

The investigator(s) hypothesize that Rituximab together with combination chemotherapy, followed by Rituximab maintenance therapy, will provide better disease control with improved response rates and overall survival in patients with previously untreated Mantle Cell Lymphoma (MCL).

Study Overview

• Status: Completed
• Conditions: Mantle-Cell Lymphoma
• Intervention / Treatment: Biological: G-CSF; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Doxorubicin; Drug: Etoposide; Drug: Ifosfamide; Drug: Leucovorin; Drug: Mesna; Drug: Methotrexate; Drug: Vincristine

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33186
      • University of Miami

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Previously untreated, histologically confirmed mantle cell lymphoma,
2. Measurable or evaluable disease (at least one site with >1.5 cm in diameter
3. All stages are eligible
4. Age > 18 years
5. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2

6. Adequate hepatic function:

   • Bilirubin < 3 mg/dL
   • Transaminases (serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamate-pyruvate transaminase (SGPT)) < than 2.5 times the upper limit of normal for the institution, unless due to lymphomatous involvement
7. Serum creatinine< 1.5 mg/dl
8. Ability to give informed consent
9. Women of childbearing potential must have a negative pregnancy test within 72 hours of entering into the study. Males and females must agree to use adequate birth control if conception is possible during the study. Women must avoid pregnancy and men avoid fathering children while in the study.
10. Life expectancy greater than 6 months.

Exclusion Criteria:

1. Previous chemotherapy, immunotherapy or radiotherapy for this mantle cell lymphoma
2. Concurrent active malignancies, with the exception of in situ carcinoma of the cervix and basal cell carcinoma of the skin.
3. Grade 3 or 4 cardiac failure and/or ejection fraction < 50.
4. Psychological, familial, sociological or geographical conditions that do not permit treatment and/or medical follow-up required to comply with the study protocol.
5. Patients with a known history of human immunodeficiency virus (HIV) or Acquired Immunodeficiency Syndrome (AIDS).
6. Presence of hepatitis or hepatitis B virus (HBV) infection.
7. Pregnant or breast-feeding women.
8. Central Nervous System (CNS) involvement.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• 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: R-MACLO/IVAM Group; Participants in this group will receive four 21-day cycles of combination R-MACLO/IVAM induction therapy, followed by Rituximab maintenance therapy as follows: Induction Therapy: Cycles 1 and 3: Rituximab, Doxorubicin, Vincristine, Cyclophosphamide, Methotrexate, Leucovorin and Granulocyte-colony stimulating factor (G-CSF); Cycles 2 and 4: Rituximab, Cytarabine, Ifosfamide, Mesna, Etoposide, and G-CSF. Maintenance Therapy: Rituximab: For study participants in complete remission. Every 6 months for up to 3 years. Total participation duration is about 4 years. Participants will be followed for survival.

Biological: G-CSF; Granulocyte-colony stimulating factor (G-CSF) 480 mcg subcutaneously starting on Day 13 of Cycles 1 and 3; and Day 7 of Cycles 2 and 4.; Other Names: Filgrastim; Neupogen; Drug: Rituximab; Rituximab 375 mg/m^2 intravenously (IV) on Day 1 for 4 Cycles during induction therapy. Participants achieving complete remission will then receive Rituximab maintenance therapy every 6 months for up to three years.; Other Names: Rituxan; Drug: Cyclophosphamide; Cyclophosphamide 800 mg/m^2 IV on Day 1 and 200 mg/m^2 IV on Days 2 through 5 of Cycles 1 and 3.; Other Names: Cytoxan; Drug: Cytarabine; Cytarabine (AraC) 2 grams/m^2 IV on Days 1 and 2 of Cycles 2 and 4.; Other Names: AraC; Drug: Doxorubicin; Doxorubicin 45 mg/m^2 IV bolus on Day 1 of Cycles 1 and 3.; Other Names: Adriamycin; Drug: Etoposide; Etoposide (VP16) 60 mg/m^2 IV on Days 1 through 5 of Cycles 2 and 4.; Other Names: VP16; Drug: Ifosfamide; Ifosfamide 1.5 grams/m^2 IV on Days 1 through 5 of Cycles 2 and 4.; Other Names: Ifex; Drug: Leucovorin; Leucovorin 100 mg/m^2 IV beginning 36 (+/-4) hours after start of Methotrexate infusion, and then 10 mg/m^2 at 6 hour (+/- 30 min) intervals until Methotrexate level is < 0.1 µmol/L during Cycles 1 and 3.; Other Names: Folinic acid; Drug: Mesna; Mesna 360 mg/m^2 IV on Days 1 through 5 of Cycles 2 and 4.; Other Names: Mesnex; Drug: Methotrexate; Methotrexate (MTX) 1,200 mg/m^2 in 250 mL with Dextrose 5% in water (D5W) IV over 1 hour, followed by Methotrexate 3,000 mg/m^2 in 1,000 mL D5W by continuous infusion over 23 (+/-2) hours on Day 10 of Cycles 1 and 3.; Other Names: MTX; Drug: Vincristine; Vincristine 1.5 mg/m^2 IV push (maximum of 2 mg) on Days 1 and 8 of Cycles 1 and 3.; Other Names: Oncovin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Progression-Free Survival (PFS) among study participants. PFS is defined as the time in years from start of treatment to the earliest one of the following events: relapse (in patients who achieve complete response), disease progression (in patients with partial response or stable disease), or death. PFS will be evaluated by treating physician from staging Computed Tomography (CT) or Positron Emission Tomography (PET) scans.	Up to 12 years
Progression-Free Survival (PFS) Rate at 5 Years Using Kaplan-Meier Method	Progression-Free Survival (PFS) rate at 5 years estimated by the Kaplan-Meier method will be reported as percentage probability of participants alive without relapse or disease progression at 5 years after starting study therapy. PFS is defined as the time from start of treatment to the earliest one of the following events: relapse (in patients who achieve complete response), disease progression (in patients with partial response or stable disease), or death. PFS will be evaluated by treating physician from staging Computed Tomography (CT) or Positron Emission Tomography (PET) scans.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) Rate at 5 Years Using Kaplan-Meier Method	Overall Survival (OS) rate at 5 years estimated by the Kaplan-Meier method will be reported as percentage probability of survival beyond 5 years. OS is defined as elapsed time from start date of treatment to date of death from any cause. Alive participants will be censored at last date known to be alive.	5 years
Rate of Response to Study Therapy	The rate of response to study therapy will be reported as the number of participants achieving complete response (CR), complete response/unconfirmed (CRu) or partial response (PR) to protocol therapy according to criteria assignable to Non-Hodgkin's Lymphoma (NHL). Response assessment will be done by CT and Positron emission tomography (PET) scans, and bone marrow biopsy/aspirate, if clinically indicated.	Up to 8 years
Number of Participants Experiencing Treatment-Related Serious Adverse Events During R-MACLO/IVAM Induction Therapy	The number of participants experiencing treatment-related serious adverse events (SAEs) during R-MACLO/IVAM induction therapy. AEs and SAEs will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0, as evaluated by treating physician.	Up to 4 months
Number of Participants Experiencing Treatment-Related Adverse Events During R-MACLO/IVAM Induction Therapy	The number of participants experiencing treatment-related adverse events (AEs) during R-MACLO/IVAM induction therapy. AEs and SAEs will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0, as evaluated by treating physician.	Up to 4 months

Collaborators and Investigators

• Sponsor: University of Miami
• Investigators: Principal Investigator: Izidore S. Lossos, MD, University of Miami

Publications and helpful links

General Publications

• Alderuccio JP, Saul EE, Iyer SG, Reis IM, Alencar AJ, Rosenblatt JD, Lossos IS. R-MACLO-IVAM regimen followed by maintenance therapy induces durable remissions in untreated mantle cell lymphoma - Long term follow up results. Am J Hematol. 2021 Jun 1;96(6):680-689. doi: 10.1002/ajh.26163. Epub 2021 Apr 7.

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2009
• Primary Completion (Actual): June 28, 2024
• Study Completion (Actual): May 30, 2025

Study Registration Dates

• First Submitted: April 7, 2009
• First Submitted That Met QC Criteria: April 7, 2009
• First Posted (Estimated): April 8, 2009

Study Record Updates

• Last Update Posted (Actual): July 23, 2025
• Last Update Submitted That Met QC Criteria: July 2, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Non-Hodgkin's Lymphoma
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Mantle-Cell; Antineoplastic Agents, Immunological; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Antiviral Agents; Micronutrients; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Topoisomerase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Protective Agents; Antidotes; Vitamin B Complex; Vitamins; Rituximab; Methotrexate; Cyclophosphamide; Cytarabine; Etoposide; Leucovorin; Doxorubicin; Vincristine; Ifosfamide
• Other Study ID Numbers: 20080803; SCCC-2008043 (Other Identifier: University of Miami Sylvester Comprehensive Cancer Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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