Bendamustine and Rituximab Alternating With Cytarabine and Rituximab for Untreated Mantle Cell Lymphoma

• ClinicalTrials.gov Identifier: NCT02728531
• Recruitment Status: Active, not recruiting
• First Posted: April 5, 2016
• Last Update Posted: May 19, 2020
• Sponsor: Washington University School of Medicine
• Information provided by (Responsible Party): Washington University School of Medicine

Tracking Information

• First Submitted Date: March 30, 2016
• First Posted Date: April 5, 2016
• Last Update Posted Date: May 19, 2020
• Actual Study Start Date: April 18, 2016
• Actual Primary Completion Date: January 16, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 19, 2018)

Stem cell mobilization success rate [ Time Frame: Completion of stem cell mobilization (approximately 25 weeks) ]

-Stem cell mobilization success is defined as a yield of ≥ 2 x 106 CD34+ stem cells/kg with a maximum of 5 courses of apheresis.

Original Primary Outcome Measures (submitted: March 30, 2016)

Stem cell mobilization success rate [ Time Frame: Completion of stem cell mobilization (approximately 20 weeks) ]

-Stem cell mobilization success is defined as a yield of ≥ 2 x 106 CD34+ stem cells/kg with a maximum of 5 courses of apheresis.

Current Secondary Outcome Measures (submitted: December 19, 2018)

• Overall response rate [ Time Frame: Completion of treatment (approximately 24 weeks) ]
  -Response to treatment is guided based upon the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification.
• Pre-transplant complete response rate (CRR) [ Time Frame: Completion of treatment (approximately 24 weeks) ]
  CRR=

  • Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.
  • London Deauville score of 1 and 2 in lymph nodes and extra lymphatic sites is considered to represent complete metabolic response. A London Deauville score 3 in the post treatment PET scan may be considered to represent complete metabolic response especially if it is not higher than the surrounding normal physiologic uptake.
  • No evidence of FDG avid disease in the bone marrow
  • No new lesions
  • If the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy.
• Progression-free survival (PFS) [ Time Frame: 5 years ]
  -PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
• Overall survival (OS) [ Time Frame: 5 years ]
• Safety and tolerability of bendamustine and rituximab alternating with cytarabine and rituximab as measured by grades 3 or higher toxicities [ Time Frame: 30 days following completion of treatment (approximately 29 weeks) ]
  The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.

Original Secondary Outcome Measures (submitted: March 30, 2016)

• Overall response rate [ Time Frame: Completion of treatment (approximately 18 weeks) ]
  -Response to treatment is guided based upon the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification.
• Pre-transplant complete response rate (CRR) [ Time Frame: Completion of treatment (approximately 18 weeks) ]
  • Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.
  • London Deauville score of 1 and 2 in lymph nodes and extra lymphatic sites is considered to represent complete metabolic response. A London Deauville score 3 in the post treatment PET scan may be considered to represent complete metabolic response especially if it is not higher than the surrounding normal physiologic uptake.
  • No evidence of FDG avid disease in the bone marrow
  • No new lesions
  • If the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy.
• Progression-free survival (PFS) [ Time Frame: 5 years ]
  -PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
• Overall survival (OS) [ Time Frame: 5 years ]
• Safety and tolerability of bendamustine and rituximab alternating with cytarabine and rituximab as measured by grades 3 or higher toxicities [ Time Frame: 30 days following completion of treatment (approximately 22 weeks) ]
  The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Bendamustine and Rituximab Alternating With Cytarabine and Rituximab for Untreated Mantle Cell Lymphoma
• Official Title: A Pilot Study of Bendamustine and Rituximab Alternating With Cytarabine and Rituximab for Untreated Mantle Cell Lymphoma
• Brief Summary: Given the established role of high dose cytarabine (HiDAC) combined with rituximab, along with recent data showing the encouraging efficacy of bendamustine, the investigators seek to integrate the synergistic effects of these medicines in alternating cycles as induction therapy prior to autologous stem cell transplant (ASCT). Based on prior experience with bendamustine and rituximab (BR) based induction therapy, the investigators seek to evaluate the efficacy and safety of stem cell mobilization in this pilot study
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Mantle Cell Lymphoma

Intervention

• Drug: Bendamustine
  Other Names:

  • Bendamustine Hydrochloride
  • Treanda
• Drug: Rituximab
  Other Name: Rituxan
• Drug: Cytarabine
  Other Names:

  • Cytosar-U
  • Tarabine PFS
• Drug: Pegfilgrastim
  Other Names:

  • Neulasta
  • G-CSF
• Procedure: Leukapheresis
• Drug: Filgrastim
  Other Name: Neupogen
• Procedure: Autologous stem cell transplant

Study Arms

Experimental: Bendamustine, Rituximab, Cytarabine

• Bendamustine on Days 1 and 2 of Cycles 1, 3, and 5.
• In Cycle 1, rituximab on Day 1 or 2 at the investigator's discretion. Given on Day 1 of Cycles 2 through 6.
• On Days 1 and 2 of Cycles 2, 4, and 6, cytarabine will be administered every 12 hours for a total of 4 doses.
• Growth factor will be administered subcutaneously within 72 hours of completion of each even-numbered cycles of chemotherapy.
• Leukapheresis will begin when the total WBC ≥ 5000/ μL and continue daily until collection of ≥ 2x106 CD34+ cells/kg (with a maximum of 5 courses of apheresis).
• Standard of care peripheral blood autologous stem cell harvest will proceed per institutional guidelines and begin during Cycle 6 following rituximab and cytarabine therapy, when the total WBC ≥ 5000/ μL. Collection will continue on a daily basis until collection of ≥ 2x106 CD34+ cells/kg.

Interventions:

• Drug: Bendamustine
• Drug: Rituximab
• Drug: Cytarabine
• Drug: Pegfilgrastim
• Procedure: Leukapheresis
• Drug: Filgrastim
• Procedure: Autologous stem cell transplant

• Publications *: Merryman RW, Edwin N, Redd R, Bsat J, Chase M, LaCasce A, Freedman A, Jacobson C, Fisher D, Ng S, Crombie J, Kim A, Odejide O, Davids MS, Brown JR, Jacene H, Cashen A, Bartlett NL, Mehta-Shah N, Ghobadi A, Kahl B, Joyce R, Armand P, Jacobsen E. Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma. Blood Adv. 2020 Mar 10;4(5):858-867. doi: 10.1182/bloodadvances.2019001355.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 5, 2018): 18
• Original Estimated Enrollment (submitted: March 30, 2016): 15
• Estimated Study Completion Date: September 30, 2023
• Actual Primary Completion Date: January 16, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed mantle cell lymphoma with documented expression of CD20 (or CD 19) and cyclin D1 (BCL1) by immunohistochemical stains and/or t (11; 14) by cytogenetics or FISH
• Eighteen to 65 years of age, inclusive.
• Presence of evaluable disease by PET imaging per the Lugano classification (Cheson 201418)
• Eligible for autologous stem cell transplantation.
• ECOG performance status ≤ 2

• Normal bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1,000/mcl unless in the opinion of the treating physician, neutropenia is due to splenomegaly or bone marrow involvement
  • Platelets ≥ 100,000/mcl unless in the opinion of the treating physician, thrombocytopenia is due to splenomegaly or bone marrow involvement
  • Total bilirubin ≤ 2 x IULN and AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN except when, in the opinion of the treating physician, is due to direct involvement of lymphoma (e.g., hepatic infiltration or biliary obstruction due to lymphoma) or Gilbert's disease
  • Creatinine ≤ IULN OR creatinine clearance ≥ 40 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
• Negative HIV serology.

Exclusion Criteria:

• Any previous chemotherapy or radiation for mantle cell lymphoma. Short course of steroids for symptom relief prior to presentation is permissible.
• Symptomatic meningeal or parenchymal brain lymphoma.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to rituximab, cytarabine, bendamustine or other agents used in the study.
• Severe concurrent illness, which would limit compliance with study requirements.
• Subjects with serologic status reflecting active viral hepatitis B or C infection are not eligible. Subjects whoare hepatitis B core antibody positive but antigen negative will need negative polymerase chain reaction (PCR) prior to enrollment. Hepatitis B surface antigen positive or PCR positive patients will be excluded. Subjects who are hepatitis C antibody positive will need negative PCR prior to enrollment. Patients with positive hepatitis C will be excluded.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days of study entry.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02728531
• Other Study ID Numbers: 201603149
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Washington University School of Medicine
• Study Sponsor: Washington University School of Medicine
• Collaborators: Not Provided

Investigators

• Principal Investigator: Brad S Kahl, M.D.; Washington University School of Medicine

• PRS Account: Washington University School of Medicine
• Verification Date: May 2020