EPOCH-R Chemotherapy Plus Bortezomib to Treat Mantle Cell Lymphoma

NCT00114738 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 05017005-C-0170
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate the effectiveness of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin-rituximab (EPOCH-R) chemotherapy plus bortezomib for treating mantle cell lymphoma, a cancer of white blood cells called lymphocytes. EPOCH-R consists of the drugs prednisone, etoposide, doxorubicin and vincristine, with the addition of a new drug called rituximab. In a recent study of patients with newly diagnosed mantle cell lymphoma, 92 percent had a complete remission of their disease after treatment with EPOCH-R. This study will test whether adding bortezomib as "maintenance therapy" once chemotherapy is finished will lengthen the time before the disease relapses and improve the overall cure rate. Patients 18 years of age and older with mantle cell lymphoma may be eligible for this study. Candidates are screened with a medical history and physical examination, blood and urine tests, electrocardiogram, multi-gated acquisition scan (MUGA) or echocardiogram, imaging studies and biopsy to determine the extent of disease, and possible colonoscopy. Participants undergo treatment in three parts, as follows:

• Part 1: Bortezomib alone: Patients receive 4 doses of bortezomib over 3 weeks. The drug is injected into a vein over about 30 seconds.
• Part 2: EPOCH-R chemotherapy plus bortezomib: This phase of treatment begins 3 to 4 weeks after completing Part 1. Treatment is given on an outpatient basis in six 3-week cycles, with all drugs administered over the first 5 days of each cycle. Patients take prednisone by mouth on days 1 to 5 and etoposide, doxorubicin, and vincristine as a 96-hour infusion through a vein over days 1 to 5. The infused drugs are delivered through a lightweight, portable infusion pump. Rituximab is given by vein over several hours on day 1 immediately before the chemotherapy infusion begins. Bortezomib is given by vein over 30 seconds on day 1 before the rituximab and again on day 4. Cyclophosphamide is given by vein over about 15 minutes on day 5 immediately after the chemotherapy infusion is completed. Patients are taught how to self inject granulocyte colony stimulating factor (G-CSF), a drug that helps boost white cell counts after chemotherapy. They inject the drug under the skin (like an insulin shot) for 10 days of each cycle beginning day 6. Patients also take an antibiotic to help prevent infection during chemotherapy.
• Part 3: Bortezomib alone: After completing EPOCH-R-B therapy, patients are randomly assigned to receive or not to receive bortezomib alone. The drug is given in 2 doses over 5 days, with a break of 16 days before the next dose. These 3-week cycles continue for up to 18 months or until the disease comes back or worsens. Patients who are assigned to the group that does not receive bortezomib will be offered the drug if their disease relapses. During therapy, patients have tests performed on their bone marrow, tumor tissue, blood or other fluids to look at different genes and proteins that may be involved in the development of their lymphoma or the reaction of the immune system. A tissue biopsy is done before treatment begins and a day after treatment starts. Disease progress is followed with computed tomography (CT) scans and blood tests. When treatment is completed, patients whose cancer has disappeared are scheduled for periodic follow-up examinations and tests. Those whose disease remains or recurs may be offered participation in another protocol if an appropriate one is available or are returned to the care of their local physician. ...

Conditions

Lymphoma, Mantle Cell; Mantle Cell Lymphoma

Keywords

Proteasome Inhibition; NF-Kappa-B; Gene Expression Signature; Cyclin D1; Translational Studies; Lymphoma; Mantle Cell Lymphoma; MCL

Outcome Measures

Primary Outcomes (4)

• Progression Free Survival (PFS)

  Time interval from start of treatment to documented evidence of disease progression. Progression is defined by at least one of the following: ≥50% increase in the sum of the products of at least two lymph nodes, appearance of new lymph nodes, ≥50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin, appearance of new palpable hepatomegaly or splenomegaly that was not previously present, and ≥50% increase in the absolute number of circulating lymphocytes.The primary evaluation will be a Kaplan-Meier analysis with a two tailed log rank test.

  up to 5 years

• Median Overall Survival (OS)

  Overall Survival is the time between the first day of treatment to the day of death. The primary evaluation will be a Kaplan-Meier analysis with a two tailed log rank test.

  up to 9.9 years

• Overall Progression Free Survival

  Time interval from start of treatment to documented evidence of disease progression. Progression is defined by at least one of the following: ≥50% increase in the sum of the products of at least two lymph nodes, appearance of new lymph nodes, ≥50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin, appearance of new palpable hepatomegaly or splenomegaly that was not previously present, and ≥50% increase in the absolute number of circulating lymphocytes.

  up to 9.9 years

• Overall Survival

  Overall Survival is the time between the first day of treatment to the day of death. The primary evaluation will be a Kaplan-Meier analysis with a two tailed log rank test.

  up to 9.9 years

Secondary Outcomes (2)

• Count of Participants With Serious and Non-Serious Adverse Events

  Date treatment consent signed to date off study, approximately 143 months and 7 days

• Clinical Response

  up to 22 weeks after initiation of therapy

Study Arms (4)

EPOCH-R + Bortezomib

EXPERIMENTAL

Combo chemo etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-Rituxan (R) + Bortezomib (B)

Drug: Rituximab (R); Biological: EPOCH; Drug: Bortezomib

Bortezomib "window"

EXPERIMENTAL

Bortezomib alone

Drug: Bortezomib (B)

Bortezomib maintenance

ACTIVE COMPARATOR

Bortezomib maintenance

Drug: Bortezomib

Observation

OTHER

At the beginning of part C patients are randomized to receive bortezomib maintenance or observation without bortezomib.

Drug: Bortezomib or observation

Interventions

Rituximab (R) DRUG

Rituximab is given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and bortezomib every 3 weeks for 6 cycles.

Also known as: Rituxan

EPOCH-R + Bortezomib

EPOCH BIOLOGICAL

EPOCH is given with Rituximab and bortezomib every 3 weeks for 6 cycles.

EPOCH-R + Bortezomib

Bortezomib (B) DRUG

Bortezomib is given alone for one cycle.

Also known as: Velcade

Bortezomib "window"

Bortezomib DRUG

Bortezomib is given with EPOCH and rituximab every 6 weeks for 12 cycles.

Also known as: Velcade

Bortezomib maintenance; EPOCH-R + Bortezomib

Bortezomib or observation DRUG

At the beginning of Part C, patients are randomized to receive bortezomib maintenance or be observed w/o bortezomib.

Also known as: Velcade

Observation

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

* ELIGIBILITY CRITERIA: Diagnosis of mantle cell lymphoma (confirmed at National Cancer Institute (NCI)). All variants are eligible. Age greater than or equal to 18 years. No prior treatment except for local radiation or a short course of steroids for control of symptoms. All stages of disease. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 3. Adequate major organ function (serum creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than 50 ml/min; bilirubin less than 2 mg/dl (total) except less than 5 mg/dl in patients with Gilbert's syndrome as defined by greater than 80% unconjugated; Absolute neutrophil count (ANC) greater than 1000 and platelets greater than 75,000) unless impairment due to organ involvement by lymphoma. No myocardial infarction within 6 months prior to enrollment or New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any electrocardiogram (ECG) abnormality at Screening has to be documented by the investigator as not medically relevant. No grade 2 greater than or equal to peripheral neuropathy within 14 days before enrollment. Ability to give informed consent. Human immunodeficiency virus (HIV) antibody negative. Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Female subject is not pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-human chorionic gonadotropin (hCG)) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women Male subject agrees to use an acceptable method for contraception for the duration of the study. No history of a prior invasive malignancy in past 5 years No known involvement of central nervous system by lymphoma No history of hypersensitivity to boron or mannitol. Patient has not received other investigational drugs with 14 days before enrollment. No serious medical or psychiatric illness likely to interfere with participation in this clinical study. Exclusion for fludeoxyglucose (FDG) scan is anyone exceeding the weight limit of the scanner (350 lb).

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (6)

• Velders GA, Kluin-Nelemans JC, De Boer CJ, Hermans J, Noordijk EM, Schuuring E, Kramer MH, Van Deijk WA, Rahder JB, Kluin PM, Van Krieken JH. Mantle-cell lymphoma: a population-based clinical study. J Clin Oncol. 1996 Apr;14(4):1269-74. doi: 10.1200/JCO.1996.14.4.1269.

  PMID: 8648383 BACKGROUND

• Campo E, Raffeld M, Jaffe ES. Mantle-cell lymphoma. Semin Hematol. 1999 Apr;36(2):115-27.

  PMID: 10319380 BACKGROUND

• Hiddemann W, Unterhalt M, Herrmann R, Woltjen HH, Kreuser ED, Trumper L, Reuss-Borst M, Terhardt-Kasten E, Busch M, Neubauer A, Kaiser U, Hanrath RD, Middeke H, Helm G, Freund M, Stein H, Tiemann M, Parwaresch R. Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group. J Clin Oncol. 1998 May;16(5):1922-30. doi: 10.1200/JCO.1998.16.5.1922.

  PMID: 9586911 BACKGROUND

• Lakhotia R, Melani C, Dunleavy K, Pittaluga S, Saba N, Lindenberg L, Mena E, Bergvall E, Lucas AN, Jacob A, Yusko E, Steinberg SM, Jaffe ES, Wiestner A, Wilson WH, Roschewski M. Circulating tumor DNA predicts therapeutic outcome in mantle cell lymphoma. Blood Adv. 2022 Apr 26;6(8):2667-2680. doi: 10.1182/bloodadvances.2021006397.

  PMID: 35143622 DERIVED

• Chang BY, Francesco M, De Rooij MF, Magadala P, Steggerda SM, Huang MM, Kuil A, Herman SE, Chang S, Pals ST, Wilson W, Wiestner A, Spaargaren M, Buggy JJ, Elias L. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013 Oct 3;122(14):2412-24. doi: 10.1182/blood-2013-02-482125. Epub 2013 Aug 12.

  PMID: 23940282 DERIVED

• Perez-Galan P, Mora-Jensen H, Weniger MA, Shaffer AL 3rd, Rizzatti EG, Chapman CM, Mo CC, Stennett LS, Rader C, Liu P, Raghavachari N, Stetler-Stevenson M, Yuan C, Pittaluga S, Maric I, Dunleavy KM, Wilson WH, Staudt LM, Wiestner A. Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation. Blood. 2011 Jan 13;117(2):542-52. doi: 10.1182/blood-2010-02-269514. Epub 2010 Oct 18.

  PMID: 20956803 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoma, Mantle-Cell; Lymphoma

Interventions

Rituximab; Bortezomib; Observation

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Methods; Investigative Techniques

Results Point of Contact

• Title: Dr. Wyndham Wilson
• Organization: National Cancer Institute

wyndham_wilson@nih.gov

301-435-2415

Study Officials

• Wyndham H Wilson, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 17, 2005
• First Posted: June 17, 2005
• Study Start: June 15, 2005
• Primary Completion: August 11, 2016
• Study Completion: August 11, 2022
• Last Updated: October 10, 2022
• Results First Posted: July 3, 2018

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)