Chemotherapy Plus Vaccination to Treat Mantle Cell Lymphoma

NCT ID: NCT00005780

Last Updated: 2023-01-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2000-06-01
• Study Completion Date: 2021-06-16

Brief Summary

This study will evaluate the safety and effectiveness of an experimental cancer vaccine for mantle cell lymphoma a form of cancer of the white blood cells called lymphocytes. Although standard treatments for lymphoma may achieve disease remission, none provides a cure.

Patients with mantle cell lymphoma 18 years and older who have not been treated previously with chemotherapy may participate in this study. Candidates will be screened for eligibility with a medical history and physical examination. Other tests that may be required include blood and urine tests; lung function studies; imaging tests such as magnetic resonance imaging, computed tomography and X-rays; and biopsy (surgical removal of a small tissue sample) of tumor, bone marrow, or other tissue.

Patients enrolled in the study will begin treatment with chemotherapy designed to reduce disease to a minimum that is, to achieve remission or shrink the tumor as much as possible. Chemotherapy will be administered on an outpatient basis over a period of around 12 to 18 weeks in 3-week cycles as follows: prednisone by mouth on days 1 through 5; etoposide, doxorubicin and vincristine intravenously through (a vein) on days 1 through 5; and cyclophosphamide intravenously on day 5. Starting day 6, patients receive no chemotherapy for 16 days. In addition, an antibody called rituximab, which attaches to lymphoma cells and may increase the effectiveness of the chemotherapy, will be given on day 1 of the cycle. Patients will also receive a protein called granulocyte colony-stimulating factor (G-CSF) starting day 6 of the cycle and continuing until the white blood cell count recovers or until day 19. G-CSF is naturally produced by bone marrow and may boost the immune system. The chemotherapy drugs and rituximab are infused through a vein by means of a lightweight portable pump, which patients are taught how to use. Patients are also how taught how to give themselves G-CSF injections under the skin, similar to insulin injections.

The first vaccination will be given at least 3 months after chemotherapy ends and will be repeated every 4 weeks for a maximum of 5 vaccinations. The vaccinations will be given in the clinic. Patients will also receive daily injections of granulocyte-macrophage colony-stimulating factor (GM-CSF), a growth factor naturally produced by bone marrow that can boost the immune system. These injections will be given the day of the vaccination and for the next 3 days.

When vaccine therapy is completed, patients who were treated successfully will be followed with periodic clinic visits for follow-up examinations and tests. Patients in whom the lymphoma did not disappear entirely or who have a recurrence of disease will be advised of further treatment possibilities....

Detailed Description

Background:

• Mantle cell lymphoma presents a particular clinical challenge because it is aggressive and incurable with chemotherapy. Thus, novel treatment approaches are needed.
• In follicular center cell lymphomas, another incurable disease, recent evidence suggests that molecular complete remissions may be achieved following idiotype vaccination in patients who have achieved minimal residual disease with combination chemotherapy.
• These results suggest that idiotype vaccines may be able to induce a clinically significant immune response against lymphoma.

Objectives:

• To assess if etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R)/idiotype vaccination is associated with a median progression-free survival consistent with 36 months;
• To assess if rituximab affects generation of T-cell immunity against the idiotype.
• To compare T-cell immunity using two different methods of isolating the idiotype protein.

Eligibility:

• Tissue diagnosis of mantle cell lymphoma.
• Age greater than or equal to 18 years.
• Previously untreated with cytotoxic chemotherapy. All stages of disease.
• Lymph node of greater than or equal to 2 cm accessible for biopsy/harvest or greater than 1000/microl of circulating tumor cells in the blood.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 3.

Design:

• In the present study, we propose to investigate the efficacy of idiotype vaccine treatment in previously untreated patients with mantle cell lymphomas. In order to achieve minimal residual disease, patients will receive 6 cycles EPOCH chemotherapy and rituximab (EPOCH-R) followed by 5 idiotype vaccine injections.
• This study has completed accrual of 26 patients and study is closed as of 4/18/2022.

Conditions

Mantle Cell Lymphoma; Lymphoma, Mantle Cell

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab

Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) followed by idiotype vaccine and granulocyte-macrophage colony-stimulating factor (GM-CSF).

Group Type: EXPERIMENTAL

EPOCH-R

Intervention Type: DRUG

EPOCH-R for 6 cycles

GM-CSF

Intervention Type: BIOLOGICAL

Granulocyte-macrophage colony-stimulating factor (GM-CSF) monthly with the vaccine for 5 doses

Idiotype vaccine

Intervention Type: BIOLOGICAL

1 injection of vaccine monthly for 5 doses

Interventions

EPOCH-R

EPOCH-R for 6 cycles

Intervention Type: DRUG

GM-CSF

Granulocyte-macrophage colony-stimulating factor (GM-CSF) monthly with the vaccine for 5 doses

Intervention Type: BIOLOGICAL

Idiotype vaccine

1 injection of vaccine monthly for 5 doses

Intervention Type: BIOLOGICAL

Other Intervention Names

Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; Sargramostim

Eligibility Criteria

Inclusion Criteria

Tissue diagnosis of mantle cell lymphoma (confirmed in Laboratory of Pathology). Blastic cell variant will be eligible.

Age greater than or equal to 18.

Previously untreated with cytotoxic chemotherapy. Patients may have received local radiation or a short course of steroids for control of symptoms.

All stages of disease.

Lymph node of greater than or equal to 2 cm accessible for biopsy/harvest or greater than 1000/microliters of circulating tumor cells in the blood.

Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 3.

Adequate major organ function (serum creatinine 1.5 mg/dl or creatinine clearance greater than 60 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 100,000) unless impairment due to organ involvement by lymphoma.

No active symptomatic ischemic heart disease, myocardial infarction or congestive heart failure within the past year. If multigated acquisition (MUGA) scan is obtained, the left ventricular ejection fraction (LVEF) should exceed 40%.

Ability to give informed consent.

Exclusion Criteria

Antibodies to human immunodeficiency virus (HIV) or presence of hepatitis B surface antigen.

Pregnant or lactating.

Prior malignancy in past 5 years except squamous or basal cell carcinoma or curatively treated in situ of the cervix.

Involvement of central nervous system by lymphoma.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Christopher Melani, MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Christopher J Melani, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute (NCI)

Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States

Countries

United States

References

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Reference Type: BACKGROUND

PMID: 8639796 (View on PubMed)

Armitage JO. Management of mantle cell lymphoma. Oncology (Williston Park). 1998 Oct;12(10 Suppl 8):49-55.

Reference Type: BACKGROUND

PMID: 9830633 (View on PubMed)

Weisenburger DD, Armitage JO. Mantle cell lymphoma-- an entity comes of age. Blood. 1996 Jun 1;87(11):4483-94. No abstract available.

Reference Type: BACKGROUND

PMID: 8639814 (View on PubMed)

Grant C, Neelapu SS, MD2, Kwak LW, Dunleavy K, White T, Miller BW, Jaffe ES, Steinberg SM, Healey Bird B, MB, Wilson WH. Eleven-Year Follow-up of Idiotype Vaccine and DA-EPOCH-Rituximab in Untreated Mantle Cell Lymphoma: Correlation of Survival with Idiotype Immune Response. Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 2707.

Reference Type: RESULT

Neelapu SS, Kwak LW, Kobrin CB, Reynolds CW, Janik JE, Dunleavy K, White T, Harvey L, Pennington R, Stetler-Stevenson M, Jaffe ES, Steinberg SM, Gress R, Hakim F, Wilson WH. Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma. Nat Med. 2005 Sep;11(9):986-91. doi: 10.1038/nm1290. Epub 2005 Aug 21.

Reference Type: RESULT

PMID: 16116429 (View on PubMed)

Roschewski M, Dunleavy K, Neelapu SS, Pittaluga S, Melani CJ, Jaffe ES, Shovlin M, Crossley B, Kong K, Jacob A, Kwak L, Wilson WH. Quantitative Baseline Circulating Tumor DNA Levels Correlate with GM-CSF Response to Idiotype Vaccine in Untreated Mantle Cell Lymphoma (ASH Annual Meeting Abstracts). Blood. 2016;128:2943-2943.

Reference Type: RESULT

Wilson WH, Neelapu S, White T, et al: Idiotype Vaccine Following EPOCH-Rituximab Treatment in Untreated Mantle Cell Lymphoma. Pro Am Soc Heme, 2002.

Reference Type: RESULT

Neelapu S, Wilson WH, Baskar W, et at: Induction of T-cell responses by tumor antigen vaccination in mantle cell lymphoma following rituximab-based treatment. Pro Am Soc Clin Oncol, 2003.

Reference Type: RESULT

Rosenwald A, Wright G, Wiestner A, Chan WC, Connors JM, Campo E, Gascoyne RD, Grogan TM, Muller-Hermelink HK, Smeland EB, Chiorazzi M, Giltnane JM, Hurt EM, Zhao H, Averett L, Henrickson S, Yang L, Powell J, Wilson WH, Jaffe ES, Simon R, Klausner RD, Montserrat E, Bosch F, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Fisher RI, Miller TP, LeBlanc M, Ott G, Kvaloy S, Holte H, Delabie J, Staudt LM. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003 Feb;3(2):185-97. doi: 10.1016/s1535-6108(03)00028-x.

Reference Type: RESULT

PMID: 12620412 (View on PubMed)

Wilson WH, Neelapu S, Rosenwald A, et al: Idiotype Vaccine and Dose-Adjusted EPOCH-Rituximab Treatment in Untreated Mantle Cell Lymphoma: Preliminary Report on Clinical Outcome and Analysis of Immune Response. 2003, Blood 102 (11) #358.

Reference Type: RESULT

Fu K, Weisenburger DD, Greiner TC, Dave S, Wright G, Rosenwald A, Chiorazzi M, Iqbal J, Gesk S, Siebert R, De Jong D, Jaffe ES, Wilson WH, Delabie J, Ott G, Dave BJ, Sanger WG, Smith LM, Rimsza L, Braziel RM, Muller-Hermelink HK, Campo E, Gascoyne RD, Staudt LM, Chan WC; Lymphoma/Leukemia Molecular Profiling Project. Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling. Blood. 2005 Dec 15;106(13):4315-21. doi: 10.1182/blood-2005-04-1753. Epub 2005 Aug 25.

Reference Type: RESULT

PMID: 16123218 (View on PubMed)

Wiestner A, Tehrani M, Chiorazzi M, Wright G, Gibellini F, Nakayama K, Liu H, Rosenwald A, Muller-Hermelink HK, Ott G, Chan WC, Greiner TC, Weisenburger DD, Vose J, Armitage JO, Gascoyne RD, Connors JM, Campo E, Montserrat E, Bosch F, Smeland EB, Kvaloy S, Holte H, Delabie J, Fisher RI, Grogan TM, Miller TP, Wilson WH, Jaffe ES, Staudt LM. Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. Blood. 2007 Jun 1;109(11):4599-606. doi: 10.1182/blood-2006-08-039859. Epub 2007 Feb 13.

Reference Type: RESULT

PMID: 17299095 (View on PubMed)

Dunleavy K, Neelapu SS, Kwak LW, Grant C, Santos CF, Popa M, White T, Miller B, Jaffe ES, Steinberg SM and Wilson WH. Association of idiotype vaccine-induced T-cell response with improved survival and time-to-next treatment (TTNT) in untreated mantle cell lymphoma (MCL). Journal of Clinical Oncology, 2012 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 30, No 15_suppl (May 20 Supplement), 2012: 2528.

Reference Type: RESULT

Lai C, Cole DE, Steinberg SM, Lucas N, Dombi E, Melani C, Roschewski M, Balis F, Widemann BC, Wilson WH. Doxorubicin pharmacokinetics and toxicity in patients with aggressive lymphoma and hepatic impairment. Blood Adv. 2023 Feb 28;7(4):529-532. doi: 10.1182/bloodadvances.2022007431.

Reference Type: DERIVED

PMID: 35882475 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Related Links

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2000-C-0133.html

NIH Clinical Center Detailed Web Page

Other Identifiers

00-C-0133

Identifier Type: -

Identifier Source: secondary_id

000133

Identifier Type: -

Identifier Source: org_study_id

NCT00020215

Identifier Type: -

Identifier Source: nct_alias