Chemotherapy Plus Vaccination to Treat Mantle Cell Lymphoma

Phase 2

Completed

Conditions: Mantle Cell Lymphoma
Lymphoma, Mantle Cell

Interventions: Drug: EPOCH-R
Biological: GM-CSF
Biological: Idiotype vaccine

Registration Number: NCT00005780

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With an Antibody Response to Idiotype Vaccine	Weeks 12 to 32	Participants with an immune response to idiotype vaccine measured by enzyme-linked immunosorbent assay (ELISA) to detect antibody binding to tumor cells. Positive response was defined as at least a fourfold increase in antibody titer.
Median Progression-free Survival (PFS) in Participants Treated With Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, and Rituximab (EPOCH-R)	From participants on study date until date of disease relapse or progression, death, or date of last follow-up, assessed up to 245.8 months	PFS is time from on study date until disease relapse or progression, death, or date of last follow-up. Progression was measured by the International Workshop to Standardize Response Criteria for non-Hodgkin's Lymphoma and is defined as ≥50% increase from nadir in the sum of the products of the greatest diameters (SPD) of any previously involved node or the appearance of any new lesion.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Antibodies to Keyhole Limpet Haemocyanin (KLH)	After vaccinations administered at 0, 1, 2, 3 and 5 months	Participants with an immune response against carrier molecule KLH measured by enzyme-linked immunosorbent assay (ELISA) to detect antibody binding to tumor cells. Positive response was defined as at least a fourfold increase in antibody titer.
Time to Recovery of CD4 T Lymphocytes (CD4+)	After chemotherapy before vaccination, up to 6 months	Recovery of CD4+ was measured by flow cytometry. Blood samples were collected via apheresis and analyzed by multicolor flow cytometry in peripheral blood mononuclear cells (PBMCs) for cluster of differentiation 4 (CD4). Time to recovery of CD4 T lymphocytes was defined as the time required for CD4 T lymphocytes to increase above the lower limit of normal of the normal laboratory value range of 359 cells/mcL
Percentage of Participants Whose Cancer Shrinks or Disappears After Treatment With Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, and Rituximab (EPOCH-R)	After 6 cycles of EPOCH-R therapy, an average of 18 weeks	Response was measured by the International Workshop to Standardize Response Criteria for non-Hodgkin's Lymphoma. Complete Response (CR) is a complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities (e.g., Lactate dehydrogenase (LDH) definitely assignable to the lymphoma. Complete Response Unconfirmed (CRu) is as per CR criteria except that if a residual node is \> 1.5cm, it must have regressed by \> 75% in the sum of the products of the greatest diameters (SPD). Partial Response (PR) is ≥50% decreased in the SPD of 6 largest dominant nodes or nodal masses. Stable Disease (SD) is defined as less than a PR but not progressive disease. Progression is ≥50% increase from nadir in the SPD of any previously involved node or the appearance of any new lesion.
Percentage of Participants With Grade 3 or Higher Serious and/or Non-serious Toxicity That Occurred That is at Least Possibly Related to Drug or Vaccine	Up to 30 days after last intervention, up to 12.5 months or 1.04 years	Serious and/or non-serious adverse events were assessed by the Common Toxicity Criteria (CTC v2.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.
Overall Survival (OS)	Time from treatment start date until date of death or date last follow-up, up to 250 months	OS was determined by the Kaplan-Meier method and is defined as the time from treatment start date until date of death or last follow-up.
Percentage of Participants With Induction of Type 1 Cytokine T-cell Response	After vaccinations administered at 0, 1, 2, 3 and 5 months	Participants with tumor specific T-cell responses during B-cell recovery was assessed in a Clinical Laboratory Improvement Amendments (CLIA) certified lab and were measured by flow cytometry and/or enzyme-linked immunosorbent spot (ELISPOT). A positive response required the response to be at least twice the negative controls.
Progression Free Survival (PFS) in Participants Who Received Idiotype Vaccine	Time from treatment start date until date of disease relapse or progression, death, or date last follow-up, an average of 25 months	PFS is defined as the time from start of treatment until disease relapse or progression, death, or last follow-up. Progression was measured by the International Workshop to Standardize Response Criteria for non-Hodgkin's Lymphoma and is defined as ≥50% increase from nadir in the sum of the products of the greatest diameters (SPD) of any previously involved node or the appearance of any new lesion