Title

Universal Granulocyte Macrophage-colony Stimulating Factor (GM-CSF)-Producing and GM.CD40L for Autologous Tumor Vaccine in Mantle Cell Lymphoma
A Phase II Trial Using a Universal GM-CSF-Producing and CD40L-Expressing Bystander Cell Line (GM.CD40L) in the Formulation of Autologous Tumor Cell-Based Vaccines for Patients With Mantle Cell Lymphoma
  • Phase

    Phase 2
  • Study Type

    Interventional
  • Study Participants

    43
RATIONALE: Vaccines made from gene-modified cells and a person's cancer cells may make the body build an effective immune response to kill cancer cells. Interleukin-2 (IL-2) may stimulate the white blood cells to kill cancer cells. Giving booster vaccinations may make a stronger immune response and prevent or delay the recurrence of cancer. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Giving vaccine therapy together with IL-2 after combination chemotherapy may be a more effective treatment for mantle cell lymphoma.

PURPOSE: This phase II trial is studying how well giving vaccine therapy together with IL-2 after combination chemotherapy works in treating patients with relapsed or de novo stage II, stage III, or stage IV mantle cell lymphoma.
Patients were treated with 3-6 cycles of chemotherapy +/- rituximab, with type and duration at the discretion of the individual clinician. Evaluation for response was performed 1 month after completing chemotherapy, and included computed tomography (CT) scan, bone marrow biopsy, endoscopy, and colonoscopy. Minimal residual disease (MRD) was assessed qualitatively on bone marrow specimens using polymerase chain reaction (PCR) with standardized primers for evaluation for B-cell receptor gene rearrangement. Responses were defined according to revised Cheson criteria. Patients with successful lymph node harvest who had obtained complete or partial response could proceed to bystander vaccination.

The GM.CD40L bystander vaccine administered intradermally into the bilateral axillary and inguinal nodal basins via eight separate injections (0.125 ml / injection). Low dose IL-2 (0.5 x 10^6 units) was given subcutaneously twice daily for 14 days following vaccination. Patients were restaged with CT and/or CT/PET and bone marrow biopsy every 6 months, beginning from the last date of chemotherapy. Follow-up bone marrow biopsy evaluation included an assessment for MRD as described above. Patients without disease progression or toxicity attributable to the vaccine were eligible for 4 monthly booster vaccines at 12 months and 24 months.
Study Started
Jul 31
2004
Primary Completion
Oct 31
2012
Study Completion
Jul 31
2022
Anticipated
Results Posted
Sep 04
2013
Estimate
Last Update
Sep 16
2021

Drug Cyclophosphamide

Participants receive conventional chemotherapy comprising 6 courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) OR 3 courses of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD) for patients who have relapsed after CHOP.

  • Other names: Cytoxan

Drug Doxorubicin

Participants receive conventional chemotherapy comprising 6 courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) OR 3 courses of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD) for patients who have relapsed after CHOP.

  • Other names: adriamycin, Rubex

Drug Vincristine

Participants receive conventional chemotherapy comprising 6 courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) OR 3 courses of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD) for patients who have relapsed after CHOP.

  • Other names: Oncovin, leurocristine, VCR

Drug Prednisone

Participants receive conventional chemotherapy comprising 6 courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) OR 3 courses of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD) for patients who have relapsed after CHOP.

  • Other names: Deltasone, Liquid Pred, Meticorten, Orasone

Drug Dexamethasone

Participants receive conventional chemotherapy comprising 6 courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) OR 3 courses of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD) for patients who have relapsed after CHOP.

  • Other names: Decadron, Dexasone, Diodex, Hexadrol

Biological Autologous Tumor Cell-Based Vaccine

Participants receive vaccine comprising autologous tumor cells and GM.CD40L intradermally on day 1 and low-dose interleukin-2 (IL-2) subcutaneously twice daily on days 1-14. Treatment repeats every 28 days for 4 courses. Patients who have stable or responding disease at 12 months receive 4 additional courses of booster vaccine and low-dose IL-2 as above.

Drug IL-2

Participants receive vaccine comprising autologous tumor cells and GM.CD40L intradermally on day 1 and low-dose interleukin-2 (IL-2) subcutaneously twice daily on days 1-14. Treatment repeats every 28 days for 4 courses. Patients who have stable or responding disease at 12 months receive 4 additional courses of booster vaccine and low-dose IL-2 as above.

  • Other names: cytokine, aldesleukin, interleukin-2

Vaccine and Conventional Therapy Experimental

Patients were treated with 3-6 cycles of chemotherapy +/- rituximab, with type and duration at the discretion of the individual clinician. Chemotherapy: 6 courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) OR 3 courses of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD) for patients who have relapsed after CHOP. Patients who achieve a partial or complete response after completion of chemotherapy proceed to autologous tumor cell-based vaccine therapy. Patients who have stable or responding disease at 12 months receive 4 additional courses of booster vaccine and low-dose IL-2. Treatment continues in the absence of disease progression or unacceptable toxicity.

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed mantle cell lymphoma

Stage II, III, or IV disease
Relapsed or de novo disease
No symptomatic brain metastasis

PATIENT CHARACTERISTICS:

Age

18 and over

Performance status

Eastern Cooperative Oncology Group (ECOG) 0-2

Life expectancy

Not specified

Hematopoietic

White blood count (WBC) > 3,000/mm^3
Absolute neutrophil count > 1,500/mm^3
Platelet count > 100,000/mm^3
Hematocrit > 25%
Hemoglobin > 8 g/dL

Hepatic

Bilirubin < 2.0 mg/dL

Renal

Creatinine < 2.0 mg/dL OR
Creatinine clearance > 60 mL/min

Immunologic

No serious ongoing infection
No known HIV infection
No other pre-existing immunodeficiency condition

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception for 1 month before, during, and for 3 months after study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

No other concurrent immunotherapy

Chemotherapy

More than 4 weeks since prior chemotherapy
No other concurrent chemotherapy

Endocrine therapy

More than 4 weeks since prior steroids
No concurrent corticosteroids except as replacement doses in patients who are hypoadrenal

Radiotherapy

More than 2 weeks since prior radiotherapy
No concurrent radiotherapy

Surgery

Not specified

Other

No other concurrent immunosuppressive therapy

Summary

Vaccine and Conventional Therapy

All Events

Event Type Organ System Event Term Vaccine and Conventional Therapy

Rate of Immunological Response to Vaccination

Immunological response to vaccination, as measured by in vitro testing of peripheral blood mononuclear cells (PBMCs) for interferon gamma secretion, delayed type hypersensitivity reaction (DTH) in response to irradiated autologous tumor cells, and lymphocyte accumulation at DTH and vaccine injection sites. DTH Skin Testing was performed within 2 weeks prior to first vaccine, and again after fourth vaccine was administered. Aliquots containing 10^6 irradiated autologous tumor cells were re-suspended in 0.2 mL of Plasma-Lyte A and injected intradermally in the forearm and marked. 48 hours later, injection site was inspected for induration and erythema. 3mm punch biopsy of DTH injection site and vaccine site was obtained 48 hours after administration of irradiated tumor cells before and after the vaccine series. Vaccine site biopsy was obtained 2-5 days after the second vaccine had been given. Granulocytic and lymphocytic accumulation at these sites was graded by a pathologist.

Vaccine and Conventional Therapy

Clinical DTH

Increase in Interferon Gamma Secretion

15.0
participants

Occurrence of Related Serious Adverse Events (SAEs)

Patients were monitored for toxicity every 4 weeks in clinic throughout the 4-month vaccination phase. This included clinical and laboratory evaluation (CBC, blood urea nitrogen (BUN), creatinine, electrolytes, liver function test (LFT), and serum LDH). Toxicity was defined according to the NCI Common Terminology Criteria for Adverse Events (CTCAE-3) Version 3.0 (www.ctep.cancer.gov). Grade 3 or higher SAEs attributed to vaccination: Toxicity was assessed in the 23 patients who received at least one vaccine injection.

Vaccine and Conventional Therapy

Median Event Free Survival (EFS)

Vaccine Response - EFS among participants who received vaccination. Event free survival (EFS) was calculated from date of enrollment until progression or death from any cause. Progressive disease (PD): At least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Vaccine and Conventional Therapy

9.0
months (Median)
95% Confidence Interval: 5.0 to 18.0

Age, Continuous

65
participants (Median)
Full Range: 47.0 to 81.0

Age, Categorical

Region of Enrollment

Sex: Female, Male

Overall Study

Vaccine and Conventional Therapy

Drop/Withdrawal Reasons

Vaccine and Conventional Therapy