Stem Cell Transplant, Chemotherapy, and Biological Therapy in Treating Patients With High-Risk or Refractory Multiple Myeloma
- Conditions
- Multiple Myeloma and Plasma Cell Neoplasm
- Interventions
- Biological: CMV pp65 peptideBiological: hTERT I540/R572Y/D988Y multipeptide vaccineBiological: pneumococcal polyvalent vaccineBiological: survivin Sur1M2 peptide vaccine
- Registration Number
- NCT00499577
- Lead Sponsor
- University of Maryland Greenebaum Cancer Center
- Brief Summary
RATIONALE: Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Thalidomide may stop the growth of cancer cells by stopping blood flow to the cancer. A stem cell transplant using stem cells from the patient may be able to replace immune cells that were destroyed by chemotherapy used to kill cancer cells. Giving an infusion of the donor's T cells after the transplant may help destroy any remaining cancer cells.
PURPOSE: This phase I/II trial is studying the side effects of stem cell transplant given together with chemotherapy and biological therapy and to see how well it works in treating patients with high-risk or refractory multiple myeloma.
- Detailed Description
OBJECTIVES:
Primary
* To evaluate the safety of combination immunotherapy using activated T-cells and an hTERT/survivin multipeptide vaccine in the post-autotransplant (autologous stem cell transplantation) setting and whether it delays hematopoietic recovery or induces autoimmune events.
* To determine whether the strategy of infusing vaccine-primed T-cells early after transplant in conjunction with post-transplant booster immunizations leads to the induction of cellular immune responses to the putative tumor antigens hTERT ( the catalytic subunit of telomerase) and survivin.
* To determine if combination immunotherapy as delivered to arm I patients increases the frequency of delayed paraprotein responses between 60 days and 6 months post-transplant, sufficient to upgrade the maximal level of myeloma response, when compared to non-vaccinated (arm II) patients.
Secondary
* To determine if adoptive transfer of hTERT/survivin-primed T-cells in conjunction with multi-peptide booster immunizations generates cytotoxic T-cell responses to autologous myeloma cells in vivo.
* To evaluate myeloma clinical responses including the frequency of complete and partial responses and the 1 \& 2-year event-free and overall survivals.
* To measure antibody responses to 4 of the 7 serotypes contained in the pneumococcal polyvalent vaccine as well as T-cell responses to the CRM-197 carrier protein and to a CMV peptide antigen.
* To evaluate levels of hTERT and survivin expression in patient myeloma cells.
OUTLINE: This is a multicenter study. Patients are stratified according to HLA-A2 status (positive vs negative). Patients are assigned to 1 of 2 treatment groups based on stratification.
* Immunization 1:
* Group 1 (HLA-A2 positive): Patients receive the following peptides emulsified in incomplete Freund's adjuvant VG: I) hTERT I540 peptide; ii) hTERT R572Y peptide; iii) hTERT D988Y peptide; iv) survivin Sur1M2 peptide ; and v) CMV control peptide N495 subcutaneously (SC). Patients also receive sargramostim (GM-CSF) SC and pneumococcal conjugate vaccine (PCV) intramuscularly (IM).
* Group 2: Patients receive PCV vaccine IM and GM-CSF SC.
* Steady-state T-cell harvesting:About 10 days (range 7-14) after immunization #1, all patients undergo a mononuclear cell apheresis procedure to collect steady-state T-cells that are cryopreserved for later expansion.
* Stem cell mobilization: After completion of the mononuclear cell apheresis procedure, all patients are offered DT-PACE chemotherapy for cytoreduction and stem cell mobilization. This regimen is as follows: dexamethasone once daily for 4 days; thalidomide once daily for 4 days; cisplatin IV continuously over 4 days (patients with serum creatinine levels ≥ 2.0 mg/dL do not receive cisplatin); doxorubicin hydrochloride IV continuously over 4 days; cyclophosphamide IV continuously over 4 days; etoposide IV continuously over 4 days. Patients also receive filgrastim (G-CSF) SC once daily starting on the day after completion of chemotherapy. An acceptable alternative for stem cell mobilization is to use cyclophosphamide IV over 12 hours or, for patients who require that outpatient stem cell mobilization procedures be performed, cyclophosphamide IV over 2 hours. The cyclophosphamide mobilization regimen should be used if the patient has already received DTPACE as part of the pre-transplant therapy.
* High-dose therapy: High-dose therapy will consist of melphalan IV over 20 minutes on day -1. Autologous stem cell infusion takes place on day 0, at least 18 hours after the administration of the high-dose melphalan. Stem cells are infused IV over 20-60 minutes. G-CSF SC should be administered beginning on day +5.
* Autologous T-cell expansion and infusion: Cryopreserved cells are expanded ex vivo for up to 12 days and prepared for infusion on day 2 post-transplant.
* Infusion of autologous T-cells: The costimulated ("activated") T-cells are infused over 20-60 minutes on day +2 of transplant.
* Immunizations 2, 3, and 4:
* Group 1: On days 14, 42, and 90 post-transplant, patients receive peptides, PCV, and GM-CSF as in group I of immunization # 1.
* Group 2: On day 14, 42, 90 post-transplant, patients receive PCV and GM-CSF as in group II of immunization # 1.
* Maintenance therapy: At day 180 post-transplant, after completion of post-transplant immunological assessments, patients receive low-dose thalidomide in the absence of disease progression or unacceptable toxicity.
Blood is collected at T-cell harvest and days 14, 60, 100, and 180 post-transplant. Samples are analyzed by quantitative CD3/CD4/CD8 studies, cellular immunoassays, antibody immunoassays, and gene expression.
After completion of study treatment, patients are followed periodically.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 56
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Group 1 (HLA-A2 positive) pneumococcal polyvalent vaccine Patients receive the following peptides emulsified in incomplete Freund's adjuvant VG: I) hTERT I540 peptide; ii) hTERT R572Y peptide; iii) hTERT D988Y peptide; iv) survivin Sur1M2 peptide ; and v) CMV control peptide N495 subcutaneously (SC). Patients also receive sargramostim (GM-CSF) SC and pneumococcal conjugate vaccine intramuscularly. Group 1 (HLA-A2 positive) CMV pp65 peptide Patients receive the following peptides emulsified in incomplete Freund's adjuvant VG: I) hTERT I540 peptide; ii) hTERT R572Y peptide; iii) hTERT D988Y peptide; iv) survivin Sur1M2 peptide ; and v) CMV control peptide N495 subcutaneously (SC). Patients also receive sargramostim (GM-CSF) SC and pneumococcal conjugate vaccine intramuscularly. Group 1 (HLA-A2 positive) hTERT I540/R572Y/D988Y multipeptide vaccine Patients receive the following peptides emulsified in incomplete Freund's adjuvant VG: I) hTERT I540 peptide; ii) hTERT R572Y peptide; iii) hTERT D988Y peptide; iv) survivin Sur1M2 peptide ; and v) CMV control peptide N495 subcutaneously (SC). Patients also receive sargramostim (GM-CSF) SC and pneumococcal conjugate vaccine intramuscularly. Group 1 (HLA-A2 positive) survivin Sur1M2 peptide vaccine Patients receive the following peptides emulsified in incomplete Freund's adjuvant VG: I) hTERT I540 peptide; ii) hTERT R572Y peptide; iii) hTERT D988Y peptide; iv) survivin Sur1M2 peptide ; and v) CMV control peptide N495 subcutaneously (SC). Patients also receive sargramostim (GM-CSF) SC and pneumococcal conjugate vaccine intramuscularly. Group 2 CMV pp65 peptide Patients receive pneumococcal conjugate vaccine intramuscularly and GM-CSF subcutaneously. Second group 1 CMV pp65 peptide On days 14, 42, and 90 post-transplant, patients receive peptides and GM-CSF subcutaneously and pneumococcal conjugate vaccine intramuscularly. Second group 1 hTERT I540/R572Y/D988Y multipeptide vaccine On days 14, 42, and 90 post-transplant, patients receive peptides and GM-CSF subcutaneously and pneumococcal conjugate vaccine intramuscularly. Second group 1 pneumococcal polyvalent vaccine On days 14, 42, and 90 post-transplant, patients receive peptides and GM-CSF subcutaneously and pneumococcal conjugate vaccine intramuscularly. Second group 1 survivin Sur1M2 peptide vaccine On days 14, 42, and 90 post-transplant, patients receive peptides and GM-CSF subcutaneously and pneumococcal conjugate vaccine intramuscularly. Second group 2 CMV pp65 peptide On day 14, 42, 90 post-transplant, patients receive pneumococcal conjugate vaccine intramuscularly and GM-CSF subcutaneously.
- Primary Outcome Measures
Name Time Method Toxicity at 21 and 28 days post-transplant T-cell responses against the hTERT vaccine as measured by tetramer assays at 100 days post-transplant Paraprotein levels in the blood or urine and serum free light chain analyses at 60 days and at 6 months post-transplant
- Secondary Outcome Measures
Name Time Method Cytotoxic T-cell responses against autologous myeloma cell at day 100 post-transplant via chromium-51 release or flow-based assays Maximum clinical response 1 and 2-year event-free survival Overall survival rates CD4 and CD8 T-cell responses against cytomegalovirus (CMV) at days 60 and 100 post-transplantation by CFSE dye dilution assays Composite binding antibody responses at days 60 and day 100 post-transplant by ELISA
Trial Locations
- Locations (2)
Greenebaum Cancer Center at University of Maryland Medical Center
🇺🇸Baltimore, Maryland, United States
Abramson Cancer Center of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States