Stem Cell Transplant, Chemotherapy, and Biological Therapy in Treating Patients With High-Risk or Refractory Multiple Myeloma

NCT ID: NCT00499577

Last Updated: 2014-01-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 56 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-12-31

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.

Conditions

Multiple Myeloma and Plasma Cell Neoplasm

Study Design

• Primary Study Purpose: TREATMENT

Study Groups

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 intramuscularly.

Group Type: EXPERIMENTAL

CMV pp65 peptide

Intervention Type: BIOLOGICAL

Given intramuscularly

hTERT I540/R572Y/D988Y multipeptide vaccine

Intervention Type: BIOLOGICAL

Given subcutaneously

pneumococcal polyvalent vaccine

Intervention Type: BIOLOGICAL

Given intramuscularly

survivin Sur1M2 peptide vaccine

Intervention Type: BIOLOGICAL

Given subcutaneously

Group 2

Patients receive pneumococcal conjugate vaccine intramuscularly and GM-CSF subcutaneously.

Group Type: EXPERIMENTAL

CMV pp65 peptide

Intervention Type: BIOLOGICAL

Given intramuscularly

Second group 1

On days 14, 42, and 90 post-transplant, patients receive peptides and GM-CSF subcutaneously and pneumococcal conjugate vaccine intramuscularly.

Group Type: EXPERIMENTAL

CMV pp65 peptide

Intervention Type: BIOLOGICAL

Given intramuscularly

hTERT I540/R572Y/D988Y multipeptide vaccine

Intervention Type: BIOLOGICAL

Given subcutaneously

pneumococcal polyvalent vaccine

Intervention Type: BIOLOGICAL

Given intramuscularly

survivin Sur1M2 peptide vaccine

Intervention Type: BIOLOGICAL

Given subcutaneously

Second group 2

On day 14, 42, 90 post-transplant, patients receive pneumococcal conjugate vaccine intramuscularly and GM-CSF subcutaneously.

Group Type: EXPERIMENTAL

CMV pp65 peptide

Intervention Type: BIOLOGICAL

Given intramuscularly

Interventions

CMV pp65 peptide

Given intramuscularly

Intervention Type: BIOLOGICAL

hTERT I540/R572Y/D988Y multipeptide vaccine

Given subcutaneously

Intervention Type: BIOLOGICAL

pneumococcal polyvalent vaccine

Given intramuscularly

Intervention Type: BIOLOGICAL

survivin Sur1M2 peptide vaccine

Given subcutaneously

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

• No known history of myelodysplasia

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2 (unless due solely to bone pain)
• Creatinine ≤ 3.0 mg/dL and not on dialysis
• WBC ≥ 3,000/mm³
• Platelet count ≥ 100,000/mm³
• AST ≤ 2 times upper limit of normal
• Bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's syndrome)
• LVEF ≥ 45%

• A lower LVEF is permissible if a formal cardiologic evaluation reveals no evidence for clinically significant functional impairment
• FEV1, FVC, TLC, and DLCO ≥ 40% predicted

• Patients who are unable to complete pulmonary function tests due to bone pain or fracture must have a high-resolution CT scan of the chest and must have acceptable arterial blood gases (room air PO_2 > 70 mmHg)
• Women of child-bearing potential and their spouses or partners must be willing to use adequate contraception for the duration of the active treatment phase of the study

• Contraceptive measures must be continued as long as the patient remains on maintenance thalidomide in accordance with the STEPS program

• Recovered from any toxicities related to prior therapy or at least returned to their baseline level of organ function
• Patients should be off of glucocorticoids for at least 2 weeks and/or thalidomide therapy for at least 1 week prior to enrollment
• At least 2 weeks since prior steroid therapy or chemotherapy

Exclusion Criteria

• Pregnant or nursing
• HIV, HTLV-1/2 seropositivity
• Known history of chronic active hepatitis or liver cirrhosis (if suspected by laboratory studies, should be confirmed by liver biopsy)
• Active hepatitis B (as defined by positive hepatitis B surface antigen)

• Positive hepatitis C virus (HCV) antibody is NOT an exclusion
• History of severe autoimmune disease requiring steroids or other immunosuppressive treatments
• Active immune-mediated diseases including:

• Connective tissue diseases
• Uveitis
• Sarcoidosis
• Inflammatory bowel disease
• Multiple sclerosis
• Evidence or history of other significant cardiac, hepatic, renal, ophthalmologic, psychiatric, or gastrointestinal disease that might increase the risks of participating in the study
• Active bacterial, viral or fungal infections.

PRIOR CONCURRENT THERAPY:

• Prior autotransplant or allogeneic transplant
• More than 4 distinct, prior courses of therapy for myeloma
• Also see Disease Characteristics

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

University of Maryland Greenebaum Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

University of Pennsylvania

Principal Investigators

Aaron P. Rapoport, MD

Role: PRINCIPAL_INVESTIGATOR

University of Maryland Greenebaum Cancer Center

Locations

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

Countries

United States

References

Rapoport AP, Aqui NA, Stadtmauer EA, Vogl DT, Fang HB, Cai L, Janofsky S, Chew A, Storek J, Akpek G, Badros A, Yanovich S, Tan MT, Veloso E, Pasetti MF, Cross A, Philip S, Murphy H, Bhagat R, Zheng Z, Milliron T, Cotte J, Cannon A, Levine BL, Vonderheide RH, June CH. Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma. Blood. 2011 Jan 20;117(3):788-97. doi: 10.1182/blood-2010-08-299396. Epub 2010 Oct 28.

Reference Type: RESULT

PMID: 21030558 (View on PubMed)

Stadtmauer EA, Vogl DT, Luning Prak E, Boyer J, Aqui NA, Rapoport AP, McDonald KR, Hou X, Murphy H, Bhagat R, Mangan PA, Chew A, Veloso EA, Levine BL, Vonderheide RH, Jawad AF, June CH, Sullivan KE. Transfer of influenza vaccine-primed costimulated autologous T cells after stem cell transplantation for multiple myeloma leads to reconstitution of influenza immunity: results of a randomized clinical trial. Blood. 2011 Jan 6;117(1):63-71. doi: 10.1182/blood-2010-07-296822. Epub 2010 Sep 23.

Reference Type: RESULT

PMID: 20864577 (View on PubMed)

Other Identifiers

MSGCC-0610-GCC

Identifier Type: -

Identifier Source: secondary_id

UPCC-0610-GCC

Identifier Type: -

Identifier Source: secondary_id

CDR0000552988

Identifier Type: -

Identifier Source: org_study_id