Phase I/II Combination Immunotherapy After ASCT for Advanced Myeloma to Study HTERT Vaccination Followed by Adoptive Transfer of Vaccine-Primed Autologous T Cells
18 Years
80 Years
Both
Multiple Myeloma and Plasma Cell Neoplasm
Trial Information
Phase I/II Combination Immunotherapy After ASCT for Advanced Myeloma to Study HTERT Vaccination Followed by Adoptive Transfer of Vaccine-Primed Autologous T Cells
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.
Inclusion Criteria
DISEASE CHARACTERISTICS:
- Diagnosis of myeloma meeting 1 of the following criteria:
- Myeloma has relapsed, progressed, or failed to respond after at least one prior
course of therapy (consisting of at least 2 treatment cycles or months of
therapy)
- Failure to respond would correspond to a reduction of less than or equal to
25% of the original, diagnostic serum or urine paraprotein measurement
- Myeloma has responded partially to initial therapy but a complete response
(immunofixation negative) has NOT developed after a minimum of 3 cycles or
months of initial therapy
- Myeloma has high-risk features as defined by the presence of one or more
cytogenetic abnormalities known to confer a poor outcome even after standard
autotransplants (e.g., complex karyotype [≥ 3 abnormalities], t(4;14), t(14;16),
del (17) (p13.1), and/or chromosome 13 abnormalities)
- May be enrolled even while in complete or near-complete remission
- Extended disease-free survival after autotransplantation would be
unexpected for these patients and therefore especially meaningful
- Must have measurable disease
- Measurable disease may include quantifiable or detectable levels of serum or
urine paraprotein
- For patients with minimally secretory disease or non-secretory myeloma on
study entry, serum free λ or κ light chain levels may be measured and used
for disease monitoring if abnormal
- Patients who are in complete remission at the time of proposed study entry
(serum and urine immunofixation consistently negative) are not eligible
unless their disease meets the criteria for high-risk disease
- No known history of myelodysplasia
PATIENT CHARACTERISTICS:
Inclusion criteria:
- 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
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:
Inclusion criteria
- 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
- Prior autotransplant or allogeneic transplant
- More than 4 distinct, prior courses of therapy for myeloma
- Also see Disease Characteristics
Type of Study:
Interventional
Study Design:
Primary Purpose: Treatment
Outcome Measure:
Toxicity at 21 and 28 days post-transplant
Safety Issue:
Yes
Principal Investigator
Aaron P. Rapoport, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
University of Maryland Greenebaum Cancer Center
Authority:
United States: Food and Drug Administration
Study ID:
CDR0000552988
NCT ID:
NCT00499577
Start Date:
December 2006
Completion Date:
Related Keywords:
- Multiple Myeloma and Plasma Cell Neoplasm
- stage I multiple myeloma
- stage II multiple myeloma
- stage III multiple myeloma
- refractory multiple myeloma
- Neoplasms
- Multiple Myeloma
- Neoplasms, Plasma Cell
- Plasmacytoma
Name | Location |
|---|---|
| Abramson Cancer Center of the University of Pennsylvania | Philadelphia, Pennsylvania 19104-4283 |
| Greenebaum Cancer Center at University of Maryland Medical Center | Baltimore, Maryland 21201 |
