Vaccine Therapy and 1-MT in Treating Patients With Metastatic Breast Cancer
Male Breast Cancer
Recurrent Breast Cancer
Stage IV Breast Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Biological: adenovirus-p53 transduced dendritic cell (DC) vaccine
Other: Laboratory biomarker analysis
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase 1/2 Study of Ad.p53 DC Vaccine in Combination With 1-methyl-D-tryptophan in Metastatic Solid Tumors and Invasive Breast Cancer|
- Phase 1 - Maximum Tolerated Dose (MTD) in Milligrams (mg) [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: Yes ]MTD of 1-methyl-d-tryptophan (indoximod) given by mouth (PO), twice a day (BID), with up to 6 fixed doses Ad.p53 DC vaccinations every 2 weeks (q2wks). This phase 1 study used a 3+3 design with 7 indoximod dose levels (DL) (100 mg, 200 mg, 400 mg, 800 mg daily (QD) then 800 mg, 1,200 mg, and 1,600 mg PO BID +up to 6 fixed dose Ad.p53 DC vaccinations q2wks. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0. The MTD is the highest dose level below the maximally administered dose (MAD) that is safely tolerated among 6 treated patients, that is, 0 or 1 out of 6 patients experiences a dose limiting toxicity (DLT).
- Phase 2 - Number of Participants With Stable Disease In Response to Study Therapy [ Time Frame: Up to 16 weeks ] [ Designated as safety issue: No ]Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
- Phase 1 - Number of Participants With Objective Response at 6 Weeks [ Time Frame: At 6 weeks ] [ Designated as safety issue: No ]Immunologic Response defined as Interferon-γ (IFN-γ) p53 T cell specific enzyme-linked immunospot (ELISPOT) assay count Summarized using both point estimates and the 95% exact confidence intervals based on the binomial distribution. Briefly, 2x10^5 mononuclear cells obtained from the peripheral blood of patients will be plated in quadruplicates in 96-well multiscreen mixed cellulose ester (HA) filtration plates, processed and incubated, spots will be visualized. The number of spots will be calculated per 10^6 cells. Untreated peripheral blood mononuclear cells (PBMNC) will represent a negative control and PBMNC stimulated with 10 µg/ml Concanavalin A (ConA) - positive control.
- Phase 2 - Number of Participants With Clinical Benefit From Chemotherapy After Vaccination [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]Clinical response rate evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
- Phase 2 - Median Progression Free Survival (PFS) in Weeks [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. PFS: Time from study entry to documentation of radiologic progressive disease or death, assessed up to 3 years.
- Phase 2 - Change in Biomarker Level [ Time Frame: Baseline to week 16 ] [ Designated as safety issue: No ]Biomarkers include serum kynurenine, serum tryptophan, C reactive protein, and circulating T-regulatory cell levels (CD4+ 25+ CD127low forkhead box protein 3+ (FoxP3+). Appropriate t-tests and/or Wilcoxon test will be employed to study changes over time.
|Study Start Date:||December 2009|
|Estimated Study Completion Date:||December 2016|
|Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
Experimental: Treatment (vaccine therapy, 1-methyl-d-tryptophan)
Participants receive adenovirus-p53 transduced dendritic cell (Ad.p53-DC) vaccine ID in weeks 1, 3, 5, and 10, and then every 3 weeks for 6 total doses. Participants also receive 1-methyl-d-tryptophan (indoximod) orally (PO) daily (QD) on days 1-21. Treatment with 1-methyl-d-tryptophan repeats every 28 days (patients with stable disease) for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Biological: adenovirus-p53 transduced dendritic cell (DC) vaccine
Given intradermally (ID)
Other Name: Ad.p53-DC vaccineDrug: 1-methyl-d-tryptophan
Given orally (PO)
Other Names:Other: Laboratory biomarker analysis
I. To determine the maximum tolerated dose (MTD) and safety using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, of the combination Ad.p53 DC vaccine (adenovirus-p53 transduced dendritic cell vaccine) plus 1-MT in patients with any solid malignancy that has mutated p53 by immunohistochemistry (IHC). (Phase I) II. To determine efficacy (objective response rate) of the combination Ad.p53 DC vaccine plus 1-MT in metastatic breast cancer patients whose tumor expresses mutated p53 by IHC. (Phase II)
I. To collect preliminary data on and study the p53 specific interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot (ELISPOT) measurement at baseline, week 7 and week 16. (Phase I) II. To collect preliminary data on and study the percentage of p53 specific IFN-gamma ELISPOT responders at week 7 and 16. (Phase II) III. To collect preliminary data on and study progression-free survival on the study treatment. (Phase II) IV. To collect preliminary data on and study response and progression-free survival on the subsequent chemotherapy if administered. (Phase II) V. To collect preliminary data on and study the effects of 1-methyl-D-tryptophan (1-MT) on serum kynurenine, serum tryptophan, C reactive protein, and circulating T-regulatory cells (clusters of differentiation (CD)4+ 25+ CD127low forkhead box P3+ (FoxP3+)) by flow cytometry at each vaccination point on study when compared their corresponding baseline. (Phase II)
OUTLINE: This is a phase I, dose escalation study followed by a phase II study.
Patients receive adenovirus-p53 transduced dendritic cell vaccine intradermally (ID) in weeks 1, 3, 5, and 10, and then every 3 weeks for 6 total doses. Patients also receive 1-methyl-d-tryptophan orally (PO) once daily (QD) on days 1-21. Treatment with 1-methyl-d-tryptophan repeats every 28 days (patients with stable disease) for up to 12 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 weeks.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01042535
|United States, Florida|
|H. Lee Moffitt Cancer Center and Research Institute|
|Tampa, Florida, United States, 33612|
|Principal Investigator:||Hatem Soliman||H. Lee Moffitt Cancer Center and Research Institute|