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Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients.

ABSTRACT: BACKGROUND:E75 (nelipepimut-S) is a human leukocyte antigen (HLA)-A2/A3-restricted immunogenic peptide derived from the HER2 protein. We have conducted phase I/II clinical trials vaccinating breast cancer patients with nelipepimut-S and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adjuvant setting to prevent disease recurrence. All patients have completed 60 months follow-up, and here, we report the final analyses. PATIENTS AND METHODS:The studies were conducted as dose escalation/schedule optimization trials enrolling node-positive and high-risk node-negative patients with tumors expressing any degree of HER2 (immunohistochemistry 1-3+). HLA-A2/3+ patients were vaccinated; others were followed prospectively as controls. Local and systemic toxicity was monitored. Clinical recurrences were documented, and disease-free survival (DFS) was analyzed by Kaplan-Meier curves; groups were compared using log-rank tests. RESULTS:Of 195 enrolled patients, 187 were assessable: 108 (57.8%) in the vaccinated group (VG) and 79 (42.2%) in the control group (CG). The groups were well matched for clinicopathologic characteristics. Toxicities were minimal. Five-year DFS was 89.7% in the VG versus 80.2% in the CG (P = 0.08). Due to trial design, 65% of patients received less than the optimal vaccine dose. Five-year DFS was 94.6% in optimally dosed patients (P = 0.05 versus the CG) and 87.1% in suboptimally dosed patients. A voluntary booster program was initiated, and among the 21 patients that were optimally boosted, there was only one recurrence (DFS = 95.2%). CONCLUSION:The E75 vaccine is safe and appears to have clinical efficacy. A phase III trial evaluating the optimal dose and including booster inoculations has been initiated. CLINICAL TRIALS:NCT00841399, NCT00584789.

SUBMITTER: Mittendorf EA

PROVIDER: S-EPMC4143091 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients.

Mittendorf E A EA Clifton G T GT Holmes J P JP Schneble E E van Echo D D Ponniah S S Peoples G E GE

Annals of oncology : official journal of the European Society for Medical Oncology 20140606 9

<h4>Background</h4>E75 (nelipepimut-S) is a human leukocyte antigen (HLA)-A2/A3-restricted immunogenic peptide derived from the HER2 protein. We have conducted phase I/II clinical trials vaccinating breast cancer patients with nelipepimut-S and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adjuvant setting to prevent disease recurrence. All patients have completed 60 months follow-up, and here, we report the final analyses.<h4>Patients and methods</h4>The studies were conducte ...[more]

PMID: 24907636

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Project description:BACKGROUND:In 2016, the response to a yellow fever outbreak in Angola and the Democratic Republic of Congo led to a global shortage of yellow fever vaccine. As a result, a fractional dose of the 17DD yellow fever vaccine (containing one fifth [0.1 ml] of the standard dose) was offered to 7.6 million children 2 years of age or older and nonpregnant adults in a preemptive campaign in Kinshasa. The goal of this study was to assess the immune response to the fractional dose in a large-scale campaign. METHODS:We recruited participants in four age strata at six vaccination sites. We assessed neutralizing antibody titers against yellow fever virus in blood samples obtained before vaccination and at 1 month and 1 year after vaccination, using a plaque reduction neutralization test with a 50% cutoff (PRNT50). Participants with a PRNT50 titer of 10 or higher were considered to be seropositive. Those with a baseline titer of less than 10 who became seropositive at follow-up were classified as having undergone seroconversion. Participants who were seropositive at baseline and who had an increase in the titer by a factor of 4 or more at follow-up were classified as having an immune response. RESULTS:Among 716 participants who completed the 1-month follow-up, 705 (98%; 95% confidence interval [CI], 97 to 99) were seropositive after vaccination. Among 493 participants who were seronegative at baseline, 482 (98%; 95% CI, 96 to 99) underwent seroconversion. Among 223 participants who were seropositive at baseline, 148 (66%; 95% CI, 60 to 72) had an immune response. Lower baseline titers were associated with a higher probability of having an immune response (P<0.001). Among 684 participants who completed the 1-year follow-up, 666 (97%; 95% CI, 96 to 98) were seropositive for yellow fever antibody. The distribution of titers among the participants who were seronegative for yellow fever antibody at baseline varied significantly among age groups at 1 month and at 1 year (P<0.001 for both comparisons). CONCLUSIONS:A fractional dose of the 17DD yellow fever vaccine was effective at inducing seroconversion in participants who were seronegative at baseline. Titers remained above the threshold for seropositivity at 1 year after vaccination in nearly all participants who were seropositive at 1 month after vaccination. These findings support the use of fractional-dose vaccination for outbreak control. (Funded by the U.S. Agency for International Development and the Centers for Disease Control and Prevention.).

Project description:PurposePatients with metastatic urothelial carcinoma are often ineligible for cisplatin-based treatments. A National Cancer Institute Cancer Therapy Evaluation Program-sponsored trial assessed the tolerability and efficacy of a gemcitabine-eribulin combination in this population.MethodsPatients with treatment-naïve advanced or recurrent metastatic urothelial carcinoma of the bladder, ureter, or urethra not amenable to curative surgery and not candidates for cisplatin-based therapy were eligible. Cisplatin ineligibility was defined as creatinine clearance less than 60 mL/min (but ≥ 30 mL/min), grade 2 neuropathy, or grade 2 hearing loss. Treatment was gemcitabine 1,000 mg/m2 intravenously followed by eribulin 1.4 mg/m2, both on days 1 and 8, repeated in 21-day cycles until progression or unacceptable toxicity. A Simon two-stage phase II trial design was used to distinguish between Response Evaluation Criteria in Solid Tumors, version 1.1 objective response rates of 20% versus 50%.ResultsBetween June 2015 and March 2017, 24 eligible patients with a median age of 73 years (range, 62 to 88 years) underwent therapy. Performance status of 0, 1, or 2 was seen in 11, 11, and two patients, respectively. Sites of disease included: lymph nodes, 16; lungs, nine; liver, seven; bladder, five; bones, two. Median number of cycles received was four (range, one to 16). Of 24 patients, 12 were confirmed responders; the observed objective response rate was 50% (95% CI, 29% to 71%). Median overall survival was 11.9 months (95% CI, 5.6 to 20.4 months), and median progression-free survival was 5.3 months (95% CI, 4.5 to 6.7 months). The most common treatment-related any-grade toxicities were fatigue (83% of patients), neutropenia (79%), anemia (63%), alopecia (50%), elevated AST (50%), and constipation, nausea, and thrombocytopenia (42% each).ConclusionGemcitabine-eribulin treatment response and survival for cisplatin-ineligible patients compare favorably to other regimens. Additional research is needed.

Dataset Information

Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients.

Publications

Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients.

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