An alternative clinical trial design for early cancer vaccine development to phase 3+3 design.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2578-2578
Author(s):  
Emily Gammoh ◽  
Osama E. Rahma ◽  
Richard Simon ◽  
Samir Khleif
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
Early Development ◽  
Phase Ii ◽  
Cancer Vaccine ◽  
Dose Escalation ◽  
Cancer Vaccines ◽  
Therapeutic Cancer Vaccine ◽  
Alternative Design ◽  
Immune Modulator

2578 Background: Traditional phase I, “3+3 dose escalation” design, is conducted to identify the MTD and in some cases the optimal biologic dose. Given their unique mechanism of action and the profile of their clinical outcome, this design may not apply to cancer vaccines. The therapeutic cancer vaccine FDA guidance calls for an alternative early development design. Nevertheless, whether an alternative design should be based on “dose escalation” is still an opened question. Methods: We analyzed the toxicity profile in 241 phase 1, 1/2 and pilot therapeutic cancer vaccine trials conducted between 1990 and 2011. Results: Sixty-two grade 3/4 vaccine related systemic toxicities were reported in 4952 treated patients (1.25 events/100 patients). Interestingly, only 2 out of 127 trials that used dose escalation reported vaccine related DLTs, both trials used bacterial vectors. Furthermore, correlation of immunological response with dose level showed no consistent trend. Conclusions: Our analysis suggests that in cancer vaccines neither toxicity nor cellular immune response correlates with dose levels. Accordingly, dose escalation is not suitable for most cancer vaccine studies. Here, we propose a two-step alternative design for early development of cancer vaccines. The first step is to determine and confirm the minimum Immune-Active Dose (IAD). If a vaccine class has been used in humans, IAD dose is chosen based on previous experience if the class is non-toxic (eg. Peptide), otherwise, a traditional dose escalation will be used. For a vaccine class that has not been tested or has undetermined toxicity we recommend “One Patient Escalation Design” (OPSD): one patient is treated per tested dose until an immune response is induced. To confirm this activity, an expanded cohort of 7 patients will be tested until demonstrating an additional response. This will then be used in phase II combination therapy trial. Alternatively, IAD can be directly tested in combination with an immune modulator in a phase II clinical trial using a two-stage design. The first stage of the phase 2 trial can be set at 4-5 patients for a target response rate of over 50%. If no response is seen, then the immune modulator will be escalated in the second stage.

scholarly journals An alphavirus-based therapeutic cancer vaccine: from design to clinical trial

2018 ◽  
Vol 68 (5) ◽  
pp. 849-859 ◽  
Author(s):  
Amrita Singh ◽  
Georgia Koutsoumpli ◽  
Stephanie van de Wall ◽  
Toos Daemen
Keyword(s):  
Clinical Trial ◽  
Cancer Vaccine ◽  
Therapeutic Cancer Vaccine

Antigen dose escalation study of a VEGF-based therapeutic cancer vaccine in non human primates

Vaccine ◽  
2012 ◽  
Vol 30 (2) ◽  
pp. 368-377 ◽  
Author(s):  
Yanelys Morera ◽  
Mónica Bequet-Romero ◽  
Marta Ayala ◽  
Pedro Puente Pérez ◽  
Jorge Castro ◽  
...  
Keyword(s):  
Cancer Vaccine ◽  
Dose Escalation ◽  
Dose Escalation Study ◽  
Therapeutic Cancer Vaccine ◽  
Antigen Dose

Multi-center phase II/III randomized controlled clinical trial using TNFerade combined with chemoradiation in patients with locally advanced pancreatic cancer (LAPC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4518-4518 ◽  
Author(s):  
M. Posner ◽  
K. J. Chang ◽  
A. Rosemurgy ◽  
J. Stephenson ◽  
M. Khan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trial ◽  
Overall Survival ◽  
Phase Ii ◽  
Dose Escalation ◽  
Survival Data ◽  
Interim Analysis ◽  
Dose Escalation Study ◽  
Absolute Increase ◽  
Ct Guided

4518 Background: TNFerade is a replication-deficient adenoviral vector carrying the transgene for human TNF-a protein, regulated by the radiation-inducible promoter Egr-1. A 50 patient (pt) phase II dose-escalation study in LAPC showed a possible dose-dependent improvement in survival. To confirm these findings, the randomized Pancreatic Cancer Clinical Trial with TNFerade (PACT) study was developed. PACT is a 330 pt study, powered to detect a 20% absolute increase in the primary efficacy endpoint (overall survival at 1 year) compared to standard of care (SOC) chemoradiation. An interim analysis of safety and efficacy was planned after the first 51 pts were randomized. Survival data to 11/15/06 has been evaluated and are reported here. Methods: The TNFerade arm pts received a five- wk treatment of weekly injections of 4 x 1011 pu TNFerade, continuous infusion 5-FU (200 mg/m2/day x 5 days/wk) and 50.4 Gy radiation. TNFerade was administered by percutaneous CT-guided transabdominal injection. The SOC arm received the same regimen, without TNFerade injections. Patients were randomized 2:1 to the TNFerade and SOC arms. The first 51 randomized pts were assessed for evidence of objective response (OR) and overall survival Results: Assessment of response data is still ongoing. TNFerade + SOC was well tolerated. One year survival, the primary endpoint of the study, was 70.5% in the TNFerade + SOC arm versus 28.0% in the SOC arm, an absolute increase of 42.5%. The median survival for TNFerade + SOC pts was 515 days compared to 335 days for the SOC pts. The logrank statistic for comparison between the two arms is X2 = 2.014 (p=0.16). Conclusions: The interim survival data is preliminary. The magnitude of the difference in survival in favor of the TNFerade + SOC arm, however, is encouraging. The data appears to corroborate previous findings from the dose-escalation study, which showed an apparent survival advantage in the 4×1011 pu dose group compared to 4 x 109 pu group. A second interim analysis is planned with larger patient numbers to determine whether this early positive trend is confirmed. No significant financial relationships to disclose.

A phase II study of a yeast-based therapeutic cancer vaccine, GI-6207, targeting CEA in patients with minimally symptomatic, metastatic medullary thyroid cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3127-TPS3127
Author(s):  
Ravi Amrit Madan ◽  
Nishith K. Singh ◽  
Ann Wild Gramza ◽  
Antonio Tito Fojo ◽  
Christopher Ryan Heery ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tumor Growth ◽  
Phase Ii ◽  
Cancer Vaccine ◽  
Growth Rates ◽  
Medullary Thyroid Cancer ◽  
Phase Ii Study ◽  
Therapeutic Cancer Vaccine ◽  
Long Term Outcome ◽  
Medullary Thyroid

TPS3127 Background: Saccharomyces cerevisiae has been genetically modified to express CEA protein and developed under a CRADA with GlobeImmune/NCI as a heat-killed immune-stimulating, therapeutic cancer vaccine (GI-6207). A phase I study with GI-6207 demonstrated safety, biomarker stabilization and enhanced immune response in some patients. CEA is over-expressed in multiple malignancies, including medullary thyroid cancer (MTC). Two therapies recently approved by the FDA for metastatic MTC (vandetanib, cabozantinib) come with toxicity and should be reserved for symptomatic/progressive disease. However, a large population of asymptomatic MTC patients has small tumor burden and/or disease that is more indolent. The standard management of these patients is observation. Preliminary data suggest that tumor growth measured by the rate of CEA and calcitonin increase can be quantified in a 3-6 months. Retrospective data from prostate cancer studies suggest vaccines can alter growth rates within 3-4 months. We hypothesize that GI-6207 can alter tumor growth rates in MTC and impact long-term outcome. Methods: A phase II study will evaluate the effect of GI-6207 onthe rates ofincrease in calcitonin in metastatic MTC. 34 patients with minimally symptomatic, radiographically evaluable, metastatic MTC will be randomized 1:1. Arm A will receive vaccine for a year from the time of enrollment. Arm B will receive vaccine after 6 months of surveillance. GI-6207 will be administered subcutaneously at 4 sites (10 yeast units/site), every 2 weeks for 3 months, then monthly up to 1 year. The primary endpoint will compare the effect of GI-6207 on calcitonin kinetics between the vaccine and surveillance arms in the first 6 months. Secondary endpoints include immunologic responses (including antigen-specific T cell responses), objective responses, time to progression, and changes in CEA kinetics. If this trial can prospectively demonstrate that vaccines can alter tumor growth rates, and if such changes are associated with clinical outcomes, then changes in tumor growth rates may become a clinical metric to evaluate vaccine efficacy in MTC and other populations.

HepaVac-101 first-in-man therapeutic cancer vaccine phase I/II clinical trial for hepatocellular carcinoma patients.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. TPS3135-TPS3135 ◽  
Author(s):  
Luigi Buonaguro ◽  
Andrea Mayer-Mokler ◽  
Roberto Accolla ◽  
Yuk Ting Ma ◽  
Regina Heidenreich ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trial ◽  
Phase I ◽  
Cancer Vaccine ◽  
Therapeutic Cancer Vaccine

Clinical and Immunological responses in patients with malignant melanoma treated with a dendritic cell-based vaccine. Preliminary report from a multi-institutional phase II clinical trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3004-3004
Author(s):  
M. Ross ◽  
L. H. Camacho ◽  
E. M. Hersh ◽  
C. K. Brown ◽  
J. Richards ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Therapeutic Vaccine ◽  
Phase Ii Clinical Trial ◽  
Age Related Macular Degeneration ◽  
Ifn Γ

3004 Background: We have previously reported that vaccination with IDM therapeutic vaccine (IDD-3/Uvidem [Uvidem is co-developed with SANOFI-AVENTIS]) composed of dendritic cells (DC) loaded with three allogeneic lysates from tumor cell lines can elicit immune and anti-tumor responses. We describe here the preliminary results from a phase II clinical trial in metastatic melanoma patients. Methods: DC-MEL-202 is a single arm, two-stage phase II trial designed to evaluate clinical and immunological activities and the safety of a multivalent DC vaccine in patients with in-transit or low volume metastatic melanoma. There was no HLA restriction. Autologous DC were generated, under GMP conditions, from monocytes cultured in GM-CSF and IL-13, loaded with three allogeneic melanoma tumor lysates (M44, SK-MEL 28 and COLO 829) and matured with a combination of bacterial extract (FMKP) and IFN-γ, generating up to 15 doses of the vaccine containing 25x106 DC. Patients received six bi-weekly and two 6-weekly injections (id and sc). Clinical responders were eligible to receive additional doses. Immune response against tumor-associated antigens (TAA) peptides was assessed, at several time points, by detection of IFN-γ producing cells by flow cytometry Results: 33 patients were treated. To date: Vaccination is well tolerated with toxicity limited to mild events (only one possibly related SAE, age-related macular degeneration, was reported). Clinical response (RECIST): 6 patients showed evidence of clinical benefit (1CR, 1PR and 4 SD) with duration of response ranging from 7.5 to 22 months. Assessment of pathological response in target sites in 2 pts (1 PR, 1 SD) showed no residual disease.. 23/33 patients are still alive with a mean follow-up of 11mo (range 3–22mo). Mature data of PFS and OS will be presented. Immune response: 21 (84 %) out of 25 evaluated patients showed detectable TAA-specific CD8+ T cells with ten showing boosted or appearance of anti-TAA specific CD8+ T cells. Conclusions: Vaccination with IDD-3/Uvidem is safe and can elicit tumor specific CD8+ T cells not limited to HLA-A2+ patients. Substantial clinical benefit warrants further development of IDD3. No significant financial relationships to disclose.

A randomized phase II clinical trial of enzalutamide in combination with the therapeutic cancer vaccine, PSA tricom, in metastatic, castration resistant prostate cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS5104-TPS5104
Author(s):  
Nishith K. Singh ◽  
Joseph W. Kim ◽  
Christopher Ryan Heery ◽  
William L. Dahut ◽  
Anna Couvillon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Cancer Vaccine ◽  
Phase Iii ◽  
Cytotoxic T Cell ◽  
Phase 2 ◽  
Therapeutic Cancer Vaccine ◽  
Randomized Phase 2

TPS5104 Background: There is a strong rationale to combine therapeutic cancer vaccines with hormonal abrogation in prostate cancer. Androgen abrogation augments T-cell trafficking to prostate, decreases immune tolerance, increases production of naïve thymic T-cells, enhances cytotoxic T-cell repertoire. PSA TRICOM (PROSTVAC) is a therapeutic, viral-vector based, off-the-shelf, cancer vaccine of PSA & 3 co-stimulatory molecules in phase III testing. This was developed at the NCI in collaboration with Bavarian Nordic Immunotherapeutics. It has demonstrated safety and survival benefit in a randomized phase 2 trial of metastatic castrate resistant prostate cancer (mCRPC). Enzalutamide is a modern androgen receptor inhibitor (ARI) approved for the treatment of mCRPC. Data from the clinical trials with these therapies suggest good individual tolerability without any overlapping toxicities. Analysis of previous trials suggests that vaccines may enhance clinical outcomes with ARI. These data form the scientific basis for a combination approach of a cancer vaccine with ARI to control tumor progression in mCRPC. Methods: A randomized, phase 2, open-label clinical trial at the NCI will enroll 72 chemo-naïve, minimally symptomatic patients with mCRPC. They will be randomized (1:1) to enzalutamide (160 mg daily) alone, or enzalutamide with PSA TRICOM for treatment until radiographic progression. PSA-TRICOM will be administered in a core phase (with day 1, 15 and 29 then 4 additional monthly boosts) followed by continued boosts every 3 months. The primary end point will evaluate time to progression in each arm with secondary endpoints including overall survival and systemic immune responses (lymphocyte subsets, regulatory T-cells, regulatory T-cell function, cytokines, naïve thymic emigrants). If a therapeutic cancer vaccine can enhance the clinical efficacy of a hormonal agent such as enzalutamide, it may help define a new role for vaccines as an adjuvant to standard therapies. We will also evaluate this combination in a second trial in non-metastatic, castration-sensitive patients where this combination may yield its greatest clinical impact.

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