Ignite Creation Date:
2024-05-06 @ 7:06 PM
Last Modification Date:
2024-10-26 @ 3:00 PM
Study NCT ID:
NCT05898828
Status:
WITHDRAWN
Last Update Posted:
2024-07-15
First Post:
2023-06-09
Brief Title:
Phase III Evaluation of a Cancer Lysate Vaccine and MontanideR ISA-51 VG With Entinostat and Nivolumab as Adjuvant Therapy Following Chemoradiation Therapy With or Without Surgery for Locally Advanced Esophageal Cancer
Sponsor:
National Cancer Institute NCI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Phase III Evaluation of a Cancer Lysate Vaccine and MontanideR ISA-51 VG With Entinostat and Nivolumab as Adjuvant Therapy Following Chemoradiation Therapy With or Without Surgery for Locally Advanced Esophageal Cancer
Status:
WITHDRAWN
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
No enrollment
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a Phase III study to determine the safety and immune response of the H1299 cell lysate vaccine mixed with MontanideR ISA-51 VG adjuvant to be administered on the study in combination with Entinostat and Nivolumab in eligible participants with locally advanced esophageal cancers EsC following either neoadjuvant chemoradiation therapy nCRT or nCRT and surgery Phase I of the protocol aims to determine the safe dose of the H1299 lung cancer cell lysate vaccine mixed with MontanideR ISA-51 VG adjuvant when it is administered in combination with Entinostat and Nivolumab Phase II of the protocol will focus on assessing the level of immune response in participants receiving the study intervention when the H1299 cell lysate vaccine with MontanideR ISA-51 VG adjuvant is administered at the dose level determined in Phase I
Detailed Description:
Background
Esophageal cancers EsC are highly lethal malignancies with strong predilections for local and systemic recurrences despite aggressive multimodality interventions
Currently the standard of care for locally advanced stage IIIII EsC is neoadjuvant chemoradiation therapy nCRT and surgery
Nearly 50 of patients with esophageal squamous cell cancers ESCC and 25 of patients with esophageal adenocarcinomas EAC have pathologic complete responses pCR following nCRT
Current staging modalities cannot reliably detect all residual EsC following nCRT and the benefit of surgery in patients with pCR is unclear
Recently nivolumab was approved as adjuvant therapy for patients who have undergone complete R0 resections of locally advanced esophageal or gastro-esophageal junction GEJ carcinomas with pathologic incomplete responses pIR following nCRT
Preclinical studies and early phase clinical studies suggest that immune checkpoint inhibitors can improve the efficacy of vaccines targeting tumor associated antigens
Cancer-testis CT antigens CTA particularly those encoded by genes on the X chromosome CT-X antigens have emerged as attractive targets for cancer immunotherapy given their highly restricted expression in cancers but not normal tissues and oncogenic activities
Recent studies suggest that CT antigens are preferentially expressed in pluripotent stemtumor initiating cells that mediate treatment resistance and metastasis of human cancers
Treatment interventions that inhibit activity of immunosuppressive Treg cells significantly increase efficacy of cancer vaccines and immune checkpoint inhibitors the triple combination therapy cures nearly all mice with established highly aggressive cancers
The class I histone deacetylase HDAC inhibitor entinostat which inhibits Treg activity appears to favorably modulate immune cell subsets in patients with advanced cancers receiving nivolumab
Conceivably vaccination of EsC patients with tumor cell lysates containing high levels of CT antigens in combination with entinostat will facilitate eradication of dormant EsC cells following immune checkpoint blockade
Primary Objectives
Phase I To determine the safe dose of adjuvant H1299 lung cancer cell lysate vaccines with MontanideR ISA-51 VG administered in conjunction with entinostat and nivolumab in participants with locally advanced esophageal cancers EsC with pathologic incomplete responses pIR following neoadjuvant chemoradiation therapy nCRT
Phase II To assess the frequency of immunologic responses to purified CT antigens in EsC participants following vaccinations with H1299 cancer cell lysates and MontanideR ISA- 51 VG in combination with entinostat and nivolumab
Eligibility
Participants with clinical Stage II or Stage III EsC with pIR following nCRT within the past 16 weeks
Participants must be 18 years or older with an ECOG performance status of 0 1
Adequate bone marrow kidney liver lung and cardiac function
No prior anti-PD-1PD-L1 therapy for their EsC
Participants receiving steroids at supraphysiologic doses will be excluded
Participants with HIV or any active infections will be excluded
Design
After recovery from nCRT or nCRT and surgery eligible participants will commence oral entinostat 5 mg q week
Following a two-week entinostat run-in participants will commence monthly deep subcutaneous vaccinations with H1299 cell lysates and Montanide r ISA-51 VG until six vaccinations have been given each cycle28 days
Following the two-week entinostat 5 mg q week run-in entinostat will be administered at a dose of 3 mg q week during nivolumab therapy
Four weeks after the first vaccination participants will commence nivolumab 480 mg IV infusion monthly for 1 year
Each cycle of vaccine therapy is 4 weeks 28 days
Participants will be scanned every 12 weeks while on treatment or continued treatment and during follow up every 3 months for 3 years every 6 months for another 2 years or through disease progression
Leukapheresis will be performed at baseline and at treatment evaluation one month following completion of the six vaccinations
Systemic toxicities and immunologic responses to therapy will be recorded
Pre- and post-vaccination serologic and cell mediated responses to a panel of CT antigens will be assessed before and one month following completion of the six vaccinations
Individuals deemed to have responded to the vaccine regimen and exhibit no evidence of disease recurrence or secondary malignancy will be eligible for two additional vaccinations administered q3 months with weekly entinostat and monthly nivolumab
Numbers and percentages of immune subsets soluble factors and cytokines in peripheral blood will be assessed before and after the six vaccinations
Immunologic responses to autologous tumor cells if available as well as lysates from H1299 cells and EsC stem cells vs normal esophageal-induced pluripotent stem cells Eso-iPSC will be evaluated in an exploratory manner
Accrual ceiling will be set at 50 participants
Esophageal cancers EsC are highly lethal malignancies with strong predilections for local and systemic recurrences despite aggressive multimodality interventions
Currently the standard of care for locally advanced stage IIIII EsC is neoadjuvant chemoradiation therapy nCRT and surgery
Nearly 50 of patients with esophageal squamous cell cancers ESCC and 25 of patients with esophageal adenocarcinomas EAC have pathologic complete responses pCR following nCRT
Current staging modalities cannot reliably detect all residual EsC following nCRT and the benefit of surgery in patients with pCR is unclear
Recently nivolumab was approved as adjuvant therapy for patients who have undergone complete R0 resections of locally advanced esophageal or gastro-esophageal junction GEJ carcinomas with pathologic incomplete responses pIR following nCRT
Preclinical studies and early phase clinical studies suggest that immune checkpoint inhibitors can improve the efficacy of vaccines targeting tumor associated antigens
Cancer-testis CT antigens CTA particularly those encoded by genes on the X chromosome CT-X antigens have emerged as attractive targets for cancer immunotherapy given their highly restricted expression in cancers but not normal tissues and oncogenic activities
Recent studies suggest that CT antigens are preferentially expressed in pluripotent stemtumor initiating cells that mediate treatment resistance and metastasis of human cancers
Treatment interventions that inhibit activity of immunosuppressive Treg cells significantly increase efficacy of cancer vaccines and immune checkpoint inhibitors the triple combination therapy cures nearly all mice with established highly aggressive cancers
The class I histone deacetylase HDAC inhibitor entinostat which inhibits Treg activity appears to favorably modulate immune cell subsets in patients with advanced cancers receiving nivolumab
Conceivably vaccination of EsC patients with tumor cell lysates containing high levels of CT antigens in combination with entinostat will facilitate eradication of dormant EsC cells following immune checkpoint blockade
Primary Objectives
Phase I To determine the safe dose of adjuvant H1299 lung cancer cell lysate vaccines with MontanideR ISA-51 VG administered in conjunction with entinostat and nivolumab in participants with locally advanced esophageal cancers EsC with pathologic incomplete responses pIR following neoadjuvant chemoradiation therapy nCRT
Phase II To assess the frequency of immunologic responses to purified CT antigens in EsC participants following vaccinations with H1299 cancer cell lysates and MontanideR ISA- 51 VG in combination with entinostat and nivolumab
Eligibility
Participants with clinical Stage II or Stage III EsC with pIR following nCRT within the past 16 weeks
Participants must be 18 years or older with an ECOG performance status of 0 1
Adequate bone marrow kidney liver lung and cardiac function
No prior anti-PD-1PD-L1 therapy for their EsC
Participants receiving steroids at supraphysiologic doses will be excluded
Participants with HIV or any active infections will be excluded
Design
After recovery from nCRT or nCRT and surgery eligible participants will commence oral entinostat 5 mg q week
Following a two-week entinostat run-in participants will commence monthly deep subcutaneous vaccinations with H1299 cell lysates and Montanide r ISA-51 VG until six vaccinations have been given each cycle28 days
Following the two-week entinostat 5 mg q week run-in entinostat will be administered at a dose of 3 mg q week during nivolumab therapy
Four weeks after the first vaccination participants will commence nivolumab 480 mg IV infusion monthly for 1 year
Each cycle of vaccine therapy is 4 weeks 28 days
Participants will be scanned every 12 weeks while on treatment or continued treatment and during follow up every 3 months for 3 years every 6 months for another 2 years or through disease progression
Leukapheresis will be performed at baseline and at treatment evaluation one month following completion of the six vaccinations
Systemic toxicities and immunologic responses to therapy will be recorded
Pre- and post-vaccination serologic and cell mediated responses to a panel of CT antigens will be assessed before and one month following completion of the six vaccinations
Individuals deemed to have responded to the vaccine regimen and exhibit no evidence of disease recurrence or secondary malignancy will be eligible for two additional vaccinations administered q3 months with weekly entinostat and monthly nivolumab
Numbers and percentages of immune subsets soluble factors and cytokines in peripheral blood will be assessed before and after the six vaccinations
Immunologic responses to autologous tumor cells if available as well as lysates from H1299 cells and EsC stem cells vs normal esophageal-induced pluripotent stem cells Eso-iPSC will be evaluated in an exploratory manner
Accrual ceiling will be set at 50 participants
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 001544-C | None | None | None |