Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Neoplasm Metastasis

Melanoma

Sarcoma

Neoplasm, Residual

Neoplasms by Histologic Type

Neoplasms, Connective and Soft Tissue

Soft Tissue Sarcoma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Inflammatory Agents

Analgesics

Cyclophosphamide

Vaccines

Immunomodulating Agents

Celecoxib

Adjuvants, Vaccine

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase 2 Inhibitors

Cyclooxygenase Inhibitors

Enzyme Inhibitors

H1299 cell lysates with iscomatrix vaccine with metronomic chemotherapy

H1299 cell lysates with iscomatrix adjuvant vaccine

H1299 cell lysate with iscomatrix adjuvant vaccine via subcutaneous injections once every cycle (cycle=28 days) for 6 cycles total. Additional 2 injections for patients with immunologic response and no clinical evidence of active disease (NED).

H1299 cell lysates

50 mg by mouth (PO) twice a day (BID) for 7 days prior to the first dose of vaccine and then on days 8 through 14, and 22 through 28 of each treatment cycle.

400 mg by mouth (PO) twice a day (BID) for 7 days prior to the first dose of vaccine and then on days 1 through 28 of each treatment cycle.

Iscomatrix adjuvant

David S Schrump, M.D.

Background:

During recent years, cancer-testis (CT) antigens (CTA), particularly those encoded by genes on the X chromosome (CT-X genes), have emerged as attractive targets for cancer immunotherapy. Whereas malignancies of diverse histologies express a variety of CTAs, immune responses to these proteins appear uncommon in cancer patients, possibly due to low-level, heterogeneous antigen expression, as well as immunosuppressive regulatory T cells present within tumor sites and systemic circulation of these individuals. Conceivably, vaccination of cancer patients with tumor cells expressing high levels of CTAs in combination with regimens that deplete or inhibit T regulatory cells will induce broad immunity to these antigens. In order to examine this issue, patients with primary lung and esophageal cancers, pleural mesotheliomas, thoracic sarcomas, thymic neoplasms and mediastinal germ cell tumors, as well as sarcomas, melanomas, germ cell tumors, or epithelial malignancies metastatic to lungs, pleura or mediastinum with no evidence of disease (NED) or minimal residual disease (MRD) following standard multidisciplinary therapy will be vaccinated with H1299 tumor cell lysates with Iscomatrix adjuvant. Vaccines will be administered with or without metronomic oral cyclophosphamide (50 mg by mouth (PO) twice a day (BID) x 7day (d) every (q) 14d), and celecoxib (400 mg PO BID). Serologic responses to a variety of recombinant CTAs as well as immunologic responses to autologous tumor or epigenetically modified autologous Epstein-Barr virus (EBV) transformed lymphocytes will be assessed before and after a six month vaccination period.

Primary Objectives:

1. To assess the frequency of immunologic responses to CTAs in patients with thoracic malignancies following vaccinations with H1299 cell lysate/Iscomatrix(TM) vaccines alone in comparison to patients with thoracic malignancies following vaccinations with H1299 cell lysate/Iscomatrix vaccines in combination with metronomic cyclophosphamide and celecoxib.

Secondary Objectives:

1. To examine if oral metronomic cyclophosphamide and celecoxib therapy diminishes the number and percentage of T regulatory cells and diminishes activity of these cells in patients with thoracic malignancies are at risk of recurrence.
2. To examine if H1299 cell lysate/Iscomatrix(TM) vaccination enhances immunologic response to autologous tumor or epigenetically modified autologous EBV-transformed lymphocytes (B cells).

Eligibility:

* Patients with histologically or cytologically proven small cell or non-small cell lung cancer (SCLC;NSCLC), esophageal cancer (EsC), malignant pleural mesothelioma (MPM), thymic or mediastinal germ cell tumors, thoracic sarcomas, or melanomas, sarcomas, or epithelial malignancies metastatic to lungs, pleura or mediastinum who have no clinical evidence of active disease (NED), or minimal residual disease (MRD) not readily accessible by non-invasive biopsy or resection/radiation following standard therapy completed within the past 26 weeks.
* Patients must be 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2.
* Patients must have adequate bone marrow, kidney, liver, lung and cardiac function.
* Patients may not be on systemic immunosuppressive medications at time vaccinations commence.

Design:

* Following recovery from surgery, chemotherapy, or chemo/radiotherapy (XRT), patients with NED or MRD will be vaccinated via IM injection with H1299 cell lysates and Iscomatrix(TM) adjuvant monthly for 6 months.
* Vaccines will be administered with or without with metronomic oral cyclophosphamide and celecoxib.
* Systemic toxicities and immunologic response to therapy will be recorded. Pre and post vaccination serologic and cell mediated responses to a standard panel of CT antigens as well as autologous tumor cells (if available) and EBV-transformed lymphocytes will be assessed before and after vaccination.
* Numbers/percentages and function of T regulatory cells in peripheral blood will be assessed before, during, and after vaccinations.
* Patients will be followed in the clinic with routine staging scans until disease recurrence.
* The trial will randomize 28 evaluable patients per arm to either receive vaccine alone or vaccine plus chemotherapy in order to have 80% power to determine if the frequency of immune responses on the combination arm exceeds that of the vaccine alone arm, if the expected frequencies of immune responses on the two arms were 20% and 50%, using a one-sided 0.10 alpha level Fisher's exact test.
* Approximately 60 patients will be accrued to this trial.

Background:

During recent years, cancer-testis (CT) antigens (CTA), particularly those encoded by genes on the X chromosome (CT-X genes), have emerged as attractive targets for cancer immunotherapy. Whereas malignancies of diverse histologies express a variety of CTAs, immune responses to these proteins appear uncommon in cancer patients, possibly due to low-level, heterogeneous antigen expression, as well as immunosuppressive regulatory T cells present within tumor sites and systemic circulation of these individuals. Conceivably, vaccination of cancer patients with tumor cells expressing high levels of CTAs in combination with regimens that deplete or inhibit T regulatory cells will induce broad immunity to these antigens. In order to examine this issue, patients with primary lung and esophageal cancers, pleural mesotheliomas, thoracic sarcomas, thymic neoplasms and mediastinal germ cell tumors, as well as sarcomas, melanomas, germ cell tumors, or epithelial malignancies metastatic to lungs, pleura or mediastinum with no evidence of disease (NED) or minimal residual disease (MRD) following standard multidisciplinary therapy will be vaccinated with H1299 tumor cell lysates with Iscomatrix (Trademark) adjuvant. Vaccines will be administered with or without metronomic oral cyclophosphamide (50 mg by mouth (PO) twice a day (BID) x 7day (d) every (q) 14d), and celecoxib (400 mg PO BID). Serologic responses to a variety of recombinant CTAs as well as immunologic responses to autologous tumor or epigenetically modified autologous Epstein-Barr Virus (EBV) transformed lymphocytes will be assessed before and after receiving 6 vaccines.

Primary Objectives:

-To assess the frequency of immunologic responses to CTAs in patients with thoracic malignancies following vaccinations with H1299 cell lysate/Iscomatrix (Trademark) vaccines alone in comparison to patients with thoracic malignancies following vaccinations with H1299 cell lysate/Iscomatrix (Trademark) vaccines in combination with metronomic cyclophosphamide and celecoxib.

Eligibility:

-Patients with histologically or cytologically proven small cell or non-small cell lung cancer (SCLC;NSCLC), esophageal cancer (EsC), malignant pleural mesothelioma (MPM), thymic or mediastinal germ cell tumors, thoracic sarcomas, or melanomas, sarcomas, or

epithelial malignancies metastatic to lungs, pleura or mediastinum who have no clinical evidence of active disease (NED), or minimal residual disease (MRD) not readily accessible by non-invasive biopsy or resection/radiation following standard therapy completed within the past 56 weeks.

* Patients must be 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2.
* Patients must have adequate bone marrow, kidney, liver, lung and cardiac function.
* Patients may not be on systemic immunosuppressive medications at time vaccinations commence.

Design:

* Following recovery from surgery, chemotherapy, or chemo/XRT, patients with NED or MRD will be vaccinated via deep subcutaneous (SQ) injection with H1299 cell lysates and Iscomatrix (Trademark) adjuvant monthly until 6 vaccinations have been given.
* Vaccines will be administered with or without with metronomic oral cyclophosphamide and celecoxib.
* Systemic toxicities and immunologic response to therapy will be recorded. Pre and post vaccination serologic and cell mediated responses to a standard panel of CT antigens as well as autologous tumor cells (if available) and EBV-transformed lymphocytes will be assessed before and after vaccination.
* Numbers/percentages and function of T regulatory cells in peripheral blood will be assessed before, during, and after vaccinations.
* Patients will be followed in the clinic with routine staging scans until disease recurrence.
* The trial will randomize 28 evaluable patients per arm to either receive vaccine alone or vaccine plus chemotherapy in order to have 80% power to determine if the frequency of immune responses on the combination arm exceeds that of the vaccine alone arm, if the expected frequencies of immune responses on the two arms were 20% and 50%, using a one-sided 0.10 alpha level Fisher's exact test.
* Approximately 60 patients will be accrued to this trial.

Adjuvant Tumor Lysate Vaccine and Iscomatrix With or Without Metronomic Oral Cyclophosphamide and Celecoxib in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum

The immunologic response to autologous tumor or epigenetically-modified autologous Epstein-Barr Virus (EBV)-transformed lymphocytes will be determined by the difference, or relative difference, in values (by percentage) of T-regulatory cells at the two timepoints. The percentage of T-regulatory cells will determine if oral cyclophosphamide and celecoxib therapy decreases the percentage of T cells on each Arm/Group.

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Immunologic responses are defined as an appearance of new serologic reactivity, or increase in existing antibody response to cancer-testis on the X chromosome (CT-X) antigen. Antigens such as New York esophageal squamous cell carcinoma-1 (NY-ESO1) and melanoma antigen gene (MAGE) family members assessed by enzyme-linked immunosorbent assay (ELISA) one month after the 6th vaccine.

The Mann=Whitney U test was used to compare the fold change of intensity of PD-1 expression on Tregs between the two groups. A decrease in the fold change is consistent with a better outcome. The difference, or the relative difference, in the values at the two time points were obtained and tested to determine if the difference is equal to zero. If a paired t-test is able to be used, with at least 20 evaluable participants, there is 81% power to detect a change equal to ¾ of a standard deviation of the change at the two-sided 0.025 significance level. This was done in order to allow for a conservative adjustment due to determining the significance of the change in the percent of Tregs on two arms.

The Mann-Whitney U test was used to compare the fold change of percent Tregs between the two groups. A decrease in the fold change is consistent with a better outcome. The difference, or the relative difference, in the values at the two time points were obtained and tested to determine if the difference is equal to zero. If a paired t-test is able to be used, with at least 20 evaluable participants, there is 81% power to detect a change equal to ¾ of a standard deviation of the change at the two-sided 0.025 significance level. This was done in order to allow for a conservative adjustment due to determining the significance of the change in the percent of Tregs on two arms.

National Cancer Institute (NCI)

Principal Investigator

H1299 cell lysates with iscomatrix vaccine with metronomic chemotherapy

H1299 cell lysates: H1299 cell lysate with iscomatrix adjuvant vaccine via subcutaneous injections once every cycle (cycle=28 days) for 6 cycles total. Additional 2 injections for patients with immunologic response and no clinical evidence of active disease (NED).

Cyclophosphamide: 50 mg by mouth (PO) twice a day (BID) for 7 days prior to the first dose of vaccine and then on days 8 through 14, and 22 through 28 of each treatment cycle.

Celecoxib: 400 mg by mouth (PO) twice a day (BID) for 7 days prior to the first dose of vaccine and then on days 1 through 28 of each treatment cycle.

Iscomatrix adjuvant: H1299 cell lysate with iscomatrix adjuvant vaccine via subcutaneous injections once every cycle (cycle=28 days) for 6 cycles total. Additional 2 injections for patients with immunologic response and no clinical evidence of active disease (NED).

Cohort 1/Vaccine Plus Chemotherapy

H1299 cell lysates with iscomatrix adjuvant vaccine

H1299 cell lysates: H1299 cell lysate with iscomatrix adjuvant vaccine via subcutaneous injections once every cycle (cycle=28 days) for 6 cycles total. Additional 2 injections for patients with immunologic response and no clinical evidence of active disease (NED).

Iscomatrix adjuvant: H1299 cell lysate with iscomatrix adjuvant vaccine via subcutaneous injections once every cycle (cycle=28 days) for 6 cycles total. Additional 2 injections for patients with immunologic response and no clinical evidence of active disease (NED).

Cohort 2/Vaccine Alone

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. David Schrump

Number of Participants With an Immunologic Responses

Fold Change From Baseline of Intensity of Programmed Cell Death Protein 1(PD-1) Expression on Tregs

Fold Change From Baseline of Percent Tregs

Baseline

End of treatment

This exploratory endpoint was not assessed because the trial was suspended after only 1/3rd of the total anticipated patient accrual.

Percentage of T Regulatory Cells at the Two Timepoints: Baseline and End of Treatment

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

Overall Study

Digestive System Diseases

Esophageal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Esophageal Cancer

Nivolumab

Monatide (IMS 3015)

Entinostat

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Adjuvants, Immunologic

Histone Deacetylase Inhibitors

H1299 cell lysate vaccine with Montanide(R) ISA-51 VG, entinostat, and nivolumab (Phase I component to determine lysate dose)

H1299 cell lysate vaccine with Montanide(R) ISA-51 VG, entinostat, and nivolumab (lysate at dose determined in Phase I)

Nivolumab 480 mg flat dose via intravenous infusion on Day 3 of every cycle starting at Cycle 2, for intended duration of 1 year.

Entinostat (5 mg) self-administered on Days -14 and -7 prior to the first vaccination cycle, then entinostat (3 mg) self-administered on Days 1, 8, 15, and 22 of each vaccine cycle (Cycles 1-6). Entinostat continuation for subjects with immunologic response and NED during additional 2 vaccine injections.

H1299 cell lysate with Montanide(R) ISA-51 VG adjuvant vaccine via subcutaneous injections once every cycle (1 cycle=28 days) for 6 cycles (i.e., 6 vaccinations). Dose Level 1 (DL1) starting dose is 20 mg lysate protein in 2-2.5 mL Montanide(R) ISA-51 VG adjuvant; lysate concentration will be 8-10 mg/mL. Additional 2 vaccine injections for subjects with immunologic response and NED.

Montanide(R) ISA-51 VG Adjuvant

H1299 Cell Lysates

Deneise Francis, R.N.

National Cancer Institute Referral Office

This is a Phase I/II study to determine the safety and immune response of the H1299 cell lysate vaccine mixed with Montanide(R) 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 Montanide(R) 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 Montanide(R) ISA-51 VG adjuvant is administered at the dose level determined in Phase I.

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 II/III) 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 stem/tumor 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 Montanide(R) 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 Montanide(R) 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-1/PD-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 cycle=28 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.

Phase I/II Evaluation of a Cancer Lysate Vaccine and Montanide(R) ISA-51 VG With Entinostat and Nivolumab as Adjuvant Therapy Following Chemoradiation Therapy With or Without Surgery for Locally Advanced Esophageal Cancer

.All IPD recorded will be shared upon request.

Assessment of safety and tolerability as determined by the frequency and severity of adverse events

Assessment of immune response to CT antigens (new serologic reactivity or increase in existing antibody response to CT antigens, evidenced by IgM/IgG class switch or antibody titer)

Analyses which investigate immunologic response (i.e., immune response to CT antigens); response to vaccine will be the appearance of new serologic reactivity or an increase in existing antibody response to CT antigens, evidenced by IgM/IgG class switch or antibody titer.

Progression free survival (PFS) determined by RECIST using the Kaplan-Meier method

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Adjuvant Tumor Lysate Vaccine and Iscomatrix With or Without Metronomic Oral Cyclophosphamide and Celecoxib in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum	NCT02054104	Thoracic Sarcom... Thorasic Cancer... Cancers of Non-... Sarcoma Melanoma	H1299 cell lysa... Cyclophosphamid... Celecoxib Iscomatrix adju...	18 Years -	National Institutes of Health Clinical Center (CC)
Phase I/II Evaluation of a Cancer Lysate Vaccine and Montanide(R) ISA-51 VG With Entinostat and Nivolumab as Adjuvant Therapy Following Chemoradiation Therapy With or Without Surgery for Locally Advanced Esophageal Cancer	NCT05898828	Neoplasms Esophageal Neop... Esophagus Neopl... Esophagus Cance... Neoplasms, Esop... Esophageal Canc...	Nivolumab Entinostat Montanide(R) IS... H1299 Cell Lysa...	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Adjuvant Tumor Lysate Vaccine and Iscomatrix With or Without Metronomic Oral Cyclophosphamide and Celecoxib in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum	NCT02054104	Thoracic Sarcom... Thorasic Cancer... Cancers of Non-... Sarcoma Melanoma	H1299 cell lysa... Cyclophosphamid... Celecoxib Iscomatrix adju...	18 Years -	National Institutes of Health Clinical Center (CC)
Phase I/II Evaluation of a Cancer Lysate Vaccine and Montanide(R) ISA-51 VG With Entinostat and Nivolumab as Adjuvant Therapy Following Chemoradiation Therapy With or Without Surgery for Locally Advanced Esophageal Cancer	NCT05898828	Neoplasms Esophageal Neop... Esophagus Neopl... Esophagus Cance... Neoplasms, Esop... Esophageal Canc...	Nivolumab Entinostat Montanide(R) IS... H1299 Cell Lysa...	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for h1299 cell lysates