αDC1 Vaccine + Chemokine Modulatory Regimen (CKM) as Adjuvant Treatment of Peritoneal Surface Malignancies

Study Overview
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Brief Summary
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This trial is to determine the safest dose of a triple combination (chemokine modulatory regimen or CKM) of celecoxib, interferon alfa (IFN), and rintatolimod that can be given with a DC vaccine as treatment of peritoneal surface malignancies after standard of care surgery. The first phase of this study will determine the safest dose of IFN that can be given in combination with celecoxib and rintatolimod along with a DC vaccine. The doses of celecoxib (400 mg) and rintatolimod (200 mg) will be consistent while the dose of IFN will be increased (5, 10, or 20 MU/m2) as participants are enrolled to the trial. The high dose of IFN in combination with celecoxib and rintatolimod will be used for the next phase of the clinical trial. After surgery, participants will receive 2 cycles of the investigational treatment. The second phase of this study will test if the investigational treatment has any effects on peritoneal surface malignancies. The doses of the combination determined in the first phase will be used in this phase of the clinical trial. After surgery, participants will receive 2 cycles of the investigational treatment, followed by standard chemotherapy as determined by their oncologist, and then 2 more cycles of the investigational treatment.

Detailed Description
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This trial will evaluate the safety and effectiveness of autologous alpha-type-1 polarized dendritic cell (alpha-DC1) vaccines (patients' autologous alpha-DC1s loaded with autologous tumor material), combined with a systemic chemokine modulation regimen [CKM; intravenous rintatolimod (TLR3 ligand, a derivative of Poly-I:C) + intravenous interferon-alfa + oral celecoxib] as adjuvant therapy, after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), in patients with peritoneal surface malignancies (PSM), including but not limited to malignant peritoneal mesothelioma and peritoneal carcinomatosis (PC) of appendiceal and colorectal origin. All patients judged to have peritoneal surface malignancy and considered able to be cytoreduced to Peritoneal Cancer Index (PCI) Completeness of Cytoreduction (CC) score of 1 or less will undergo CRS + HIPEC. Postoperative immunotherapy will start at least 4 weeks after CRS + HIPEC. Immunotherapy regimen will include four cycles of intranodal (3M cells) and intradermal (3M cells) αDC1 vaccines. Each booster αDC1 vaccine dose (treatment cycles 2-4) will be followed by 4-days of systemic CKM, starting the day after vaccination (IFNα [dose-escalation: 5-20 MU/m2], intravenous [IV], once a day for 4 days; rintatolimod [short-half-life TLR3 ligand] 200 mg intravenous [IV], on Wednesday and Friday only of the CKM regimen; and celecoxib 200 mg, orally, twice a day for 4 days). In order to avoid overlap between experimental immunotherapy and potential adjuvant chemotherapy (which can be clinically indicated as a part of standard care in the subset of patients), the experimental treatments will be interrupted after cycles 1 and 2, to allow adjuvant chemotherapy that is done for each patient's clinical care, and is not a part of this research study. Whenever clinically indicated as a part of standard care, adjuvant chemotherapy may start at least 5 days after completion of the 2nd cycle of immunotherapy (first booster vaccine plus the first CKM). The 3rd cycle of immunotherapy may start at least 5 days after the completion of chemotherapy.

Official Title
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A Phase 1/2 Trial Evaluating αDC1 Vaccines Combined With Tumor-Selective Chemokine Modulation as Adjuvant Therapy After Surgical Resection of Peritoneal Surface Malignancies

Conditions
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Malignant Neoplasm of Pancreas Metastatic to Peritoneal Surface, Malignant Peritoneal Mesothelioma, Peritoneal Carcinomatosis

Intervention / Treatment
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* Biological: DC vaccine
* Drug: Celecoxib
* Drug: Interferon Alfa-2b
* Biological: rintatolimod


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically confirmed peritoneal surface malignancies, including but not limited to malignant peritoneal mesothelioma and peritoneal carcinomatosis (PC) from presumed appendiceal and colorectal primary tumors. Most patients will have received extensive prior treatments, due to the recurrent nature of PC. Prior therapies involve previous CRS, local and systemic chemotherapies. None of these prior treatments disqualifies the patient from receiving the protocol-mandated experimental treatment. Patients must be deemed able to undergo optimal cytoreductive surgery (CRS) defined as CC-score of 0 or 1 based on imaging. Cytoreduction is defined as the burden of residual disease nodules left at the end of surgery (CC-0: no visible disease; CC-1: residual tumor nodules ≤ 2.5 mm in size; CC-2: residual tumor nodules 2.5 mm - 2.5 cm in size; CC-3: residual tumor nodules > 2.5 cm in size). Patients may be enrolled in the study regardless of prior chemotherapy regimens An ECOG performance status of 0, 1 or 2 Age equal to 18 years or older Patients must be able to understand and be willing to sign a written informed consent document Able to swallow pills Must have normal organ and marrow function as defined below: Platelet ≥ 75,000/µL Hemoglobin ≥ 9.0 g/dL Hematocrit ≥ 27.0% Absolute Neutrophil Count (ANC) ≥ 1500/µL WBC >2000/mm3 Creatinine < 1.5 x institutional upper limit of normal (ULN), OR Creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels greater than 1.5 x ULN Total bilirubin ≤ 1.5 x ULN AST(SGOT) and ALT(SGPT) ≤ 2.5 X ULN Must be eligible for pheresis within 8 weeks of surgery Availability of sufficient number of tumor cells for cryopreservation and subsequent vaccine production Must have had HIPEC during surgery Must have a CC score of 0 Exclusion Criteria: Infection of tumor tissue with pathogens resistant to radiation and fungizone Patients on systemic immunosuppressive agents, including steroids. Patients who are able to be removed from immunosuppressives at least 5 days prior to the first vaccine will be considered eligible. Patients with active autoimmune disease or history of transplantation. Patients with indolent or chronic autoimmune disease not requiring steroid treatment are considered eligible. Patients who are pregnant or nursing Patients experiencing a cardiac events (acute coronary syndrome, myocardial infarction, or ischemia) within the 3 months prior to accrual Patients with a New York Heart Association classification of III or IV Prior allergic reaction or hypersensitivity to celecoxib or NSAIDs

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: vaccine + chemokine modulatory regimen<br>Week 1 (at recovery from surgery; ≥ 6 weeks post-surgery)-Priming Vaccine dose; no chemokine modulation; 1 day: αDC1 vaccine; Oral celecoxib, 200 mg, before & after treatment on day of vaccination; Weeks 2-3 -Rest; Week 4 (target) - Booster C1; Mon: αDC1 vaccine;Tues - Fri: Systemic Chemokine Modulation Regimen. Oral celecoxib, 200 mg, BID on vaccination days & CKM. Celecoxib will be dced after CKM on Fri. Rintatolimod only administered on Wed & Fri.; Week 5-7 -Rest; Week 8 (target) -Booster C2; Monday: αDC1 vaccine. Oral celecoxib, 200 mg, BID on days of vaccination and CKM. Tues - Fri:Systemic Chemokine Modulation Regimen. Rintatolimod only administered on Wed & Fri. Celecoxib will be dced after CKM on Fri.; Week 9-11 -Rest; Week 12 (target) -Booster C3; Monday: αDC1 vaccine. Tues-Fri: Systemic Chemokine Modulation Regimen. Rintatolimod only administered on Wed & Fri. Oral celecoxib, 200 mg, BID, given on days of vaccination and CKM. Celecoxib will be discontinued after CKM on Fri. | Biological: DC vaccine<br>* Administered on Monday of each cycle: 1 intranodal ultrasound-guided injection (target dose of 3 x 10e6 cells in 0.5 mL) + 1 intradermal injection (target dose of 3 x 10e6 cells in 0.5 mL)<br>* Other names: αDC1;Drug: Celecoxib<br>* Administered at 200 mg, once a day orally, starting the day of the first DC vaccine through week 4/cycle 2. Participants will not take celecoxib while receiving standard of care chemotherapy as instructed by their local oncologist. Celecoxib will continue starting week 20/cycle 3 and continue until the Friday of the last day of the CKM administration, cycle 4. Administered at 400 mg, 200 mg twice a day orally, on days participants receive vaccine and CKM.<br>* Other names: Onsenal;Drug: Interferon Alfa-2b<br>* Intravenous infusion over 20 minutes: doses tested in Phase 1 portion (5, 10, or 20 MU/m2) will determine the Phase 2 dose. Administered on the Tuesday of each CKM cycle.<br>* Other names: NSC #377523;Biological: rintatolimod<br>* Intravenous infusion of 200 mg on Wednesday and Friday only of the CKM regimen. The protocol allows for de-escalation to 100 mg if attributable adverse effects are observed.<br>* Other names: polyriboinosinic/polyribocytidylic (uridylic) acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose (RP2D) (Phase 1) | Number of patients treated at each of the three possible dose levels of Interferon α (5 MU/m^2, 10 MU/m^2 or 20 MU/m^2) during the Phase 1 portion of the study. | Up to 24 weeks | 
| Adverse Events Possibly, Probably or Definitely Related to Study Treatment | Number of participants with adverse events (by Grade) that were possibly, probably or definitely related to the combined study immunotherapy regimen (αDC1 vaccines + CKM) per CTCAE v 4.0 (Common Terminology Criteria for Adverse Events). | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) | The length of time from the start of treatment until disease progression, per RECIST 1.1 considering only patients whose deaths were from cancer. Disease progression per RECIST 1.1 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | Up to18 months | 
| Overall Survival (OS) | The length of time from the start of treatment that diagnosed patients are still alive. | Up to 5 years | 
| Progression-free Survival (PFS) | The length of time during and after the treatment that patients remain alive with disease that does not progress. Per RECIST 1.1, Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | Up to 5 years | 
| CXCL10 (Interferon Gamma-induced Protein 10) Levels | Chemokine CXCL10 (Interferon gamma-induced protein 10) concentration levels measures in peripheral blood as a biomarker of anti-tumor activity. Increased levels can be predictive of good prognosis. | Prior to vaccine administration (Week 1), prior to vaccine booster (Week 4) and after vaccine booster (Week 8) | 
| CXCL11 (C-X-C Motif Chemokine 11) Levels | CXCL11 (C-X-C motif chemokine 11) protein concentration levels measures in peripheral blood. Increased levels can be predictive of good prognosis. | Prior to vaccine administration (Week 1), prior to vaccine booster (Week 4) and after vaccine booster (Week 8) | 
| Interleukin 10 (IL-10) Levels | Interleukin 10 (IL-10) (human cytokine synthesis inhibitory factor (CSIF)) concentration levels measures in peripheral blood. Increased levels of IL-10 is associated with advanced disease and poor prognosis. | Prior to vaccine administration (Week 1), prior to vaccine booster (Week 4) and after vaccine booster (Week 8) | 
| Interleukin 6 (IL-6) Cytokine Levels | Interleukin 6 (IL-6) concentration levels measures in peripheral blood. Increased levels of IL-6 is associated with associated with advanced disease and poor prognosis. | Prior to vaccine administration (Week 1), prior to vaccine booster (Week 4) and after vaccine booster (Week 8) | 
| Interleukin-8 (IL-8) Cytokine Levels | Interleukin-8 (IL-8) cytokine concentration levels measures in peripheral blood. Increased levels of IL-8 is associated with associated with advanced disease and poor prognosis. | Prior to vaccine administration (Week 1), prior to vaccine booster (Week 4) and after vaccine booster (Week 8) | 
| Stromal Derived Factor 1 Alpha (SDF-1A/CXCL-12) Chemokine Levels | Levels of stromal derived factor 1 alpha (SDF-1A/CXCL-12) chemokine in peripheral blood. Higher levels of SDF-1A/CXCL-12 is associated with good prognosis. | Prior to vaccine administration (Week 1), prior to vaccine booster (Week 4) and after vaccine booster (Week 8) | 
| Tumor Necrosis Factor (TFNα) Cytokine Levels | Tumor necrosis factor (TFNα) cytokine concentration levels measures in peripheral blood. Higher TFNα levels is associated with good prognosis. | Prior to vaccine administration (Week 1), prior to vaccine booster (Week 4) and after vaccine booster (Week 8) |