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Durvalumab

Tremelimumab

Antineoplastic Agents, Immunological

Pexa-Vec escalation dose levels + Durvalumab

Maximum tolerated dose (MTD) of Pexa-Vec after the MTD is established +Durvalumab

Pexa-Vec escalation dose levels + Durvalumab +Tremelimumab

MTD of Pexa-Vec after the MTD is established+Durvalumab + Tremelimumab

1500 mg of durvalumab via intravenous (IV) infusion on Day 1 of each cycle until patients meet off treatment criteria

300 mg of tremelimumab via intravenous (IV) infusion on Day 1 of cycle 1

3 x 10E\^8 plaque-forming unit (pfu) (Dose Level (DL) 1) via intravenous (IV) infusion for 4 doses: Day 12, Day 2, Day 16 of Cycle 1 and Day 2 of Cycle 2.

Pexa-Vec

1 x 10E\^9 pfu (DL 2) via intravenous (IV) infusion for 4 doses: Day 12, Day 2, Day 16 of Cycle 1 and Day 2 of Cycle 2.

Tim F Greten, M.D.

Background:

* Immune-based approaches in colorectal cancer have unfortunately with the notable exception of immune checkpoint inhibition in microsatellite instable (MSI-hi) disease been largely unsuccessful. The reasons for this are unclear but no doubt relate to the fact that in advanced disease colorectal cancer appears to be less immunogenic, as evidenced by the lack of infiltrating lymphocytes with advancing T stage
* Pexa-Vec (JX-594) is a thymidine kinase gene-inactivated oncolytic vaccinia virus engineered for the expression of transgenes encoding human granulocyte- macrophage colony-stimulating factor (GM-CSF) and beta-galactosidase. Apart from the direct oncolytic activity, oncolytic viruses such as Pexa-Vec have been shown to mediate tumor cell death via the induction of innate and adaptive immune responses
* Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed on the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Durvalumab is a human monoclonal antibody directed against programmed death-ligand 1 (PD-L1).
* The aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec oncolytic viral therapy can be enhanced by immune checkpoint inhibition.

Objective:

-To determine the safety, tolerability and feasibility of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in patients with refractory metastatic colorectal cancer.

Eligibility:

* Histologically confirmed metastatic colorectal cancer.
* Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and irinotecan-containing, fluorouracil-based, chemotherapeutic regimen and have disease that is not amenable to potentially curative resection. Patients who have a known Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type tumor must have progressed, been intolerant of or refused cetuximab or panitumumab based chemotherapy.
* Patients tumors must be documented to be microsatellite-stable (MSS) either by genetic analysis or immunohistochemistry OR microsatellite-high with documented disease progression following anti-programmed cell death protein 1 (PD1)/Programmed death-ligand 1 (PDL1) therapy.
* Patients must have at least one focus of metastatic disease that is amenable to pre- and on-treatment biopsy.
* Willingness to undergo mandatory tumor biopsy.

Design:

-The proposed study is Phase I/II study of Pexa-Vec oncolytic virus at two dose levels in combination with immune checkpoint inhibition in patients with metastatic colorectal cancer.

Background:

* Immune-based approaches in colorectal cancer have unfortunately with the notable exception of immune checkpoint inhibition in microsatellite instable (MSI-hi) disease been largely unsuccessful. The reasons for this are unclear but no doubt relate to the fact that in advanced disease colorectal cancer appears to be less immunogenic, as evidenced by the lack of infiltrating lymphocytes with advancing T stage
* Pexa-Vec (JX-594) is a thymidine kinase gene-inactivated oncolytic vaccinia virus engineered for the expression of transgenes encoding human granulocyte- macrophage colony-stimulating factor (GM-CSF) and beta-galactosidase. Apart from the direct oncolytic activity, oncolytic viruses such as Pexa-Vec have been shown to mediate tumor cell death via the induction of innate and adaptive immune responses
* Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed on the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Durvalumab is a human monoclonal antibody directed against programmed death-ligand 1 (PD-L1).
* The aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec oncolytic viral therapy can be enhanced by immune checkpoint inhibition.

Objective:

-To determine the safety, tolerability and feasibility of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in patients with refractory metastatic colorectal cancer.

Eligibility:

* Histologically confirmed metastatic colorectal cancer.
* Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and irinotecan-containing, fluorouracil-based, chemotherapeutic regimen and have disease that is not amenable to potentially curative resection. Patients who have a known Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type tumor must have progressed, been intolerant of or refused cetuximab or panitumumab based chemotherapy.
* Patient's tumors must be documented to be microsatellite-stable (MSS) either by genetic analysis or immunohistochemistry OR microsatellite-high with documented disease progression following anti-programmed cell death protein 1 (PD1)/Programmed death-ligand 1 (PDL1) therapy.
* Patients must have at least one focus of metastatic disease that is amenable to pre- and on-treatment biopsy.
* Willingness to undergo mandatory tumor biopsy.

Design:

* The proposed study is Phase I/II study of Pexa-Vec oncolytic virus at two dose levels in combination with immune checkpoint inhibition in patients with metastatic colorectal cancer.
* Patients will receive Pexa-Vec, administered intravenous (IV) every 2 weeks for 4 doses, in 4 separate arms A1, A2, B1, and B2. The first administration will be on Day (minus) 12, followed by administration on Days 2, 16 and 30 (i.e. 4 doses in total).

  * Arms A1 and A2: In addition to the oncolytic virus patients will also receive durvalumab at a flat dose of 1500 mg beginning on Day 1 followed by q28days until off-treatment criteria are met.
  * Arms B1 and B2: In addition to the oncolytic virus patients will also receive tremelimumab 300 mg and durvalumab 1500 mg on Day 1 followed by q28days subsequent continuation of the durvalumab alone until off-treatment criteria are met.
* All patients will undergo a baseline tumor biopsy and a post treatment biopsy.
* Accrual ceiling will be set at 35 to allow for patients replaceable for reasons other than toxicity.
* Patients will be restaged every 8 weeks +/- 3 days

A Phase I/II Study of Pexa-Vec Oncolytic Virus in Combination With Immune Checkpoint Inhibition in Refractory Colorectal Cancer

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP)

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.3). 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.

Number of participants with Grade 1-5 Adverse events. Grade 1 is mild, Grade 2 is moderate, Grade 3 severe or medically significant, Grade 4 is life-threatening consequences, and Grade 5 is death related to adverse event.

Median amount of time subject survives without disease progression after treatment at 5 months. Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

Median amount of time subject survives without disease progression after treatment. Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

Median amount of time subject survives after therapy.

Changes in tumor size and occurrence of metastases was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response is disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). And Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.

National Cancer Institute (NCI)

Principal Investigator

Cohort A/Dose Level 1 Durvalumab 1500mg every(q) 28 day(d); Pexa-Vec 3 x 10\^8/plaque-forming unit(pfu)

1/Arm A1 Pexa-Vec 3 x 10E^8 Plaque-forming Unit (Pfu) + Durvalumab 1500 mg

Cohort A/Dose Level 2 Durvalumab 1500mg every(q) 28 day(d); Pexa-Vec 1 x 10\^9/plaque-forming unit(pfu)

2/Arm A2 Pexa-Vec 1 x 10E^9 Plaque-forming Unit (Pfu) +Durvalumab 1500 mg

Cohort B/Dose Level 1 Tremelimumab 300mg 1x; Durvalumab 1500mg every(q) 28 day(d); Pexa-Vec 3 x 10\^8/plaque-forming unit(pfu)

3/Arm B1 Pexa-Vec 3 x 10E^8 Plaque-forming Unit (Pfu) + Durvalumab 1500 mg +Tremelimumab 300 mg

Cohort B/Dose Level 2 Tremelimumab 300mg; Durvalumab 1500mg every(q) 28 day(d); Pexa-Vec 1 x 10\^9/plaque-forming unit(pfu)

Spots Global Cancer Trial Database for oncolytic vaccinia virus