Recombinant Vaccinia Virus Administered Intravenously in Patients With Metastatic, Refractory Colorectal Carcinoma

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety, tolerability, and efficacy of JX-594 (Pexa-Vec) administered intravenously either alone or in combination with Irinotecan in colorectal carcinoma patients who are refractory to or intolerant to standard therapy.

Detailed Description
-----------------
This was a Phase 1/2a, open-label, dose-escalation study in patients with advanced colorectal cancer (CRC)

Official Title
-----------------
A Phase 1/2a Dose-escalation Study of JX 594 Administered by Multiple Intravenous (IV) Infusions Alone and in Combination With Irinotecan in Patients With Metastatic, Refractory Colorectal Carcinoma.

Conditions
-----------------
Colorectal Carcinoma, CRC

Intervention / Treatment
-----------------
* Biological: JX-594
* Drug: Irinotecan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically-confirmed, advanced metastatic colorectal cancer failed treatment with fluoropyrimidine (fluoruracil or capecitabine) and oxaliplatin based therapies or had contradictions to treatment with these drugs as determined by the investigator Failed treatment with irinotecan Kras mutant tumor or Kras wild-type having failed cetuximab (Erbitux) or panitumumab (Vectibix) or had contradictions to treatment Regorafenib-naïve (have not received regorafenib) Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1 or 2 Measurable tumor (≥1 cm longest diameter) Acceptable health status as determined by the investigator and blood work (Chemistry, Complete Blood Count, Coagulation) Exclusion Criteria: Intolerant to Irinotecan (if assigned to the combination arm: Cohort 3, Cohort 4 or Combination Expansion Arm) Treatment with ketoconazole, enzyme-inducing anticonvulsants and St. John's Wort (if assigned to combination arm) Significant immunodeficiency due to underlying illness and/or medication History of severe exfoliative skin condition requiring systemic therapy within the past 2 years Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural effusions Active cardiovascular disease, including but not limited to significant coronary artery disease (e.g., requiring angioplasty or stenting) or congestive heart failure within the preceding 12 months Viable Centrual Nervous System (CNS) malignancy associated with clinical symptoms Received anti-cancer therapy within 4 weeks prior to first treatment (6 weeks for mitomycin c or nitrosoureas) Prior participation in any other research protocol involving an investigational medicinal product within 4 weeks prior to first treatment Use of prohibited anti-viral medication, interferon/pegylated interferon (PEG-IFN) or ribavirin that cannot be discontinued within 14 days prior to any JX 594 dose Inability to suspend treatment with anti-hypertensive medication for 48 hours prior to and 48 hours after all JX-594 treatments. Pregnant or nursing an infant Diagnosis of chronic inflammatory bowel disease and/or bowel obstruction.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Agent_ Cohort 1<br>JX-594 administered intravenously weekly for 5 weeks followed by up to 3 additional intravenous infusion boosts. JX-594: Recombinant Vaccinia Granulocyte-Macrophage Colony-Stimulating Factor (RAC VAC GM-CSF) Cohort 1: JX-594 3 x 10^8 plaque forming unit (pfu), Days 1, 8,15, 22, and 29 | Biological: JX-594<br>* Recombinant Vaccinia GM-CSF; RAC VAC GM-CSF (JX-594)<br>|
| Experimental: Single Agent_Cohort 2<br>JX-594 administered intravenously weekly for 5 weeks followed by up to 3 additional intravenous infusion boosts. JX-594: RAC VAC GM-CSF Cohort 2: JX-594 1 x 10^9 pfu, Days 1, 8,15, 22, and 29 | Biological: JX-594<br>* Recombinant Vaccinia GM-CSF; RAC VAC GM-CSF (JX-594)<br>|
| Experimental: Combination_Cohort 3<br>JX-594 administered intravenously weekly for 5 weeks followed by up to three additional intravenous infusion boosts in combination with Irinotecan administered every 14 days beginning at Day 9. JX-594: RAC VAC GM-CSF Irinotecan: 180 mg/m2 IV every 2 weeks. JX-594 3 x 10^8 pfu Day 1,8, 15, 22, 29 + irinotecan 180 mg/m2 biweekly starts on Day 9. | Biological: JX-594<br>* Recombinant Vaccinia GM-CSF; RAC VAC GM-CSF (JX-594)<br>Drug: Irinotecan<br>* 180 mg/m2 IV every 2 weeks.<br>|
| Experimental: Combination_Cohort 4<br>JX-594 administered intravenously weekly for 5 weeks followed by up to three additional intravenous infusion boosts in combination with Irinotecan administered every 14 days beginning at Day 9. JX-594: RAC VAC GM-CSF JX-594 1 x 10^9 pfu Day1, 8, 15, 22, 29 + irinotecan 180 mg/m2 biweekly starts on Day 9. | Biological: JX-594<br>* Recombinant Vaccinia GM-CSF; RAC VAC GM-CSF (JX-594)<br>Drug: Irinotecan<br>* 180 mg/m2 IV every 2 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Radiographic Response Rate of Patients Enrolled in the Phase 2a Portion of the Study | Percentage of participants who showed overall response during their participation in the study. Per Modified Response Evaluation Criteria In Solid Tumors Criteria (mRECIST) and assessed by tri-phasic contrast enhanced CT: Complete Response (CR), Disappearance of intratumoral enhancing area; Partial Response (PR), >=30% decrease in the sum of the diameters of enhancing area; Overall Response (OR) = CR + PR. | Scans Every 8 weeks until radiographic progression was confirmed by the site. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Vaccinia, Vaccinia Virus, JX-594, Jennerex, Colorectal Carcinoma, Colorectal cancer, Colon Cancer, Rectal Cancer, oncolytic virus, viral therapy, RAS mutant, Erbitux failure, Oxaliplatin failure, FOLFOX failure, FOLFIRI failure, Irinotecan failure, Pexa-Vec