This is a Trial of MG1-E6E7 With Ad-E6E7 and Atezolizumab in Patients With HPV Associated Cancers

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1/1b open-label dose escalation trial of Ad/MG1-E6E7 and sequential treatment with atezolizumab in patients with HPV associated cancers. This study will consist of two arms. Both arms will dose escalate (MG1-E6E7) using a 3 + 3 design in Phase 1 to establish initial safety and the maximum tolerated dose (MTD) / maximum feasible dose (MFD). Arm 1 - intravenous (IV) administration of MG1-E6E7 following intramuscular (IM) AD-E6E7 priming and subsequent treatment with IV atezolizumab. Arm 2 - intratumoral (IT) and IV injection of MG1-E6E7 following (IM) Ad-E6E7 priming and subsequent treatment with IV atezolizumab. In the Phase 1b expansion for each arm, additional patients will be enrolled at the MTD as determined in Phase 1 in order to more thoroughly explore immune response, pharmacokinetics/dynamics, and safety for the patient populations with Cervical cancer, HPV positive (HPV+) Oropharyngeal cancer (Phase 1B, Arm 1, Cohorts A and B respectively) and HPV+ tumors with injectable lesions (Phase 1B, Arm 2, Cohort 3).

Official Title
-----------------
Phase 1/1b, Multicenter, Open-label Trial of Oncolytic MG1 Virus (MG1-E6E7) With Adenovirus Vaccine (Ad-E6E7) Both Expressing Mutant Human Papilloma Virus (HPV) E6 and E7 and Atezolizumab in Pts With HPV Assoc. Cancers

Conditions
-----------------
HPV-Associated Cancers

Intervention / Treatment
-----------------
* Biological: Ad-E6E7
* Biological: MG1-E6E7
* Biological: Atezolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Histologically or cytologically confirmed recurrent or metastatic HPV associated tumor (cervical, oropharyngeal, vulvar, vaginal, anal, or penile) with documented disease progression. Arm 1, Phase 1 dose escalation: Cervical, HPV+ oropharyngeal, vulvar, vaginal, anal, or penile Arm 1, Cohort A: Cervical cancer Arm 1, Cohort B: HPV+ Oropharyngeal cancer Arm 2 Phase 1 dose escalation and Cohort C: Cervical, oropharyngeal, vulvar, vaginal, anal, or penile Failed, refused or intolerant to systemic therapy Measurable disease based on RECIST 1.1 At least one tumor mass amenable to core needle biopsy Arm 2 only: At least one tumor judged as being safely injectable ECOG performance status 0 or 1 Demonstrate adequate organ function Additional Inclusion criteria exist Key Exclusion Criteria: Prior systemic therapy within 4 weeks. Patients receiving prior XRT must have recovered from any acute toxicity. Currently receiving/received experimental therapy within 4 weeks. Prior treatment with any HPV vaccine therapy for cancer. Requires use of anti-platelet or anti-coagulant therapy that cannot be safely suspended for per protocol biopsies or intra-tumoral injections. Known active CNS metastases and/or carcinomatous meningitis. Clinically significant tumor invasion/ rapidly accumulating ascites, pericardial or pleural effusions. Active infection requiring systemic therapy. Active autoimmune disease that has required systemic therapy in the past 2 years. Conditions likely to have resulted in splenic dysfunction. Known HIV/AIDS, active HBV or HCV infection. Received prior treatment with vesicular stomatitis (VSV) viral vector. Received immunosuppressive medication within 4 weeks. (>10mg/day prednisone) ≥ Grade 2 dyspnea and/or require supplemental oxygen Known intolerance to anti-PD-1 or anti-PD-L1 antibody therapy Additional Exclusion criteria exist Exclusion Criteria Household Contacts: Patients with household contacts meeting any of the following criteria are ineligible for study entry unless alternate living arrangements can be made, while under contact precautions. Women who are pregnant or nursing an infant Children < 1 year old Individuals who are severely immunocompromised Contact precautions are from initial treatment with MG1-E6E7 to 7 days after the last dose of MG1-E6E7

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (Intravenous dosing)<br>Fixed dose of Ad-E6E7 administered IM on study Day 1. Followed by one of 3 dose levels (escalation) of MG1-E6E7 administered as 4 infusion (IV) doses over 2 weeks starting at study day 15. Fixed dose of atezolizumab administered IV every 3weeks starting at study day 43. | Biological: Ad-E6E7<br>* Adenovirus vaccine expressing mutant HPV E6 and E7<br>Biological: MG1-E6E7<br>* MG1 Maraba oncolytic virus expressing mutant HPV E6 and E7<br>Biological: Atezolizumab<br>* monoclonal antibody; checkpoint inhibitor<br>* Other names: Tecentriq;|
| Experimental: Arm 2 (Intravenous and Intra-tumoral injection dosing)<br>Fixed dose of Ad-E6E7 administered IM on study Day 1. Followed by one of 2 dose levels (escalation) of MG1-E6E7 administered as 1 IV dose, starting at study day 15, followed by 2 intratumoral (IT) doses administered on study days 18 & 29. Fixed dose of atezolizumab administered IV every 3weeks starting at study day 43. | Biological: Ad-E6E7<br>* Adenovirus vaccine expressing mutant HPV E6 and E7<br>Biological: MG1-E6E7<br>* MG1 Maraba oncolytic virus expressing mutant HPV E6 and E7<br>Biological: Atezolizumab<br>* monoclonal antibody; checkpoint inhibitor<br>* Other names: Tecentriq;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Ad/MG1-E6E7 administration in HPV associated cancers | Safety will be determined by assessing the severity and frequency of treatment emergent Adverse Events and clinical laboratory toxicity using NCI CTCAE v 4.03. | 8 months | 
| Determine the maximum tolerated dose (MTD)/ maximum feasible dose (MFD) of Ad/MG1-E6E7 in HPV associated cancers | MTD/MFD of Ad/MG1-E6E7 administered by IV infusion alone and IV infusion followed by direct injection of tumor (IT injection) in HPV associated cancers | 4 to 6 weeks after first treatment with Ad/MG1-E6E7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of Ad/MG1-E6E7 in blood | Change over time in the number of MG1-E6E7 genomes (qPCR) and MG1-E6E7 infectious units (PFU) in blood | 4 to 6 weeks after first treatment with Ad/MG1-E6E7 | 
| Assess for the biodistribution and shedding of Ad/MG1-E6E7 | Determine if there is any shedding of Ad/MG1-E6E7 into the environment by detecting the presence of viral plaque forming units (PFUs) in urine samples, cheek swabs, and rectal swabs after Ad/MG1-E6E7 treatment | 6 weeks after first treatment with Ad/MG1-E6E7 | 
| Measure the differences in pre- and post treatment levels of T cell subsets and T cell activation status | Analyze the change over time in the the frequencies, absolute numbers and subsets of T cells (including regulatory T cells) | Before and after each dose of Ad/MG1-E6E7 and then every 3 weeks until treatment discontinuation | 
| Anti-tumor activity | Evaluate tumor response by CT scan using RECIST v1.1 and irRECIST criteria in the overall patient population and the HPV16/18 positive patient population | Every 6 weeks for the first course of treatment and then every 9 weeks until date of documented progression by irRECIST, up to 2 years |