A Study of ADXS11-001 or MEDI4736 Alone or Combination In Cervical or Human Papillomavirus (HPV)+ Head & Neck Cancer

Study Overview
=================
Brief Summary
-----------------
This was a multicenter, open-label, 2-part randomized study of MEDI4736 administered as monotherapy or in combination with ADXS11-001 to participants with recurrent/persistent or metastatic squamous or non-squamous carcinoma of the cervix or metastatic human papillomaviruses (HPV)+ squamous cell carcinoma of the head and neck (SCCHN).

Detailed Description
-----------------
The study was conducted in 2 parts Part A (dose-escalation and expansion) and Part B (expansion). Part A: Part A of the study was a Phase 1 dose escalation evaluation of the combination treatment of ADXS11-001 at a fixed dose of 1×10^9 colony-forming units (CFU) administered intravenously (IV) every 4 weeks (Q4W) and escalating doses of MEDI4736 (3 mg/kg and 10 mg/kg) administered IV every 2 weeks (Q2W) to determine the safety and tolerability of the combination and to identify a recommended Phase 2 dose (RP2D). Part A also included an expansion cohort of participants with metastatic SCCHN only. Once the RP2D was identified, the expansion cohort of Part A of the study were to commence. Part B: Part B of the study was a Phase 2 design in which participants who had failed at least 1 prior systemic treatment for their recurrent, persistent or metastatic cervical cancer were enrolled and randomized 1:1 to receive either MEDI4736 10 mg/kg alone or MEDI4736 10 mg/kg in combination with ADXS11-001 1×10^9 CFU.

Official Title
-----------------
Phase 1-2 Study of ADXS11-001 or MEDI4736 Alone or Combination In Previously Treated Locally Advanced or Metastatic Cervical or HPV+ Head & Neck Cancer

Conditions
-----------------
Cervical Cancer, Cancer, Head and Neck Cancer

Intervention / Treatment
-----------------
* Drug: ADXS11-001
* Drug: MEDI4736


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have histological diagnosis of SCCHN with confirmation of HPV positivity or squamous, non-squamous, adenosquamous, carcinoma or adenocarcinoma of the cervix which HPV positivity is not required Have measurable and/or evaluable disease by response evaluation criteria in solid tumors (RECIST) 1.1 Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Have adequate organ function defined by the protocol. Exclusion Criteria: Has any prior Grade ≥3 immune-related adverse event (irAE) while receiving immunotherapy, including anti-CTLA-4 treatment, or any unresolved irAE >Grade 1. Has a diagnosis of immunodeficiency or is receiving any systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to Day 1 of trial treatment. Has any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for invasive malignancy within 2 years. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Has implanted medical device(s) that pose a high risk for colonization and/or cannot be easily removed (e.g., prosthetic joints, artificial heart valves, pacemakers, orthopedic screw(s), metal plate(s), bone graft(s), or other exogenous implant(s)). NOTE: More common devices and prosthetics which include arterial and venous stents, dental and breast implants, and venous access devices (e.g., Port-a-Cath or Mediport) are permitted. Sponsor must be contacted prior to consenting any subject who has any other device and/or implant

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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Escalation (Cervical): 1×10^9 CFU ADXS11-001/ 3 mg/kg MEDI4736<br>Participants with cervical cancer received MEDI4736 3 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 2 weeks (Q2W) at an infusion rate of approximately 60 minutes followed by ADXS11-001 1×10^9 CFU IV infusion every 4 weeks (Q4W) at an infusion rate of approximately 60 minutes. Treatment cycles were 8-week in duration and participants were to continue therapy for up to 1 year or until documented progression, unacceptable toxicity, withdrawal of consent, or other treatment discontinuation criteria were met. | Drug: ADXS11-001<br> <br> Drug: MEDI4736<br> <br> |
| Experimental: Part A Escalation (Cervical and Head and Neck): 1×10^9 CFU ADXS11-001/ 10 mg/kg MEDI4736<br>Participants with cervical cancer and SCCHN received MEDI4736 10 mg/kg IV infusion Q2W at an infusion rate of approximately 60 minutes followed by ADXS11-001 1×10^9 CFU IV infusion Q4W at an infusion rate of approximately 60 minutes. Treatment cycles were 8-week in duration and participants were to continue therapy for up to 1 year or until documented progression, unacceptable toxicity, withdrawal of consent, or other treatment discontinuation criteria were met. | Drug: ADXS11-001<br> <br> Drug: MEDI4736<br> <br> |
| Experimental: Part A Expansion (Head and Neck): 1×10^9 CFU ADXS11-001/ 10 mg/kg MEDI4736<br>Participants with SCCHN received MEDI4736 10 mg/kg IV infusion Q2W at an infusion rate of approximately 60 minutes followed by ADXS11-001 1×10^9 CFU IV infusion Q4W at an infusion rate of approximately 60 minutes. Treatment cycles were 8-week in duration and participants were to continue therapy for up to 1 year or until documented progression, unacceptable toxicity, withdrawal of consent, or other treatment discontinuation criteria were met. | Drug: ADXS11-001<br> <br> Drug: MEDI4736<br> <br> |
| Experimental: Part B Expansion (Cervical): 10 mg/kg MEDI4736<br>Participants with cervical cancer received MEDI4736 10 mg/kg IV infusion Q2W at an infusion rate of approximately 60 minutes. Treatment cycles were 8-week in duration and participants were to continue therapy for up to 1 year or until documented progression, unacceptable toxicity, withdrawal of consent, or other treatment discontinuation criteria were met. | Drug: MEDI4736<br> <br> |
| Experimental: Part B Expansion (Cervical): 1×10^9 CFU ADXS11-001/ 10 mg/kg MEDI4736<br>Participants with cervical cancer received MEDI4736 10 mg/kg IV infusion Q2W at an infusion rate of approximately 60 minutes followed by ADXS11-001 1×10^9 CFU IV infusion Q4W at an infusion rate of approximately 60 minutes. Treatment cycles were 8-week in duration and participants were to continue therapy for up to 1 year or until documented progression, unacceptable toxicity, withdrawal of consent, or other treatment discontinuation criteria were met. | Drug: ADXS11-001<br> <br> Drug: MEDI4736<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part A and Part B | An adverse event (AE) was any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. Any worsening (ie, any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also considered an AE. A serious adverse event (SAE) was any AE that: results in death; life threatening; resulted in or prolonged an existing inpatient hospitalization, persistent or significant disability/incapacity; congenital anomaly; a new cancer; associated with an overdose; another important medical event. Treatment emergent was defined as events with onset dates on or after the first dose of study medication and within 30 days following the last dose of study medication. | From first dose until 30 days after last dose (maximum duration: 98 weeks) | 
| Progression Free Survival (Part A and Part B): Cervical Cancer Population | Progression-free survival (PFS) was defined as the time from randomization until objective tumor progression based on response evaluation criteria in solid tumors (RECIST) version 1.1 or death. The progressive disease is defined at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, the appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. Participants who had not experienced disease progression or who were still alive at the time of evaluation were censored for the analysis. The PFS was estimated using Kaplan-Meier method. | From randomization until objective tumor progression or death (maximum duration: 146 weeks) | 
| Progression Free Survival (Part A): Human Papillomavirus (HPV)+ Head and Neck Cancer Population | PFS was defined as the time from randomization until objective tumor progression based on RECIST version 1.1 or death. The progressive disease is defined at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, the appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. Participants who had not experienced disease progression or who were still alive at the time of evaluation were censored for the analysis. The PFS was estimated using Kaplan-Meier method. | From randomization until objective tumor progression or death (maximum duration: 146 weeks) | 
| Percentage of Participants With Objective Response as Per RECIST Criteria (Part A and Part B): Cervical Cancer Population | The objective response is defined as confirmed complete response (CR) or partial response (PR) based on RECIST v1.1 guidelines. The CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm). The PR is defined as >= 30% decrease in the sum of the longest diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. | From randomization until objective tumor progression or death (maximum duration: 146 weeks) | 
| Percentage of Participants With Objective Response as Per RECIST Criteria (Part A): HPV+ Head and Neck Cancer Population | The objective response is defined as confirmed CR or PR based on RECIST v1.1 guidelines. The CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. The PR is defined as >= 30% decrease in the sum of the longest diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. | From randomization until objective tumor progression or death (maximum duration: 146 weeks) | 
| Percentage of Participants With Objective Response as Per irRECIST Criteria (Part A and Part B): Cervical Cancer Population | The objective response is defined as confirmed CR or confirmed PR based on immune-related RECIST (irRECIST) v1.1 guidelines. The irCR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The irPR is defined as >= 30% decrease in tumor burden compared with baseline. | From randomization until objective tumor progression or death (maximum duration: 146 weeks) | 
| Percentage of Participants With Objective Response as Per irRECIST Criteria (Part A): HPV+ Head and Neck Cancer Population | The objective response is defined as confirmed CR or confirmed PR based on irRECIST v1.1 guidelines. The irCR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The irPR is defined as >= 30% decrease in tumor burden compared with baseline. | From randomization until objective tumor progression or death (maximum duration: 146 weeks) | 
| Percentage of Participants With Disease Control as Per RECIST Criteria (Part A and Part B): Cervical Cancer Population | The DCR is defined percentage of participants with CR, PR, or stable disease (SD) based on RECIST v1.1 guidelines. The CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. The PR is defined as >= 30% decrease in the sum of the longest diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter since the study treatment started. The PD is defined as at least 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. | From randomization until objective tumor progression or death (maximum duration: 146 weeks) | 
| Percentage of Participants With Disease Control as Per RECIST Criteria (Part A): HPV+ Head and Neck Cancer Population | The DCR is defined percentage of participants with CR, PR, or SD based on RECIST v1.1 guidelines. The CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. The PR is defined as >= 30% decrease in the sum of the longest diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter since the study treatment started. The PD is defined as at least 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. | From randomization until objective tumor progression or death (maximum duration: 146 weeks) | 
| Percentage of Participants With Disease Control as Per irRECIST Criteria (Part A and Part B): Cervical Cancer Population | The DCR is defined percentage of participants with irCR, irPR, or irSD based on irRECIST v1.1 guidelines. The irCR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The irPR is defined as >= 30% decrease in tumor burden compared with baseline. The irSD is defined as neither a 30% decrease in tumor burden compared with baseline nor a 20% increase compared with nadir can be established. | From randomization until objective tumor progression or death (maximum duration: 146 weeks) | 
| Percentage of Participants With Disease Control as Per irRECIST Criteria (Part A): HPV+ Head and Neck Cancer Population | The DCR is defined percentage of participants with irCR, irPR, or irSD based on irRECIST v1.1 guidelines. The irCR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The irPR is defined as >= 30% decrease in tumor burden compared with baseline. The irSD is defined as neither a 30% decrease in tumor burden compared with baseline nor a 20% increase compared with nadir can be established. | From randomization until objective tumor progression or death (maximum duration: 146 weeks) | 
| Overall Survival: Cervical Cancer Population | Overall survival is defined as the time from the date of start of study treatment until death due to any cause. Any participant not died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. The OS was estimated using Kaplan-Meier method. | From first dose until death (maximum duration: 146 weeks) | 
| Overall Survival: HPV+ Head and Neck Cancer Population | Overall survival is defined as the time from the date of start of study treatment until death due to any cause. Any participant not died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. The OS was estimated using Kaplan-Meier method. | From first dose until death (maximum duration: 146 weeks) |