Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies

Phase 1

Active, not recruiting

Conditions: Cervical Cancer
Oropharyngeal Cancer
Anal Cancer
HPV Cancers
Vulvar, Vaginal, Penile, Rectal Cancer

Interventions: Biological: PDS0101
Biological: M7824
Biological: NHS-IL12

Registration Number: NCT04287868

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

More than 30,000 cases of human papillomavirus (HPV) associated cancers occur annually in the United States. When these cancers spread, they do not respond well to standard treatments and are often incurable. Researchers want to see if a mix of drugs can help.

Objective:

To learn if a mix of immunotherapy drugs can shrink tumors in people with HPV associated cancers.

Eligibility:

People ages 18 and older with locally advanced or metastatic HPV associated cancer, such as cervical cancers; cyclin-dependent kinase inhibitor 2A (P16+) oropharyngeal cancers; anal cancers; vulvar, vaginal, penile, and squamous cell rectal cancers; or other locally advanced or metastatic solid tumors (e.g., lung, esophagus) that are known HPV+ cancers

Design:

Participants will be screened with:

* medical history

* disease confirmation (or tumor biopsy)

* physical exam

* body scans (computed tomography (CT), magnetic resonance imaging (MRI), and/or nuclear)

* blood tests

* electrocardiogram (to measure the electrical activity of the heart)

* urine tests.

Participants will get PDS0101 injected under the skin every 4 weeks for 6 doses. Then they will get it every 3 months for 2 doses.

Participants will get M7824 (MSB0011395C) by intravenous infusion every 2 weeks. For this, a needle is inserted into a vein. The drug is given over a 1-hour period.

Participants will get NHS-IL12 injected under the skin every 4 weeks.

Participants will get the study drugs for up to 1 year. They will visit the NIH every 2 weeks. They will repeat the screening tests during the study.

About 28 days after treatment ends, participants will have a follow-up visit or telephone call. Then they will be contacted every 3 months for 1 year, and then every 6 months after that, for the rest of their life.

Patients with cervical cancer with prior pelvic radiation and boost brachytherapy will be enrolled in a separate cohort to evaluate safety and preliminary evidence of efficacy...

Detailed Description: Background:

Metastatic or refractory/recurrent HPV associated malignancies (cervical, anal, oropharyngeal cancers etc.) are poorly palliated by standard therapies. There is an unmet need for active treatments for these tumors.

In a phase I trial of M7824 (MSB0011395C) (NCT02517398) 15 out of 43 (34.9%) participants with HPV associated malignancies had radiographic tumor responses according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or Immune Response Evaluation Criteria in Solid Tumors (iRECIST).

While the response rate observed with M7824 appears to be higher than single agent programmed cell death protein 1 (PD-1) inhibitors alone (15-20%), the majority of patients with these diseases still do not seem to benefit from immunotherapy.

Preclinical studies suggest that the use of a combination of multiple immunotherapy agents may have improved anti-tumor efficacy.

Specifically, preclinical studies have shown that the combination of three immunotherapy agents (1) a therapeutic vaccine against human papilloma virus (HPV) positive cancers (PDS0101), (2) a bifunctional fusion protein targeting programmed death-ligand 1 (PD-L1) and transforming growth factor (TGF) beta (M7824), and (3) a tumor targeted immunocytokine (NHS-IL12) produces greater anti-tumor activity than any single or dual combination of these agents.

Objective:

To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (RECIST 1.1) of the combination of (1) a therapeutic vaccine against HPV positive cancers (PDS0101), (2) a tumor targeted immunocytokine (NHS-IL12) and (3) a bifunctional fusion protein targeting PD-L1 and TGF beta (M7824) in subjects with checkpoint naive advanced HPV associated malignancies.

Eligibility:

Age \>= 18 years old.

Subjects with cytologically or histologically confirmed locally advanced or metastatic HPV associated malignancies:

Cervical cancers;

P16+ Oropharyngeal cancers;

Anal cancers;

Vulvar, vaginal, penile, and squamous cell rectal cancers;

Other locally advanced or metastatic solid tumors (e.g. lung, esophagus) that are known HPV+.

Prior first line systemic therapy is required unless the participant declines standard treatment after appropriate counseling has been provided.

Subjects must have measurable disease.

Design:

This is a phase I/II trial of combination immunotherapy.

The trial will be conducted using a Simon optimal two-stage design.

Participants will receive HPV vaccine + NHS-IL12 + M7824.

The first six participants will be evaluable for dose limiting toxicities (DLTs) and accrual will only continue to 8 participants who have not been treated with checkpoint inhibitors if less than 2 out of the first 6 participants experience a DLT.

If three or more out of eight participants who have not been treated with checkpoint inhibitors have objective responses accrual will be expanded to enroll 20 evaluable participants.

Patients with cervical cancer with prior pelvic radiation and boost brachytherapy will be enrolled in a separate cohort to evaluate safety and preliminary evidence of efficacy.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 51

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy	PDS0101	Triple Therapy: PDS0101 + NHS-IL12 + M7824 (MSB0011395C); PDS0101 + NHS-IL12 + M7824; Reduced doses. May enroll up to 12 participants for a safety evaluation and up to 12 additional participants for preliminary evaluation of efficacy and further evaluation of safety.
Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies	M7824	Triple Therapy: PDS0101 + NHS-IL12 + M7824 (MSB0011395C); The dose level of NHS-IL12 may decrease depending on dose limiting toxicity (DLT) events. The dose level of human papillomavirus vaccine (HPV) vaccine and M7824 will remain constant. If more than 3 of 8 participants have an objective response then accrual will be expanded to 20 evaluable participants.
Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy	M7824	Triple Therapy: PDS0101 + NHS-IL12 + M7824 (MSB0011395C); PDS0101 + NHS-IL12 + M7824; Reduced doses. May enroll up to 12 participants for a safety evaluation and up to 12 additional participants for preliminary evaluation of efficacy and further evaluation of safety.
Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy	NHS-IL12	Triple Therapy: PDS0101 + NHS-IL12 + M7824 (MSB0011395C); PDS0101 + NHS-IL12 + M7824; Reduced doses. May enroll up to 12 participants for a safety evaluation and up to 12 additional participants for preliminary evaluation of efficacy and further evaluation of safety.
Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies	PDS0101	Triple Therapy: PDS0101 + NHS-IL12 + M7824 (MSB0011395C); The dose level of NHS-IL12 may decrease depending on dose limiting toxicity (DLT) events. The dose level of human papillomavirus vaccine (HPV) vaccine and M7824 will remain constant. If more than 3 of 8 participants have an objective response then accrual will be expanded to 20 evaluable participants.
Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies	NHS-IL12	Triple Therapy: PDS0101 + NHS-IL12 + M7824 (MSB0011395C); The dose level of NHS-IL12 may decrease depending on dose limiting toxicity (DLT) events. The dose level of human papillomavirus vaccine (HPV) vaccine and M7824 will remain constant. If more than 3 of 8 participants have an objective response then accrual will be expanded to 20 evaluable participants.

Primary Outcome Measures

Name	Time	Method
Best Overall Response (BOR) in Checkpoint Naive and Immune Checkpoint Blockade (ICB) Resistant Disease in Participants With Advanced or Metastatic Human Papillomavirus (HPV) Associated Malignancies	Every 2 months, up to approximately 10 months	BOR is defined as a complete response or partial response assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. 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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Grades 1, 2, 3, 4 and/or 5 Treatment Related Adverse Events	Date treatment consent signed to date off study, approximately 34 months and 20 days.	Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Progression-Free Survival (PFS) Time	PFS is defined as the time from the date of first treatment to the date of disease progression or death (any cause) whichever occurs first	PFS is defined as the time from the date of first treatment to the date of disease progression or death (any cause) whichever occurs first. Participants who do not have disease progression or have not died at the end of follow up will be censored at the last known date the participant was progression free. Progression was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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). The appearance of one or more new lesions is also considered progressions.
Overall Survival (OS)	The time from the date of first treatment to the date of death (any cause)	OS will be evaluated using Kaplan-Meier methods and is defined as the time from the date of first treatment to the date of death (any cause). Participants who are alive at the end of follow up will be censored at the last known date alive.
Ratio of Participants That Are Hospitalized Because of Adverse Events Attributed to Disease Progression.	While participant on study; an average of 3 months	Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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). The appearance of one or more new lesions is also considered progressions.
Number of Treatment Related Grades 1, 2, 3, 4 and/or 5 Adverse Events	Date treatment consent signed to date off study, approximately 34 months and 20 days.	Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Duration of Response (DOR)	At disease progression, an average of 10 months	DOR is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that progressive disease (PD) is objectively documented and is evaluated using the Kaplan-Meier method. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. 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). The appearance of one or more new lesions is also considered progressions.