Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies

NCT04287868 | Active Not Recruiting Phase 1 Results DMC FDA Drug

• 2 other identifiers: 20004520-C-0045
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

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...

Conditions

Cervical Cancer; HPV Cancers; Anal Cancer; Oropharyngeal Cancer; Vulvar, Vaginal, Penile, Rectal Cancer

Keywords

HPV Cancers; HPV Associated Malignancies; Vaccine; Immunotherapy; Immuno-oncology

Outcome Measures

Primary Outcomes (1)

• 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

  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.

  Every 2 months, up to approximately 10 months

Secondary Outcomes (6)

• 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.

• 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

• Overall Survival (OS)

  The time from the date of first treatment to the date of death (any cause)

• Ratio of Participants That Are Hospitalized Because of Adverse Events Attributed to Disease Progression.

  While participant on study; an average of 3 months

• 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.

Other Outcomes (1)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  Date treatment consent signed to date off study, approximately 34 months and 20 days.

Study Arms (2)

Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies

EXPERIMENTAL

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.

Biological: PDS0101; Biological: M7824; Biological: NHS-IL12

Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy

EXPERIMENTAL

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.

Biological: PDS0101; Biological: M7824; Biological: NHS-IL12

Interventions

PDS0101 BIOLOGICAL

PDS0101 will be administered on Day (D)1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. Subcutaneous 1.0mL (2.4mg of total peptide and 3 mg of R-DOTAP) injection.

Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies; Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy

M7824 BIOLOGICAL

M7824 will be administered at a flat dose of 1,200 mg intravenous (IV) (over 1 hour) once every 2 weeks.

Also known as: MSB0011395C

Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies; Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy

NHS-IL12 BIOLOGICAL

NHS-IL12 will be administered at as dose of potentially de-escalating doses by subcutaneous (SC) injection every 4 weeks.

Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies; Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects with cytologically or histologically confirmed locally advanced or metastatic human papilloma virus (HPV) associated malignancies:
• Cervical cancers;
• cyclin-dependent kinase inhibitor 2A (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+.
• Subjects must have measurable disease, per response evaluation criteria in solid tumors (RECIST) 1.1.
• Subjects must have received one prior line of systemic chemotherapy as well as checkpoint therapy if checkpoint therapy is Food and Drug Administration (FDA) approved for that specific tumor type (e.g., head and neck squamous cell carcinoma (HNSCC) and programmed death-ligand 1 (PDL1+) cervical cancer). Prior checkpoint therapy is not needed where checkpoint therapy has not been FDA approved for that specific tumor type (e.g., anal, vaginal, vulvar, penile, PDL1 negative cervical). Exceptions to the above include participant who are not eligible to receive the above therapies or who decline these standard treatment options after appropriate counseling has been provided.
• Age \>= 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status \<= 2.
• Adequate hematologic function at screening, as follows:
• Absolute neutrophil count (ANC) \>=1 x 10\^9/L;
• Hemoglobin \>= 9 g/dL;
• Platelets \>=75,000/microliter.
• Adequate renal and hepatic function at screening, as follows:

You may not qualify if:

• Participants with prior investigational drug, chemotherapy, immunotherapy or any prior radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to the first drug administration except if the investigator has assessed that all residual treatment-related toxicities have resolved or are minimal and feel the participant is otherwise suitable for enrollment. Participants may continue adjuvant hormonal therapy in the setting of a definitively treated cancer (e.g., breast cancer).
• Known intolerance to or life-threatening side effects resulting from prior checkpoint inhibitor therapy.
• Major surgery within 28 days prior to the first drug administration (minimally invasive procedures such as diagnostic biopsies are permitted).
• Known active brain or central nervous system metastasis (less than a month out from definitive radiotherapy or surgery), seizures requiring anticonvulsant treatment (\<3 months) or clinically significant cerebrovascular accident (\<3 months). In order to be eligible participant must have repeat central nervous system (CNS) imaging at least a month after definitive treatment showing stable CNS disease. Participants with evidence of intra-tumoral or peritumoral hemorrhage on baseline imaging are also excluded unless the hemorrhage is grade \<= 1 and has been shown to be stable on two consecutive imaging scans.
• Pregnant women are excluded from this study because these drugs have not been tested in pregnant women and there is potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these immunotherapies, breastfeeding should be discontinued if the mother is treated on this protocol.
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent with exception of:
• Diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease or other mild autoimmune disorders not requiring immunosuppressive treatment;
• Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses \<= 10 mg of prednisone or equivalent per day;
• Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable;
• Subjects on systemic intravenous or oral corticosteroid therapy with the exception of physiologic doses of corticosteroids (\<= the equivalent of prednisone 10 mg/day) or other immunosuppressives such as azathioprine or cyclosporin A are excluded on the basis of potential immune suppression. For these subjects these excluded treatments must be discontinued at least 1 weeks prior to enrollment for recent short course use (\<= 14 days) or discontinued at least 4 weeks prior to enrollment for long term use (\> 14 days). In addition, the use of corticosteroids as premedication for contrast- enhanced studies is allowed prior to enrollment and on study.
• Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months) clinically significant bleeding events, or other illness considered by the Investigator as high risk for investigational drug treatment.
• Subjects unwilling to accept blood products as medically indicated.
• History of non-HPV associated second malignancy within 3 years of enrollment except localized malignancy which has been adequately treated or malignancy which does not require active systemic treatment (e.g., low risk chronic lymphocytic leukemia (CCL). Patients taking adjuvant hormonal therapy for definitively treated cancers (e.g., breast cancer) are eligible.
• Subjects with a known severe hypersensitivity reaction to a monoclonal antibodies (grade \>/= 3 National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v5) will be evaluated by the allergy/immunology team prior to enrollment.
• Receipt of prior lymphodepleting chemotherapy (e.g., cyclophosphamide, fludarabine) or any organ transplantation requiring ongoing immunosuppression.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Floudas CS, Goswami M, Donahue RN, Pastor DM, Redman JM, Brownell I, Turkbey EB, Cordes LM, Steinberg SM, Manu M, Francis DC, Lamping E, Marte JL, Kackley M, Krauss E, Manukyan M, Jochems C, Schlom J, Gulley JL, Strauss J. Novel Combination Immunotherapy and Clinical Activity in Patients With HPV-Associated Cancers: A Nonrandomized Clinical Trial. JAMA Oncol. 2025 Apr 1;11(4):394-399. doi: 10.1001/jamaoncol.2024.6998.

  PMID: 39976981 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Uterine Cervical Neoplasms; Anus Neoplasms; Oropharyngeal Neoplasms; Rectal Neoplasms

Interventions

NHS-IL12 immunocytokine

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Anus Diseases; Rectal Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases

Results Point of Contact

• Title: Dr. Charalampos Floudas
• Organization: National Cancer Institute

charalampos.floudas@nih.gov

240-858-3032

Study Officials

• Charalampos Floudas, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 26, 2020
• First Posted: February 27, 2020
• Study Start: June 9, 2020
• Primary Completion: July 26, 2022
• Study Completion (Estimated): July 1, 2026
• Last Updated: April 13, 2026
• Results First Posted: November 18, 2023

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to the Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Locations

US (1)