Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies

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.

• 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.
• M7824 (Biological), also known as MSB0011395C: M7824 will be administered at a flat dose of 1,200 mg intravenous (IV) (over 1 hour) once every 2 weeks.
• NHS-IL12 (Biological): NHS-IL12 will be administered at as dose of potentially de-escalating doses by subcutaneous (SC) injection every 4 weeks.

Primary outcomes

• 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 outcomes

• 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, up to 53 months]: 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), up to 67 months]: 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.

Other outcomes

• 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.]: Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Sex: All, ages: 18 Years to any

* INCLUSION CRITERIA:

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:

* Serum creatinine <= 1.5 x upper limit of normal (ULN) OR Measured or calculated creatinine clearance >=40 mL/min for participant with creatinine levels > 1.5 X institutional ULN (GFR can also be used in place of creatinine or CrCl);
* Bilirubin <= 1.5 x ULN OR in subjects with Gilbert's syndrome, a total bilirubin <= 3.0 x ULN;
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5 x ULN, unless liver metastases are present, then values must be <= 3 x ULN).

The effects of the immunotherapies on the developing human fetus are unknown. For this reason and because immunotherapeutic agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for two months after study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

Participants serologically positive for human immunodeficiency virus (HIV), hepatitis (Hep) B, Hep C are eligible as long as the viral loads are undetectable by quantitative polymerase chain reaction (PCR). HIV positive participants must have clusters of differentiation 4 (CD4) count >= 200 cells per cubic millimeter at enrollment, be on stable antiretroviral therapy for at least 4 weeks and have no reported opportunistic infections or Castleman's disease within 12 months prior to enrollment.

Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

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.

Participant flow

Outcome results

• 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 (Primary), Count of participants, Participants: All Participants 4; Participants With Human Papillomavirus 16 (HPV16+) Tumors 4; Human Papillomavirus 16 Tumors (HPV-16+), Immune Checkpoint Blockade (ICB) - Naive 2; Human Papillomavirus 16 Tumors (HPV-16+), Immune Checkpoint Blockade (ICB) - Resistant 2
• Number of Participants With Grades 1, 2, 3, 4 and/or 5 Treatment Related Adverse Events (Secondary), Count of participants, Participants: Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies 45
• Progression-Free Survival (PFS) Time (Secondary), Median, Months: Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies 1.9 (0.6 to 52.6); Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy 8.7 (1.87 to 13.8)
• Overall Survival (OS) (Secondary), Median, Months: Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies 16 (2.13 to 66.7); Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy NA (5.8 to 21.6)
• Ratio of Participants That Are Hospitalized Because of Adverse Events Attributed to Disease Progression. (Secondary), Number, Proportion of participants: Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies 0.04; Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy 0
• Number of Treatment Related Grades 1, 2, 3, 4 and/or 5 Adverse Events (Secondary), Number, adverse events: Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy 3
• Duration of Response (DOR) (Secondary), Median, Months: Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies 10.6 (3.7 to NA); Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy 10.2 (NA to NA)
• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) (Other pre specified), Count of participants, Participants: Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies 47; Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy 3

Adverse events

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

Serious adverse events by term

Other adverse events by term

206 more terms not shown.

• Results publication: 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

• Study Protocol and Statistical Analysis Plan (PDF, 2025-04-03)
• Informed Consent Form (PDF, 2023-06-08)

• Charalampos Floudas, M.D., Principal investigator, National Cancer Institute (NCI)