Combination Immunotherapy for Human Papillomavirus Cancers

Overseen By Deneise Francis, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Active brain metastasis, Autoimmune disease, Pregnancy, Recent major surgery, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

Duration: 52 weeks

51 Participants Needed

Trial Summary

What is the purpose of this trial?

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...

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on systemic corticosteroids or other immunosuppressive drugs, you may need to stop them at least 1 to 4 weeks before enrolling, depending on the duration of use.

What data supports the effectiveness of this drug for HPV cancers?

Research shows that bintrafusp alfa, a key component of the treatment, has shown promising results in patients with HPV-associated cancers, with response rates of 35% compared to 12-24% with other standard treatments. Additionally, combining bintrafusp alfa with an HPV vaccine and an IL-12 immunocytokine has shown better outcomes than standard therapies in early studies. ^{1 2 3 4 5}

Is combination immunotherapy for HPV cancers safe for humans?

The safety of combination immunotherapy, including drugs like M7824, Bintrafusp alfa, NHS-IL12, and PDS0101, has been studied in various contexts. While these treatments can improve outcomes, they may cause immune-related side effects, such as neurological issues and gastrointestinal problems, which can be serious but are often manageable. More research is needed to fully understand their long-term safety. ^{6 7 8 9 10}

What makes the combination immunotherapy for HPV cancers unique?

This treatment is unique because it combines bintrafusp alfa, a first-of-its-kind drug that acts as both a checkpoint inhibitor and a 'trap' for TGFβ (a protein that can help tumors grow), with other immune-modulating agents to enhance the body's immune response against HPV-associated cancers. This approach has shown promising results, outperforming standard treatments in some cases. ^{1 2 3 4 5}

Research Team

Charalampos Floudas, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults with advanced HPV-related cancers, including cervical, oropharyngeal, anal, vulvar, vaginal, penile and certain lung or esophageal cancers. Participants must have had one prior chemotherapy and checkpoint therapy if FDA-approved for their cancer type (exceptions apply). They need adequate organ function and an ECOG status <=2. Pregnant women are excluded.

Inclusion Criteria

I have HIV or Hepatitis with undetectable viral load and stable health.

My cancer is HPV-related and in an advanced or metastatic stage.

Adequate hematologic function at screening, as follows: Absolute neutrophil count (ANC) >=1 x 10^9/L; Hemoglobin >= 9 g/dL; Platelets >=75,000/microliter.

Exclusion Criteria

I had severe reactions to previous immunotherapy.

I haven't had cancer treatments except for hormone therapy or palliative bone therapy in the last 28 days.

I am not pregnant or breastfeeding.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive PDS0101, M7824, and NHS-IL12 for up to 1 year

52 weeks

Visits every 2 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

1 follow-up visit or call, then contact every 3 months for 1 year, and every 6 months thereafter

Treatment Details

Interventions

• M7824
• NHS-IL12
• PDS0101

Trial Overview The trial tests a combination of immunotherapy drugs: PDS0101 injected under the skin every 4 weeks then quarterly; M7824 infused every 2 weeks; NHS-IL12 injected monthly. The treatment lasts up to a year with regular NIH visits and lifelong follow-ups after completion.

Participant Groups

Group I: Cohort 2, Arm 2: Cervical Cancer With Prior Pelvic Radiation and Boost Brachytherapy Experimental Treatment 3 Interventions

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.

Group II: Cohort 1, Arm 1: Human Papillomavirus (HPV) Associated Malignancies Experimental Treatment 3 Interventions

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.

M7824 is already approved in United States, European Union for the following indications:

Approved in United States as Bintrafusp alfa for:

• Biliary tract cancer

Approved in European Union as Bintrafusp alfa for:

• No approved indications listed; under investigation for various cancers

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Bintrafusp alfa, a treatment for HPV-associated cancers, shows promise as it acts both as a checkpoint inhibitor and traps TGFβ in the tumor environment, with clinical activity observed in early studies involving 65 patients.

Analysis of the patients' immune profiles before and after treatment revealed specific immune factors that could predict clinical response, suggesting that understanding the peripheral immunome can help identify which patients are likely to benefit from bintrafusp alfa therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune correlates of clinical parameters in patients with HPV-associated malignancies treated with bintrafusp alfa. Tsai, YT., Strauss, J., Toney, NJ., et al.[2022]

Bintrafusp alfa, a bifunctional agent targeting PD-L1 and TGFβRII, has shown promising immune-mediated and antitumor activity, particularly in patients with HPV-associated malignancies, achieving a response rate of 35% compared to 12-24% with standard therapies.

In clinical studies, while bintrafusp alfa did not show superiority over standard treatments in lung and biliary tract cancers, its combination with HPV therapeutic vaccines and IL-12 immunocytokines demonstrated improved outcomes, highlighting the importance of tailored therapies based on tumor microenvironment factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical and clinical studies of bintrafusp alfa, a novel bifunctional anti-PD-L1/TGFβRII agent: Current status. Gameiro, SR., Strauss, J., Gulley, JL., et al.[2023]

The PDS0101 therapeutic vaccine effectively generated HPV-specific T cells and showed antitumor activity in mouse models of HPV-expressing cancers, indicating its potential as a treatment for HPV-related malignancies.

Combining PDS0101 with NHS-IL12 significantly enhanced antitumor effects and increased T cell activity in the tumor microenvironment, while bintrafusp alfa alone did not show antitumor effects, highlighting the importance of combination therapies in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine. Smalley Rumfield, C., Pellom, ST., Morillon Ii, YM., et al.[2021]

Cervical cancer, largely driven by persistent HPV infection, has limited treatment options and a low 5-year survival rate of less than 20% for advanced cases, highlighting the need for new therapies.

Bintrafusp alfa, a novel bifunctional fusion protein that targets both TGF-β and PD-L1, has shown promising results in early clinical trials for advanced cervical cancer, suggesting it may improve treatment outcomes for patients who currently have few options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Changing Landscape of Systemic Treatment for Cervical Cancer: Rationale for Inhibition of the TGF-β and PD-L1 Pathways. Birrer, MJ., Fujiwara, K., Oaknin, A., et al.[2022]

In a study involving 59 patients with advanced HPV-associated cancers, bintrafusp alfa demonstrated a confirmed objective response rate of 30.5%, indicating its potential effectiveness as a treatment option.

The treatment was generally well-tolerated, with 83.1% of patients experiencing treatment-related adverse events, but no treatment-related deaths, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies. Strauss, J., Gatti-Mays, ME., Cho, BC., et al.[2021]

A study analyzing 735 reports of peripheral neuropathies (PNs) in cancer patients treated with immune checkpoint inhibitors (ICIs) from 2010 to 2020 found serious adverse reactions, including Guillain-Barré syndrome, which can lead to significant disability or hospitalization.

The analysis indicated that atezolizumab was associated with a higher frequency of PNs compared to other ICIs, highlighting the need for ongoing safety monitoring of these treatments in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Do peripheral neuropathies differ among immune checkpoint inhibitors? Reports from the European post-marketing surveillance database in the past 10 years. Ruggiero, R., Balzano, N., Di Napoli, R., et al.[2023]

Immunotherapies, particularly anti-PD-1 checkpoint inhibitors like nivolumab and pembrolizumab, have significantly improved survival rates for metastatic melanoma patients while being less toxic than traditional treatments.

Despite their better tolerability, anti-PD-1 therapies can still cause a range of immune-related adverse events, most of which are mild, but there is a pressing need to understand and manage severe side effects due to the increased life expectancy of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of anti PD-1 therapeutics for the treatment of melanoma. Ramelyte, E., Schindler, SA., Dummer, R.[2018]

Nivolumab and ipilimumab, two FDA-approved immunotherapeutic agents targeting PD-1 and CTLA-4, are effective in treating various cancers but can cause significant immune-related adverse effects (irAEs).

In a case study of a 66-year-old female patient, steroid-resistant colitis induced by these checkpoint inhibitors was successfully treated with infliximab, highlighting a potential management strategy for severe irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. Tidwell, C., Gutnik, S.[2020]

A study analyzing 70,330 adverse events reported to the FDA found that immune checkpoint inhibitors (ICIs) significantly increase the risk of gastrointestinal (GI) toxicities, particularly colitis, hepatobiliary disorders, and pancreatitis, with colitis showing the highest reporting odds ratio of 17.2.

The risk of these GI adverse events was notably higher with anti-CTLA-4 treatments compared to anti-PD-1 and anti-PD-L1 therapies, and factors such as female gender and polytherapy were identified as strong risk factors for these complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Common Immune-Related Adverse Events of Immune Checkpoint Inhibitors in the Gastrointestinal System: A Study Based on the US Food and Drug Administration Adverse Event Reporting System. Bai, X., Jiang, S., Zhou, Y., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Immune correlates of clinical parameters in patients with HPV-associated malignancies treated with bintrafusp alfa. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Preclinical and clinical studies of bintrafusp alfa, a novel bifunctional anti-PD-L1/TGFβRII agent: Current status. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

The Changing Landscape of Systemic Treatment for Cervical Cancer: Rationale for Inhibition of the TGF-β and PD-L1 Pathways. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Do peripheral neuropathies differ among immune checkpoint inhibitors? Reports from the European post-marketing surveillance database in the past 10 years. [2023]

7. England pubmed.ncbi.nlm.nih.gov

The safety of anti PD-1 therapeutics for the treatment of melanoma. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Neurological Manifestations Related to Immune Checkpoint Inhibitors: Reverse Translational Research by Using the European Real-World Safety Data. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Common Immune-Related Adverse Events of Immune Checkpoint Inhibitors in the Gastrointestinal System: A Study Based on the US Food and Drug Administration Adverse Event Reporting System. [2021]