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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a combination of immunotherapy drugs can reduce tumors in individuals with cancers linked to the human papillomavirus (HPV), such as cervical, anal, and certain throat cancers. The treatment includes three drugs: PDS0101, NHS-IL12 (an experimental treatment), and M7824 (also known as Bintrafusp alfa, an experimental treatment), administered through injections and infusions. Suitable candidates for the trial have advanced HPV-related cancers and have not responded to standard treatments. Participants will receive treatment for up to a year and will undergo regular check-ups to monitor progress. As a Phase 1, Phase 2 trial, this research focuses on understanding the treatment's effects and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the treatments in this trial have manageable safety profiles based on previous studies.

For M7824, also known as bintrafusp alfa, studies indicate it has a safety profile similar to other drugs in its group (PD-1/PD-L1 inhibitors), meaning the side effects are generally manageable and comparable to those of similar treatments.

NHS-IL12, another drug in this trial, has been tested at different doses. Research shows it is safe at certain levels and has demonstrated some biological activity, indicating it might work as intended without causing excessive side effects.

PDS0101 has also been studied and is generally well-tolerated. Previous data show it does not cause significant or unexpected side effects when used with other treatments like pembrolizumab.

These findings suggest that the combination of the three drugs is expected to be safe for participants. However, as with any medical treatment, individual experiences can vary. Researchers will closely monitor participants during the trial to ensure safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for HPV-related cancers, like chemotherapy and radiation, target rapidly dividing cells but can harm healthy tissues too. However, the combination of M7824, NHS-IL12, and PDS0101 offers a fresh approach by harnessing the power of the immune system. M7824 is a novel bifunctional fusion protein that blocks the PD-L1 pathway, which cancers use to hide from immune cells. NHS-IL12 acts as an immune booster, enhancing the body's ability to attack cancer cells, while PDS0101 is a therapeutic vaccine designed to train the immune system to specifically recognize and fight HPV-infected cancer cells. This triple therapy is promising because it targets and stimulates the immune system to attack cancer more precisely, potentially improving efficacy and reducing side effects compared to traditional treatments.

What evidence suggests that this trial's treatments could be effective for HPV associated cancers?

Research shows that the drug combination tested in this trial may help treat cancers linked to HPV. Participants will receive M7824, NHS-IL12, and PDS0101. M7824 has effectively shrunk tumors, with 37.5% of patients responding positively. NHS-IL12, when combined with other treatments, has demonstrated strong tumor-fighting effects and improved survival rates in patients with HPV-related cancers. PDS0101, especially when paired with chemoradiation, achieved a 100% response rate and significant tumor reduction in high-risk cervical cancer patients. These findings suggest that this drug combination could potentially treat HPV-associated cancers effectively. ^{1 3 6 7 8}

Who Is on the Research Team?

Charalampos Floudas, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. international-journal-of-gynecological-cancer.com international-journal-of-gynecological-cancer.com/article/S1048-891X(24)14349-6/fulltext

P37 Phase 1 evaluation of bintrafusp alfa (M7824), a ... As of 9 January 2019, 25 patients were treated for a median duration of 9.6 (range, 2.0–72.0) weeks. Six patients had confirmed responses per RECIST 1.1 (ORR, ...

2. jitc.bmj.com jitc.bmj.com/content/8/2/e001395

Bintrafusp alfa, a bifunctional fusion protein targeting TGF- ... Conclusion Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings ...

3. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2821597

Bintrafusp Alfa for Recurrent or Metastatic Cervical Cancer ... A DRR of 6 months or more was reported in 19 of 146 patients (13.0%; 95% CI, 8.0-19.6) and in 19 of 32 patients (59.4%) who achieved an ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38165683/

Phase I Trial of First-line Bintrafusp Alfa in Patients with ... Bintrafusp alfa had manageable safety and demonstrated clinical activity, further supporting the investigation of TGFβ/PD-L1 inhibition in human papillomavirus ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2018.36.15_suppl.3007

Safety and activity of M7824, a bifunctional fusion protein ... Conclusions: Data from a phase 1 trial of M7824 suggests a manageable safety profile and an ORR of 37.5% in pts with HAC including a confirmed ORR of 45.5% in ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7745517/

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β ... Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33323462/

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β ... Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03427411

M7824 in Subjects With HPV Associated Malignancies Immune related adverse events with M7824 in the phase I trial to date have been on par with other PD-1/PD-L1 inhibitors, suggesting a manageable safety profile.