Combination Immunotherapy for Human Papillomavirus & Colorectal Cancer

Overseen By National Cancer Institute Referral Offic

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Active brain metastasis, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: 4

55 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Often, metastatic human papillomavirus (HPV) associated cancers cannot be cured. They also do not respond well to treatment. Some forms of colon cancer also have poor responses to treatment. Researchers want to see if a new drug treatment can help people with these types of cancers. Objective: To find a safe dose of entinostat in combination with PDS01ADC and bintrafusp alfa and to see if this treatment will cause tumors to shrink. Eligibility: Adults ages 18 and older who have cervical, oropharyngeal, anal, vulvar, vaginal, penile, squamous cell rectal, or another cancer that may be associated with HPV infection or microsatellite stable small bowel or colorectal cancer. Design: Participants will be screened with a medical history and physical exam. Their ability to do daily activities will be assessed. They may have imaging scans of the brain and/or chest, abdomen, and pelvis. They may have nuclear bone scans. They will have an electrocardiogram to test heart function. They will have blood and urine tests. They may have a tumor biopsy. Participants with skin lesions may have them photographed. Some screening tests will be repeated during the study. Treatment will be done in 28-day cycles. Participants will get bintrafusp alfa through an intravenous catheter every 2 weeks. They will get PDS01ADC as an injection under the skin every 4 weeks. They will take entinostat by mouth once a week. They will complete a medicine diary. Participants will get treatment for 2 years. They will have 1-2 follow-up visits in the 30 days after treatment ends. Then they will be contacted every 6 months to check on their health.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must 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 week prior to enrollment for short-term use or 4 weeks for long-term use.

What data supports the effectiveness of the drug combination immunotherapy for HPV and colorectal cancer?

Research shows that bintrafusp alfa, a component of the treatment, has demonstrated 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 other immune-modulating agents has shown enhanced effectiveness in preclinical and preliminary clinical studies. ^{1 2 3 4 5}

Is the combination immunotherapy treatment generally safe for humans?

Entinostat, one of the components of the combination immunotherapy, has been tested in various clinical trials for different cancers. Common side effects observed include low phosphate levels, low white blood cell counts, and low calcium levels, but these were temporary. Overall, entinostat has shown promising safety results in combination with other treatments. ^{6 7 8 9 10}

What makes the drug combination of Bintrafusp Alfa, Entinostat, and NHS-IL12 unique for treating HPV and colorectal cancer?

This drug combination is unique because Bintrafusp Alfa acts as both a checkpoint inhibitor and a 'trap' for TGFβ, which helps the immune system attack cancer cells more effectively. NHS-IL12 targets the tumor environment to boost the immune response, and Entinostat may enhance the overall effectiveness of the treatment by modifying immune cell behavior. This multi-faceted approach is different from standard treatments that typically target only one pathway. ^{1 2 3 4 5}

Research Team

Hoyoung M Maeng, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults 18+ with advanced or metastatic HPV-associated cancers (like cervical, anal, vulvar) or microsatellite stable small bowel/colorectal cancer. Must have had prior chemotherapy and be HIV/Hep B/C positive with undetectable viral loads. Participants need good blood counts, organ function, and must use effective contraception.

Inclusion Criteria

Subjects must have measurable disease, per RECIST 1.1.

My kidney and liver are functioning well.

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5 x ULN,

Exclusion Criteria

I use steroids only in forms that don't significantly affect my whole body.

I have not had major surgery in the last 28 days.

I need regular procedures to remove excess fluid from my body due to my condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Lead-in Treatment

Participants receive a one-week lead-in treatment with entinostat alone

1 week

1 visit (in-person)

Combination Treatment

Participants receive combination treatment with entinostat, PDS01ADC, and bintrafusp alfa in 28-day cycles

2 years

Bi-weekly visits for bintrafusp alfa, monthly visits for PDS01ADC

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days

1-2 visits (in-person)

Long-term Follow-up

Participants are contacted every 6 months to check on their health

Ongoing

Treatment Details

Interventions

• Bintrafusp Alfa
• Entinostat
• NHS-IL12

Trial Overview The trial is testing a combination of three drugs: Bintrafusp Alfa (IV every 2 weeks), NHS-IL12 (injection every 4 weeks), and Entinostat (oral once a week). The goal is to find safe doses that may shrink tumors in patients with certain advanced cancers over treatment cycles lasting up to two years.

Participant Groups

Group I: 3/Arm3 Experimental Treatment 2 Interventions

Entinostat and PDS01ADC (without bintrafusp alfa)

Group II: 2/Arm 2 Experimental Treatment 3 Interventions

RP2D of entinostat, PDS01ADC, and bintrafusp alfa

Group III: 1/Arm 1 Experimental Treatment 3 Interventions

Dose escalation/de-escalation of entinostat and dose escalation of PDS01ADC with fixed dose of bintrafusp alfa

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

Approved in United States as Bintrafusp Alfa for:

• Non-small cell lung cancer (NSCLC)

Approved in European Union as Bintrafusp Alfa for:

• Biliary tract cancer

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]

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]

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 phase I/II clinical study involving 47 patients with metastatic clear cell renal cell carcinoma, the combination of the HDAC inhibitor entinostat and high-dose IL2 showed a promising objective response rate of 37% and a median overall survival of 65.3 months.

Treatment with entinostat led to a decrease in regulatory T cells (Tregs), which was associated with better treatment responses, indicating a potential mechanism of action for enhancing the efficacy of immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870). Pili, R., Quinn, DI., Hammers, HJ., et al.[2022]

Entinostat, both as a monotherapy and in combination with exemestane, was well tolerated in a phase 1 study involving 12 Japanese postmenopausal women with advanced hormone receptor-positive breast cancer, showing no dose-limiting toxicities or severe adverse events.

Half of the patients achieved stable disease for at least 6 months, with a median progression-free survival of 13.9 months, indicating that entinostat may be an effective treatment option for patients resistant to standard endocrine therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer. Masuda, N., Tamura, K., Yasojima, H., et al.[2022]

Entinostat, a class I histone deacetylase (HDAC) inhibitor, shows promise in treating various subtypes of breast cancer, particularly in overcoming resistance to anti-tumor treatments and enhancing immune response.

Clinical trials indicate that combining entinostat with antiestrogen therapy may effectively target resistance pathways in hormone-positive breast cancer, suggesting a potential new strategy for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entinostat for the treatment of breast cancer. Trapani, D., Esposito, A., Criscitiello, C., et al.[2017]

In a phase II study involving 130 postmenopausal women with ER+ advanced breast cancer, the combination of entinostat and exemestane improved median progression-free survival (PFS) to 4.3 months compared to 2.3 months with exemestane alone, suggesting enhanced efficacy of the combination treatment.

Entinostat was generally well tolerated, although there was a higher rate of treatment discontinuation due to adverse events in the entinostat group (11% vs. 2%). Additionally, changes in protein lysine acetylation were linked to prolonged PFS, indicating a potential biomarker for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. Yardley, DA., Ismail-Khan, RR., Melichar, B., et al.[2022]

The combination of the HDAC inhibitor entinostat and 13-cis retinoic acid (CRA) was found to be reasonably well tolerated in a study of 19 patients with advanced solid tumors, with a recommended dose of entinostat at 4 mg/m² once weekly and CRA at 1 mg/kg per day.

While no objective tumor responses were observed, some patients experienced prolonged stable disease, and the treatment led to increased tumor histone acetylation, suggesting potential mechanisms for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours. Pili, R., Salumbides, B., Zhao, M., 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

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

4. England pubmed.ncbi.nlm.nih.gov

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

5. 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]

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

Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870). [2022]

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

Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Entinostat for the treatment of breast cancer. [2017]

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

Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours. [2021]