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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug combination to determine if it can shrink tumors in certain HPV-related cancers and some types of colon cancer that typically resist treatment. The trial aims to find a safe dose of three drugs used together: entinostat (a histone deacetylase inhibitor), NHS-IL12 (an experimental treatment), and bintrafusp alfa. Suitable participants include those who have undergone previous treatments for cervical, anal, and other HPV-linked cancers or colorectal cancer and still have measurable disease. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

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

Research has shown that bintrafusp alfa has been tested for safety and effectiveness in treating various cancers. One study showed promising results for patients with advanced cancers, and it was generally well-tolerated. However, some patients experienced side effects like skin reactions and tiredness.

Entinostat has also undergone testing in clinical trials. Studies have indicated it might help treat solid tumors. While it has demonstrated anti-tumor effects, some patients experienced side effects such as nausea and tiredness.

Researchers continue to study both treatments to determine the best dose and to better understand their safety. As these treatments are in the early stages of testing, more information on their safety and effectiveness will be gathered over time. Participants interested in joining a trial should discuss potential risks and benefits with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a unique approach to fighting Human Papillomavirus (HPV) and colorectal cancer. Unlike traditional treatments like chemotherapy and radiation, these investigational drugs combine immune system boosters and targeted therapies. For instance, Bintrafusp Alfa is designed to block two immune checkpoints at once, potentially enhancing the body's ability to attack cancer cells. Entinostat is an HDAC inhibitor that might make cancer cells more susceptible to immune attack. NHS-IL12 is an engineered cytokine aimed at supercharging the immune response. Together, these treatments could provide a more effective way to tackle these cancers by directly engaging and empowering the immune system.

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

Research has shown that combining bintrafusp alfa and NHS-IL12 can enhance tumor-fighting abilities, as demonstrated in animal studies. This trial will explore various treatment combinations, including bintrafusp alfa, entinostat, and NHS-IL12, across different arms. One arm will test bintrafusp alfa with entinostat and PDS01ADC, while another will evaluate entinostat and PDS01ADC without bintrafusp alfa. Past studies have shown that entinostat combined with NHS-IL12 has strong tumor-fighting effects and improves survival. These combinations could be promising for treating HPV-related cancers and some colon cancers. Although human data remains limited, these early results are encouraging for the potential effectiveness of these treatments. ^{6 7 8 9 10}

Who Is on the Research Team?

Hoyoung M Maeng, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

Citations

1. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04708470/

Clinical Trial: NCT04708470 Objective: To find a safe dose of entinostat in combination with NHS-IL12 and bintrafusp alfa and to see if this treatment will cause tumors to shrink.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34954456/

NHS-IL12 and bintrafusp alfa combination therapy ... This study investigated whether two such immunotherapies, with complementary mechanisms of action, could enhance antitumor activity in murine ...

3. fightcolorectalcancer.org fightcolorectalcancer.org/blog/trial_drug_generic_name/bintrafusp-alfa/

Bintrafusp alfa Archives Phase I/II Trial of the Combination of Bintrafusp Alfa (M7824), Entinostat and NHS-IL12 (M9241) in Patients With Advanced Cancer.

4. ccr.cancer.gov ccr.cancer.gov/news/article/combination-therapy-tested-in-clinical-trial-for-metastatic-genitourinary-cancers

Combination therapy tested in clinical trial for metastatic ... Investigators want to see if NHS-IL12 and bintrafusp alfa together can fight metastatic, non-prostate GU tumors, with or without the help of SBRT.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11273284/

Bintrafusp Alfa for Recurrent or Metastatic Cervical Cancer ... This phase 2 nonrandomized controlled trial evaluates the safety and response rates of bintrafusp alfa in patients with recurrent or metastatic cervical cancer.

6. researchgate.net researchgate.net/publication/327453385_Safety_and_activity_of_M7824_a_bifunctional_fusion_protein_targeting_PD-L1_and_TGF-b_in_patients_with_HPV_associated_cancers

Safety and activity of M7824, a bifunctional fusion protein ... 31 Here, we report the efficacy and safety results of a phase I trial of bintrafusp alfa monotherapy in patients with advanced SCCHN that ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03436563

M7824 in Patients With Metastatic Colorectal Cancer or ... This phase Ib/II trial studies how well anti-PD-L1/TGFbetaRII fusion protein M7824 (M7824) works in treating patients with colorectal cancer (or with other ...

8. jtocrr.org jtocrr.org/article/S2666-3643(24)00118-8/fulltext

Efficacy and Safety of Bintrafusp Alfa, a Bifunctional Fusion ... In a phase 1 study, bintrafusp alfa was found to have an encouraging clinical activity in patients with previously treated advanced NSCLC.

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

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β ... Safety and efficacy data are presented from a post hoc combined analysis of 59 patients with advanced pretreated, checkpoint inhibitor-naive HPV ...

10. sciencedirect.com sciencedirect.com/science/article/pii/S2666364324001188

Efficacy and Safety of Bintrafusp Alfa, a Bifunctional Fusion ... This study evaluated the safety and efficacy of bintrafusp alfa with chemotherapy in patients with stage IV NSCLC regardless of the programmed death-ligand 1 ( ...