A Phase I/II Study of Combination Immunotherapy for Advanced Cancers Including HPV-Associated Malignancies, Small Bowel, and Colon Cancers

Plain English Summary

A Phase I/II Study of Combination Immunotherapy for Advanced Cancers Including HPV-Associated Malignancies, Small Bowel, and Colon Cancers is a Phase 2 clinical trial sponsored by National Cancer Institute (NCI) studying Oropharyngeal Cancer, Neck Cancer, Human Papillomavirus, HPV, Anal Cancer, Cervical Cancer, Penile Cancer, Vulvar Cancer, Vaginal Cancer, Colon Cancer. This trial tests a combination of three drugs (bintrafusp alfa, PDS01ADC, and entinostat) to see if they can shrink tumors in advanced cancers. It is for adults with advanced HPV-associated cancers (like oropharyngeal, anal, cervical) or certain types of colon and small bowel cancer. Participation involves regular clinic visits for drug infusions, injections, and oral medication, along with various medical tests and scans. Alternative treatments may include standard chemotherapy, radiation, or other targeted therapies depending on the specific cancer type and stage. The trial aims to enroll 55 participants.

Official Summary

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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18 and older with specific types of advanced HPV-associated cancers or colon/small bowel cancer. Patients must have had at least one prior line of chemotherapy (or checkpoint therapy if applicable for their cancer type). Must have measurable disease and generally good health, with adequate blood counts, kidney, and liver function. Individuals with active brain metastases or certain autoimmune conditions may not be eligible. This trial is studying Oropharyngeal Cancer, Neck Cancer, Human Papillomavirus, HPV, Anal Cancer, Cervical Cancer, Penile Cancer, Vulvar Cancer, Vaginal Cancer, Colon Cancer, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures how often tumors shrink with this new drug combination, indicating its potential to control or reduce cancer growth. The specific primary outcome measures are: Ojective response rate (ORR) of triple combination (two years); Determine RP2D of entinostat (two years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial addresses the need for more effective treatments for advanced HPV-associated cancers and certain colon cancers that often do not respond well to current therapies. Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Oropharyngeal Cancer, Neck Cancer, Human Papillomavirus, HPV, Anal Cancer, Cervical Cancer, Penile Cancer, Vulvar Cancer, Vaginal Cancer, Colon Cancer, where improved treatment options are needed.

Investor Insight

This trial explores novel immunotherapy combinations for difficult-to-treat cancers, potentially opening new treatment avenues and representing an investment in next-generation cancer therapies. Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the specific drugs used, how they are given, and the potential side effects. Be prepared for regular visits for treatments and monitoring, which may include scans, blood tests, and biopsies. Understand the commitment to treatment for up to two years and follow-up thereafter. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 55 participants

Interventions

• DRUG: Bintrafusp Alfa — Subjects will receive bintrafusp alfa via IV infusion over 1 hour (-10 minutes / +20 minutes, that is, over 50 to 80 minutes) once every 2 weeks. Bintrafusp alfa will be administered as a "flat" dose of 300 mg independent of body weight. Bintrafusp alfa is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.
• DRUG: PDS01ADC — PDS01ADC will be administered at as dose of 4, 8, 12, or 16.8 micrograms/kg by SC injection every 2 or 4 weeks. The dose of PDS01ADC will be calculated based on the weight of the subject determined within 72 hours prior to the day of drug administration. The dose of PDS01ADC used for the previous administration can be repeated if the change in the subject's weight is 10% or less than the weight used for the last dose calculation.
• DRUG: Entinostat — The entinostat used in this study is a self-administered investigational agent and will be given orally at a designated dose once a week or as directed. Number of entinostat tablets will be calculated based on the dose for the participant.

Primary Outcomes

• Ojective response rate (ORR) of triple combination (two years)
• Determine RP2D of entinostat (two years)

Secondary Outcomes

• Safety of Triple Combination Therapy (two years)
• Progression-Free Survival (PFS) (two years)
• Hospitalization due to AEs attributed to PD (two years)
• Duration of Response (DoR) (two years)

Full Eligibility Criteria

* INCLUSION CRITERIA:
* Phase I: Subjects with cytologically or histologically confirmed locally advanced or metastatic HPV associated malignancies or MSS small bowel or colorectal cancer (Cohort 1).
* Phase II: Subjects with cytologically or histologically confirmed locally advanced or metastatic HPV associated malignancies (Cohort 2), or MSS small bowel or colorectal cancer (Cohort 3).
* Cohort 2 includes:

  * 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+.
* Subjects with MSS colorectal or small bowel cancer must have received two prior lines of systemic chemotherapy. Subjects with HPV associated malignancies must have received one prior line of systemic chemotherapy as well as checkpoint therapy if checkpoint therapy is FDA approved for that specific tumor type (e.g., HNSCC and 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.
* Subjects must have measurable disease, per RECIST 1.1.
* Age \>=18 years.
* ECOG performance status \<=2
* Adequate hematologic function at screening, as follows:

  * Absolute neutrophil count (ANC) \>=1.5 x 10\^9/L;
  * Hemoglobin \>= 9 g/dL;
  * Platelets \>= 100,000/microliter.
* Adequate renal and hepatic function at screening, as follows:

  * Measured or calculated creatinine clearance (using the Cockcroft-Gault equation) \> 50 mL/min
  * 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, individuals of child-bearing potential and those who can father children must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) at the study entry and for 4 months after the last bintrafusp alfa dose, 3 months after the last entinostat dose and 2 months after the last PDS01ADC dose, whichever occurs later.
* Participants serologically positive for HIV, Hep B, Hep C are eligible as long as the viral loads are undetectable by quantitative PCR. HIV positive participants must have 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.
* Subjects must be able to understand and be willing 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 enrollment except if the investigator has assessed that all residual treatment-related toxicities have resolved or are at grade 1 severity and feel the participant is otherwise suitable for enrollment.
* Administration of live vaccine within 30 days prior to enrollment
* Major surgery within 28 days prior to enrollment (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 participants must have repeat CNS imaging at least a month after definitive treatment showing CNS disease that has not progressed. Participants with CNS disease that has not progressed at least a month after definitive treatment and continued on \<=10 mg of prednisone (or equivalent) for treatment of brain or central nervous system metastasis are eligible to enroll in this study. Participants with evidence of intratumoral 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.
* 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;
  * Administration of steroids for other conditions through a route known to result in a minimal systemic

Trial Locations

• National Institutes of Health Clinical Center, Bethesda, Maryland, United States

Frequently Asked Questions

Related Conditions

• Oropharyngeal Cancer
• Anal Cancer
• Cervical Cancer
• Vulvar Cancer
• Vaginal Cancer
• Penile Cancer
• Rectal Cancer
• Colon Cancer
• Small Bowel Cancer
• Head and Neck Squamous Cell Carcinoma

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