HPV ctDNA Response-Adapted Chemoradiation +/- Retifanlimab Treatment in Advanced-Stage Anal Cancer

NCT07425054 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: CASE1224
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 2

Brief Summary

This study is for people who have anal cancer and have not yet had treatment. The regular treatment for people who have anal cancer is chemoradiation therapy (CRT). CRT is when chemotherapy and radiation therapy are given at the same time. Studies show that CRT works well to treat anal cancer and prevents many people from needing surgery which may require a colostomy bag. Doctors know that CRT is an effective way to treat anal cancer. But, they are doing studies to find out how much dose of radiation and chemotherapy should be given during the CRT. Higher doses of chemotherapy and radiation could increase the risk of side effects, but lowering the dose of chemoradiation has the risk of not being as effective to treat the cancer. One way to predict whether participants need higher or lower doses of radiation therapy is to do a blood test called ctDNA (circulating tumor DNA) to test for the presence of human papillomavirus (HPV). This test is done at certain times while participants are getting CRT. This has been shown to be a marker for the presence of anal cancer. In this study, doctors will tailor lower versus higher doses of CRT based on the tumor response that is measured by ctDNA. The purpose of this study is to see if customizing the dose of chemoradiation based on the amount of ctDNA will increase survival in participants with anal cancer and/or decrease the risk of side effects. Some participants in this study whose cancer does not respond as well to the CRT may have the opportunity to receive a drug called Retifanlimab that stimulates the body's immune system. Retifanlimab is approved by the Federal Drug Administration (FDA) for treating anal cancer that is recurrent or metastatic since there is proven benefit in these situations.

Conditions

Anal Cancer; HPV-Related Carcinoma; Squamous Cell Carcinoma of the Anus

Keywords

Chemoradiation; Retifanlimab

Outcome Measures

Primary Outcomes (1)

• 1-year Disease-free survival (DFS) by response subgroup

  DFS is defined the occurrence of progression of local disease, distant metastases, second primary or death. 1-year DFS, will be analyzed using the Kaplan-Meier method and be compared using a 0.05-level one-sided two-proportion test. DFS will be compared among the three subgroups: favorable response subgroup, intermediate response subgroup, unfavorable response subgroup.

  1 year

Secondary Outcomes (9)

• 2-year disease free survival by response subgroup

  2 years

• 1-year disease control by response subgroup

  1 year

• 2-year disease control by response subgroup

  2 years

• Toxicity Index as assessed by the number of CTCAE events

  3 months post-treatment (up to 2 years)

• Change in patient-reported outcomes (PRO) as assessed by FISI (Fecal Incontinence Severity Index)

  Baseline (Day 1), Year 2

Study Arms (1)

Chemoradiation based on HPV ctDNA response

EXPERIMENTAL

All participants will receive CRT for one cycle (4 weeks), while undergoing HPV ctDNA testing. Investigators will then modify the treatment plan based on HPV ctDNA response: * Favorable response: Dose reduction (total of 28 fractions of CRT) * Intermediate response: Standard dose (total of 30 fractions of CRT) * Unfavorable response: Dose-intensification (total of 34 fractions of CRT)

Radiation: HPV ctDNA Response based radiation; Drug: Chemotherapy; Drug: Retifanlimab

Interventions

HPV ctDNA Response based radiation RADIATION

Total radiation doses per response group: * Favorable response: 5040 cGy in 28 fractions * Intermediate response: 5400 cGy in 30 fractions * Unfavorable response: 6120 cGy in 34 fractions

Chemoradiation based on HPV ctDNA response

Chemotherapy DRUG

1. Mitomycin-C(MMC) 12 mg/m2 on day 1 AND one of the following: 2. Capecitabine 825 mg/m2 twice daily on all days of radiotherapy for all response groups OR 5-Fluorouracil: 1000 mg/m²/day as a continuous infusion for 96 hours on days 1-4 and 29-32

Chemoradiation based on HPV ctDNA response

Retifanlimab DRUG

Only participants who have an unfavorable response to treatment (measured on blood tests at Weeks 4 and 5) will be eligible to receive Retifanlimab. Retifanlimab is a 500 mg infusion administered intravenously (by IV) over 30 minutes and begins two weeks after participants finish chemoradiation therapy (at Weeks 7-9). Retifanlimab will be administered on Day 1 of each cycle (each cycle is 4 weeks) as tolerated for up to 1 year.

Also known as: ZYNYZ

Chemoradiation based on HPV ctDNA response

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have histologically proven stage T1-4N+M0 or T3-T4N0M0 anal canal or anal margin squamous cell carcinoma. This may include tumors of non-keratinizing histology such as basaloid, transitional cell or cloacogenic histology. Special considerations include the following:
• Participants with excision of the primary tumor but with node positive disease or residual disease at the primary if T3-T4N0 will be eligible.
• Age ≥18 years
• ECOG performance status 0-2
• Creatinine clearance \>30 ml/min by Cockcroft-Gault Equation.
• HIV-infected participants are eligible if they meet the following eligibility criteria:
• A CD4 T-cell count \>= 200/mm3 and a viral load \< 200 copies/mm3
• No history of AIDS-related complications within past year other than history of low CD4+ T-cell count (\>200/mm3) prior to initiation of combination antiretroviral therapy.
• Participant must be healthy on the basis of HIV disease with high likelihood of near normal life span were it not for the anal cancer.
• Participant MUST receive appropriate care and treatment for HIV infection, including antiretroviral medications when clinically indicated, and should be under the care of a physician experienced in HIV management. Participants will be eligible regardless of antiretroviral medication provided the regimen has been stable for at least 4 weeks.
• Participants must be PPD negative. Alternatively, the QuantiFERON-TB assay can be used. An individual is considered positive for M. tuberculosis infection if the IFN-γ response to TB antigens is above the test cut-off (after subtracting the background IFN-γ response in the negative control). The result must be obtained within 20 weeks prior to enrollment. PPD positive (or Quantiferon assay positive) participants are permitted if prophylaxis has been completed prior to enrollment.
• Tumor size must be documented based on physical examination including digital rectal exam and/or anoscopy/proctoscopy within 4 weeks prior to enrollment.
• Staging imaging studies must include a PET scan AND either a CT with contrast of the abdomen/pelvis or an MRI with contrast of the pelvis. It is preferred that participants receive contrast. For participants with an allergy who cannot receive pre-medication, or any other reason they can't receive IV contrast, it is recommended that they undergo an MRI of the pelvis.
• Participant must have no history of prior chemotherapy for anal cancer.
• Participant must not have had prior potentially curative surgery (i.e. abdominal-perineal resection) for carcinoma of the anus. However, participants who undergo local excision or excisional biopsy are eligible provided there was tumor involvement of the anal canal and/or anal verge prior to the resection, if the margins were positive, and/or if the stage is T2N0 based on tumor size before the procedure. This means that participants with T1N0M0 anal margin squamous cell carcinoma who underwent surgical excision with negative margins and no involvement of the anal verge and/or anal canal are not eligible.

You may not qualify if:

• Any prior pelvic radiation or previous radiation that would result in overlapping radiation fields.
• History of allergic reactions to compounds similar to capecitabine,
• Participants with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen in the opinion of the investigator.
• Participants with inflammatory bowel disease, scleroderma, or known homozygosity for DPYD deficiency.
• Participants with a fistula between the tumor and invaded organ
• Participant must not have active autoimmune disease or inflammatory bowel disease that has required systemic treatment in past 2 years
• No prior treatment with an immune checkpoint inhibitor (anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 monoclonal antibody)
• No participants with immunodeficiency or receiving systemic steroid therapy equivalent to \> 10 mg prednisone per day or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication. Topical corticosteroid or occasional inhaled corticosteroids are allowed.
• No live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.
• Participants must not have known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• Participants must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to retifanlimab.
• Participants are excluded if known to be homozygous for Dihydropyrimidine Dehydronase

Sponsors & Collaborators

• Jennifer Dorth: lead
• Incyte Corporation: collaborator

Study Sites (2)

University Hospitals Cleveland Medical Center, Seidman Cancer Center, Cleveland Clinic Taussig Cancer Center, Case Comprehensive Cancer Center

Cleveland, Ohio, 44106, United States

Location

Case Comprehensive Cancer Center, Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, 44195, United States

Location

MeSH Terms

Conditions

Anus Neoplasms

Interventions

Drug Therapy

Condition Hierarchy (Ancestors)

Rectal Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Anus Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Jennifer Dorth, MD, MHSc

  Case Comprehensive Cancer Center, University Hospitals

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jennifer Dorth, MD, MHSc

CONTACT

216-844-2536; Jennifer.dorth@uhhospitals.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 13, 2026
• First Posted: February 20, 2026
• Study Start: March 1, 2026
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2029
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: During the study and for 6 months after the study

Locations

US (2)