Phase II Multicenter Randomized Trial of Radiochemotherapy With or Without Durvalumab in Locally-Advanced Anal Carcinoma (Stage IIB-IIIC)

Trial ID: 2024-513914-36-00
Protocol: RADIANCE
Sponsor: Goethe University Frankfurt

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Diseases & Conditions

Anal cancer stage II Anal cancer stage III

Objectives

The primary objective of this study is to evaluate **disease-free survival** (DFS) in patients with locally-advanced anal carcinoma, specifically stages II and III. DFS is defined as the time from randomization to the occurrence of one of the following events: non-complete clinical response at restaging MRI and proctoscopy, loco-regional recurrence after initial complete clinical response, distant metastases, second primary cancer, or death from any cause. The study aims to improve DFS by adding the PD-L1 immune checkpoint inhibitor **durvalumab** to the standard MMC/5-FU-based radiochemotherapy (RCT) regimen. The hypothesis is that the addition of durvalumab will increase the 3-year DFS rate from 60% in the control arm to 80% in the experimental arm. This is clinically relevant as it could significantly enhance treatment outcomes for patients with this condition.

Secondary objectives include: - Assessing acute and late toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. - Evaluating treatment compliance and safety. - Determining the complete clinical response rate 26 weeks after initiation of RCT. - Measuring overall survival, defined as the time between randomization and death from any cause. - Assessing colostomy-free survival. - Evaluating the cumulative incidence of locoregional and distant recurrences. - Assessing quality of life according to EORTC QLQ–C30 and functional outcome per EORTC ANL27. - Investigating the value of various MRI sequences, including diffusion-weighted MRI, for prediction and monitoring of treatment response. - Conducting translational/biomarker studies.

Participants

The clinical trial involves a total of **8 participants** diagnosed with **locally-advanced anal carcinoma**, specifically **anal cancer stage II and III**. The study population includes both male and female subjects, aged 18 years and older, with no upper age limit specified. Participants are required to have a histologically-confirmed diagnosis of anal squamous cell carcinoma (ASCC) of the anal canal or margin. The trial population was selected based on specific health criteria, including adequate leukocyte, neutrophil, and platelet counts, as well as normal liver and kidney function tests. Participants must have an ECOG performance score of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle considerations include the requirement for female and male subjects of childbearing potential to use highly effective contraception during the study and for a specified period after the last dose of the investigational drug. The trial also includes HIV-positive patients, provided they are on combined antiretroviral therapy with an undetectable viral load. Participants must have a life expectancy of more than 12 months and a body weight greater than 30 kg. The study does not specify any dietary or physical activity requirements beyond these health and lifestyle criteria.

Plans and Procedures

The clinical trial is a **randomized**, phase II study designed to evaluate the efficacy and safety of adding **durvalumab** to standard radiochemotherapy in patients with locally-advanced anal carcinoma, specifically stages II and III. The trial employs a **double-blind** methodology to ensure unbiased results, with participants randomly assigned to either the experimental arm receiving durvalumab or the control arm receiving standard treatment. The primary endpoint is disease-free survival (DFS), with secondary endpoints including acute and late toxicity, treatment compliance, overall survival, and quality of life assessments. The trial is expected to run until December 31, 2026, with recruitment having commenced on January 7, 2020.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on criteria such as histologically-confirmed anal squamous cell carcinoma (ASCC), adequate organ function, and a life expectancy of over 12 months. Follow-up visits will occur at regular intervals to monitor treatment response, assess adverse events, and ensure compliance with the protocol. The end-of-study visit will evaluate the final outcomes and collect data on long-term effects. The expected duration of participant involvement is up to 52 weeks, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with the study protocol.

Treatment

The clinical trial involves the administration of **IMFINZI** (durvalumab), a **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, and it is administered via **intravenous infusion**. The active substance, durvalumab, is a protein-based therapeutic agent classified under the ATC code L01XC28. The maximum daily dose of durvalumab is 1500 mg, with a total maximum dose of 18000 mg over the treatment period. The treatment duration is set for a maximum of 52 weeks. Durvalumab is provided by AstraZeneca AB and is not formulated for pediatric use. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.

In addition to the experimental treatment with durvalumab, the study includes a standard-of-care therapy consisting of mitomycin C (MMC) and 5-fluorouracil (5-FU) based radiochemotherapy (RCT). This standard treatment serves as the comparator in the trial, with the primary aim of evaluating the efficacy of adding durvalumab to the existing RCT regimen. The trial is designed to assess the improvement in disease-free survival (DFS) in patients with stage IIB-IIIC anal squamous cell carcinoma (ASCC) by comparing the experimental arm with the control arm receiving only the standard RCT.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the measurement of **disease-free survival (DFS)**. DFS is defined as the time from randomization to the occurrence of one of the following events: non-complete clinical response at restaging MRI and proctoscopy, loco-regional recurrence after initial complete clinical response, distant metastases, second primary cancer, or death from any cause. Patients without any of these events will be censored at the time of their last observation. The primary aim is to evaluate whether the addition of the PD-L1 immune checkpoint inhibitor **durvalumab** to standard MMC/5-FU-based radiochemotherapy (RCT) improves DFS in patients with stage IIB-IIIC anal squamous cell carcinoma (ASCC). The hypothesis is that durvalumab will increase the 3-year DFS rate from 60% in the control arm to 80% in the experimental arm.

Secondary endpoints include acute and late toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, treatment compliance and safety, complete clinical response rate assessed 26 weeks after initiation of RCT, overall survival, colostomy-free survival, and cumulative incidence of locoregional and distant recurrences. Quality of life will be evaluated using the EORTC QLQ-C30 (version 3.0) and functional outcome per EORTC ANL27. Additionally, the value of various MRI sequences, including diffusion-weighted MRI, for prediction and monitoring of treatment response will be assessed, along with translational and biomarker studies.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically-confirmed ASCC (both genders) of the anal canal or the anal margin
UICC-Stage IIB-IIIC including T2>4cm Nany (IIB: T3N0M0; IIIA: T1- 2N1M0; IIIB: T4N0M0; IIIC: T3-4N1M0; T2>4cm Nany) according to proctoscopy, pelvic MRI, CT scan of thorax and abdomen, all within 30 days prior to recruitment
Age ≥ 18 years, no upper age limit
ECOG-Performance score 0-1
History/physical examination within 30 days prior to recruitment
Written informed consent and any locally-required authorization (e.g. EU Data Privacy Directive in the EU) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations
Life expectancy of > 12 months
Body weight >30kg
Hemoglobin ≥9.0 g/dl
Leukocytes >3.5 x 10^9/l
Absolute neutrophil count (ANC) 1.5 x 109/l (> 1500 per mm3)
Platelet count ≥100 x 109/l (>100,000 per mm3)
Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). <>
AST (SGOT), ALT (SGPT), AP ≤ 3x institutional ULN
Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula creatinine clearance
Female subject of childbearing potential should have a negative serum pregnancy within 72 hours prior to receiving the first dose of durvalumab. A highly sensitive pregnancy test must be used
Female subjects of childbearing potential must be willing to use a highly effective contraceptive measure as defined in the Clinical Trial Facilitation Group (CTFG) guideline ("Recommendations related to contraception and pregnancy testing in clinical trials."). For details see Section 6.1 of the study protocol. Highly effective contraception is required from screening to 90 days after the last dose of durvalumab. (Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.)
Male subjects of childbearing potential must agree to use a highly effective method of contraception as outlined in Section 6.1. Contraception, starting from screening to 90 days after the last dose of durvalumab. (Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.)
Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
For HIV-positive patients: running combined antiretroviral therapy (CART) and undetectable HIV-viral load (HIV Viral load <50 copies/mL and CD4>200/µL).

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Exclusion Criteria

UICC-Stage I-IIA ASCC defined as cT1N0M0 or cT2 <4cm N0M0 disease
Second malignancy other than basalioma or cervical/genital/ neoplasia in situ
History of another primary malignancy except for -Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of durvalumab and of low potential risk for recurrence -Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease -Adequately treated carcinoma in situ without evidence of disease
Known DPD-deficiency
Participation in another clinical study with an investigational product during the last 12 months
Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
Any previous treatment with other immunotherapy, a PD1 or PD-L1 inhibitor
QT interval corrected for heart rate (QTc) ≥470 ms
Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/d of prednisone, or an equivalent corticosteroid. In case of recent introduction of CART, inclusion will be possible provided subjects had at least 4 weeks of treatment prior to inclusion.
Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria: -Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Chairman. -Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Chairman
Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment, other than the study medication. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
Previous radiotherapy treatment to the pelvis or radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of durvalumab.
History of allogenic organ transplantation.
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: -Patients with vitiligo or alopecia -Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement -Any chronic skin condition that does not require systemic therapy -Patients without active disease in the last 5 years may be included but only after consultation with the study chairman -Patients with celiac disease controlled by diet alone
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
History of leptomeningeal carcinomatosis or any other metastatic disease
History of active primary immunodeficiency
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab and up to 30 days after the last dose of durvalumab.
Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab.