Radiochemotherapy +/- Durvalumab for Locally-advanced Anal Carcinoma. a Multicenter, Randomized, Phase II Trial of the German Anal Cancer Study Group

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 scanof 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 DataPrivacy Directive in the EU) obtained from the patient prior to performing anyprotocol-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 10 9/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). (This will notapply to patients with confirmed Gilbert's syndrome (persistent or recurrenthyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis orhepatic pathology), who will be allowed only in consultation with their physician.

• AST (SGOT), ALT (SGPT), AP ≤ 3x institutional ULN

• Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula creatinineclearance

• Female subject of childbearing potential should have a negative serum pregnancywithin 72 hours prior to receiving the first dose of durvalumab. A highly sensitivepregnancy test must be used.

• Female subjects of childbearing potential must be willing to use a highly effectivecontraceptive measure as defined in the Clinical Trial Facilitation Group (CTFG)guideline ("Recommendations related to contraception and pregnancy testing inclinical trials"). Highly effective contraception is required from screening to 90days after the last dose of durvalumab. (Note: Abstinence is acceptable if this isthe usual lifestyle and preferred contraception for the subject.)

• Male subjects of childbearing potential must agree to use a highly effective methodof contraception, starting from screening to 90 days after the last dose ofdurvalumab. (Note: Abstinence is acceptable if this is the usual lifestyle andpreferred contraception for the subject.) Male patients should refrain fromfathering a child or donating sperm during the study and for 180 days after the lastdose of durvalumab + any drug combination therapy or 90 days after the last dose ofdurvalumab monotherapy, whichever is the longer time period.

• Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up.

• For HIV-positive patients: running combined antiretroviral therapy (CART) on astable dose at study entry and undetectable HIV-viral load (HIV Viral load <50copies/mL and CD4>200/mircoliter). Patients will be closely monitored and CARTmanagement will be performed according to appropriate labelling guidance of theantiviral therapy. CART should be on a stable dose at study entry.

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 ≥5years before the first dose of durvalumab and of low potential risk forrecurrence

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease

• Adequately treated carcinoma in situ without evidence of disease

• Known DPD-deficiency

• Participation in another clinical study with an investigational product during thelast 12 months

• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional 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 firstdose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids orsystemic corticosteroids at physiological doses, which are not to exceed 10 mg/d ofprednisone, or an equivalent corticosteroid. In case of recent introduction of CART,inclusion will be possible provided subjects had at least 4 weeks of treatment priorto inclusion.

• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria:

• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basisafter consultation with the Study Chairman.

• Patients with irreversible toxicity not reasonably expected to be exacerbatedby treatment with durvalumab may be included only after consultation with theStudy Chairman

• Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment,other than the study medication. Concurrent use of hormonal therapy fornon-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 firstdose of study drug

• Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of durvalumab.

• History of allogenic organ transplantation.

• Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions tothis criterion:

• Patients with vitiligo or alopecia

• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement

• Any chronic skin condition that does not require systemic therapy

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study chairman

• Patients with celiac disease controlled by diet alone

• Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhoea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten informed consent

• History of leptomeningeal carcinomatosis or any other metastatic disease

• History of active primary immunodeficiency

• Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and TB testing in line withlocal practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),hepatitis C. Patients with a past or resolved HBV infection (defined as the presenceof hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patientspositive for hepatitis C (HCV) antibody are eligible only if polymerase chainreaction is negative for HCV RNA.

• Receipt of live attenuated vaccine within 30 days prior to the first dose ofdurvalumab. Note: Patients, if enrolled, should not receive live vaccine whilstreceiving durvalumab and up to 30 days after the last dose of durvalumab.

• Known allergy or hypersensitivity to any of the study/investigational drugs or anyof the study/investigational drug excipients and/or radiochemotherapy with 5-FU andMitomycin C.

• Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 90 days after the last dose of durvalumab.