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Radiochemotherapy with Durvalumab for anal cancer

Patients recieve chemotherapy cycles as followed:

Mitomycin-C 12 mg/m², day 1 (maximum single dose 20 mg) 5-FU: 1000 mg/m² per day, continuous i.v. infusion, on day 1-4 and 29-32

Chemotherapy

PTV_A (primary tumor): T1-T2\<4cm N+: 28 x 1.9 Gy=53.2 Gy, five fractions per week or PTV_A (primary tumor): T2\>=4cm, T3-4 Nany: 31 x 1.9 Gy=58.9 Gy, five fractions per week PTV_N (involved node): 28 x 1.8 Gy=50.4 Gy, five fractions per weeks PTV_Elec (elective node): 28 x 1.43 Gy=40.0 Gy, five fractions per week

Radiation

1500 mg, 1h-civ, every 4 weeks (q4w) applied on day -14 (that is 14 days prior to initiation of RCT), day 15 (during RCT), and thereafter q4w (+/- 3d) for a total of 12 doses

The RADIANCE multicenter, randomized phase II trial will assess the efficacy of durvalumab, a PD-L1 immune checkpoint inhibitor, in combination with primary mitomycin C (MMC)/5-fluorouracil (5-FU)-based radiochemotherapy (RCT) in patients with locally-advanced anal squamous cell carcinoma (ASCC).

Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world. There is a strong rationale for combining the PD-L1 immune checkpoint inhibitor durvalumab with radiochemotherapy (RCT) in patients with ASCC. First, although primary RCT with concurrent mitomycin C and 5-fluorouracil (MMC/5-FU) is the standard treatment for ASCC, the 3-year DFS in patients with locally-advanced disease is only in the range of 60%. Second, approximately 80-90% of patients with ASCC are human papilloma virus (HPV)-positive, which is associated with higher tumor "immunogenicity" in this malignancy that is known to correlate with better response to RCT as well as PD-1/PD-L1 immune checkpoint inhibitors. Also, PD-L1 expression was observed in 33%-62% of patients with locally advanced non-metastatic ASCC that correlated with tumor stage. Third, inhibition of the PD-1/PD-L1 axis showed encouraging responses in recurrent/metastatic ASCC in two phase Ib/II trials. Fourth, several data indicate complementary roles between R(C)T and immunotherapy. Fifth, R(C)T can induce PD-L1 upregulation with resulting dysfunction in CD8+ T-cells, and addition of anti-PD-L1 to R(C)T can overcome T-cell suppression to reinvigorate immune surveillance. First clinical studies have demonstrated promising findings for the combination of RCT and immunotherapies. Thus, based on the above data, RCT combined with durvalumab is expected to be more effective than primary RCT alone. Altogether, the hereby proposed RADIANCE multicenter, randomized phase II trial aims to improve the current standard treatment by incorporating durvalumab to the primary MMC/5-FU-based RCT in patients with locally-advanced ASCC (T2=\>4cm Nany, stage IIB-IIIC).

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

Radiochemotherapy +/- Durvalumab for Locally-advanced Anal Carcinoma.

DFS is defined as the time between randomization and the first of the following events: (a) non-complete clinical response at restaging MRI and proctoscopy, including biopsies of suspicious findings, 26 weeks after initiation of radiochemotherapy, (b) locoregional recurrence after initial complete clinical response (cCR), (c) distant metastases, (d) second primary cancer, or (e) death from any cause, whichever occurs first. Patients without any of these events are censored at the time point of last observation.

Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0

Complete clinical response rate assessed 26 weeks after initiation of radiochemotherapy

Overall survival defined as the time between randomization and death from any cause

Colostomy-free survival defined as time between randomization and a definitive colostomy for progression, relapse, or complication

Cumulative incidence of locoregional recurrence defined as the incidence of locoregional recurrence form the time of randomization

Cumulative incidence of distant recurrence defined as the incidence of distant recurrence form the time of randomization

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Radiochemotherapy +/- Durvalumab for Locally-advanced Anal Carcinoma. A Multicenter, Randomized, Phase II Trial of the German Anal Cancer Study Group	NCT04230759	Anal Cancer Anal Carcinoma Anal Cancer Sta... Anal Cancer Sta...	Chemotherapy Radiation Durvalumab	18 Years -	Goethe University
Radiochemotherapy +/- Durvalumab for Locally-advanced Anal Carcinoma. A Multicenter, Randomized, Phase II Trial of the German Anal Cancer Study Group	NCT04230759	Anal Cancer Anal Carcinoma Anal Cancer Sta... Anal Cancer Sta...	Chemotherapy Radiation Durvalumab	18 Years -	Goethe University
Radiochemotherapy +/- Durvalumab for Locally-advanced Anal Carcinoma. A Multicenter, Randomized, Phase II Trial of the German Anal Cancer Study Group	NCT04230759	Anal Cancer Anal Carcinoma Anal Cancer Sta... Anal Cancer Sta...	Chemotherapy Radiation Durvalumab	18 Years -	Goethe University

Spots Global Cancer Trial Database for anal cancer stage ii