Radiochemotherapy +/- Durvalumab for Locally-advanced Anal Carcinoma.
Overview
- Phase
- Phase 2
- Intervention
- Chemotherapy
- Conditions
- Anal Cancer
- Sponsor
- Goethe University
- Enrollment
- 180
- Locations
- 25
- Primary Endpoint
- Disease-free survival (DFS)
- Status
- Active, Not Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
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).
Detailed Description
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).
Investigators
Daniel Martin
PD MD
Goethe University
Eligibility Criteria
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
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
Arms & Interventions
5FU+Mitomycin C
Radiochemotherapy for anal cancer
Intervention: Chemotherapy
5FU+Mitomycin C
Radiochemotherapy for anal cancer
Intervention: Radiation
5FU+Mitomycin C+Durvalumab
Radiochemotherapy with Durvalumab for anal cancer
Intervention: Chemotherapy
5FU+Mitomycin C+Durvalumab
Radiochemotherapy with Durvalumab for anal cancer
Intervention: Radiation
5FU+Mitomycin C+Durvalumab
Radiochemotherapy with Durvalumab for anal cancer
Intervention: Durvalumab
Outcomes
Primary Outcomes
Disease-free survival (DFS)
Time Frame: 3 years
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.
Secondary Outcomes
- Major adverse events(3 Years)
- cCR(26 weeks)
- Colostomy-free survival(3 Years)
- Cumulative incidence of locoregional recurrence(3 Years)
- Overall survival(3 Years)
- Cumulative incidence of distant recurrence(3 Years)
- Quality of life questionnaires(3 Years)