Neoplasms

All Conditions

Symptoms and General Pathology

Digestive System Diseases

Rare Diseases

Carcinoma

Carcinoma, Squamous Cell

Recurrence

Anus Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Anal Cancer

Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Carboplatin

Albumin-Bound Paclitaxel

Tubulin Modulators

Antimitotic Agents

Participants will receive carboplatin on Day 1,paclitaxel on Day1,8, 15, and placebo on Day 1 of each 28 day cycle

Participants will receive carboplatin on Day 1,paclitaxel on Day1,8, 15, and retifanlimab on Day 1 of each 28 day cycle

carboplatin will be administered intravenous on Day 1 of each 28 day cycle

carboplatin

paclitaxel will be administered intravenous on Days 1,8, and 15 of each 28 day cycle

paclitaxel

retifanlimab will be administered intravenous on Day 1 of each 28 day cycle

retifanlimab

This study is a Phase 3 global, multicenter, placebo-controlled double-blind randomized study that will enroll participants with inoperable locally recurrent or metastatic SCAC not previously treated with systemic chemotherapy.

Carboplatin-paclitaxel With Retifanlimab or Placebo in Participants With Locally Advanced or Metastatic Squamous Cell Anal Carcinoma (POD1UM-303/InterAACT 2).

A Phase 3 Global, Multicenter, Double-Blind Randomized Study of Carboplatin-Paclitaxel With INCMGA00012 or Placebo in Participants With Inoperable Locally Recurrent or Metastatic Squamous Cell Carcinoma of the Anal Canal Not Previously Treated With Systemic Chemotherapy (POD1UM-303/InterAACT 2)

Incyte shares data with qualified external researchers after a research proposal is submitted. These requests are reviewed and approved by a review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

The trial data availability is according to the criteria and process described on https://www.incyte.com/our-company/compliance-and-transparency

Defined as the time from the date of randomization until disease progression according to RECIST v1.1 by BICR or death due to any cause.

Defined as the time from the date of randomization until death due to any cause.

Defined as the proportion of participants who have a confirmed complete response or partial response per RECIST v1.1 based on BICR.

Defined as the time from the earliest date of documented response until earliest date of disease progression (per RECIST v1.1 based on BICR) or death from any cause, whichever comes first.

Defined as the number of participants maintaining either an ORR or stable disease.

Defined as any adverse event either reported for the first time or worsening of a pre-existing event after first dose of study treatment up to 90 days after last dose of study treatment.

Maximum observed plasma or serum concentration.

Minimum observed plasma or serum concentration over the dose interval

Area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t

Incyte Corporation

Disease Attributes

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Anus Diseases

Rectal Diseases

Sandr GRANIER, MD

Squamous cell carcinoma of the anal canal is a rare cancer with an increasing incidence. It represents 2.5% of digestive cancers and occurs more frequently in immunocompromised persons, in particular HIV positive. It is a cancer that develops essentially locally, with only 5% of metastases at diagnosis. The reference treatment for forms deemed localized after clinico-bio-radiological pre-therapeutic evaluation is radiochemotherapy allowing a 5-year survival rate of about 80%. However, up to 30% of patients fail radiochemotherapy. Failure is defined as persistent disease (non response or progression in 10 to 15% of patients) or relapse (local or metastatic in 10 to 15% of patients). Salvage surgery by abdominoperineal amputation is indicated in this case after elimination of the metastatic character with an overall survival rate at 5 years varying from 23 to 69%. This complex and cumbersome surgery is burdened with significant postoperative morbidity with alteration of the quality of life. Investigators would like to perform a retrospective and prospective study in the Paris Saint-Joseph hospital group to evaluate the interest of abdominoperineal amputation in case of failure of radiochemotherapy in patients with squamous cell carcinoma of the anal canal.

Tumor Recurrence After Abdominal-perineal Amputation in Squamous Cell Carcinoma of the Anus

This outcome corresponds to the Recurrence-free survival (local, metastatic) after abdominal and perineal amputation in case of failure of radio chemotherapy.

This outcome corresponds to the number of death.

Fondation Hôpital Saint-Joseph

Atezolizumab

Fluorouracil

Cisplatin

Immunomodulating Agents

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

TIRANUS is a Phase II, single-arm, open-label, non-randomized, multicenter clinical trial of atezolizumab and tiragolumab in concomitance with standard chemoradiotherapy as first-line in treatment-naïve, localized squamous cell carcinoma of the anal canal who are candidates for radical chemoradiotherapy. Patients with well differentiated stage I anal margin cancer or previously treated with immunotherapy are not eligible.

All patients receive atezolizumab (1200mg) plus tiragolumab (600 mg) for 2 cycles (Q3W) in concomitance with the 6 weeks of standard scheduled chemoradiotherapy (cisplatin: 60 mg/m² on days 1 and 29; 5-FU: 1000 mg/m² per day on days 1-4 and 29-32; radiotherapy: 1.8 Gy per day / total dose 54 Gy). After the concomitant phase, patients receive atezolizumab and tiragolumab for 6 additional cycles (consolidation phase).

All patients receive atezolizumab (1200mg) plus tiragolumab (600 mg) for 2 cycles (Q3W) in concomitance with the 6 weeks of standard scheduled chemoradiotherapy (cisplatin: 60 mg/m² on days 1 and 29; 5-FU: 1000 mg/m² per day on days 1-4 and 29-32; radiotherapy: 1.8 Gy per day / total dose 54 Gy). After the concomitant phase, patients receive atezolizumab and tiragolumab for 6 additional cycles (consolidation phase).

Atezolizumab plus Tiraglolumab

A responsible person Designated by the Sponsor

A responsible person Designated by the sponsor

Principal InvestigatoI Designated by the sponsor, M.D. ; PhD.

Principal Investigator Designated by the Sponsor, M.D. ; PhD.

A responsible person Designated by the sponsor, M.D. ; PhD.

Principal Investigator Designated by the sponsor, M.D. ; PhD.

A responsible person Designated by the Sponsor, M.D. ; PhD.

A responsible person Designated by the sponsor,

Principal investigator Designated by the sponsor, M.D. ; PhD.

Jaume Capdevila

The peculiarity of anal cancers, with well-established radical chemoradiotherapy that allows tumor-neoantigen formation with platinum-based chemotherapy and radiotherapy with radio-sensitizing chemotherapy could create the perfect environment for immunotherapy in this setting, not only to increase the probability of pathological complete response (CCR) but also creating neoantigen exposure and immune-prevention to reduce the relapse after surgery.

TIRANUS trial is a Phase II, single-arm, open-label, non randomized, non controlled recruiting treatment-naive localized squamous cell carcinoma of the anal canal and are candidates for radical chemoradiotherapy. The trial hypothesizes that the addition of immunotherapy (atezolizumab and tiragolumab) to standard chemoradiotherapy in localized squamous cell carcinoma of the anal canal may improve the CCR at the end of consolidation phase. The study will assess, as the primary endpoint, the CCR, defined as the percentage of patients who have achieved complete response (CR), disappearance of all target lesions and no presence of residual disease assessed by biopsy at the end of consolidation phase. Secondary objectives include survival, safety of the combination, patient reported quality of life, and a substudy of molecular biomarkers determined in tumor biopsy and blood samples.

The main question\[s\] it aims to answer are:

1. To determine the efficacy of atezolizumab plus tiragolumab concomitantly with chemoradiotherapy in patients with localized squamous cell carcinoma of the anal canal evaluating the clinical response to treatment.
2. To evaluate safety of the intended treatment regimen and Health-related quality of life (HRQoL) in this treatment regimen

All patients will receive atezolizumab plus tiragolumab for 2 cycles in concomitance with the 6 weeks of standard scheduled chemoradiotherapy. (cisplatin, 5-Fluorouracil and radiotherapy). After the concomitant phase, patients will enter a consolidation phase and will receive atezolizumab in combination with tiragolumab up to 24 weeks. Patients will discontinue treatment in case of confirmed progression, toxicity, patient criteria, or physician criteria.

The TIRANUS trial is a Phase II, single-arm, open-label, non randomized, non controlled, proof-of-concept clinical trial of atezolizumab and tiragolumab in concomitancy with standard chemoradiotherapy (RT, 5-Fluorouracil, and Cisplatin) as first-line in localized squamous cell carcinoma of the anal canal.

1. Objectives 1.1 Primary Objectives To determine if atezolizumab plus tiragolumab in concomitancy with chemoradiotherapy is effective in achieving complete remission in patients with localized squamous cell carcinoma of the anal canal assessed by means of clinical complete response (CCR), defined as the percentage of patients who have achieved complete response (CR), disappearance of all lesions according to RECIST 1.1 criteria and no presence of residual disease assessed by biopsy at the end of consolidation phase (week 26).

1.2. Secondary Objectives

Efficacy secondary objectives:

* To evaluate the locoregional failure rate (LFR), defined as the percentage of patients who present progression/relapse of disease in the anal canal and/or regional organs and/or regional lymph nodes. Locoregional failure rate will be estimated using the appropriate logistic regression model at 1-year, 2-years, and 3-years after the first dose of study treatment and end of study.
* To evaluate the disease-free survival (DFS) of patients with localized squamous cell carcinoma of the anal canal, defined as the time elapsed from the first dose of study treatment to progression, relapse, or death from any cause, whichever occurs first. The investigators will assess the DFS rate at 1, 2, and 3 years. The 1-year, 2-years, and 3-years DFS rates are defined as the rate of patients alive and free of relapse or progression at 1, 2, and 3 years after the first dose of study treatment respectively, estimated by Kaplan-Meier.
* To evaluate the colostomy-free survival (CFS) of patients with localized squamous cell carcinoma of the anal canal, defined as the time elapsed from the first dose of study treatment to the date the colostomy was required or death from any cause, whichever occurs first. The 1-year, 2-years, and 3-years CFS rates are defined as the rate of patients alive and free of colostomy at 1, 2, and 3 years after the first dose of study treatment respectively, estimated by Kaplan-Meier.
* To determine the overall survival (OS) of patients with localized squamous cell carcinoma of the anal canal, defined as the time elapsed from the first dose of study treatment until death from any cause. The investigators will assess the OS rate at 3 and 5 years. The 3-years and 5-years OS rates are defined as the rate of patients alive at 3 and 5 years after the first dose of study treatment respectively, estimated by Kaplan-Meier.

Safety secondary objectives

* To evaluate safety of the intended treatment regimen based on the frequency and severity of adverse events and Treatment-emergent adverse events (TEAEs) assessed by NCI CTCAE v5.0.
* Health-related quality of life (HRQoL), assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) version 3.

Exploratory objectives

* To determine molecular or clinical predictive biomarkers of clinical complete response.
* To evaluate the relationship between the treatment activity and the expression of:

  * Immune checkpoint proteins (including but not limited to PD-1, PD-L1, CD28, OX40, CD40)
  * Presence of infiltrating T cell lymphocytes and immune infiltrate characterization (including but not limited to CD45, CD3, CD8, CD4, CD56, IFNbeta, STAT1, CD 163, H2AX)
  * T-cell clonality (TCR) by multiplex PCR-based clonality (polymerase chain reaction amplification based clonality) // NGS (Next-Generation Sequencing)
  * Tumor mutational burden (TMB) by means of a gene panel with \>300 genes.
  * Presence of infections: poliovirus receptor (PVR) and human papillomavirus (HPV)
  * Presence of potential molecular biomarkers in ctDNA (including but not limited to HPV, KRAS, or TP53)

The TIRANUS trial is a Phase II, single-arm, open-label, non randomized, non controlled, proof-of-concept clinical trial of atezolizumab and tiragolumab in concomitancy with standard chemoradiotherapy (RT, 5-FU, and Cisplatin) as first-line in localized squamous cell carcinoma of the anal canal.

Tiraglolumab Atezolizumab and Chemoradiotherapy in Localized Anal Carcinoma (TIRANUS)

Phase II Study of Atezolizumab Plus Tiraglolumab in Combination With Chemoradiotherapy in Localized Squamous Cell Carcinoma of the Anal Canal

The individual participant data (IPD) anonymized could be shared upon request if the use is within the scope and protection level authorized by the patients by the signature of the informed consent

The EORTC QLQ-C30 questionnaire is a specific questionnaire validated for cancer that is composed of 30 questions or items. The questionnaire is structured in 5 functional scales (physical functioning, daily activities, emotional functioning, cognitive functioning and social functioning), 3 symptom scales (fatigue, pain and nausea, vomiting), 1 global health status scale, and 6 independent items (dyspnea, insomnia, anorexia, constipation, diarrhea and economic impact). Values between 1 and 4 (1: not at all, 2: a little, 3: quite, 4: a lot) are assigned according to the patient's responses to the item, only in items 29 and 30 are they evaluated with a score of 1 to 7 (1: dreadful, 7: excellent). The scores obtained are standardized and a score between 0 and 100 is obtained, which determines the level of impact of the cancer on the patient on each of the scales. A higher score indicating a better HRQoL.

Percentage of patients presenting alterations or deregulation in any of the following (composite endpoint)

* The expression of immune checkpoint proteins (PD-1, PD-L1, CD28, OX40, CD40, or others) in blood and tumor samples.
* The expression of potential molecular biomarkers (HPV, KRAS, TP53) in liquid biopsy (ctDNA) and tumor samples.
* The expression of poliovirus receptor (PVR) and HPV status.
* The presence of infiltrating T cell lymphocytes (CD45, CD3, CD8, CD4, CD56, IFNbeta, STAT1,CD 163, H2AX, or others) in tumor samples.
* The T-cell clonality (TCR) in blood samples
* The presence of ctDNA in blood samples

Clinical complete response (CCR), defined as the percentage of patients who have achieved complete response (CR), disappearance of all lesions according to RECIST 1.1 criteria (locally assessed by the PI) and no presence of residual disease assessed by biopsy at the end of consolidation phase (week 26).

Clinical response rate: Patients will be classified as responders (complete or partial responders) and non-responders based on: 1) the presence of residual disease on tumor biopsy and 2) CT or MRI scans post-treatment (week 26). The binomial proportion and its 95% confidence interval will be used to estimate the CCR rate. Logistic regression analysis will be used to evaluate the effect of baseline characteristics and other covariates with response rate.

locoregional failure rate (LFR), defined as the percentage of patients who present progression/relapse of disease in the anal canal and/or regional organs and/or regional lymph nodes

Disease-free survival (DFS): defined as the time elapsed from the first dose of study treatment to progression, relapse, or death from any cause, whichever occurs first. The investigators will assess the median DFS and the DFS rate at 1, 2, and 3 years, at the end of study (approximately 5 years after the first dose of study treatment). The 1-year, 2-years, and 3-years DFS rates are defined as the rate of patients alive and free of relapse or progression at 1, 2, and 3 years after the first dose of study treatment respectively, estimated by Kaplan-Meier. Patients alive and free of events at the date of the analysis will be censored at their last known tumor assessment.

Colostomy-free survival (CFS): defined as the time elapsed from the first dose of study treatment to the date the colostomy was required or death from any cause, whichever occurs first. The investigators will assess the median CFS and the CFS rate at 1, 2, and 3 years, and at the end of study (approximately 5 years after the first dose of study treatment). The 1-year, 2-years, and 3-years CFS rates are defined as the rate of patients alive and free of colostomy at 1, 2, and 3 years after the first dose of study treatment respectively, estimated by Kaplan-Meier. Patients alive and free of events at the date of the analysis will be censored at their last known contact.

Overall survival (OS): defined as the time elapsed from the first dose of study treatment until death from any cause. The investigators will assess the median OS and the OS rate at 3 and 5 years. The 3-years and 5-years OS rates are defined as the rate of patients alive at 3 and 5 years after the first dose of study treatment respectively, estimated by Kaplan-Meier. Patients alive and free of events at the date of the analysis will be censored at their last known contact.

To evaluate safety of the intended treatment regimen based on the frequency and severity of adverse events (AE) assessed by NCI CTCAE v5.0. Incidence of adverse events (AEs) evaluated as percentage of patients experiencing an adverse event.

To evaluate safety of the intended treatment regimen based on the frequency and severity of Treatment-emergent adverse events (TEAEs) assessed by NCI CTCAE v5.0. Incidence of Treatment-emergent adverse events (TEAEs) evaluated as percentage of patients experiencing an treatment-emergent adverse events.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Carboplatin-paclitaxel With Retifanlimab or Placebo in Participants With Locally Advanced or Metastatic Squamous Cell Anal Carcinoma (POD1UM-303/InterAACT 2).	NCT04472429	Squamous Cell C...	carboplatin paclitaxel retifanlimab	18 Years -	Incyte Corporation
Carboplatin-paclitaxel With Retifanlimab or Placebo in Participants With Locally Advanced or Metastatic Squamous Cell Anal Carcinoma (POD1UM-303/InterAACT 2).	NCT04472429	Squamous Cell C...	carboplatin paclitaxel retifanlimab	18 Years -	Incyte Corporation
Carboplatin-paclitaxel With Retifanlimab or Placebo in Participants With Locally Advanced or Metastatic Squamous Cell Anal Carcinoma (POD1UM-303/InterAACT 2).	NCT04472429	Squamous Cell C...	carboplatin paclitaxel retifanlimab	18 Years -	Incyte Corporation
Tumor Recurrence After Abdominal-perineal Amputation in Squamous Cell Carcinoma of the Anus	NCT05201105	Squamous Cell C...		18 Years -	Fondation Hôpital Saint-Joseph
Tiraglolumab Atezolizumab and Chemoradiotherapy in Localized Anal Carcinoma (TIRANUS)	NCT05661188	Squamous Cell C...	Atezolizumab pl...	18 Years -	Grupo Espanol Multidisciplinario del Cancer Digestivo
Tumor Recurrence After Abdominal-perineal Amputation in Squamous Cell Carcinoma of the Anus	NCT05201105	Squamous Cell C...		18 Years -	Fondation Hôpital Saint-Joseph

Spots Global Cancer Trial Database for squamous cell carcinoma of the anal canal