Neoplasms

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Digestive System Diseases

Rare Diseases

Carcinoma

Carcinoma, Squamous Cell

Adenocarcinoma

Stomach Neoplasms

Carcinoma, Hepatocellular

Esophageal Squamous Cell Carcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Gastrointestinal Diseases

Neoplasms, Squamous Cell

Esophageal Neoplasms

Head and Neck Neoplasms

Esophageal Diseases

Stomach Cancer

Esophageal Cancer

Antineoplastic Agents

All Drugs and Chemicals

Pharmaceutical Solutions

Pembrolizumab

Cetuximab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

SAR444245 and pembrolizumab are administered every 3 weeks on Day 1 of each cycle (21 days per cycle) for up to 35 cycles.

SAR444245 is administered every 3 weeks on Day 1 of each cycle (21 days per cycle) and cetuximab is administered on Day 1, Day 8 and Day 15 of each cycle until progressive disease.

Solution for infusion: intravenous infusion

THOR-707

The study is a phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical benefit of SAR444245 (THOR-707) combined with other anticancer therapies for the treatment of participants aged 18 years and older with advanced and metastatic gastrointestinal cancer. This study is structured as a master protocol for the investigation of SAR444245 with other anticancer therapies.

Sub study 01 - Cohort A aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic esophageal squamous cell carcinoma (ESCC).

Sub study 02 - Cohort B1, B2 and B3 would focus on non MSI-H tumors with a large unmet need to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma (GC/GEJ), especially with low PD-L1 expression or after progression on prior PD1/PD-L1-based regimens.

Sub study 03 - Cohort C aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in participants with advanced unresectable or metastatic HCC who relapsed on prior PD1/PD-L1-based regimens.

Sub study 04 - Cohort D1 and D2 aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with either the anti-PD1 antibody pembrolizumab or with the anti-EGFR IgG1 antibody cetuximab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic colorectal cancer (mCRC).

The duration of the study for an individual patient will start from the signature of the main informed consent and include a screening period of up to 28 days, a treatment period \[max 35 cycles {cohort A; B1,B2, B3, C and D1} = 735 days or until PD {cohort D2}\], an end-of-treatment visit at least 30 days following the last administration of study drug (or until the patient receives another anticancer therapy, whichever is earlier), and a follow-up visit 3 months after treatment discontinuation and every 3 months following, until disease progression, or initiation of another antitumor treatment, or death, whichever is earlier.

A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With Gastrointestinal Cancer (Master Protocol) (Pegathor Gastrointestinal 203)

A Phase 2 Non-randomized, Open-label, Multi-cohort, Multi-center Study Assessing the Clinical Benefit of SAR444245 (THOR-707) Combined With Other Anticancer Therapies for the Treatment of Participants With Advanced and Metastatic Gastrointestinal Cancer

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Objective response rate (ORR) defined as proportion of participants who have a confirmed complete response (CR) or partial response (PR) determined by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

Incidence TEAEs according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V 5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading

Incidence of SAEs and laboratory abnormalities according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V 5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading

Defined as the time from the first administration of investigational medicinal product (IMP) to the first tumor assessment at which the overall response was recorded as PR or CR that is subsequently confirmed and determined by Investigator per RECIST 1.1.

Defined as the time from first tumor assessment at which the overall response was recorded as CR or PR that is subsequently confirmed until documented progressive disease (PD) determined by Investigator per RECIST 1.1 or death from any cause, whichever occurs first.

Including confirmed Complete Response (CR) or Partial Response (PR) at any time or stable disease (SD) of at least 6 months (determined by investigator per RECIST 1.1)

Defined as the time from the date of first IMP administration to the date of first documented disease progression determine by Investigator as per RECIST 1.1, or death due to any cause, whichever occurs first

Concentration observed just after treatment administration during repeated dosing

Merck Sharp & Dohme LLC

Sanofi

Symptoms and General Pathology

Postoperative Complications

A pre-operative personalised exercise programme (my-PEP).

A pre-operative personalised exercise programme (my-PEP) consisting of: 1) actions to promote exercise, using behavioural change techniques (BCTs), 2) home inspiratory muscle training (IMT), 3) a home exercise programme (HEP) - which is also current standard care, 4) a 4 week hospital-supervised aerobic and muscle strengthening programme (Hos-PEP) .

Pre-operative Exercise Programme (my-PEP)

Home Exercise Programme (HEP)

Professor Andrew Hart

Dr Stephen Lam

The purpose of this feasibility study is to determine whether a structured exercise programme prior to oesophagectomy has: acceptable adherence, is safe, and improves physiological measures of physical fitness above standard care.

The number of patients with oesophageal cancer is rising dramatically in the UK. Curative cancer surgery (oesophagectomy) is offered to around 40% of affected patients. However, oesophagectomy is a major operation with a high risk of complications. Around 1 in 3 patients will suffer such a complication after surgery, mostly due to heart or lung problems. Most complications are not due to the surgery itself, but related to the patient's physical fitness before their operation. Studies in other surgeries, but not oesophagectomy, have shown that complications may be reduced by improving a patient's physical fitness before their operation. The ExPO team has developed a pre-operative Personalised Exercise Programme (my-PEP), specifically for patients undergoing oesophagectomy. my-PEP has 4 main components: three are exercise modalities (aerobic exercise, breathing exercises and muscle strengthening); the fourth is where a participant's potential barriers to exercise are assessed and behavioural change techniques (BCTs) are suggested to improve exercise engagement in the trial. In total, 32 patients who are due to undergo oesophagectomy at the Norfolk and Norwich Hospital will be recruited and then randomly divided into 2 arms of 16 each. One arm will receive my-PEP in the standard 3-4 months prior to surgery, the other will receive standard care advice to exercise at home. The research objectives are to obtain feasibility data on whether my-PEP is acceptable, adhered to and safe, and whether it improves patient fitness above standard care. Follow up will be 90 days after surgery to obtain a preliminary imprecise estimate of whether my-PEP reduces complications. If the ExPO trial shows promise in these areas, this will inform and justify a future large multi-centre trial to definitively answer whether my-PEP can reduce complications after oesophagectomy. If so, my-PEP could potentially change and improve the pre-operative management of oesophageal cancer patients across the NHS.

Exercise Prior to Oesophagectomy

A Pre-operative Personalised Exercise Programme to Improve Physical Fitness and Reduce Post-operative Cardiopulmonary Complications After Oesophagectomy in Patients With Oesophageal Adenocarcinoma: A Feasibility Randomised Controlled Trial

The number of participants recruited from all eligible patients

Number of patients that drop-out from trial

Number of patients that decline to participate in the trial

Measured with International Physical Activity Questionnaire (IPAQ)

Measured with Determinates of Physical Activity Questionnaire (DPAQ)

Physical activity diary used to assess adherence

The number of adverse events during the trial assessed using CTCAE

Assessed with maximal cardiopulmonary exercise test on a bicycle ergometer

Assessed with mean inspiratory pressure testing in cmH20

Cardiopulmonary complication rates as per ECCG definition.

Inpatient, 30-day and 90-day non-cardiopulmonary complication rates as per ECCG definition.

University of East Anglia

200 patients following oesophagogastric cancer resection recruited into BIORESOURCE 1. Following surgery at 3 months, 6 months, 1 year and 2 years: saliva, urine, blood, breath and quality of life questionnaires will be collected.

Collection of saliva, urine, blood, breath and quality of life questionnaires.

Biosample collection

Bhamini Vadhwana, MRCS, PhD

Bhamini Vadhwana

Professor George Hanna, PhD FRCS

Oesophagogastric cancer (cancer of the gullet and stomach) is the fifth most common cancer in England and Wales with 16,000 new cases diagnosed every year. Survival rates are poor with only 15% surviving beyond 5 years. There is also increasing research to understand the cancer biology and factors allowing cancers to progress. It is likely there is a relationship between the cancer-specific microbiome, cells related to inflammation, which promotes cancer progression. The BIORESOURCE 1 study has established a comprehensive resource of matched samples from patients with oesophageal and gastric cancer. This longitudinal study aims to obtain further matched biosamples in the follow-up period after cancer surgery to find biomarkers that may predict treatment response, recurrence and/or long term prognosis.

Longitudinal Assessment of Biomarkers After Oesophagogastric Cancer Surgery

The LABS Study: Longitudinal Assessment of Biomarkers After Oesophagogastric Cancer Surgery (BIORESOURCE 2: Longitudinal)

Changes in the presence and/or abundance of bacteria over a 2 year period, measured primarily within saliva.

Changes in the VOC profile using gas chromatography mass spectrometry.

Assessment in the longitudinal changes of quality of life measures using validated questionnaires.

Cancer Research UK

Imperial College London

Spartalizumab

Capmatinib 400mg BID for a maximum of 12 months or until progression, patient's refusal or unacceptable toxicity

Capmatinib

Spartalizumab 300mg Q3W for a maximum of 12 months or until progression, patient's refusal or unacceptable toxicity

Immunotherapy with anti-PD1 antibodies provides encouraging results on a subset of patients. Capmatinib, a MET inhibitor, has shown an imunomodulatory effect and a synergy with spartalizumab a PD-1 inhibitor. The purpose of this phase II trial is to evaluate the efficacy and safety of the combination of capmatinib + spartalizumab in adult patients with advanced oesogastric adenocarcinoma.

Multicenter single-arm adaptive phase II trial with 2 cohorts according to MET amplification level :

* Cohort 1: tumor without MET amplification (\< 6 copies);
* Cohort 2: tumor with MET amplification (≥6 copies).

Combination of Capmatinib + Spartalizumab in Advanced Oesogastric Adenocarcinoma

Phase II Trial to Evaluate the Combination of Capmatinib + Spartalizumab in Advanced Oesogastric Adenocarcinoma

Overall response rate defined as the proportion of patients with at least one objective tumour response (complete or partial) according to response evaluation criteria in solid tumours (RECIST) v1.1 within 6 months.

Presence of at least one of (composite endpoint):

* Adverse event (AE) grade \>3 (NCI-CTCAE v5), at least possibly related to the treatment or unrelated to disease, progression, intercurrent illness, concomitant medications
* Non-hematological AE grade ≥3
* Recurring grade 2 pneumonitis, Myocarditis grade ≥2
* Autoimmune hemolytic anemia, hemolytic uremic syndrome, acquired hemophilia grade ≥3
* Guillain-Barre, severe peripheral or autonomic neuropathy, transverse myelitis, encephalitis, aseptic meningitis
* Laboratory abnormality grade ≥3 for \>7days (except nephritis grade 3-4, combined elevations of aspartate or alanine transaminase and total bilirubin, hyperglycemia, serum electrolytes/enzymes changes without clinical impact)
* Febrile neutropenia, documented infection with absolute neutrophil count\<10\^9/L, grade 3 neutropenia \>7days, grade 4 neutropenia or thrombocytopenia, or bleeding with platelet transfusion
* AE with discontinuation \>21days
* Significant drug-related AE

All adverse events during the whole treatment course

Time between the first occurrence of tumor objective response, partial or complete (RECIST 1.1) and the first radiological progression, with response assessment every 9 weeks, up to 24 months

Time between inclusion and the first occurrence of tumor objective response (complete or partial, according to RECIST 1.1) or the end of the study, with response assessment every 9 weeks, up to 24 months

Time between inclusion and the date of the first radiological progression (according to RECIST 1.1), death (any cause), or last follow-up (maximum=24 months), whichever occurs first.

Time between inclusion and death (any cause) or last follow-up (maximum=24 months), whichever occurs first

Assistance Publique - Hôpitaux de Paris

Gemcitabine

Etoposide

Capecitabine

Cisplatin

Etoposide phosphate

Antimetabolites

The trial is a single arm study. Different populations are recruited to each stage and the stages run independently of each other. Stage A1 \& A2 will commence before Stage B so that safety data can be obtained in the palliative setting prior to Stage B commencing. Stage A1 may be ongoing when Stage B begins. Each Stage has a separate eligibility criteria.

Stage A1: M6620 \& palliative radiotherapy Stage A2: M6620 \& palliative chemotherapy (Cisplatin \& Capecitabine) Stage B: M6620 \& definitive chemoradiotherapy

M6620 is an unlicensed small molecule ATR inhibitor which can be used in combination with DNA damaging agents. In pre-clinical models it has substantial activity when given with DNA damaging drugs or ionising radiation. The clinical agent (M6620) is currently studied in a phase I trial in Oxford and other centres in combination with gemcitabine, cisplatin, gemcitabine/cisplatin and cisplatin/etoposide.

M6620

Cisplatin is a platinum based chemotherapy drug licensed to treat a number of different types of cancer. Cisplatin use is not considered standard practice in Stage A2 \& B, therefore Cisplatin is considered an investigational medicinal product for the purpose of this trial.

Capecitabine is a chemotherapy drug licensed to treat a number of different types of cancer, it is a noncytotoxic pre-cursor of the cytotoxic 5-fluourouracil. Capecitabine use is not considered standard practice in Stage A2 \& B, therefore Capecitabine is considered an investigational medicinal product for the purpose of this trial.

Stage A1 uses palliative radiotherapy. Stage B uses definitive radiotherapy.

Radiotherapy

Maria A Hawkins, MD FRCR MRCP

This Phase I study will test the combination of a novel ATR inhibitor (M6620) with chemoradiotherapy in oesophageal cancer; utilizing three experimental cohorts (Stage A1, A2 and B).

There is strong scientific rationale for combining ATR inhibitors with DNA damaging agents such as radiation and cisplatin. In particular, ATR inhibition has been shown to be cytotoxic to tumor cells with an impaired DNA damage response, such as those with deficiency in the ATM- or p53 pathway. The high incidence of p53 mutations and the fact that cisplatin and radiation are key therapeutics, makes oesophageal cancer an attractive tumor type to test the activity of an ATR inhibitor. Given the reported synthetic lethal relationship between ATM and ATR, it is likely that ATR inhibition in an ATM- or p53- deficient background will offer a specific and effective way of targeting OAC and SCC of the oesophagus, and enhance the current standard of care.

The trial will be divided into three stages. Stage A1 will explore the combination of M6620 plus radiotherapy in the palliative setting and Stage A2 will explore the combination of M6620 plus chemotherapy in the palliative setting. Stage B, will explore the combination of all 3 (M6620 plus chemoradiotherapy in the radical setting).

In Stage A1 of the study M6620 will be combined with radiotherapy for the first time and the starting dose will be 140mg/m2 M6620, which has been well-tolerated. M6620 will be administered with daily palliative radiotherapy during this stage in order to study the specific interaction of M6620 with radiotherapy (acting as the DNA damaging agent during this trial stage).

In Stage A2 of the study, M6620 will be combined with Cisplatin and Capecitabine combination chemotherapy for the first time; with a starting dose of 90mg/m2 M6620. M6620 will be administered 24 hours post cisplatin infusion, aiming to achieve maximum treatment benefit. Stage A1 and A2 together will help give an indication of a toxicity profile before administration with chemoradiotherapy (Stage B).

CHARIOT will use a single arm, open-label, dose escalation, Time-To-Event Continual Reassessment Method (TiTE-CRM) to find the optimal treatment schedule.

M6620 Plus Standard Treatment in Oesophageal and Other Cancer

A Phase 1 Dose Escalation Safety Study Combining the ATR Inhibitor M6620 With Chemoradiotherapy in Oesophageal Cancer & Other Solid Cancers Using Time to Event Continual Reassessment Method

To enable evaluation of pharmacokinetics of M6620 when administered in combination with Cisplatin and Capecitabine

To explore change in level of ATR inhibition and apoptosis in M6620 treated tissue

Highest treatment schedule resulting in less than 25% dose limiting toxicity rate

Highest treatment schedule resulting in less than 30% dose limiting toxicity rate

Highest treatment schedule resulting in less than 45% dose limiting toxicity rate

To determine the safety and toxicity profile of M6620 administered concomitantly with RT only in the palliative treatment of oesophageal cancer

Proportion of patients completing at least 75%, 90% and 100% of the planned radiotherapy dose

Objective tumor response as evaluated by CT scan as quantified by RECIST 1.1. PFS and OS from D1

To determine the safety and toxicity profile of M6620 administered concomitantly with chemotherapy (Cisplatin and Capecitabine) only in the palliative treatment of solid cancer

Proportion of patients completing at least 75%, 90% and 100% of the planned dose

Objective tumor response as evaluated by CT scan and quantified by RECIST 1.1; PFS and OS from D1; in field radiotherapy control

To determine safety and toxicity profile of M6620 administered concomitantly with dCRT in combination with cisplatin and capecitabine in the radical treatment of oesophageal cancer

To determine the tolerance and ability to deliver M6620 in combination with standard dCRT

To determine the efficacy of the long term safety of the treatment combination

Merck KGaA, Darmstadt, Germany

University of Oxford

Stomach Diseases

Micronutrients

Hematinics

Vitamins

Docetaxel

Oxaliplatin

Atezolizumab

Leucovorin

Fluorouracil

Levoleucovorin

Avelumab

Immunomodulating Agents

Folic Acid

Folinic Acid

Folate

Vitamin B9

Avelumab 10mg/kg (or Maximum Administered Dose established in safety run-in) iv infusion over 1 hour.

Followed by FLOT: Oxaliplatin 85mg/m2 iv infusion day 1 over 2 hours, Folinic acid 200mg/m2 iv infusion day 1 over 2 hours, Docetaxel 50mg/m2 iv day 1 over 1 hour, Fluorouracil 2600mg/m2 over 24 hours iv

This is a single-arm study with all patients receiving combination FLOT-A

FLOT-A

Marco Gerlinger, MD, FRCP

A single centre phase II trial of peri-operative chemo-immunotherapy in operable gastro-oesophageal adenocarcinoma (GOA). This trial is designed to evaluate the safety and efficacy of administering Avelumab, an anti-PD-L1 monoclonal antibody, with cytotoxic FLOT chemotherapy for patients with operable GOA treated according to a peri-operative protocol.

This trial is in 2 stages: the first stage will establish the safe and tolerated maximum administered dose (MAD) of Avelumab in combination with FLOT and the second stage will assess the efficacy of this combination therapy in achieving pathological complete response (pCR) and peri-operative safety.

Patients will receive chemo-immunotherapy consisting of FLOT chemotherapy (Folinic acid 200mg/m2 iv infusion day 1, Oxaliplatin 85mg/m2 iv infusion day 1, Docetaxel 50mg/m2 iv day 1, Fluorouracil 2600mg/m2 over 24 hours iv) and the PD-L1 inhibiting monoclonal antibody Avelumab. The safe dose of Avelumab in combination with FLOT will be established in a safety run-in phase with a standard 3+3 design, starting with the recommended dose of 10mg/kg iv Avelumab (dose level 0) in which a dose reduction to 7mg/kg iv (dose level -1) may occur. Four cycles of two-weekly chemo-immunotherapy will be administered before surgery and four further cycles post-operatively in patients who are fit enough to receive further chemo-immunotherapy after surgery. Resectional surgery will take place 4-8 weeks following the last dose of chemo-immunotherapy in patients who remain fit.

Study Objectives:

To evaluate the safety, efficacy and toxicities and to explore biomarkers of peri-operative chemo-immunotherapy with Avelumab and FLOT.

All patients will receive chemo-immunotherapy consisting of FLOT chemotherapy and the PD-L1 inhibiting monoclonal antibody Avelumab. Four cycles of two-weekly chemo-immunotherapy will be administered before surgery and four further cycles post-operatively in patients who are fit enough to receive further chemo-immunotherapy after surgery. Resectional surgery will take place 4-8 weeks following the last dose of chemo-immunotherapy in patients who remain fit.

Study Title: Peri-operative Immuno-Chemotherapy in Operable Oesophageal and Gastric Cancer

Study Title: Peri-operative Immuno-Chemotherapy in Operable Oesophageal and Gastric Cancer (ICONIC Trial)

The primary objective is to assess the efficacy of FLOT-A in the peri-operative setting in patients with operable GOAs. We aim to increase the pCR rate after peri-operative treatment from 10% (minimum expected path CR rate for peri-operative FLOT chemotherapy), to a superior pCR rate of \>25%, by adding Avelumab to FLOT.

Complete histopathologic response is defined by no vital tumour cells neither in the oesophagus, the stomach nor in the regional lymph nodes. In cases of residual tumour, the response assessment will follow criteria described by Mandard et al.

Safety of peri-operative FLOT-A will be assessed by summarising grade 3-4 toxicity and DLT rates as proportions.

Radiological response rate assessed at the pre-operative scan using RECIST 1.1 criteria. Radiological tumour response before surgery will be defined as partial response or complete response.

PFS will be summarised using Kaplan Meier methods, presenting median survival with 95% confidence intervals. PFS is defined as time from registration to clinical/radiological progression or death from any cause. Patients event free at time of analysis will be censored at last follow-up date.

OS will be summarised using Kaplan Meier method, presenting median survival with 95% confidence intervals. OS is defined as time from registration to date of death of any cause. Patients event free at time of analysis will be censored at last follow-up date.

Royal Marsden NHS Foundation Trust

Death

Bone Density Conservation Agents

Antibodies

Paclitaxel

Carboplatin

Albumin-Bound Paclitaxel

Durvalumab

Calcium

Immunoglobulins

Calcium, Dietary

Tremelimumab

Protective Agents

Tubulin Modulators

Antimitotic Agents

Immunosuppressive Agents

Immunologic Factors

Antidotes

Vitamin B Complex

Trace Elements

Durvalumab (750 mg IV every two weeks \[Q2W\]) was to be given for up to 11 doses. Oxaliplatin (130 mg/m\^2 IV)/capecitabine (1250 mg/m\^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.

Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (37.5 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m\^2 IV)/capecitabine (1250 mg/m\^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.

Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (75 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m\^2 IV)/capecitabine (1250 mg/m\^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.

Durvalumab (750 mg IV Q2W) was to be given for up to 5 doses. Two cycles of neoadjuvant oxaliplatin (130 mg/m\^2 IV)/capecitabine (1250 mg/m\^2/day given orally) chemotherapy were to be administered before surgery. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.

Durvalumab (750 mg IV Q2W) was to be given for up to 6 doses. Two cycles of neoadjuvant 5-fluorouracil (5-FU) (2600 mg/m\^2 24-hr IV), leucovorin (200 mg/m\^2 IV), oxaliplatin (85 mg/m\^2 IV), and docetaxel (50 mg/m\^2 IV) chemotherapy (FLOT) were to be administered before surgery starting on the day of the third dose of durvalumab. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions), FLOT or durvalumab plus FLOT at the discretion of the Investigator once recovered from surgery, provided that this was within 3 months of surgery.

Durvalumab (750 mg IV Q2W) was to be given for 2 doses. This was followed by five weekly doses of neoadjuvant paclitaxel (50 mg/m\^2 IV) / carboplatin (AUC 2) IV chemotherapy + radiotherapy (41.4 Gy radiotherapy given over 23 fractions) before surgery. Subjects could receive an additional dose of durvalumab after completion of chemoradiation.

In Cohort D2, subjects continued durvalumab for 3 additional doses while receiving chemoradiation. Subjects were to undergo surgery 6 to 8 weeks after completing chemo(radio)therapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.

5-fluorouracil (5-FU)

Mark Middleton

This is an open-label, Phase 1/2 study to evaluate the safety of durvalumab (MEDI4736) in combination with oxaliplatin/capecitabine chemotherapy in metastatic/locally advanced oesophageal cancer (OC) and with neoadjuvant chemo(radio)therapy before surgery in operable OC. The immunotherapy will be given for a 4-week period before starting the standard chemo(radio)therapy, continuing durvalumab treatment once the chemotherapy starts. The study will include 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion Phase 2 (Cohorts B, C, C-FLOT, D/D2).

This is an open-label, Phase 1/2 study to evaluate the safety of immunotherapy in combination with chemo (radio) therapy with the following cohorts:

* Cohorts A1, A2, and B: Oxaliplatin/capecitabine chemotherapy in metastatic/locally advanced oesophageal cancer (OC).
* Cohort C: Neoadjuvant oxaliplatin/capecitabine chemotherapy before surgery in operable OC.
* Cohort C-FLOT: Neoadjuvant 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy before surgery in operable OC.
* Cohort D/D2: Neoadjuvant paclitaxel/carboplatin chemotherapy + radiotherapy before surgery in operable OC.

The immunotherapy will be given for a 4-week period before starting the standard chemo(radio)therapy, continuing durvalumab treatment once the chemotherapy starts for all cohorts except Cohort D.

The study will include 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion Phase 2 (Cohorts B including the higher dose tremelimumab cohort from Cohort A2, C, C-FLOT, and D/D2).

Phase 1 will evaluate the safety of durvalumab alone (Cohort A1) administered before chemotherapy (oxaliplatin + capecitabine) in subjects with metastatic or locally advanced OC. After completion of Cohort A1, Phase 2 in Cohorts C, C-FLOT, and D/D2 will begin, and a safety review will determine whether to explore the tremelimumab + durvalumab combination (Cohort A2).

Phase 2 includes the expansion into Cohorts B, C, C-FLOT, and D/D2. Once Cohort A1 is cleared, there will be concurrent enrollment into Phase 2 expansion for Cohorts C, C-FLOT and D/D2 (subjects with operable OC with neoadjuvant chemotherapy or chemoradiotherapy before surgery) and the tremelimumab dose-escalation phase for Cohort A2 (37.5 mg and 75 mg). Once Cohort A2 is completed, another safety review will determine the dose of tremelimumab to be included in the recommended combination dose (RCD) to start enrollment into the Cohort B (subjects with metastatic/locally advanced OC) expansion phase. Subjects treated at the RCD in Cohort A2 (tremelimumab 75 mg) will be included in Cohort B.

Subjects in Cohorts C, C-FLOT and D/D2 will undergo surgery after completing treatment, and they will be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this is within 3 months of surgery. Subjects in Cohort C-FLOT may receive durvalumab, FLOT, or durvalumab plus FLOT at the discretion of the investigator.

Study of Anti-PD-L1 in Combination With Chemo(Radio)Therapy for Oesophageal Cancer

Phase 1/2 Study of Anti-PD-L1 in Combination With Chemo(Radio)Therapy for Oesophageal Cancer

Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) were reported based on clinical laboratory tests, vital signs, physical examinations, and any other medically indicated assessments, including subject interviews, from the time informed consent is signed through 110 days after the last dose of study treatment. Treatment-emergent AEs were those that occurred or worsened after administration of the first dose of study treatment.

In Cohorts A1, A2 and B, 12, 5 and 7 subjects, respectively, were monitored for dose limiting toxicities (DLTs) during the first 10 weeks of treatment (DLT evaluation period).

Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), and in Cycles 1, 3, 5 and 6 in Cohorts A1, A2 and B. In the other cohorts, tumor response was assessed at baseline, post-surgery and 14 days after the last dose. In Cohorts C-FLOT and D, an additional assessment was done prior to surgery and in Cohorts C and D, an additional assessment was done in Cycle 3. Per irRECIST, measurable lesions are categorized as follows: Immune-related Complete Response (irCR): Complete disappearance of all target lesions; Immune-related Partial Response (irPR): ≥ 30% decrease from baseline in the Total Measurable Tumor Burden (TMTB); Immune-related Progressive Disease (irPD): ≥ 20% increase from nadir in TMTB; Immune-related Stable Disease (irSD): not meeting above criteria; irNon-CR/Non-PD: irNon-CR/Non-PD is preferred over SD when no lesions can be measured.

Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), and in Cycles 1, 3, 5 and 6 in Cohorts A1, A2 and B. Per irRECIST, measurable lesions are categorized as follows: irCR: Complete disappearance of all target lesions; irPR: ≥ 30% decrease from baseline in the Total Measurable Tumor Burden (TMTB); irPD: ≥ 20% increase from nadir in TMTB; irSD: not meeting above criteria; irNon-CR/Non-PD: irNon-CR/Non-PD is preferred over SD when no lesions can be measured.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With Gastrointestinal Cancer (Master Protocol) (Pegathor Gastrointestinal 203)	NCT05104567	Oesophageal Squ... Gastric Cancer Hepatocellular ... Colorectal Canc... Oesophageal Ade...	THOR-707 Pembrolizumab Cetuximab	18 Years -	Sanofi
Exercise Prior to Oesophagectomy	NCT02962219	Postoperative C... Oesophageal Ade...	Pre-operative E... Home Exercise P...	18 Years -	University of East Anglia
Longitudinal Assessment of Biomarkers After Oesophagogastric Cancer Surgery	NCT06289374	Oesophageal Ade... Gastric Adenoca...	Biosample colle...	18 Years - 90 Years	Imperial College London
A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With Gastrointestinal Cancer (Master Protocol) (Pegathor Gastrointestinal 203)	NCT05104567	Oesophageal Squ... Gastric Cancer Hepatocellular ... Colorectal Canc... Oesophageal Ade...	THOR-707 Pembrolizumab Cetuximab	18 Years -	Sanofi
A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With Gastrointestinal Cancer (Master Protocol) (Pegathor Gastrointestinal 203)	NCT05104567	Oesophageal Squ... Gastric Cancer Hepatocellular ... Colorectal Canc... Oesophageal Ade...	THOR-707 Pembrolizumab Cetuximab	18 Years -	Sanofi
Combination of Capmatinib + Spartalizumab in Advanced Oesogastric Adenocarcinoma	NCT05135845	Oesophageal Ade... Gastric Adenoca...	Capmatinib Spartalizumab	18 Years -	Assistance Publique - Hôpitaux de Paris
M6620 Plus Standard Treatment in Oesophageal and Other Cancer	NCT03641547	Oesophageal Ade... Squamous Cell C... Solid Tumor	M6620 Cisplatin Capecitabine Radiotherapy	16 Years -	University of Oxford
Study Title: Peri-operative Immuno-Chemotherapy in Operable Oesophageal and Gastric Cancer	NCT03399071	Gastric Adenoca... Oesophageal Ade...	FLOT-A	18 Years -	Royal Marsden NHS Foundation Trust
Study of Anti-PD-L1 in Combination With Chemo(Radio)Therapy for Oesophageal Cancer	NCT02735239	Esophageal Canc...	Durvalumab Tremelimumab Oxaliplatin Capecitabine Radiotherapy Paclitaxel Carboplatin 5-fluorouracil ... Leucovorin Docetaxel	18 Years -	Ludwig Institute for Cancer Research

Spots Global Cancer Trial Database for oesophageal adenocarcinoma