Neoplasms

All Conditions

Digestive System Diseases

Rare Diseases

Carcinoma

Carcinoma, Squamous Cell

Esophageal Neoplasms

Esophageal Squamous Cell Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Esophageal Cancer

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Capecitabine

Cisplatin

Epirubicin

Antimetabolites

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Epirubicin, Cisplatin, Capecitabine

Surgical Resection

David Cunningham

This is a study to investigate the efficacy and safety of epirubicin, cisplatin and capecitabine (ECX) as neoadjuvant therapy prior to radical chemoradiotherapy using capecitabine and cisplatin as radio-sensitisers in patients with newly diagnosed localized squamous cell carcinoma of the oesophagus.

Neoadjuvant Epirubicin, Cisplatin and Capecitabine (ECX) Followed by Definitive Chemoradiation With/Without Surgery for Squamous Cell Carcinoma of the Oesophagus

Neoadjuvant Epirubicin, Cisplatin and Capecitabine (Xeloda) [ECX] Followed by Definitive Chemoradiation With or Without Surgery for Patients With Newly Diagnosed Localized Squamous Cell Carcinoma of the Oesophagus

Royal Marsden NHS Foundation Trust

Jane Lawrence

Fluorouracil

Taxane

Patients who had chemoradiotherapy before surgery.

Patients who had chemotherapy before surgery.

Patients who only had oesophagectomy. Various surgical oesophagectomy methods were used, such as Ivor Lewis, transthoracic, three-hole, transhiatal, and left transthoracic. The appropriate surgical approach for each patient was chosen according to the tumour location, size, and depth.

In most patients, the chemotherapy regimens before surgery were consisted of cisplatin combined with either fluorouracil or taxanes.

Neoadjuvant chemoradiotherapy

Various surgical oesophagectomy methods were used, such as Ivor Lewis, transthoracic, three-hole, transhiatal, and left transthoracic,and the appropriate surgical approach for each patient was chosen according to the tumour location, size, and depth.

Oesophagectomy

Neoadjuvant chemotherapy

Herui Yao, PhD

Haiyu Zhou, PhD

Michael Lanuti, PhD

To provide comprehensive efficacy and safety profiles of neoadjuvant chemoradiotherapy (NCRT) versus neoadjuvant chemotherapy (NCT) versus surgery alone in resectable oesophageal carcinoma.

Neoadjuvant chemotherapy (NCT) or neoadjuvant chemoradiotherapy (NCRT) has been shown to be better than surgery alone in patients with resectable oesophageal carcinoma, but higher quality evidence is needed as new findings have emerged regarding this issue.Previous evidence-based findings and the current guidelines have not established a survival advantage of NCRT over NCT or an acceptable safety profile of the addition of radiotherapy to NCT; whether NCRT or NCT is more effective for the treatment of adenocarcinoma or squamous cell carcinoma of the oesophagus is unclear.This study aims to provide comprehensive efficacy and safety profiles of NCRT versus NCT versus surgery alone in resectable oesophageal carcinoma.

Neoadjuvant Chemotherapy or Chemoradiotherapy in Resectable Oesophageal Carcinoma（NewEC Study）

Clinical Evidence for Association of Neoadjuvant Chemotherapy or Chemoradiotherapy With Efficacy and Safety in Patients With Resectable Esophageal Carcinoma (NewEC Study)

The datasets used or analysed during the current study are available from the corresponding author on reasonable request.

The OS was calculated as the time from the date of the histologically documented diagnosis to the date of death or the final follow-up.

DFS was calculated from the date of R0 resection to the date of disease recurrence or death from any cause

R0 resection was defined as gross disease removed with negative margins (tumour-free resection margin).

pCR was defined as no evidence of residual tumour cells in the primary site and resected lymph nodes of the operative specimens.

Guangdong Provincial People's Hospital

Massachusetts General Hospital

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Principal Investigator

The trial regimen consists of the investigational agent APR-246, along with standard chemotherapy, Cisplatin and 5-FU. A maximum of 8 cycles of treatment will be given.

APR-246 and 5-FU must both commence on Day 1 and given on days 1 to 4 via intravenous infusion over 6 hours, whilst 5-FU must be given as a continuous infusion over 96 hours.

On Days 2-4, APR-246 must be given first via intravenous infusion over 6 hours, then commence cisplatin via intravenous infusion over one hour.

This is a dose-escalation study to determine the maximum tolerated dose (MTD) of the combination therapy. The 3 dose levels are described as follows:

Dose Level 1:

APR-246 Dose: 75mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI

Dose Level 2:

APR-246 Dose: 100mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI

Dose Level -1:

APR-246 Dose: 50mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI

APR-246 (also known as PRIMA-1MET), a first-in-class agent targeting mutant p53 resulting in re-expression of wild-type p53 activity.

APR-246

Lara Lipton, MB.BS FRACP

The purpose of this study is to determine whether APR-246, 5-FU and cisplatin are safe and effective in the treatment of platinum resistant oesophageal cancer.

Cancer of the oesophagus (OC) is distinguished by having a poor outcome for most patients and an incidence that is rising faster than any other solid cancer. It is already the eighth most common cancer, and the sixth most common cause of death from cancer, worldwide. The majority of patients are diagnosed with late stage disease, which is incurable with the current standard multimodality therapy. Thus, there is a critical need to develop new treatments for this disease.

Surprisingly, despite its high prevalence in developing countries, and its increasing incidence in Western populations, metastatic OC remains an 'orphan disease' with very few good quality or randomised trials available to guide practice. As a result, treatment for OC has changed little over the past few decades, and as a consequence there has been only modest improvement in overall survival for patients with this disease.

TP53, a key tumour suppressor gene, is mutated in 70-80% of OC (both adenocarcinoma and squamous cell carcinoma) providing an attractive potential target for an OC therapy.

Although paired tissue studies in primary and metastatic OC are lacking, p53 mutations occur very early in oesophageal carcinogenesis and are unlikely to be lost in advanced disease. OC with mutant (mut)-p53 are more resistant to conventional chemotherapy and mut-p53 is associated with poor patient prognosis. Over the last decade, several novel drugs have been developed that target mut-p53 and restore wild-type (wt)-p53 function in cancer cells. Of these, APR-246 (also known as PRIMA-1MET), a first-in-class agent targeting mutant p53 resulting in re-expression of wild-type p53 activity, has proven to be the most effective against a wide range of mutants. APR-246 is a pro-drug that gives rise to the active compound methylene quinuclidinone (MQ), which covalently binds to thiol groups on cysteine residues in the p53 core domain resulting in refolding of mut-p53 protein and restoration of its tumour suppressor activity.

While the reactivation of mut-p53 is thought to be the primary mode of action of APR-246, preclinical studies have suggested potential alternative mechanisms (e.g. through the depletion of cellular glutathione levels) may also be contributing to the efficacy of APR-246, especially when used in combination with cisplatin/5-FU chemotherapy. Thus, the anti-tumour activity of APR-246 may not be limited to mut-p53 bearing tumours.

Mutation of p53 is the most common genetic aberration in oesophageal cancer being detected in up to 80% of both oesophageal squamous cell cancers and adenocarcinomas.

APR-246 is a first-in-class agent targeting mutant p53. In vitro and in vivo preclinical models have demonstrated that APR-246 has excellent efficacy in OC (both adenocarcinoma and squamous cell carcinoma) and potently synergises with chemotherapies used in the treatment of OC, restoring sensitivity to chemotherapy-resistant tumours. An initial phase I clinical trial has shown APR-246 to be safe in humans and early results from a currently running phase Ib/II trial of APR-246 with carboplatin and liposomal doxorubicin in ovarian cancer have been promising. Together, these data provide a strong rationale for investigating the efficacy of APR-246 in OC.

A Study of APR-246 in Oesophageal Cancer

A phase1b/2 Study Evaluating the Efficacy of APR-246, a First-in-class Agent Targeting Mutant p53 in the Treatment of Platinum Resistant Advanced and Metastatic Oesophageal or Gastro-oesophageal Junction Cancers

Peter MacCallum Cancer Centre, Australia

Skin and Connective Tissue Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Symptoms and General Pathology

Blood and Lymph Conditions

Immune System Diseases

Breast Neoplasms

Triple Negative Breast Neoplasms

Melanoma

Carcinoma, Non-Small-Cell Lung

Carcinoma, Transitional Cell

Stomach Neoplasms

Carcinoma, Renal Cell

Neoplasm Metastasis

Lung Neoplasms

Lymphoma

Hodgkin Disease

Mesothelioma

Mesothelioma, Malignant

Squamous Cell Carcinoma of Head and Neck

Endometrial Neoplasms

Skin Diseases

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Breast Diseases

Adenoma

Neoplasms, Mesothelial

Uterine Neoplasms

Genital Neoplasms, Female

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Transitional Cell Carcinoma

Renal Cell Carcinoma

Stomach Cancer

Lymphosarcoma

Clear Cell Renal Cell Carcinoma

Hodgkin Lymphoma

Malignant Mesothelioma

Micronutrients

Hematinics

Vitamins

Pembrolizumab

Docetaxel

Leucovorin

Levoleucovorin

Folic Acid

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Antidotes

Protective Agents

Vitamin B Complex

Trace Elements

Folinic Acid

Folate

Vitamin B9

This Module is designed to evaluate the tolerability and the overall safety profile of NUC-3373 (1875 mg/m2) + LV (400 mg/m2) + pembrolizumab (200 mg) in the treatment of patients with advanced solid tumours (dose validation phase).

NUC-3373 and LV will be administered on Days 1, 8 and 15 and pembrolizumab will be administered on Day 1 of 21-day cycles. The dosing schedule may be adjusted based on emerging data with agreement from the Safety Review Committee. Following completion of the dose validation phase, expansion cohorts may be initiated at the selected dose level.

This Module is designed to assess NUC-3373 (750 mg/m2) + LV (400 mg/m2) + docetaxel (55 mg/m2) for the treatment of patients with advanced/metastatic NSCLC or pleural mesothelioma who have progressed on, or were unable to tolerate, 1 or 2 prior lines of cytotoxic chemotherapy-containing regimens for advanced/metastatic disease (dose validation phase).

NUC-3373 and LV will be administered on Days 1 and 22 and docetaxel will be administered on Day 8 of 28-day cycles. The dosing schedule may be adjusted based on emerging data with agreement from the Safety Review Committee. Following completion of the dose validation phase, expansion cohorts may be initiated at the selected dose level.

Fosifloxuridine Nafalbenamide

NuTide:303 Project Manager

Elisabeth Oelmann, MD, PhD

This study is an open-label, multi-arm, parallel cohort, dose validation and expansion design. The study is modular in design, allowing evaluation of the safety, efficacy and pharmacokinetics (PK) of NUC-3373 in combination with other agents for the treatment of patients with different tumour types.

Each module is designed to evaluate a different NUC-3373 combination and consists of a dose-validation phase (Phase Ib) and a dose-expansion phase (Phase II).

Phase Ib of each module will determine the safety and tolerability of the combinations for further clinical evaluation in Phase II. Approximately 6-20 evaluable patients will be enrolled in the Phase Ib stage of each module to determine safety, tolerability, and preliminary efficacy of NUC-3373 in combination with other agents. Each module will then move into Phase II to enable a further assessment of safety and efficacy in approximately 20-40 patients.

Module 1 will assess NUC-3373 + leucovorin (LV) in combination with pembrolizumab for the treatment of patients with advanced/metastatic solid tumours who have progressed on ≤2 prior therapies for metastatic disease, that may have included 1 prior immunotherapy-containing regimen (either monotherapy or in combination with chemotherapy) or who have not progressed but where addition of NUC-3373 + LV to standard pembrolizumab monotherapy may be appropriate (e.g., patients who could not tolerate post- immuno-oncology (IO) standard of care therapy).

Module 2 will assess NUC-3373 + LV in combination with docetaxel for the treatment of patients with advanced/metastatic non-small cell lung cancer (NSCLC) or pleural mesothelioma who have progressed on, or were unable to tolerate, 1 or 2 prior lines of cytotoxic chemotherapy-containing regimens for advanced/metastatic disease.

The opening of each module will be at the discretion of the Sponsor. Further modules may be added as non-clinical and clinical data become available to support additional NUC-3373 combinations and tumour types.

NUC-3373 in Combination With Other Agents in Patients With Advanced Solid Tumours

A Phase Ib/II Open Label, Multi-arm, Parallel Cohort Dose Finding and Expansion Study to Assess the Safety, Pharmacokinetics and Efficacy of NUC-3373, a Nucleotide Analogue, Given in Combination With Standard Approved Agents in Patients With Advanced Solid Tumours

MTD of NUC-3373 in each of the combinations in each patient

TEAEs in each patient, including clinically significant laboratory changes, and changes in physical exam, vital signs and serial electrocardiograms (ECGs)

ORR, defined as the percentage of patients achieving a confirmed complete or partial response to treatment, based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria or immune-related RECIST criteria (iRECIST).

NuCana plc

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Neoadjuvant Epirubicin, Cisplatin and Capecitabine (ECX) Followed by Definitive Chemoradiation With/Without Surgery for Squamous Cell Carcinoma of the Oesophagus	NCT00220129	Oesophageal Car...	Epirubicin, Cis... Surgical Resect...	18 Years -	Royal Marsden NHS Foundation Trust
Neoadjuvant Epirubicin, Cisplatin and Capecitabine (ECX) Followed by Definitive Chemoradiation With/Without Surgery for Squamous Cell Carcinoma of the Oesophagus	NCT00220129	Oesophageal Car...	Epirubicin, Cis... Surgical Resect...	18 Years -	Royal Marsden NHS Foundation Trust
Neoadjuvant Chemotherapy or Chemoradiotherapy in Resectable Oesophageal Carcinoma（NewEC Study）	NCT04027543	Radiotherapy Si... Chemotherapy Ef... Oesophageal Car... Effect of Drugs Safety Issues	Neoadjuvant che... Oesophagectomy Neoadjuvant che...	18 Years - 80 Years	Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
A Study of APR-246 in Oesophageal Cancer	NCT02999893	Oesophageal Car...	APR-246	18 Years -	Peter MacCallum Cancer Centre, Australia
Neoadjuvant Chemotherapy or Chemoradiotherapy in Resectable Oesophageal Carcinoma（NewEC Study）	NCT04027543	Radiotherapy Si... Chemotherapy Ef... Oesophageal Car... Effect of Drugs Safety Issues	Neoadjuvant che... Oesophagectomy Neoadjuvant che...	18 Years - 80 Years	Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Neoadjuvant Epirubicin, Cisplatin and Capecitabine (ECX) Followed by Definitive Chemoradiation With/Without Surgery for Squamous Cell Carcinoma of the Oesophagus	NCT00220129	Oesophageal Car...	Epirubicin, Cis... Surgical Resect...	18 Years -	Royal Marsden NHS Foundation Trust
NUC-3373 in Combination With Other Agents in Patients With Advanced Solid Tumours	NCT05714553	Advanced Cancer Advanced Solid ... Neoplasm Malign... Metastatic Canc... Melanoma Classical Hodgk... Non Small Cell ... Renal Cell Carc... Urothelial Carc... Head and Neck S... Subungual Squam... Oesophageal Car... MSI-H Colorecta... Gastric Cancer Triple Negative... Endometrial Car... Pleural Mesothe...	Fosifloxuridine... Leucovorin Pembrolizumab Docetaxel	18 Years -	NuCana plc

Spots Global Cancer Trial Database for oesophageal carcinoma