M6620 Plus Standard Treatment in Oesophageal and Other Cancer

NCT03641547 | Completed Phase 1 Results

• 1 other identifier: OCTO_072
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 5

Brief Summary

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).

Conditions

Oesophageal Adenocarcinoma; Squamous Cell Carcinoma; Solid Tumor

Keywords

Oesophageal cancer

Outcome Measures

Primary Outcomes (3)

• STAGE A1 - Number of Dose Limiting Toxicities for M6620 (Berzosertib) Administered Concomitantly With Radiotherapy (RT) in the Palliative Treatment of Oesophageal Cancer.

  To determine the best tolerated M6620 (Berzosertib) treatment schedule (or phase II recommended dose, RPTD) administered concomitantly with radiotherapy (RT) only in the palliative treatment of oesophageal cancer.

  From start of M6620 (Berzosertib) treatment to 6-week follow up visit (9 weeks)

• STAGE A2 - Number of Dose Limiting Toxicities for M6620 (Berzosertib) Administered Concomitantly With Chemotherapy (Cisplatin and Capecitabine) in the Palliative Treatment of Solid Cancer.

  To determine the best tolerated M6620 (Berzosertib) treatment schedule (or phase II recommended dose, RPTD) administered concomitantly with chemotherapy (cisplatin and capecitabine) only in the palliative treatment of solid cancer.

  From start of M6620 (Berzosertib) treatment to end of first week of cycle two of chemotherapy (4 weeks)

• STAGE B - To Determine the Best Tolerated M6620 (Berzosertib) Treatment Schedule (or RPTD) Administered Concomitantly With Radiotherapy (dCRT) in Combination With Cisplatin and Capecitabine in the Radical Treatment of Oesophageal Cancer.

  Highest treatment schedule resulting in less than 45% dose limiting toxicity (DLT) rate.

  24 weeks

Secondary Outcomes (9)

• STAGE A1 - Severity of Worst Adverse Events for M6620 (Berzosertib) Administered Concomitantly With Radiotherapy (RT) in the Palliative Treatment of Oesophageal Cancer.

  From start of M6620 (Berzosertib) treatment to 9-week follow up visit (12 weeks)

• STAGE A1 - Number of Patients Completing at Least 75%, 90% and 100% of the Planned Treatment Dose of M6620 (Berzosertib) in Combination With Palliative Radiotherapy

  From start of M6620 (Berzosertib) treatment to last dose (3 weeks)

• STAGE A1 - Objective Tumour Response to M6620 (Berzosertib) Plus Radiotherapy, as Evaluated by CT Scan and Quantified by RECIST 1.1.

  At 12 weeks following start of M6620 (Berzosertib) treatment

• STAGE A2 - Severity of Worst Adverse Events for M6620 (Berzosertib) Administered Concomitantly With Chemotherapy (Cisplatin and Capecitabine) in the Palliative Treatment of Solid Cancer

  From start of M6620 (Berzosertib) treatment to 8-week post-end of treatment follow up visit (26 weeks)

• STAGE A2 - Number of Patients Completing at Least 75%, 90% and 100% of the Planned Treatment Dose of M6620 (Berzosertib) in Combination With Chemotherapy (Cisplatin and Capecitabine) in the Palliative Treatment of Solid Cancer.

  From start of M6620 (Berzosertib) treatment to last dose (18 weeks)

Study Arms (1)

Stage A1, A2 & B

EXPERIMENTAL

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

Drug: M6620; Drug: Cisplatin; Drug: Capecitabine; Radiation: Radiotherapy

Interventions

M6620 DRUG

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.

Stage A1, A2 & B

Cisplatin DRUG

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.

Stage A1, A2 & B

Capecitabine DRUG

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, A2 & B

Radiotherapy RADIATION

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

Stage A1, A2 & B

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• For Stage A1:
• Histologically confirmed adenocarcinoma or squamous cell carcinoma of the oesophagus (not including cervical oesophagus)
• Tumor length 15cm or less
• Any stage of disease that is unsuitable for radical CRT or surgery but suitable for palliative RT
• Baseline investigations available: staging CT scan (within 42 days before first study dose) and endoscopy
• Previous chemotherapy treatment completed 28 days before first study dose
• No oesophageal stent in-situ
• Any gender, aged ≥16 years.
• Life expectancy of at least 12 weeks
• ECOG performance score of 0-1
• Able to comply with protocol fully - absence of any physical, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Able to give written (signed and dated) informed consent according to GCP before registration
• Hematological and biochemical indices within the ranges below:
• Haemoglobin: ≥8.0g/dL
• Platelet count : ≥100x10\^9/L

You may not qualify if:

• Pregnant or breast-feeding women, or women of childbearing potential unless highly effective contraception is used
• Untreated and multiple brain metastases
• Clinically significant cardiovascular event within 6 months before study entry to include: a) congestive heart failure requiring therapy, b) unstable angina pectoris, c) myocardial infarction, d) class II/III/IV cardiac disease (New York Heart Association), e) presence of severe valvular heart disease, f) presence of ventricular arrhythmia requiring treatment
• History of arrhythmia that is symptomatic or requires treatment (CTCAE 3), symptomatic or uncontrolled atrial fibrillation, despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted.
• Uncontrolled hypertension (blood pressure ≥160/100 despite optimal therapy)
• Second or third degree heart block with or without symptoms
• QTc \>450msec in adult male and \>470 msec in adult females (by Fridericia's correction) not due to electrolyte abnormality and that does not resolve with correction of electrolytes.
• History of congenital long QT syndrome
• History of torsades de pointes (or any concurrent medication with a known risk of inducing torsades de pointes)
• Trachea-oesophageal fistula or invasion of the tracheo-bronchial tree
• Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to the start of treatment
• Strong CYP3A inhibitors and inducers or haemopoietic growth factors within 14 days before first dose of M6620 (Berzosertib)
• HER2 gastro-oesophageal positive cancer where anti-Her2 therapies may be more appropriate (however patients who have failed anti-HER2 therapy may be eligible for stage A1 and A2)
• Unable to have or unwilling to change to low molecular weight heparin instead of Warfarin
• Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results.

Sponsors & Collaborators

• University of Oxford: lead
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (5)

Velindre Cancer Centre

Cardiff, CF14 2TL, United Kingdom

Location

Beatson Cancer Centre

Glasgow, United Kingdom

Location

St James's University Hospital

Leeds, LS9 7TF, United Kingdom

Location

The Christie

Manchester, M20 4BX, United Kingdom

Location

The Churchill Hospital, Oxford University Hospitals Trust

Oxford, OX3 7LE, United Kingdom

Location

Related Publications (2)

• Javed SR, Lord S, El Badri S, Harman R, Holmes J, Kamzi F, Maughan T, McIntosh D, Mukherjee S, Ooms A, Radhakrishna G, Shaw P, Hawkins MA. CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method. Br J Cancer. 2024 Feb;130(3):467-475. doi: 10.1038/s41416-023-02542-1. Epub 2023 Dec 21.

  PMID: 38129525 DERIVED

• van Werkhoven E, Hinsley S, Frangou E, Holmes J, de Haan R, Hawkins M, Brown S, Love SB. Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples. BMC Med Res Methodol. 2020 Jun 22;20(1):162. doi: 10.1186/s12874-020-01012-z.

  PMID: 32571298 DERIVED

MeSH Terms

Conditions

Adenocarcinoma Of Esophagus; Carcinoma, Squamous Cell; Esophageal Neoplasms

Interventions

Cisplatin; Capecitabine; Radiotherapy

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Squamous Cell; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Therapeutics

Results Point of Contact

• Title: Dr Ruth Harman, Trial Manager
• Organization: OCTO, University of Oxford

octo-CHARIOT@oncology.ox.ac.uk

01865 617018

Study Officials

• Maria A Hawkins, MD FRCR MRCP

  University College, London

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

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

Study Record Dates

• First Submitted: July 10, 2018
• First Posted: August 22, 2018
• Study Start: December 4, 2018
• Primary Completion: April 4, 2022
• Study Completion: April 4, 2022
• Last Updated: July 18, 2024
• Results First Posted: July 18, 2024

Record last verified: 2022-04

Locations

GB (5)