Phase I Study to Assess Safety of AZD6738 Alone and in Combination With Radiotherapy in Patients With Solid Tumours

NCT02223923 | Unknown Phase 1 DMC

• 1 other identifier: CCR4087
• Study Type: interventional
• Target: 87
• Locations: 1 country
• Sites: 3

Brief Summary

This study will investigate the use of a new drug targeting the DNA repair pathway AZD6738, an ATR inhibitor). Many tumours have lost important DNA repair functions and rely more heavily on a few remaining repair pathways to survive. Preclinical studies indicate that, in these tumours, preventing the function of the remaining pathways will lead to tumour cell death, while sparing normal cells. This study aims to investigate the safety and tolerability of the new drug in patients with advanced cancer, as well as in combination with palliative radiotherapy, where the drug may increase the effectiveness of radiotherapy by preventing repair of the radiationinduced DNA damage. As the drug has only been given to a small number of patients, the study will focus on safety and finding the correct dose to proceed to further studies, although preliminary signs of drug activity will also be examined. The initial part of the study will administer increasing doses of the drug to groups of patients with advanced cancer who have no standard anticancer treatment options available. Testing will establish whether the drug levels in the body and tumour are adequate for the drug to have an effect, and any toxicity will be assessed. After the recommended dose is established, the recommended dose schedule will be stablished by trialing different schedules. Participants will be tested to see if their tumours lack the main DNA repair pathway (those who are predicted to have a better response to this drug). Finally, the drug will be given to patients with advanced cancer who require a course of radiotherapy for symptom control - the drug will be tested at different doses and with different doses of radiotherapy. Side effects will be monitored and tests will establish whether the drug is enhancing the radiotherapy effect in the tumours or normal tissues.

Conditions

Solid Tumour Refractory to Conventional Treatment

Keywords

Phase 1; Maximimum tolerated dose; ATR Inhibitor; Radiotherapy

Outcome Measures

Primary Outcomes (1)

• Identifying the maximum tolerated dose (MTD) of AZD6738 as a single-agent; and in combination with palliative radiation schedules.

  4 weeks

Secondary Outcomes (3)

• Determining causality of each adverse event in relation to AZD6738 and grading severity according to CTCAE version 4;

  4 weeks

• Single and multiple dose pharmacokinetics: measurement of plasma levels of AZD6738 at pre-defined intervals in the dose-escalation part of the study in order to establish pharmacokinetic parameters;

  Day 0 and Day 1

• Any response (stable disease, partial response or complete response) in any of the patients by physical, tumour marker and/or radiographic assessments of tumours as determined by RECIST 1.1.

  8 weeks

Study Arms (4)

Dose Escalation

EXPERIMENTAL

AZD6738 PO 20 to 380mg BD increasing

Drug: AZD6738

AZD6738 - Expansion Phase

EXPERIMENTAL

AZD6738 starting dose and regimen to be determined in dose escalation phase

Drug: AZD6738

AZD6738 + Radiotherapy (Head and Neck)

EXPERIMENTAL

AZD6738 starting dose to be determined in dose escalation phase + increasing doses of radiotherapy (20 or 30Gy)

Drug: AZD6738; Radiation: Palliative radiotherapy

AZD6738 + Radiotherapy (Abdomen / Pelvis)

EXPERIMENTAL

AZD6738 starting dose to be determined in dose escalation phase + increasing doses of radiotherapy (20 or 30Gy)

Drug: AZD6738; Radiation: Palliative radiotherapy

Interventions

AZD6738 DRUG

AZD6738 + Radiotherapy (Abdomen / Pelvis); AZD6738 + Radiotherapy (Head and Neck); AZD6738 - Expansion Phase; Dose Escalation

Palliative radiotherapy RADIATION

AZD6738 + Radiotherapy (Abdomen / Pelvis); AZD6738 + Radiotherapy (Head and Neck)

Eligibility Criteria

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

You may qualify if:

• Histologically or cytologically documented solid tumour refractory to conventional treatment
• Evidence of measurable or evaluable disease by RECIST 1.1
• Age must be 18 years or over.
• ECOG performance status 0-1 (part A); 0-2 (parts B and C)
• Life expectancy of at least 3 months.
• Patients must have normal organ and bone marrow function measured within 7 days prior to administration of study treatment as defined below:
• Signed informed consent indicating that the subject is aware of the neoplastic nature of their disease and have been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts.
• Willing and able to comply with scheduled visits, tissue sampling, treatment plan, and laboratory tests.
• Able to swallow, absorb and retain oral medication.

You may not qualify if:

• Therapy with any other investigational medical product (IMP) concurrently or within 28 days prior to signing of consent.
• Pregnant or breast-feeding women.
• Ability to become pregnant (or already pregnant or lactating).
• Clinically significant cardiac disease including:
• Known HIV positive or active hepatitis B or C infection
• Uncontrolled active infection
• Symptomatic and progressive or steroid-requiring brain metastases or leptomeningeal disease involvement.
• Uncontrolled hypertension requiring clinical intervention, hypertension requiring 2 or more antihypertensive agents
• Dementia or altered mental status that would prohibit informed consent.
• Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Principal Investigator, would make the subject inappropriate for this study.

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• AstraZeneca: collaborator
• Cancer Research UK: collaborator
• RM/ICR Biomedical Research Centre: collaborator

Study Sites (3)

University College Hospital

London, NW1 2BU, United Kingdom

Location

Guys and St Thomas' NHS Foundation Trust

London, SE1 9RT, United Kingdom

Location

Royal Marsden Hospital

London, SW3 6JJ, United Kingdom

Location

Related Publications (1)

• Dillon MT, Guevara J, Mohammed K, Patin EC, Smith SA, Dean E, Jones GN, Willis SE, Petrone M, Silva C, Thway K, Bunce C, Roxanis I, Nenclares P, Wilkins A, McLaughlin M, Jayme-Laiche A, Benafif S, Nintos G, Kwatra V, Grove L, Mansfield D, Proszek P, Martin P, Moore L, Swales KE, Banerji U, Saunders MP, Spicer J, Forster MD, Harrington KJ. Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation. J Clin Invest. 2024 Jan 16;134(2):e175369. doi: 10.1172/JCI175369.

  PMID: 37934611 DERIVED

MeSH Terms

Interventions

ceralasertib

Study Officials

• Kevin Harrington, MBBS MRCP FRCR

  Institute of Cancer Research, United Kingdom

  PRINCIPAL INVESTIGATOR

• Martin Forster

  University College London Hospitals

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: August 21, 2014
• First Posted: August 22, 2014
• Study Start: July 1, 2014
• Primary Completion: December 30, 2025
• Study Completion: December 30, 2025
• Last Updated: August 1, 2025

Record last verified: 2023-10

Locations

GB (3)