ATr Inhibitor in Combination With Olaparib/Durvalumab (MEDI4736) in Gynaecological Cancers With ARId1A Loss or no Loss

NCT04065269 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: ICR-CTSU/2018/100662018-003779-36
• Study Type: interventional
• Target: 174
• Locations: 2 countries
• Sites: 9

Brief Summary

ATARI trial tests the ATR inhibitor drug ceralasertib (AZD6738) alone and in combination with either a PARP inhibitor drug called olaparib, or an anti-PD-L1 immunotherapy called durvalumab (MEDI4736) in patients with relapsed gynaecological cancers to assess the response in groups of patients selected based on their cancer cell subtype and the presence of an abnormality in the ARID1A gene.

Conditions

Gynaecological Cancers

Keywords

Clear cell ovarian carcinoma; Clear cell endometrial carcinoma; Endometrioid carcinoma; Carcinosarcoma; Cervical carcinoma; ARID1A; Endometrial cancer

Outcome Measures

Primary Outcomes (1)

• Confirmed overall objective response rate (complete or partial response) as defined by RECIST version 1.1.

  A patient will be said to have had an overall objective response if they have a complete/partial response as assessed radiologically according to RECIST 1.1 at any point during trial treatment. A second scan to confirm response will be taken ≥ 4 weeks after the first scan showing an objective response.

  From start of treatment until treatment discontinuation - minimum follow-up of 16 weeks (if not progressed earlier), up to max study period (estimated 36 months).

Secondary Outcomes (6)

• Disease control rate

  From start of treatment until treatment discontinuation - minimum follow-up of 16 weeks (if not progressed earlier), up to max study period (estimated 36 months).

• Duration of disease control

  From start of treatment until treatment discontinuation - minimum follow-up of 16 weeks (if not progressed earlier), up to max study period (estimated 36 months).

• Progression Free Survival (PFS)

  From start of treatment until progression or death, whatever occurs first - estimated 6-9 months, up to max study period (36 months).

• Time to Progression (TTP)

  From start of treatment until disease progression - estimated 6-9 months, up to max study period (36 months)

• Proportion of patients experiencing drug interruption, reduction or discontinuation due to drug related adverse events

  Assessed throughout the treatment period, up to and including the 30-day follow-up period - estimated 7 months, up to max study period (36 months).

Study Arms (6)

1A: ceralasertib (AZD6738)

EXPERIMENTAL

Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with loss of ARID1A expression treated with single agent AZD6738.

Drug: Ceralasertib

1B: ceralasertib (AZD6738) + olaparib

EXPERIMENTAL

In second stage of trial, opening of this cohort depends on response rate in cohort 1A during first stage of trial. Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with loss of ARID1A expression treated with AZD6738 in combination with olaparib.

Drug: Ceralasertib; Drug: Olaparib

2: ceralasertib (AZD6738) + olaparib

EXPERIMENTAL

Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with NO loss of ARID1A expression treated with AZD6738 in combination with olaparib.

Drug: Ceralasertib; Drug: Olaparib

3: ceralasertib (AZD6738) + olaparib

EXPERIMENTAL

Women with other rare relapsed gynaecological cancers (endometrioid ovarian carcinoma, endometrioid endometrial carcinoma, cervical adenocarcinoma, cervical squamous, ovarian carcinosarcoma and endometrial carcinosarcoma) irrespective of ARID1A status, treated with AZD6738 in combination with olaparib.

Drug: Ceralasertib; Drug: Olaparib

4: ceralasertib (AZD6738) + durvalumab

EXPERIMENTAL

Women with endometrial cancers (serous, clear cell, endometroid, carcinosarcoma) with ARID1A loss.

Drug: Ceralasertib; Drug: Durvalumab

5: ceralasertib (AZD6738) + durvalumab

EXPERIMENTAL

Women with endometrial cancers (serous, clear cell, endometroid, carcinosarcoma) with NO loss of ARID1A.

Drug: Ceralasertib; Drug: Durvalumab

Interventions

Olaparib DRUG

PARP inhibitor

1B: ceralasertib (AZD6738) + olaparib; 2: ceralasertib (AZD6738) + olaparib; 3: ceralasertib (AZD6738) + olaparib

Durvalumab DRUG

Anti-PD-L1 immunotherapy

Also known as: MEDI4736

4: ceralasertib (AZD6738) + durvalumab; 5: ceralasertib (AZD6738) + durvalumab

Ceralasertib DRUG

ATR inhibitor

Also known as: AZD6738

1A: ceralasertib (AZD6738); 1B: ceralasertib (AZD6738) + olaparib; 2: ceralasertib (AZD6738) + olaparib; 3: ceralasertib (AZD6738) + olaparib; 4: ceralasertib (AZD6738) + durvalumab; 5: ceralasertib (AZD6738) + durvalumab

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed progressive or recurrent gynaecological carcinomas of the following histological subtypes:
• Cohorts 1A, 1B, 2 and 3:
• Clear cell (Ovarian, endometrial or endometriosis-related, (\>50% clear cell carcinoma with no serious differentiation)
• Endometrioid (ovarian, endometrial or endometriosis-related)
• Cervical (adenocarcinomas or squamous)
• Carcinosarcomas (ovarian or endometrial)
• Cohorts 4 and 5:
• Endometrial carcinomas (serous, clear cell, endometrioid, carcinosarcoma) Note: patients who have an original diagnosis based on cytology only will not be eligible for entry into the study unless a biopsy confirming above histology is performed
• Histological tissue specimen (tissue block or 8-10 unstained slides) must be available (specimen can be the sample at diagnosis or taken at relapse). Otherwise, a biopsy must be carried out to obtain sufficient tissue for histological assessment
• Evidence of radiological disease progression since last systemic anti-cancer therapy and prior to trial entry
• Patients who have progressed after ≥1 prior platinum containing regimen. Platinum-based therapy does not need to be the last treatment prior to study entry. For Cohorts 1A, 1B, 2 and 3, patients who have disease progression within 6 months of last dose of a platinum-containing regimen, no more than two further lines of systemic therapy are permitted prior to trial entry
• Patients entering Cohorts 4 or 5 must have had prior anti-PD-1/anti-PD-L1/anti-CTLA-4 immunotherapy treatment, with a minimum duration of treatment is 6 weeks. Other previous immunotherapy treatments may be permissible following discussion with the Chief Investigator and ICR-CTSU. Patients who experienced toxicity leading to permanent discontinuation of prior immunotherapy are ineligible.
• All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
• Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to enrol if they are stably maintained on appropriate replacement therapy and are asymptomatic.
• Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of \> 10 mg prednisone or equivalent per day.

You may not qualify if:

• Patients receiving, or having received
• Cohort 1A, Cohort 4 and Cohort 5: Prior treatment with ATR inhibitor
• Cohort 1B, Cohort 2 and Cohort 3: Prior treatment with ATR or PARP inhibitors
• Patients receiving, or having received:
• cytotoxic treatment for their malignancy within 21 days prior to Cycle 1 Day 1
• exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1. The minimum washout for immunotherapy is 42 days
• treatment with bevacizumab within 30 days prior to Cycle 1 Day 1
• palliative radiotherapy within 21 days prior to Cycle 1 Day 1 (with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study treatment). Patients can receive bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 4 weeks prior to commencing study treatment.
• Treatment with any other investigational medicinal product within the 4 weeks prior to trial entry
• Receiving, or having received, concomitant medications, herbal supplements and/or foods that are strong or moderate inhibitors or inducers of CYP3A4 and/or CYP1A2 for cohorts 1B, 2 and 3, and strong inhibitors or inducers of CYP3A4 and/or CYP1A2 for cohorts 1A, 4 and 5, sensitive CYP3A4 and/or CYP1A2 substrates or CYP3A4 and/or CYP1A2 substrates with a narrow therapeutic index that significantly modulate CYP3A4 and/or CYP1A2 or P-gp activity (washout period 5 half-lives or three weeks for St. John's Wort). Note these include common azole antifungals, macrolide antibiotics and other medications (Refer to Sections 22, 23 \& 24 and Appendix A6 for further details)
• Pregnant or lactating women.
• Women of childbearing age and potential who are not willing to use one highly effective form of contraception AND a condom as detailed in Section 5.5.1
• Any other malignancy which has been active or treated within the past three years, with the exception of cervical intra-epithelial neoplasia and non-melanoma skin cancer
• Clinical/radiological evidence of bowel obstruction (e.g. hospitalisation) or symptoms of sub-acute bowel obstruction within 6 weeks prior to trial entry
• Any clinically significant haematuria (as deemed by the investigator)

Sponsors & Collaborators

• Institute of Cancer Research, United Kingdom: lead
• Cancer Research UK: collaborator
• AstraZeneca: collaborator

Study Sites (9)

The Ottawa Hospital Cancer Centre

Ottawa, Ontario, K1H 8L6, Canada

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

University of Montreal Hospital Centre

Montreal, Quebec, H2X 3E4, Canada

Location

Royal United Hospital

Bath, BA1 3NG, United Kingdom

Location

Western General Hospital

Edinburgh, United Kingdom

Location

The Beatson

Glasgow, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

London, SW3 6JJ, United Kingdom

Location

Imperial College NHS Trust

London, United Kingdom

Location

The Christie

Manchester, United Kingdom

Location

Related Publications (1)

• Smith G, Alholm Z, Coleman RL, Monk BJ. DNA Damage Repair Inhibitors-Combination Therapies. Cancer J. 2021 Nov-Dec 01;27(6):501-505. doi: 10.1097/PPO.0000000000000561.

  PMID: 34904813 DERIVED

MeSH Terms

Conditions

Carcinoma, Endometrioid; Carcinosarcoma; Uterine Cervical Neoplasms; Endometrial Neoplasms

Interventions

ceralasertib; olaparib; durvalumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Ovarian Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases; Neoplasms, Complex and Mixed; Sarcoma; Neoplasms, Connective and Soft Tissue; Uterine Cervical Diseases; Uterine Diseases

Study Officials

• Susana Banerjee

  Royal Marsden NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open-label, multiple two-stage parallel cohorts

Study Record Dates

• First Submitted: August 1, 2019
• First Posted: August 22, 2019
• Study Start: November 27, 2019
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: February 20, 2026

Record last verified: 2026-02

Locations

CA (3); GB (6)