ATr Inhibitor in Combination With Olaparib in Gynaecological Cancers With ARId1A Loss or no Loss (ATARI)

• ClinicalTrials.gov Identifier: NCT04065269
• Recruitment Status: Unknown
• First Posted: August 22, 2019
• Last Update Posted: September 3, 2020
• Sponsor: Institute of Cancer Research, United Kingdom
• Collaborators: Cancer Research UK; AstraZeneca
• Information provided by (Responsible Party): Institute of Cancer Research, United Kingdom

Tracking Information

• First Submitted Date: August 1, 2019
• First Posted Date: August 22, 2019
• Last Update Posted Date: September 3, 2020
• Actual Study Start Date: November 27, 2019
• Estimated Primary Completion Date: March 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 21, 2019)

Confirmed overall objective response rate (complete or partial response) as defined by RECIST version 1.1. [ Time Frame: 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). ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 22, 2019)

• Disease control rate [ Time Frame: 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). ]
  The proportion of patients experiencing complete or partial response, or stable disease lasting at least 16 weeks from start of treatment as assessed radiologically by RECIST version 1.1.
• Duration of disease control [ Time Frame: 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). ]
  Length of maintained response, measured according to RECIST v1.1
• Progression Free Survival (PFS) [ Time Frame: From start of treatment until progression or death, whatever occurs first - estimated 6-9 months, up to max study period (36 months). ]
  Measured according to RECIST v1.1 or death. Time to last tumour assessment will be used if patient has not progressed or died, and PFS time for the patient will be considered censored. PFS will be used to calculate the proportion of patients alive and free of progression at 6 months.
• Time to Progression (TTP) [ Time Frame: From start of treatment until disease progression - estimated 6-9 months, up to max study period (36 months) ]
  Measured according to RECIST v 1.1 or clinical progression of disease. Time to last tumour assessment will be used if patient has not progressed, and the patient will be considered censored. If the patient has died without prior progression, the patient will be censored at the date of death. Death will not count as a TTP event.
• Proportion of patients experiencing drug interruption, reduction or discontinuation due to drug related adverse events [ Time Frame: 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). ]
  Adverse events thought to be related to drug will be graded according to NCI-CTCAE version 5.0, and coded using MedDRA (current version). Any dose reductions and delays in administration of drug due to toxicity will also be collected.
• Overall Survival (OS) [ Time Frame: From start of treatment until death - estimated 9 months, up to max study period (36 months). ]
  Defined by the time from start of treatment until death

Original Secondary Outcome Measures (submitted: August 21, 2019)

• Disease control rate [ Time Frame: 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). ]
  The proportion of patients experiencing complete or partial response, or stable disease lasting at least 16 weeks from start of treatment as assessed radiologically by RECIST version 1.1.
• Duration of disease control [ Time Frame: 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). ]
  Length of maintained response, measured according to RECIST v1.1
• Progression Free Survival (PFS) [ Time Frame: From start of treatment until progression or death, whatever occurs first - estimated 6-9 months, up to max study period (36 months). ]
  Measured according to RECIST v1.1 or death. Time to last tumour assessment will be used if patient has not progressed or died, and PFS time for the patient will be considered censored. PFS will be used to calculate the proportion of patients alive and free of progression at 6 months.
• Time to Progression (TTP) [ Time Frame: From start of treatment until disease progression - estimated 6-9 months, up to max study period (36 months) ]
  Measured according to RECIST v 1.1 or clinical progression of disease. Time to last tumour assessment will be used if patient has not progressed, and the patient will be considered censored. If the patient has died without prior progression, the patient will be censored at the date of death. Death will not count as a TTP event.
• Safety and Toxicity (proportion of patients having dose reduction or delay due to toxicity) [ Time Frame: 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). ]
  Adverse events thought to be related to drug will be graded according to NCI-CTCAE version 5.0, and coded using MedDRA (current version). Any dose reductions and delays in administration of drug due to toxicity will also be collected.
• Overall Survival (OS) [ Time Frame: From start of treatment until death - estimated 9 months, up to max study period (36 months). ]
  Defined by the time from start of treatment until death

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: ATr Inhibitor in Combination With Olaparib in Gynaecological Cancers With ARId1A Loss or no Loss
• Official Title: ATARI: ATr Inhibitor in Combination With Olaparib in Gynaecological Cancers With ARId1A Loss
• Brief Summary: ATARI trial tests the ATR inhibitor drug AZD6738 and a PARP inhibitor drug olaparib in patients with relapsed gynecological cancers to assess the response in groups of patients selected based on their cancer cell subtype and the presence of an abnormality in ARID1A gene.

Detailed Description

ATARI is a multi-centre, open-label, multiple two-stage parallel cohorts phase II clinical trial for patients with relapsed gynaecological cancers, with ARID1A-deficient ('loss') and "no loss."

The trial tests the ATR inhibitor drug AZD6738 and a PARP inhibitor drug olaparib to assess the response in groups of patients selected based on their cancer cell subtype and the presence of an abnormality in ARID1A.

The treatment groups are: 1A - Women with clear cell subtype with (ovarian/uterus) ARID1A loss treated with AZD6738. 1B - Women with clear cell subtype with (ovarian/uterus) ARID1A loss treated with AZD6738 + olaparib. 2 - Women with clear cell subtype (ovarian/uterus) with no ARID1A loss treated with AZD6738 and olaparib. 3 - Women with other rare gynaecological cancers (carcinosarcoma, cervical, endometrioid type) irrespective of ARID1A loss treated with AZD6738 and olaparib.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Open-label, multiple two-stage parallel cohorts

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Gynaecological Cancers

Intervention

• Drug: AZD6738
  ATR inhibitor
• Drug: Olaparib
  PARP inhibitor

Study Arms

• Experimental: 1A: AZD6738
  Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with loss of ARID1A expression treated with single agent AZD6738.
  Intervention: Drug: AZD6738
• Experimental: 1B: AZD6738 + olaparib

  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.

  Interventions:

  • Drug: AZD6738
  • Drug: Olaparib
• Experimental: 2: AZD6738 + olaparib
  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.
  Interventions:

  • Drug: AZD6738
  • Drug: Olaparib
• Experimental: 3: AZD6738 + olaparib
  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.
  Interventions:

  • Drug: AZD6738
  • Drug: Olaparib

• Publications *: 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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: August 21, 2019): 40
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2023
• Estimated Primary Completion Date: March 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Histologically confirmed progressive or recurrent gynaecological carcinomas of the following histological subtypes:

   • Ovarian and endometrial clear cell (>50% clear cell carcinoma with no serous differentiation)
   • Endometrioid
   • Cervical - adenocarcinomas and squamous
   • Carcinosarcomas 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
2. 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
3. Evidence of radiological disease progression since last systemic anti-cancer therapy and prior to trial entry
4. 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 patients who have disease progression within 6 months of last dose of a platinum-containing regime, no more than two further lines of systemic therapy are permitted prior to trial entry
5. Measurable disease by RECIST criteria v1.1, which can be accurately assessed at baseline by CT (or MRI where CT is contradicted or unclear). Patients with CA125 progression in the absence of measurable disease will NOT be eligible
6. ECOG performance status 0 or 1 with no deterioration over the previous 2 weeks
7. Life expectancy > 16 weeks

8. Adequate hepatic, bone marrow, coagulation and renal function as defined by the following values within 14 days prior to starting treatment:

   • Haemoglobin ≥10.0 g/dL with no blood transfusion in the past 14 days
   • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   • Platelet count ≥ 100 x 109/L with no platelet transfusion in the past 28 days
   • Creatinine clearance ≥51 mL/min (estimated using Cockcroft-Gault equation or measured GFR clearance test as appropriate); • Total bilirubin ≤1.5 x ULN (where bilirubin rise > 1.5 x ULN due to Gilbert's syndrome a conjugated bilirubin ≤1.5 x ULN is required)
   • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤2.5 x ULN if no demonstrable liver metastases or ≤5 times ULN if patient has documented liver metastases
9. No significant medical illness which in the opinion of the Investigator would preclude entry to ATARI

10. Women of child-bearing potential who are confirmed NOT to be pregnant. This should be evidenced by a negative urine or serum pregnancy test within 72 hours prior to start of trial treatment. Patients will be considered to be not of child-bearing potential if they are:

    • Post-menopausal - defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, OR women under 50 years old who have been amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments and have serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the post-menopausal range for the institution
    • Able to provide documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
    • Radiation or chemotherapy-induced oophorectomy or menopause with > 1 year since last menses
11. Patients with prior synchronous tumours or history of prior malignancy are eligible provided that there is biopsy evidence that the disease measurable on CT and/or MRI is of the histological subtypes stated in 1
12. Willingness to commit to scheduled visits, treatments plans, laboratory tests and study procedures
13. Able to swallow, absorb, retain oral medication
14. Able to provide written, informed consent

Exclusion Criteria:

1. Prior treatment with ATR or PARP inhibitors, including AZD6738 and olaparib

2. 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
3. Treatment with any other investigational medicinal product within the 4 weeks prior to trial entry
4. Receiving, or having received, concomitant medications, herbal supplements and/or foods that are strong or moderate inhibitors or inducers of CYP3A4, sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index that significantly modulate CYP3A4 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 Section 11 and Appendix A5 for further details)
5. Pregnant or lactating women.
6. 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
7. 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
8. Clinical/radiological evidence of bowel obstruction (e.g. hospitalisation) or symptoms of sub-acute bowel obstruction within 6 weeks prior to trial entry
9. Any clinically significant haematuria (as deemed by the investigator)
10. With the exception of alopecia, any unresolved toxicities from prior therapy should be no greater than CTCAE Grade 2 at trial entry

11. Clinically significant cardiac disease currently or within the last 6 months including:

    a. Pre-existing arrhythmia: i. Mean resting QTc >470 msec obtained from 3 electrocardiograms (ECGs) performed 2-5 minutes apart at study screening (within 14 days prior to Cycle 1 Day 1) using the Fredericia formula ii. Clinically important abnormalities in rhythm, conduction or morphology of resting ECG (including complete left bundle-branch block, third degree heart block) b. Any factor increasing the risk of QTc prolongation or arrhythmia, including: i. Hypokalaemia ii. Congenital long QT syndrome iii. Immediate family history of long QT syndrome or unexplained sudden death below the age of 40 years c. Unstable angina pectoris d. Acute myocardial infarction e. Unstable cardiac arrhythmias f. Cardiac failure i. Known reduced LVEF <55% ii. New York Heart Association (NYHA) class II, III or IV cardiac failure

12. Clinically relevant orthostatic hypotension
13. Patients who have a diagnosis of ataxia telangiectasia
14. Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access) or minor surgery (excluding tumour biopsies) within 2 weeks of entry into the study (excluding placement of vascular access)
15. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
16. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
17. Known leptomeningeal involvement or brain metastases, unless asymptomatic, treated (with no evidence of progression since completion of CNS-directed therapy), presence of disease outside the CNS and stable off steroids for at least 4 weeks prior to registration
18. Known hypersensitivity to investigational drugs or excipients
19. Receiving, or having received during the four weeks prior to registration, corticosteroids at a dose >10mg prednisolone/day or equivalent for any reason
20. Any haemopoietic growth factors (e.g., G-CSF, GM-CSF) and blood transfusions within 14 days prior to trial entry. Use of erytropoeitin is not permitted for 4 weeks prior to Cycle 1 Day 1 and for the duration of the study
21. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases e.g., severe hepatic impairment, extensive interstitial lung disease on high resolution CT scan (bilateral, diffuse, parenchymal lung disease), uncontrolled chronic renal diseases (glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular acidosis), current unstable or uncompensated respiratory or cardiac conditions, active bleeding diatheses or active infection including hepatitis B, hepatitis C, and immunocompromised patients e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV). Screening for chronic conditions is not required
22. Judgment by the Investigator that the patient is unsuitable to participate in the study and/or the patient is unlikely to comply with study procedures, restrictions and requirements
23. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection, with clinically significant sequelae that would preclude adequate absorption of study drug
24. Patients with uncontrolled seizures
25. Active infection requiring systemic antibiotics, antifungal or antiviral drugs
26. Patients with myelodysplastic syndromes (MDS)/acute myeloid leukaemia (AML), or with features suggestive of MDS/AML
27. Concurrent severe and/or uncontrolled medical condition (e.g., severe COPD, severe Parkinson's disease, active inflammatory bowel disease) or psychiatric condition (e.g. psychiatric disorder prohibiting obtaining informed consent)
28. Any contraindication to the combination of AZD6738 and olaparib as per local prescribing information
29. Patients unable to swallow orally administered medication

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT04065269
• Other Study ID Numbers: ICR-CTSU/2018/10066; 2018-003779-36 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Institute of Cancer Research, United Kingdom
• Original Responsible Party: Same as current
• Current Study Sponsor: Institute of Cancer Research, United Kingdom
• Original Study Sponsor: Same as current

Collaborators

• Cancer Research UK
• AstraZeneca

Investigators

• Principal Investigator: Susana Banerjee; Royal Marsden NHS Foundation Trust

• PRS Account: Institute of Cancer Research, United Kingdom
• Verification Date: September 2020