Clinical Trials /

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

NCT04065269

Description:

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.

Related Conditions:
  • Cervical Adenocarcinoma
  • Cervical Squamous Cell Carcinoma
  • Endometrial Clear Cell Adenocarcinoma
  • Endometrial Endometrioid Adenocarcinoma
  • Fallopian Tube Clear Cell Adenocarcinoma
  • Malignant Ovarian Clear Cell Tumor
  • Ovarian Carcinosarcoma
  • Ovarian Endometrioid Tumor
  • Primary Peritoneal Carcinoma
  • Uterine Corpus Carcinosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: ICR-CTSU/2018/10066
  • SECONDARY ID: 2018-003779-36
  • NCT ID: NCT04065269

Conditions

  • Gynaecological Cancers

Interventions

DrugSynonymsArms
AZD67381A
Olaparib1B

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
1AExperimentalWomen with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with loss of ARID1A expression treated with single agent AZD6738.
  • AZD6738
1BExperimentalIn 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.
  • AZD6738
  • Olaparib
2ExperimentalWomen 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.
  • AZD6738
  • Olaparib
3ExperimentalWomen 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.
  • AZD6738
  • Olaparib

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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).
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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).
Safety Issue:
Description: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.
Measure: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).
Safety Issue:
Description:Length of maintained response, measured according to RECIST v1.1
Measure: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).
Safety Issue:
Description: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.
Measure:Time to Progression (TTP)
Time Frame:From start of treatment until disease progression - estimated 6-9 months, up to max study period (36 months)
Safety Issue:
Description: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.
Measure: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).
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:From start of treatment until death - estimated 9 months, up to max study period (36 months).
Safety Issue:
Description:Defined by the time from start of treatment until death

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Institute of Cancer Research, United Kingdom

Trial Keywords

  • Clear cell ovarian carcinoma
  • Clear cell endometrial carcinoma
  • Endometrioid carcinoma
  • Carcinosarcoma
  • Cervical carcinoma
  • ARID1A

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