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About
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.
Full 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 ceralasertib (AZD6738) alone and in combination with either a PARP inhibitor drug called olaparib, or an anti-PD-L1 immunotherapy called durvalumab (MEDI4736) 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 ceralasertib. 1B - Women with clear cell subtype with (ovarian/uterus) ARID1A loss treated with ceralasertib and 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 ceralasertib and olaparib. 4 - Women with endometrial cancers (serous, clear cell, endometroid, carcinosarcoma) with ARID1A loss treated with ceralasertib and durvalumab. 5 - Women with endometrial cancers (serous, clear cell, endometroid, carcinosarcoma) with no ARID1A loss treated with ceralasertib and durvalumab.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
Inclusion Criteria:
Histologically confirmed progressive or recurrent gynaecological carcinomas of the following histological subtypes:
Cohorts 1A, 1B, 2 and 3:
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.
Body weight >30kg (Cohorts 4 and 5 only)
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
ECOG performance status 0 or 1 with no deterioration over the previous 2 weeks
Life expectancy > 16 weeks
Adequate hepatic, bone marrow, coagulation and renal function as defined by the following values within 14 days prior to starting treatment:
All cohorts:
Cohort 1A, Cohort 4 and Cohort 5:
Cohort 1B, Cohort 2 and Cohort 3:
No significant medical illness which in the opinion of the Investigator would preclude entry to ATARI
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 (cohort 4 and 5 must be serum at screening). Patients will be considered to be not of child-bearing potential if they are:
Patients with prior synchronous tumours or history of prior malignancy are eligible provided there is biopsy evidence that the disease measurable on CT and/or MRI is of the histological subtypes stated in 1
Willingness to commit to scheduled visits, treatments plans, laboratory tests and study procedures
Able to swallow, absorb, retain oral medication
Able to provide written, informed consent Exclusion Criteria
Patients receiving, or having received
Patients receiving, or having received:
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)
With the exception of alopecia, any unresolved toxicities from prior therapy should be no greater than CTCAE Grade 2 at trial entry
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 g. Uncontrolled hypertension (≥ grade 2) requiring clinical intervention (Cohort 4 and Cohort 5 only)
Clinically relevant orthostatic hypotension
Patients who have a diagnosis of ataxia telangiectasia
Major surgery within 4 weeks prior to starting trial drug (excluding placement of vascular access) or minor surgery (excluding tumour biopsies) within 2 weeks of starting trial.Local surgery of isolated lesions for palliative intent is acceptable
Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
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
Known hypersensitivity to investigational drugs or excipients
Receiving, or having received during the four weeks prior to starting trial drug, corticosteroids at a dose >10mg prednisolone/day or equivalent for any reason
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
As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases that places the patient at unacceptable risk of toxicity or non-compliance 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
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
Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection, with clinically significant sequelae that would preclude adequate absorption of study drug
Patients with uncontrolled seizures
Active infection requiring systemic antibiotics, antifungal or antiviral drugs
Patients with myelodysplastic syndromes (MDS)/acute myeloid leukaemia (AML), or with features suggestive of MDS/AML
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)
Any contraindication to the combination anti-cancer agent (ceralasertib/olaparib or ceralasertib/durvalumab) as per local prescribing information
Patients unable to swallow orally administered medication
Patients in receipt of any live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study treatment. Note: Patients, if enrolled, should not receive live vaccine whilst receiving study drug and up to 30 days after the last dose of study drug.
Patients with a confirmed COVID-19 infection by PCR test who have not made a full recovery
In addition to the above and specific for Cohorts 4 and 5 only:
Any concurrent chemotherapy, IP, biological, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
Persisting (>4 weeks) severe pancytopenia due to previous therapy rather than disease (ANC <0.5 x 109/L or platelets <50 x 109/L)
History of organ transplant that requires use of immunosuppressive medications including, but not limited to systemic corticosteroids at doses >10mg/day of prednisone or equivalent, methotrexate, azathioprine and tumour necrosis factor alpha (TNF-α) blockers. Use of immunosuppressive medications for the management of IMP-related AEs is acceptable
Active or prior documented autoimmune or inflammatory disease within the past 3 years (including, but not limited to inflammatory bowel disease [e.g., Crohn's disease or colitis], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, Wegener syndrome, Hashimoto syndrome, hyperthyroidism, Sjogren's syndrome, glomerulonephritis, multiple sclerosis, vasculitis, rheumatoid arthritis, idiopathic pulmonary fibrosis, pneumonitis, organising pneumonitis, hepatitis, sarcoidosis, active tuberculosis.
The following are exceptions to this criterion:
Patients with vitiligo or alopecia, patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement. Any chronic skin condition that does not require systemic therapy, patients without active disease in the last 5 years may be included but only after consultation with the ATARI Chief Investigator. Patients with celiac disease controlled by diet alone.
Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of the study drug and of low potential risk for recurrence
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
Adequately treated carcinoma in situ without evidence of disease 53. History of active primary immunodeficiency 54. Current or prior use of immunosuppressive medication within 14 days prior to the first dose of durvalumab. The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids or local steroid injections (e.g., intra articular injection)
Systemic corticoids at physiologic doses not to exceed 10mg/day of predisone or its equivalent
Steroids as premedication for hypersensitivity reactions (e.g., CT scan medication)
Primary purpose
Allocation
Interventional model
Masking
174 participants in 6 patient groups
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Central trial contact
Trial Manager; Christy Toms
Data sourced from clinicaltrials.gov
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