Inclusion Criteria:
1. Patients must provide written informed consent prior to performance of study-specific
procedures or assessments.
2. ARID1A Subgroup (N = 39):
1. Histologically confirmed locally advanced or metastatic solid tumor malignancy
with progression on at least one prior systemic therapy, including one of the
following tumor types:
- Renal cell carcinoma with predominant clear cell histology (Cohort A)
- Urothelial carcinoma (Cohort B)
- All pancreatic cancers (Cohort C)
- Other solid tumors excluding clear cell ovarian cancer and endometrial
cancer (Cohort D)
- Endometrial cancer (Cohort E)
2. Formalin-fixed paraffin embedded tumor tissue evaluable for BAF250a expression by
ARID1A immunohistochemistry. Primary or metastatic tumor tissue is permissible.
Patients without evaluable archival tissue may undergo optional tumor biopsy
during Screening if other eligibility criteria have been met
3. Measurable disease by RECIST 1.1
3. ATM Loss Subgroup (N = 20):
1. Histologically confirmed locally advanced or metastatic solid tumor malignancy
with progression on at least one prior systemic therapy, including one of the
following tumor types:
- Metastatic castration resistant prostate cancer (N = 10).
- Patients may have evaluable or measurable disease by RECIST 1.1
criteria.
- Prior treatment with at least one androgen signaling inhibitor (e.g.
abiraterone, enzalutamide, apalutamide, darolutamide).
- Patients will be required to maintain castrate levels of testosterone
during study treatment with use of Luteinizing hormone-releasing
hormone (LHRH) analog (except for patients with history of bilateral
orchiectomy).
- Progression by PCWG3 criteria at study entry
- All other solid tumor malignancies (N = 10). Patients are required to have
measurable soft tissue disease by RECIST 1.1 criteria.
2. Archival tumor tissue evaluable for ATM expression by immunohistochemistry (IHC)
3. Evidence of ATM loss by either pathogenic ATM mutation in Clinical Laboratory
Improvement Amendments (CLIA) (CLIA)-approved assay and/or loss of ATM expression
by IHC (Ventana Ab). An interim analysis will be performed after 10 patients are
enrolled. If less than 50% of tumors have absence of ATM expression by IHC,
subsequent enrollment of the remaining 10 patients will be required to have
evidence of both ATM mutation and loss of ATM expression (< 5% of tumor cells
expressing ATM) using CLIA-certified IHC test (Ventana).
4. Evidence of clinical or radiographic progression prior to study entry (except
metastatic castrate-resistant prostate cancer (mCRPC) cohort which requires
progression by PCWG3 criteria)
5. Age ≥ 18 years at time of signing informed consent form
6. Resolution of all prior treatment-related toxicities to grade 1 severity or lower
(except alopecia).
7. Patients must be at least 3 weeks or 5 half-lives (whichever is shorter) from last
standard or experimental non-cytotoxic therapy prior to first dose of protocol
therapy. Patients must be > 21 days from last dose of cytotoxic chemotherapy prior to
C1D1. The minimum wash-out period for immunotherapy is 42 days prior to C1D1.
8. Radiation therapy must be completed > 7 days prior to course 1 day 1 (C1D1) or > 28
days prior to C1D1 for patients receiving radiation to more than 30% of bone marrow.
9. Adequate organ function as defined by:
- Hemoglobin (Hgb) >= 10.0 g/dL in the absence of transfusion within 14 days prior
to screening laboratory assessment.
- Platelets (Plt) count > 100,000 x 10^9/L.
- Absolute neutrophil count > 1.5 x 10^9/L.
- Estimated glomerular filtration rate (GFR) >= 51 ml/min based on Cockcroft-Gault
equation or 24 hour urine collection.
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2.5 x upper
limit of normal (ULN) (< 5x ULN in patients with known liver metastases).
- Total bilirubin < 1.5 x ULN (direct bilirubin < 1.5 x ULN in patients with known
Gilbert's disease or UGT1A1 homozygote).
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
11. The effects of AZD6738 and olaparib on the developing human fetus are unknown. For
this reason and because ATR and PARP inhibitors as well as other therapeutic drugs
used in this trial are known to be teratogenic, women of child-bearing potential and
men must agree to use 2 highly effective forms of contraception prior to study entry
and for the duration of study participation. Should a woman become pregnant or suspect
she is pregnant while she or her partner is participating in this study, she should
inform her treating physician immediately.
1. Male patients who are sexually active must be willing to use barrier
contraception for the duration of the study and for 1 week after the last study
drug administration, with all sexual partners. Male patients must use a condom
during treatment and for 6 months after the last dose of study drug(s) when
having sexual intercourse with a pregnant woman or with a woman of childbearing
potential. Female partners of male patients should also use a highly effective
form of contraception for 6 months after the last dose of study drug(s) if they
are of childbearing potential. True abstinence for either sex is an acceptable
form of contraception and must be documented as such.
2. Women of childbearing potential must have a negative serum or urine pregnancy
test within 7 days prior to C1D1 treatment). Evidence of postmenopausal status or
non-child bearing status must be documented. Postmenopausal is defined as:
- Aged more than 50 years and amenorrheic for at least 12 months following
cessation of all exogenous hormonal treatments.
- Documentation of irreversible surgical sterilization by hysterectomy,
bilateral oophorectomy or bilateral salpingectomy but not tubal ligation,
radiation-induced oophorectomy with last menses > 1 year ago,
chemotherapy-induced menopause with > 1 year interval since last menses
- Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH),
luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal
range for the institution for women under 50.
- Ability to understand a written informed consent document, and able to
comply with the protocol for the duration of the study including
undergoing treatment and scheduled visits and examinations.
Exclusion Criteria:
1. History of secondary malignancy requiring treatment within 1 year prior to screening,
with the exception of carcinoma in situ of the cervix, non-melanoma skin carcinoma,
low/intermediate risk localized prostate cancer (=< Gleason 7, =< T2N0M0, and
prostate-specific antigen (PSA) =< 20 ng/mL at diagnosis) (not applicable for prostate
cancer cohort), ductal carcinoma in situ, Stage I uterine cancer, and non-muscle
invasive urothelial carcinoma
2. Patients receiving, or having received within 14 days of C1D1, corticosteroids at a
dose > 10 mg/day of prednisone (or equivalent).
3. Patients with myelodysplastic syndrome or features suggestive of myelodysplastic
syndrome.
4. Prior treatment with ATR inhibitor
5. Major surgical procedures < 28 days prior to C1D1. Patients must have recovered to
grade =< 1 for any adverse events related to the surgical procedure.
6. Untreated central nervous system (CNS) metastases. Patients with previously treated
central nervous system (CNS) metastases are eligible if:
- No requirement for corticosteroids at study entry
- Radiographically and clinically stable for at least 4 weeks prior to study entry
- No evidence of intra-tumoral hemorrhage
- No evidence of current or prior leptomeningeal disease.
7. Clinically significant gastrointestinal abnormalities that may increase the risk of
decreased absorption of medications, including:
- Inability to swallow oral medications
- Active peptic ulcer disease
- Known intra-luminal metastatic lesions
- History of abdominal fistula or bowel perforation
- History of bowel obstruction within 6 months prior to study entry
- Known malabsorption syndrome
- Significant resection of the small bowel.
8. Fridericia's QT correction formula (QTcF) > 470 ms (females) or > 450 ms (males) on
screening electrocardiography (ECG), or immediate family history of congenital long QT
syndrome or sudden cardiac death at age less than 40.
9. History of any one or more of the following cardiovascular conditions within the past
6 months:
- Myocardial infarction
- Unstable angina
- Transient ischemic attack or cerebrovascular accident
- Uncontrolled arrhythmia. Rate controlled atrial fibrillation/flutter is not an
exclusion for the study.
- Class III or IV congestive heart failure or documented left ventricle (LV)
ejection fraction of < 50% (screening not required).
10. Uncontrolled hypertension as defined by systolic blood pressure > 160 mm Hg and/or
diastolic blood pressure > 100 mm Hg. Adjustment of anti-hypertensive regimen and
re-screening is permitted.
11. Relative hypotension with resting blood pressure of less than 90 mm Hg systolic and
less than 60 mm Hg diastolic or symptomatic orthostatic hypotension.
12. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
could interfere with patient's safety or adherence to study procedures including
uncontrolled infection requiring parenteral antibiotics.
13. Concomitant use of strong cytochrome P450, family 3, subfamily A (CYP3A4) inhibitors,
strong CYP3A4 inducers, CYP3A4 substrates with narrow therapeutic index, or CYP2B6
substrates with narrow therapeutic index within 21 days or 5 half-lives, whichever is
shorter, prior to C1D1 of study treatment
- The use of herbal supplements or 'folk remedies' (and medications and foods that
significantly modulate CYP3A activity) should be discouraged. If deemed
necessary, such products may be administered with caution and the reason for use
documented in the case report form (CRF).
14. A known hypersensitivity to olaparib, AZD6738 or any excipient of the product or any
contraindication to the combination anti-cancer agent as per local prescribing
information.
15. A known chronic active hepatitis B or C (defined by positive viral load; screening not
required).
16. Immunocompromised patients, including those serologically positive for human
immunodeficiency virus (HIV), those receiving chronic immunosuppression, or those with
prior allogeneic or cord blood transplantation.
