Inclusion criteria:
For inclusion in the study, patients must fulfill the following criteria:
1. Patients ≥ 18 years of age
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a life
expectancy of at least 6 months.
3. For Cohorts A-C, and Cohort D, Part II, patients must have high grade serous ovarian,
primary peritoneal, and/or fallopian tube cancer histologically or cytologically
confirmed that is recurrent and for which standard curative measures do not exist or
are no longer effective. For Cohort D, Part I, patients may have any non-mucinous
epithelial ovarian cancer (including histology's such as clear cell, or endometrioid).
Pathology must be reviewed internally at the University of Pennsylvania, Johns Hopkins
University, or Harvard University prior to initiation of treatment.
4. All patients under consideration for Cohorts A, B, C, and D Part II, must be willing
to undergo mandatory tumor biopsies (non-target lesion). Patients should have at least
one lesion (non-target) for biopsy. However, for 50% of patients in Cohorts A, B, C,
and D Part II, if patients are found to not have a safe lesion to biopsy by the
radiology team, they may still be enrolled in the study and forego the biopsy.
Patients for consideration for Cohort D Part I (dose escalation) are not required to
undergo a biopsy for enrollment. Patients who undergo attempted biopsies that are
unsuccessful may still enroll and receive study drug.
5. All patients must have a measurable disease by RECIST v1.1.
6. Germline BRCA mutation status:
- Cohorts A and B: Patients with unknown BRCA status or negative BRCA germline
mutation status will be permitted to enroll in the study. Patients with known
BRCA germline mutations will be permitted to enroll up to a maximum of 10
subjects per cohort.
- Cohort C and Cohort D Part II: All subjects must have either a germline or
somatic BRCA mutation, or other HRD mutation, or tumor is HRD positive. Other HRD
mutations will be reviewed for consideration for enrollment by SRC or University
of Pennsylvania PI.
- Cohort D Part I: Patients will be enrolled irrespective of BRCA status.
7. Adequate renal function, defined as measured creatinine clearance ≥ 51 ml/min.
8. Adequate hepatic function, defined as AST and ALT levels ≤ 2.5 X ULN (for subjects
with liver metastases, AST or ALT ≤ 5 × ULN) and total bilirubin < 1.5 X ULN, absent
Gilbert's disease.
9. Adequate bone marrow function, defined as absolute neutrophil count (ANC ≥ 1.5 X
109/L), platelet count ≥ 100 x 109/L, and hemoglobin ≥ 10 g/dL (in the absence of
transfusion within 28 days prior to dosing).
10. Patients must be at least 2 weeks from previous therapy (chemotherapy, hormonal
therapy, and radiation therapy, or investigational agents; 6 weeks for mitomycin C) to
initiate screening and 3 weeks from previous therapy to initiate treatment.
11. Platinum-sensitive is defined as recurrence >6 months by RECIST 1.1 imaging from last
platinum. Platinum-resistant is defined as recurrence < 6 months by RECIST 1.1 imaging
from last platinum regimen).
- For Cohort A, there is no limit to number of prior regimens.
- For Cohort B, patients may not have had more than 3 prior cytotoxic therapies
since the development of platinum-resistance.
- Patients for Cohort D, Part I (dose escalation), patients may be either
platinum-sensitive with no limit on prior regimens. Platinum-resistant patients
are eligible but they may not have received more than 3 prior cytotoxic therapies
since development of platinum resistance.
- Cohort C and Cohort D, Part II, patients must be platinum-sensitive BUT with no
limit to number of prior cytotoxic therapies. These patients must demonstrate
adequate bone marrow function as determined by the treating physician.
12. Prior treatment with a PARPi is permitted but not mandatory for Cohorts A and B and
Cohort D Part I. Prior treatment with PARPi is mandatory for Cohort C and D Part II.
If a patient has received a prior PARPi, then the patient must have demonstrated a
clinical benefit of PARPi treatment by an initial response (by CA-125 or imaging) to
PARPi treatment or clinical benefit from PARPi treatment as maintenance therapy
followed by disease progression for enrollment. Clinical benefit for maintenance is
defined as: a) prior maintenance with PARPi after 1st line chemotherapy of at least 12
months or b) prior maintenance with PARPi after >1 line of chemotherapy for minimum of
6 months.
If the prior PARP inhibitor used was olaparib, then patients must have received
treatment without significant toxicity or the need for a permanent dose reduction. For
Cohort C and D Part II, patients may not have received cytotoxic chemotherapy in the
interval between PARPi monotherapy and enrollment.
13. Patients who have had major surgery (as defined by the Site PI) must be fully
recovered and ≥4 weeks post-operative prior to enrolling on study.
14. Patients must be able to swallow oral medications (capsules and tablets) without
chewing, breaking, crushing, opening, or otherwise altering the product formulation.
They should not have gastrointestinal illnesses that would preclude the absorption of
AZD6738 or olaparib, which are oral agents.
15. Postmenopausal defined as:
- Amenorrhea for 1 year or more following cessation of exogenous hormonal
treatments;
- LH and FSH levels in post-menopausal range for women under 50;
- Radiation induced oophorectomy with last menses >1 year ago;
- Chemotherapy-induced menopause with >1 yr interval since last menses;
- Surgical sterilization (bilateral oophorectomy or hysterectomy).
16. Able to understand and voluntarily sign a written informed consent, and are willing
and able to adhere to the protocol requirements.
17. Patients with a history of brain metastases diagnosed greater than one year prior to
study entry may be considered if they received sterilizing therapy to the CNS
(resection or radiation) and have been CNS recurrence-free for the one-year period.
Exclusion criteria:
1. Patients with known brain metastases diagnosed within one year will be excluded from
this clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events.
2. Patients who have had prior AZD6738 or other cell cycle checkpoint inhibitors such as
other ATM or ATR inhibitor, WEE-1 inhibitor, or CHK1 (or 1/2) inhibitors.
3. Patients with a serious cardiac condition, such as congestive heart failure; New York
Heart Association Class III/IV heart disease; unstable angina pectoris; myocardial
infarction within the last 3 months; valvulopathy that is severe, moderate, or deemed
clinically significant; or arrhythmias that are symptomatic or require treatment.
Resting ECG with QTc > 470 msec on two or more time points within a 24-hour period or
family history of long QT syndrome.
4. Patients with a systolic blood pressure <90 mm Hg at two consecutive visits or
recurrent symptomatic orthostatic hypotension.
5. Lack of recovery of prior adverse events due to prior cancer therapy to Grade ≤1 (NCI
CTCAE v5.0; except alopecia). Stable persistent Grade 2 peripheral neuropathy may be
allowed as determined on a case-by-case basis at the discretion of the PI. Patients
with platinum-related hypomagnesemia (on replacement) will be eligible.
6. Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, clinically
significant GI bleeding or hemoptysis within 28 days prior to the start of the study,
or psychiatric illness/social situations that would limit compliance with study
requirements.
7. Another previous, active or current invasive malignancy within the last five years,
with the exception of curatively treated stage IA cervical carcinoma, or resected
stage IA, Grade 1 endometrial cancer, noninvasive non-melanoma skin cancers, DCIS of
the breast or other solid tumors including lymphomas (without bone marrow involvement)
curatively treated with no evidence of disease > 5 yrs. Patients with localized triple
negative breast cancer may be eligible who are disease free at least three years out
from treatment.
8. Immunocompromised patients or HIV-positive patients on HAART due to potential drug
interaction.
9. Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
period prior to starting olaparib is two weeks.
10. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout
period prior to starting olaparib is five weeks for enzalutamide or phenobarbital and
three weeks for other agents.
11. Patients with myelodysplastic syndrome, acute myeloid leukemia, or with features
suggestive of MDS/AML.
12. Major surgery within four weeks of starting study.
13. Patients with a known hypersensitivity to AZD6738 or olaparib or any of the excipients
of the product.
14. Platinum refractory (progress in first line platinum therapy) are excluded for Cohorts
A, B, C, D PART II.
15. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons) within three weeks prior to study treatment.
16. Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of
transmitting the infection through blood and other body fluids.
17. Previous allogeneic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT).
18. Whole blood transfusions in the last 120 days prior to entry to the study.
