This phase II trial studies how well ATR kinase inhibitor AZD6738 works alone or in combination with olaparib in treating participants with renal cell carcinoma, urothelial carcinoma, all pancreatic cancers, or other solid tumors that have spread to nearby tissue or lymph nodes or other parts of the body. ATR kinase inhibitor AZD6738 and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not known if giving ATR kinase inhibitor AZD6738 with or without olaparib may work better in treating participants with solid tumors.
I. To assess objective response rate (ORR) of ATR kinase inhibitor AZD6738 (AZD6738)
monotherapy and AZD6738 + olaparib by Response Evaluation Criteria in Solid Tumors (RECIST)
I. To determine the median duration of response (DOR) in each study arm. II. To determine the
median progression-free survival and progression-free survival rate at 6 and 12 months in
each study arm.
III. To further characterize the safety and tolerability profile of AZD6738 alone and in
combination with olaparib.
|Overal Status||Start Date||Phase||Study Type|
|Recruiting||January 17, 2019||Phase 2||Interventional|
Primary Outcome 1 - Measure: Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
Primary Outcome 1 - Time Frame: Up to 2.5 years
- Patients must provide written informed consent prior to performance of study-specific
procedures or assessments.
- Histologically confirmed locally advanced or metastatic solid tumor malignancy with by
tumor type as specified below:
- Renal cell carcinoma with clear cell component (Cohort A): Patients must have
prior progression on or following, intolerance of, or patient refusal to receive
vascular endothelial growth factor (VEGF)-targeting tyrosine kinase inhibitor and
immune checkpoint blockade.
- Urothelial carcinoma (Cohort B). Patients must have prior progression on or
following, intolerance of, or patient refusal to receive platinum chemotherapy
and immune checkpoint blockade.
- All pancreatic cancers (Cohort C). Patients must have prior progression on or
following, intolerance of, or patient refusal to receive fluorouracil (5-FU),
gemcitabine, and irinotecan-based chemotherapy.
- Other solid tumors excluding clear cell ovarian cancer (Cohort D). Patients must
have prior progression on or following, intolerance of, of patient refusal of at
least one systemic therapy for locally advanced or metastatic disease and must
not have any curative treatment options available.
- Evidence of clinical or radiographic progression prior to study entry.
- Formalin-fixed paraffin embedded tumor tissue evaluable for BAF250a expression by
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.
- Measurable disease by RECIST 1.1.
- Resolution of all prior treatment-related toxicities to grade 1 severity or lower
- 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.
- 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.
- 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).
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- 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.
- 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.
- 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.
- 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), ductal carcinoma in situ,
stage I uterine cancer, and non-muscle invasive urothelial carcinoma.
- Patients receiving, or having received within 14 days of C1D1, corticosteroids at a
dose > 10 mg/day of prednisone (or equivalent).
- Patients with myelodysplastic syndrome or features suggestive of myelodysplastic
- Prior treatment with ATR or PARP inhibitor (e.g. olaparib, rucaparib, niraparib).
- Major surgical procedures < 28 days prior to C1D1. Patients must have recovered to
grade =< 1 for any adverse events related to the surgical procedure.
- 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.
- 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.
- 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.
- History of any one or more of the following cardiovascular conditions within the past
- 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).
- 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.
- Relative hypotension with resting blood pressure of less than 90 mm Hg systolic and
less than 60 mm Hg diastolic or symptomatic orthostatic hypotension.
- 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.
- 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).
- 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
- Known chronic active hepatitis B or C (defined by positive viral load; screening not
- Immunocompromised patients, including those serologically positive for human
immunodeficiency virus (HIV), those receiving chronic immunosuppression, or those with
prior allogeneic or cord blood transplantation.
Minimum Age: 18 Years
Maximum Age: N/A
Healthy Volunteers: No
Name: Rahul Aggarwal
Role: Principal Investigator
Affiliation: University of California, San Francisco