PRIMARY OBJECTIVES:
I. To compare the efficacy of single-agent olaparib and the combination of olaparib and
cediranib (and potentially other combination arms that may be added by subsequent amendment)
versus single agent cediranib as measured by progression free survival (PFS), in patients
with recurrent, persistent or metastatic endometrial cancer.
II. To compare the efficacy of the combination of olaparib and AZD5363 (capivasertib), and
the combination of olaparib and durvalumab (MEDI4736), and the combination of cediranib and
durvalumab (MEDI4736) versus single agent cediranib as measured by progression free survival
(PFS), in patients with recurrent, persistent or metastatic endometrial cancer.
SECONDARY OBJECTIVES:
I. To compare the efficacy of single-agent olaparib and the combination of olaparib and
cediranib (and potentially other combination arms that may be added by subsequent amendment)
versus single-agent cediranib as measured by overall survival (OS) in patients with
recurrent, persistent or metastatic endometrial cancer.
II. To compare the efficacy of the combination of olaparib and AZD5363 (capivasertib), and
the combination of olaparib and durvalumab (MEDI4736), and the combination of cediranib and
durvalumab (MEDI4736) versus single agent cediranib as measured by overall survival (OS), in
patients with recurrent, persistent or metastatic endometrial cancer.
III. To compare the efficacy of single-agent olaparib and the combination of olaparib and
cediranib (and potentially other combination arms may be added by subsequent amendment versus
single-agent cediranib as measured by response rate in patients with recurrent, persistent or
metastatic endometrial cancer.
IV. To compare the efficacy of the combination of olaparib and AZD5363 (capivasertib), and
the combination of olaparib and durvalumab (MEDI4736), and the combination of cediranib and
durvalumab (MEDI4736) versus single agent cediranib as measured by response rate in patients
with recurrent, persistent or metastatic endometrial cancer.
V. To assess the safety and tolerability of single-agent cediranib, single-agent olaparib,
and the combination of olaparib and cediranib (and potentially other combination arms may be
added by subsequent amendment).
VI. To assess the safety and tolerability of the combination of olaparib and AZD5363
(capivasertib), and the combination of olaparib and durvalumab (MEDI4736), and the
combination of cediranib and durvalumab (MEDI4736).
VII. To assess if mutations in deoxyribonucleic acid (DNA) homologous repair genes (assayed
prior to all treatment and prior to the study treatment) are predictive of response to
olaparib alone or in combination with cediranib. (Integrated Biomarker) VIII. To assess if
markers of angiogenesis in serial plasma samples are associated with response to cediranib
alone or in combination with olaparib. (Integrated Biomarker)
EXPLORTORY OBJECTIVE:
I. To compare the efficacy of the combination of olaparib and cediranib versus single agent
olaparib as measured by PFS, response rate and OS, if and only if the combination is superior
to the single-agent cediranib arm.
OUTLINE: Patients are randomized to 1 of 6 arms.
ARM I: Patients receive cediranib maleate orally (PO) once daily (QD). Cycles repeat every 28
days in the absence of disease progression or unaccepted toxicity.
ARM II (ENROLLMENT COMPLETE): Patients receive olaparib PO twice daily (BID). Cycles repeat
every 28 days in the absence of disease progression or unaccepted toxicity.
ARM III (ENROLLMENT COMPLETE): Patients receive olaparib PO BID and cediranib maleate PO QD.
Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.
ARM IV: Patients receive olaparib PO BID on days 1-28 and capivasertib PO BID on days 1-4
each week. Cycles repeat every 28 days in the absence of disease progression or unaccepted
toxicity.
ARM V: Patients receive olaparib PO BID on days 1-28 and durvalumab intravenously (IV) on day
1. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.
ARM VI: Patients receive cediranib maleate PO BID on days 1-28 and durvalumab IV on day 1.
Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.
Inclusion Criteria:
- Patients must have recurrent or persistent endometrial carcinoma, which is refractory
to curative therapy or established treatments; histologic confirmation of the original
primary tumor is required; patients with the following histologic epithelial cell
types are eligible: endometrioid adenocarcinoma, serous adenocarcinoma,
undifferentiated carcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise
specified (N.O.S.); NOTE: clear cell histology is excluded
- Patients must have evaluable disease as defined by Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1 or non-measurable (detectable) disease
- Measurable disease is defined as at least one lesion that can be accurately
measured in at least one dimension (longest diameter to be recorded); each lesion
must be >= 10 mm when measured by computed tomography (CT), magnetic resonance
imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured
by chest x-ray; lymph nodes must be > 15 mm in short axis when measured by CT or
MRI; patients with measurable disease must have at least one "target lesion" to
be used to assess response on this protocol as defined by RECIST version 1.1;
tumors within a previously irradiated field will be designated as "non-target"
lesions unless progression is documented or a biopsy is obtained to confirm
persistence at least 90 days following completion of radiation therapy
- Non-measurable (detectable) disease in a patient is defined in this protocol as
one who does not have measurable disease but has at least one of the following
conditions:
- Ascites and/or pleural effusion attributed to tumor;
- Solid and/or cystic abnormalities on radiographic imaging that do not meet
RECIST 1.1 definitions for target lesions
- Patients must have signed an approved informed consent and authorization permitting
release of personal health information
- Patients must have had one prior chemotherapeutic regimen for management of
endometrial carcinoma; initial treatment may include chemotherapy, chemotherapy and
radiation therapy, and/or consolidation/maintenance therapy; chemotherapy administered
in conjunction with primary radiation as a radio-sensitizer WILL be counted as a
systemic chemotherapy regimen
- Patients are allowed to receive, but are not required to receive, one additional
cytotoxic regimen for management of recurrent or persistent disease according to the
following definition: cytotoxic regimens include any agent that targets the genetic
and/or mitotic apparatus of dividing cells, resulting in dose-limiting toxicity to the
bone marrow and/or gastrointestinal mucosa; Note: patients on this non-cytotoxic study
are allowed to receive one additional cytotoxic chemotherapy regimen for management of
recurrent or persistent disease, as defined above; however, patients are encouraged to
enroll on second-line non-cytotoxic studies prior to receiving additional cytotoxic
therapy
- Patients may have received non cytotoxic therapy including immunotherapy (1 prior line
in either upfront or recurrent setting) but excluding cediranib, olaparib, AZD5363
(capivasertib), durvalumab (MEDI4736), or the combination of lenvatinib and
pembrolizumab for the management of recurrent or persistent disease; prior hormonal
therapy is allowed; hormonal therapy for grade 1 endometrial cancers with low volume
or indolent disease is encouraged
- Bevacizumab, or one course of single-agent immune-checkpoint therapy, excluding
durvalumab (MEDI4736), is permitted prior to enrollment on this trial
- Body weight > 30 kg
- The trial is open to females only (including women with an intact uterus with uterine
cancer); fertile females of childbearing potential need to agree to use adequate
contraceptive measures from 2 weeks prior to the study and until 1 month after study
treatment discontinuation, and have a negative serum or urine pregnancy test within 3
days prior to the start of study treatment
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0,1 or 2 (Karnofsky >= 60%) within 7 days prior to registration; patients should have
no deterioration over the previous two weeks
- Hemoglobin >= 10 mg/dL with no blood transfusion in the past 28 days (within 28 days
prior to administration of study drug)
- Platelet count >= 100 x 10^9/L (within 28 days prior to administration of study drug)
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 28 days prior to
administration of study drug)
- Patients must have creatinine clearance estimated of >= 51 mL/min using the Cockcroft
Gault equation or based on a 24-hour urine test (within 28 days prior to
administration of study drug)
- Serum bilirubin =< 1.5 X upper limit of normal (ULN) (within 28 days prior to
administration of study drug)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (within
28 days prior to administration of study drug)
- Urine protein: creatinine (UPC) < 1 or < 2+ proteinuria on two consecutive dipsticks
taken no less than 1 week apart. Patients with 2+ proteinuria on dipstick must also
have UPC < 0.5 on 2 consecutive samples (within 28 days prior to administration of
study drug)
- Patients must be able to swallow and retain oral medications and without
gastrointestinal illnesses that would preclude absorption of cediranib, olaparib, or
AZD5363 (capivasertib)
- Patients must have adequately controlled blood pressure (BP), with a BP no greater
than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility; patients must have a
BP of =< 140/90 mmHg taken in the clinic setting by a medical professional within 2
weeks prior to starting study; patients with hypertension may be managed with up to a
maximum of three antihypertensive medications; it is strongly recommended that
patients who are on three antihypertensive medications be followed by a cardiologist
or blood pressure specialist for management of blood pressure while on protocol
- Note: Patients must be willing and able to check and record daily blood pressure
readings
- The patient or a legally authorized representative must provide study-specific
informed consent prior to study entry
- Adequately controlled thyroid function, with no symptoms of thyroid dysfunction
- Postmenopausal or evidence of non-childbearing status for women of childbearing
potential as confirmed by a negative urine or serum pregnancy test within 7 days prior
to start of investigational products (IPs); postmenopausal is defined as:
- Age >= 60 years, or
- Age < 60 with any one or more of the conditions below:
- Amenorrheic for >= 1 year in the absence of chemotherapy and/or hormonal
treatments,
- Luteinizing hormone and/or follicle stimulating hormone and/or estradiol
levels in the post-menopausal range
- Radiation-induced oophorectomy with last menses > 1 year ago,
- Chemotherapy-induced menopause with > 1 year interval since last menses,
- Surgical sterilization (bilateral oophorectomy or hysterectomy)
- Patients must have a life expectancy of greater than 16 weeks
- Patients with a previous diagnosis of immune or inflammatory colitis or chronic
diarrhea > 1 month without immune or inflammatory colitis are eligible with adequately
controlled colitis (no diarrhea greater than grade 1 for at least 28 days) and in the
absence of symptoms related to colonic dysfunction; patients who required steroids for
prior immune related colitis are not eligible
- Females of child-bearing potential should use two forms of highly reliable methods of
contraception from the time of screening until 4 weeks after discontinuing study
treatment.
- Acceptable methods of contraception include:
- Established use of oral, injected or implanted hormonal methods of
contraception.
- Placement of an intrauterine device or intrauterine system.
- Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
- Male partner sterilization (with the appropriate post-vasectomy
documentation of the absence of sperm in the ejaculate).
- True abstinence (i.e., not engaging in sexual activity for the total
duration of study treatment and the treatment washout period is an
acceptable practice; however, periodic abstinence, the rhythm method, and
the withdrawal method are not acceptable methods of birth control).
- Bilateral tubal occlusion or salpingectomy
- Acceptable non-hormonal birth control methods include:
- Total/True abstinence: When the patient refrains from any form of sexual
intercourse and this is in line with their usual and/or preferred lifestyle;
this must continue for the total duration of the trial and for at least 1
month after the last dose of study drug <<for 3 months after last dose for
male patients>>. [Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods, or declaration of abstinence solely
for the duration of a trial) and withdrawal are not acceptable methods of
contraception]
- Vasectomised sexual partner PLUS male condom. With participant assurance
that partner received post-vasectomy confirmation of azoospermia.
- Tubal occlusion PLUS male condom
- Intrauterine device (IUD) PLUS male condom. Provided coils are
copper-banded.
- Acceptable hormonal methods:
- Normal and low dose combined oral pills PLUS male condom.
- Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only
highly efficacious progesterone-based pill.
- Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom.
- Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom.
- Norelgestromin/EE transdermal system PLUS male condom
- Intrauterine system [IUS] device (e.g., levonorgestrel releasing IUS
-Mirena) PLUS male condom.
- Intravaginal device (e.g., EE and etonogestrel) PLUS male condom
Exclusion Criteria:
- Prior enrollment into a clinical trial including cediranib or olaparib; Note: prior
bevacizumab is not an exclusion criterion
- Prior enrollment into a clinical trial including cediranib, olaparib, AZD5363
(capivasertib), durvalumab (MEDI4736), or the combination of lenvatinib and
pembrolizumab. Note: Prior bevacizumab or single-agent immune checkpoint blockade,
excluding durvalumab (MEDI4736), is not an exclusion criterion
- Prior chemotherapy, endocrine therapy, radiotherapy, or investigational agents within
4 weeks
- More than one prior line of treatment with immune checkpoint blockade therapy
- Current signs/symptoms of bowel obstruction and/or signs/symptoms of bowel obstruction
within the preceding 3 months
- History of gastrointestinal perforation; patients with a history of abdominal fistula
will be considered eligible if the fistula was surgically repaired or has healed,
there has been no evidence of fistula for at least 6 months, and patient is deemed to
be at low risk of recurrent fistula
- Uncontrolled intercurrent illness including, but not limited to known ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, extensive interstitial bilateral lung disease on high resolution
computed tomography (HRCT) scan or psychiatric illness/social situations that would
limit compliance with study requirements
- Concomitant use of known strong cytochrome (CYP) 3A 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 study treatments is 2 weeks
for strong inhibitors, and at least 1 week for moderate inhibitors
- Concomitant use of potent inhibitors or inducers of CYP3A4 within 2 weeks before the
start of study treatment (3 weeks for St John's wort), or sensitive substrates of
CYP3A4, CYP2C9 and/or CYP2D6 with a narrow therapeutic window within 1 week before the
start of study treatment. Concomitant use of drugs known to prolong the QT interval
within 5 half-lives of the first dose of study treatment
- Pregnant women are excluded from this study because cediranib and olaparib are agents
with the potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk of adverse events in nursing infants secondary to treatment
of the mother with cediranib and olaparib, breastfeeding should be discontinued if the
mother is treated with cediranib or olaparib; these potential risks may also apply to
other agents used in this study; for women of childbearing capacity a negative
pregnancy test is required
- Known human immunodeficiency virus (HIV)-positive individuals are ineligible because
of the potential for pharmacokinetic interactions between many anti-HIV drugs and
cediranib, olaparib, and/or AZD5363 (capivasertib); in addition, these individuals are
at increased risk of lethal infections when treated with marrow-suppressive therapy
- Known active hepatitis B or hepatitis C infection on antiviral treatment
- Prior history of stroke or transient ischemic attack within the last 6 months
- Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per
institutional guidelines, or < 55%, if threshold for normal not otherwise specified by
institutional guidelines, for patients with the following risk factors:
- Prior treatment with anthracyclines
- Prior treatment with trastuzumab
- Prior central thoracic radiation therapy (RT), including exposure of heart to
therapeutic doses of ionizing RT
- History of myocardial infarction within 6-12 months prior to start of IPs
- Prior history of other significant impaired cardiac function
- Patients with any of the following:
- History of myocardial infarction within 6 months prior to starting treatment
- Unstable angina
- Resting electrocardiogram (ECG) with clinically significant abnormal findings or
with corrected QT interval (QTc) > 470 msec on 2 or more time points within a 24
hour period or family history of long QT syndrome
- New York Heart Association functional classification of III or IV
- Prior history of hypertensive crisis or hypertensive encephalopathy
- Major surgical procedure within 4 weeks prior to starting treatment; patients must
have recovered from any effects of any major surgery and surgical wound should have
healed prior to starting treatment
- History of intra-abdominal abscess within 3 months prior to starting treatment
- Patients may not use any complementary or alternative medicines including natural
herbal products or folk remedies as they may interfere with the effectiveness of the
study treatments
- No prior allogeneic bone marrow transplant or double umbilical cord blood
transplantation (dUBCT)
