The combination of the three proposed agents offers the opportunity to explore synergistic
relationships between antiangiogenic and immunotherapy and antiangiogenic and PARPi.
Increasing genetic instability by PARPi and double-strand breaks may lead to a
proinflammatory state that would enhance the activity of immunotherapy, leading to
synergistic response in a category of solid tumors that lack active therapy. It is expected
that increased double-strand breaks may lead to increased expression of immunogenic antigens,
increasing the effect of anti-PD-L1 therapy. Phase I data combining the PD-L1 inhibitor
durvalamab with either olaparib or cediranib showed good tolerability and evidence of
response.
Inclusion Criteria:
1. Patients must have recurrent or persistent/progressive endometrial carcinoma, which is
refractory to curative therapy or established treatments. Histologic confirmation of
the original primary tumor is required. Stained slides of either the primary or
recurrent tumor are required. If primary FFPE samples are not available, a biopsy
demonstrating recurrent disease must be obtained. Pathologic Slides/Blocks will be
reviewed at the primary site for confirmation.
2. Patients with the following histologic epithelial cell types are eligible:
Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear
cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise
specified (N.O.S.), mucinous adenocarcinoma, squamous cell carcinoma, transitional
cell carcinoma and uterine carcinosarcoma (MMT).
3. Patients must have had one prior chemotherapeutic regimen for management of
endometrial carcinoma. Chemotherapy administered in conjunction with primary radiation
as a radio-sensitizer WILL be counted as a chemotherapy regimen. Patients may have
had, but are not required to have received, a second chemotherapeutic regimen for
recurrent disease.
4. All patients must have measurable disease, as defined by RECIST 1.1. 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 target lesion must be ≥ 10 mm
when measured by
CT or MRI. Lymph nodes must be > 15 mm in short axis when measured by CT or MRI.
5. Patients may be enrolled if they do not have a target lesion (>= 10 mm lesion or >=15
mm lymph node), if they have measurable disease. This is defined by RECIST 1.1 as a
suspicious lesion <10mm or a lymph node >=10mm but <15mm.
6. Patients must have an EGOG Performance Status of 0, 1.
7. Recovery from effects of recent surgery, radiotherapy, or chemotherapy
8. Patients should be free of active infection requiring antibiotics (with the exception
of uncomplicated UTI).
9. Any hormonal therapy directed at the malignant tumor must be discontinued at least one
week prior to registration.
10. Any other prior therapy directed at the malignant tumor, including chemotherapy and
immunologic agents, must be discontinued at least three weeks prior to first cycle of
treatment.
11. Any prior radiation therapy must be completed at least four weeks prior to first cycle
of treatment.
12. Prior hormonal therapy is allowed. There is no limit on the number of prior hormonal
therapies allowed. Hormonal therapy will not be counted as a line of therapy for
purposes of this trial.
13. Patients must have a urine protein of 2+ on dipstick. If dipstick is >2+, 24-hour
urine protein must be obtained and should be < 1g for patient to be eligible.
14. Patients must have signed an approved informed consent and authorization permitting
release of personal health information for study purposes.
15. Patients must meet pre-entry requirements, as specified in section 5.
16. Patients of childbearing potential must agree to use an accepted and effective
nonhormonal method of contraception i.e., double-barrier method (e.g., condom plus
diaphragm) from the time of signing the informed consent through six months after last
dose of study drug.
17. Patients 18 years of age or greater.
18. Be willing to provide tissue from the primary surgical resection (paraffin block).
19. Must have laboratory values in the below ranges:
System Laboratory Value Endocrine Thyroid function testing (TSH) 0.350 - 5.500 ulU/mL (Or
within institutional labarotory range).
Free T4/Total T3 If TSH is outside of laboratory range and subject is clinically euthyroid,
enrollment may occur if Free T4/Total T3 are in normal range by local lab values
Hematological
System Laboratory Value Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 /
mcL Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days
of assessment) Renal Serum creatinine OR Measured or calculateda creatinine clearance (GFR
can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum total
bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels >
1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR
≤ 5 X ULN for subjects with liver metastases Albumin >2.5 mg/dL Coagulation International
Normalized Ratio (INR) or Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of
anticoagulants
≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants aCreatinine clearance should be
calculated per institutional standard.
4.2 Exclusion Criteria
1. Patients with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer, are excluded if there is any evidence of the other
malignancy being present within the last two years. Patients with Ductal Carcinoma in
situ (DCIS) of the breast in the prior two years may be enrolled on study if the
treatment required no chemotherapy or radiation. Patients are also excluded if their
previous cancer treatment contraindicates this protocol therapy.
2. Patients must not have had exposure to Bevacizumab, PARPi, or immunotherapy. Patients
may have had exposure to anti-angiogentic therapy provided it was not Bevacizumab.
3. Patients who have received prior radiotherapy to any portion of the abdominal cavity
or pelvis OTHER THAN for the treatment of endometrial cancer within the last three
years are excluded. Prior radiation for localized cancer of the breast, head and neck
or skin is permitted, provided that it was completed more than three years prior to
registration, and the patient remains free of recurrent or metastatic disease.
4. Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER
THAN for the treatment of endometrial cancer within the last three years are excluded.
Patients may have received prior adjuvant chemotherapy for localized breast cancer,
provided that it was completed more than two years prior to registration, and that the
patient remains free of recurrent or metastatic disease.
5. Inability to tolerate an oral medication or keep pills down.
6. Patients who are pregnant or nursing.
7. Patients with a complete bowel obstruction; recent (within six months) history of
fistula, intraabdominal abscess or bowel perforation; subjects requiring total
parenteral nutrition or parenteral hydration.
8. Has a current diagnosis of immunodeficiency or is receiving systemic steroid therapy
or any other form of immunosuppressive therapy within seven days prior to the first
dose of trial treatment.
9. Patients with history or evidence upon physical examination of CNS disease, including
brain tumor, seizures not controlled with standard medical therapy or any brain
metastases.
10. Patients with clinically significant cardiovascular disease. This includes:
- Myocardial infarction or unstable angina within 12 months of the first date of
study treatment.
- New York Heart Association (NYHA) Class II or greater congestive heart failure
(Appendix I).
- History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation) or cardiac arrhythmias requiring antiarrhythmic
medications (except for atrial fibrillation that is well controlled with
antiarrhythmic medication).
- Grade 2 or greater peripheral vascular disease.
- Cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or
subarachnoid hemorrhage within six months of the first date of study treatment.
- History of arterial ischemia or thrombus.
11. Patients with uncontrolled hypertension defined as systolic > 150 mm Hg or diastolic >
90 mm Hg. The use of antihypertensive medications to control hypertension is
permitted.
12. Patients who have undergone major surgical procedure, open biopsy or significant
traumatic injury within 28 days prior to the first date of study treatment or who have
a major surgical procedure anticipated during the course of the study. Laparoscopic
biopsy is acceptable and will not require a delay in study treatment.
13. Patients with serious nonhealing wound, ulcer (including gastrointestinal) or bone
fracture.
14. Patients with any condition, which in the investigator's opinion, makes the patient
unsuitable for study participation.
15. Patients not available for follow-up assessments.
16. Patients with known sensitivity to any of the products to be administered during
dosing.
