Matched Paired Pharmacodynamics and Feasibility Study of Durvalumab in Combination With Chemotherapy in Frontline Ovarian Cancer

Study Groups:

This study has 2 parts: a safety lead-in and Phase 2.

If you are found to be eligible to take part in this study, you will be assigned to either
the Safety Lead-in or the Phase 2 portion, depending on when you join the study. Up to 12
participants will be enrolled in the Safety Lead-in, and up to 24 participants will be
enrolled in Phase 2.

If you are enrolled in the Safety Lead-in, the dose of durvalumab you receive will depend on
when you join this study. The first 4 participants will receive the first dose level of
durvalumab and be enrolled one at a time, every 3 weeks. Each new participant or group of up
to 6 participants enrolling after that will receive either the same dose as the previous
participant or group or a lower dose of either durvalumab or chemotherapy. This will continue
until a tolerable and appropriate dose of durvalumab and chemotherapy is found.

If you are enrolled in Phase 2, you will receive durvalumab at the highest dose that was
tolerated in the Safety Lead-in.

Study Drug Administration:

For all participants, the study drugs are given in 2 steps called Primary Therapy and
Maintenance.

In the Primary Therapy part of the study, each cycle is 21 days. You will receive the study
drugs on the schedule below for 3 cycles before and then 3 cycles after your planned surgery
(6 cycles total).

- You will receive paclitaxel by vein over 3 hours on Days 1, 8, and 15 of Cycles 1-6.

- You will receive carboplatin by vein over 1 hour on Day 1 of Cycles 1-6.

- You will receive durvalumab by vein over 1 hour every 2 weeks in Cycles 1-6.

After that, you may begin the Maintenance Phase. In this phase, cycles are 28 days long. You
will receive durvalumab alone every 2 weeks for 7 more cycles (28 weeks). It will continue to
be given by vein over 1 hour.

Study Visits during Primary Therapy:

At Week 1 of Cycles 1-6:

- You will have a physical exam.

- Blood (about 3 tablespoons) and urine will be collected for routine tests. In Cycles
1-3, this blood will also be used for biomarker tests. The biomarker tests in this study
may include genetic biomarkers. Biomarkers are found in the blood and tissue and may be
related to your reaction to the study drug.

- You will have an EKG to check your heart function (Cycles 1 and 6 only). In Cycle 1, an
EKG will be performed within 1 hour before the start of the study drug infusion and then
at least 1 more time in the 3 hours after the end of the infusion.

At Weeks 2 and 3 of Cycle 1:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for routine tests.

At Weeks 2 and 3 of Cycles 2-6, blood (about 3 tablespoons) will be drawn for routine tests.

After Cycle 3, you will temporarily stop receiving the study drugs as you prepare for the
surgery.

At your visit before surgery:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for routine and biomarker tests.

- You will have an EKG to check your heart function.

- You will have an MRI or CT scan to check the status of the disease.

You will sign a separate consent form for the surgery that explains the procedure and its
risks. During the surgery, tumor tissue will be collected for biomarker and genetic testing.
All samples will be stored at MD Anderson for an unlimited amount of time for testing related
to this study.

At your visit after surgery:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for routine tests.

At all visits during this part of the study except the day of surgery and the visit after
surgery, you will complete 1, 2, 5, or all 7 study questionnaires. You will be told how many
to complete each time. When you only complete 1 questionnaire at several of the visits, it
should take about 10-15 minutes.

Anytime the doctor thinks it is needed:

- If you can become pregnant, part of the routine blood sample will be used for a
pregnancy test.

- Part of the routine blood sample will be used for blood clotting tests.

Study Visits During Maintenance Therapy:

At Week 1 of Cycles 7-13:

- You will have a physical exam.

- Blood (about 1 tablespoon) and urine will be collected for routine tests.

- Blood (about 1 tablespoon) will be drawn for biomarker tests.

- You will have an EKG to check your heart function.

- You will complete 6 of the study questionnaires.

- At Week 1 of Cycle 7, you will have an MRI or CT scan to check the status of the
disease.

At Week 3 of Cycles 7-13 blood (about 1 tablespoon) will drawn for routine tests.

At Week 1 of Cycles 10 and 13, you will have an MRI or CT scan to check the status of the
disease.

At every other visit during Cycles 7-12 and at Weeks 1 and 4 of Cycle 13, you will complete
1, 6, or all 7 study questionnaires. You will be told how many to complete each time.

Anytime the doctor thinks it is needed:

- If you can become pregnant, part of the routine blood sample will be used for a
pregnancy test.

- Part of the routine blood sample will be used for blood clotting tests.

Interviews:

You will have 2 interviews with the study staff: before you receive any treatment and after
you have completed at least 2 cycles of treatment before your tumor reduction surgery and
after you have begun receiving maintenance therapy with durvalumab alone. Each interview may
take 25-45 minutes.

During the interviews, you will be asked questions about any symptoms you had during the time
when you were diagnosed, symptoms you are currently having, and any symptoms you had when you
received previous treatments for cancer. During the second interview, you will be asked how
your symptoms have changed since the first interview.

The interviews will be held over the phone or in a private conference room and will be
digitally recorded. The study staff will transcribe (create a text copy of) the interview and
will not record your name, medical record number, or any other identifying information. The
electronic files and transcription of the interview will be stored securely.

Length of Treatment:

You may receive up to 6 cycles of the study drug combination and up to 7 more cycles of
durvalumab alone. You will no longer be able to take the study drugs if the disease gets
worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up.

End-of-Treatment Visit:

After your last study drug dose:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for routine and biomarker tests.

- You will have an MRI or CT scan to check the status of the disease.

- You will have an EKG to check your heart function.

- You will complete 6 of the questionnaires.

Follow-up:

At 30 days after your last durvalumab dose:

- You will have a physical exam.

- Blood (about 2 tablespoons) will be collected for routine tests. If you can become
pregnant, part of this sample will be used for a pregnancy test.

- You will complete 6 of the questionnaires.

At Month 2 after your last durvalumab dose, blood (about 1 tablespoon) will be drawn for
routine tests.

At Month 3:

- You will have a physical exam.

- Blood (about 1 tablespoon) will be drawn for routine tests.

At Months 4, 6, 8, and 10, you will be asked how you are doing. This may also be done at
Month 9, depending on how long you took durvalumab and the reason you stopped it. The study
staff will tell you if you have this 9-month visit.

At the Month 12 and then every 6 months, depending on how long you took durvalumab and the
reason you stopped it, blood (about 3 tablespoons) may be drawn for routine tests.

As often as the doctor thinks is needed, you will have an MRI or CT scan to check the status
of the disease. This will depend on how long you took durvalumab and the reason you stopped
it.

If you choose not to return for follow-up visits, you can instead receive follow-up phone
calls at Months 2, 3, 4, 6, 8, and 10 after your last durvalumab dose and then every 2 months
starting at Month 12. You will be asked how you are doing. The calls should take about 10-15
minutes.

Inclusion Criteria:

1. Written informed consent and any locally-required authorization (e.g., Health
Information Portability and Accountability Act [HIPAA] in the USA, EU Data Privacy
Directive in the EU) obtained from the subject prior to performing any
protocol-related procedures, including screening evaluations

2. Age >/= 18 years at time of study entry.

3. Histology showing high-grade epithelial non-mucinous ovarian, primary peritoneal, or
fallopian tube cancer.

4. No prior treatment for primary advanced (Stage III or IV) epithelial ovarian, primary
peritoneal, or fallopian tube carcinoma such as irradiation, chemotherapy, hormonal
therapy, immunotherapy, investigational therapy, surgery, and/or other concurrent
agents or therapies.

5. A disposition to neoadjuvant chemotherapy with planned interval tumor reductive
surgery after 3 complete cycles of treatment.

6. Planned chemotherapy with combination carboplatin and paclitaxel given intravenously.

7. Have measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST)
version 1.1. a) Measurable disease is defined as at least one lesion that can be
accurately measured in at least one dimension (longest dimension to be recorded). Each
target lesion must be >20 mm when measured by conventional techniques, including
palpation, plain x-ray, Computerized Tomography (CT), and Magnetic Resonance Imaging
(MRI), or >10 mm when measured by spiral CT. b) Patients with non-measurable but
evaluable solid tumors may be deemed eligible contingent upon PI review. A
non-measurable but evaluable solid tumor is defined as either unidimensionally
measurable lesions, masses with margins not clearly defined, or lesions with maximal
perpendicular diameters < 10mm that can still be evaluated for the primary endpoint.

8. Peripheral neuropathy Grade 0 or 1 by National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) version 4.03.

9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

10. Life expectancy >/= 12 weeks.

11. Adequate normal organ and marrow function are defined as follows: Hemoglobin >/= 9.0
g/dL; Absolute neutrophil count (ANC) >/= 1.5 x 109/L (> 1500 per mm^3); Platelet
count >/= 100 x 109/L (>100,000 per mm^3); Serum bilirubin upper limit of normal (ULN); Aspartate Transaminase (AST) and Alanine Transaminase
(ALT) present, in which case it must be 40
mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination
of creatinine CL--Creatinine CL (mL/min)=[Weight (kg) x (140-Age)X0.85]/[72 x serum
creatinine (mg/dL)].

12. Subjects must either be of non-reproductive potential (ie, post-menopausal by history:
>/=60 years old and no menses for >/=1 year without an alternative medical cause; OR
history of hysterectomy, OR history of bilateral tubal ligation, OR history of
bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.

13. Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.

14. Pre-treatment tumor tissue available for research purposes. This tissue can be
collected from preoperative laparoscopy, other diagnostic biopsy, or a
research-specific biopsy. This pre-treatment tumor must be amenable to repeat tissue
sampling after induction therapy.

15. Signed informed consent on protocol LAB02-188

16. For participation in the Patient-reported Outcomes and Qualitative Interviews,
subjects must be fluent in English

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).

2. Previous enrollment in the present study.

3. Prior treatment for ovarian, fallopian tube, or primary peritoneal cancer.

4. Histology showing mucinous or low grade epithelial carcinoma.

5. Participation in another clinical study with an investigational product during the
last 4 weeks.

6. Any previous treatment with a Programmed Cell Death Protein 1 (PD1) or PD-L1
inhibitor, including durvalumab.

7. History of another primary malignancy except for: Malignancy treated with curative
intent and with no known active disease >/= 5 years before the first dose of study
drug and of low potential risk for recurrence; adequately treated non-melanoma skin
cancer or lentigo maligna without evidence of disease; or adequately treated carcinoma
in situ without evidence of disease eg, cervical cancer in situ.

8. Mean QT interval corrected for heart rate (QTc) >/= 470 ms calculated from 3
electrocardiograms (ECGs) using Bazett's Correction.

9. Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid.

10. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy. Any prior
Grade >/=3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE >Grade 1.

11. Active or prior documented autoimmune disease within the past 2 years. NOTE: Subjects
with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
the past 2 years) are not excluded.

12. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis).

13. History of primary immunodeficiency.

14. History of allogeneic organ transplant.

15. History of hypersensitivity to durvalumab or any excipient.

16. History of hypersensitivity to paclitaxel or carboplatin or their excipients.

17. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
bleeding diatheses including any subject known to have evidence of acute or chronic
hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
illness/social situations that would limit compliance with study requirements or
compromise the ability of the subject to give written informed consent.

18. Known history of previous clinical diagnosis of tuberculosis.

19. History of leptomeningeal carcinomatosis.

20. Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving durvalumab.

21. Female subjects who are pregnant/breast-feeding or who are of reproductive potential
and not employing acceptable methods of birth control. Acceptable methods of
contraception include true abstinence in line with the preferred and usual lifestyle
choice of the patient, tubal ligation, vasectomised partner, barrier methods (eg, cap
plus spermicide, sponge plus spermicide, diaphragm plus spermicide, or male condom
plus a spermicide), intrauterine device methods (eg, Copper T or
Levonorgestrel-releasing intrauterine system), or hormonal methods (eg, any registered
and marketed contraceptive agent that contains an estrogen and/or a progestational
agent) and that is administered via the oral, subcutaneous, transdermal, intrauterine,
or intramuscular route as an implant, hormone shot or injection, combined pill,
minipill or patch. All methods of contraception should be used in combination with the
use of a condom by their male sexual partner for intercourse.

22. Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results.

23. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive
of but not limited to surgery, radiation and/or corticosteroids.

24. Subjects with uncontrolled seizures.