Phase I/II Study of the Anti-Programmed Death Ligand-1 Antibody MEDI4736 in Combination With Olaparib and/or Cediranib for Advanced Solid Tumors and Advanced or Recurrent Ovarian, Triple Negative Breast, Lung, Prostate and Colorectal Cancers
Phase I/II Study of the Anti-Programmed Death Ligand-1 Antibody MEDI4736 in Combination With Olaparib and/or Cediranib for Advanced Solid Tumors and Advanced or Recurrent Ovarian, Triple Negative Breast, Lung, Prostate and Colorectal Cancers
Background:

 - MEDI4736 is a drug that may help people s immune systems respond to and kill cancer cells.
 Olaparib is a drug that may inhibit repairing DNA damage of cancer cells. Cediranib is a drug
 that may stop the blood vessel growth of cancer cells. This study has two components. In the
 phase 1 component of the study, researchers want to investigate how well participants
 tolerate the combination of these drugs in treating advanced solid tumors, and in the phase 2
 part of this study, researchers want to study if the combination treatments are effective in
 ovarian cancer.

 Objectives:

 - Phase 2 part of the study: To determine how effective this combination is in treating
 ovarian cancer.

 Eligibility:

 - Phase 2 part of the study: Adults age 18 or older with advanced or recurrent ovarian cancer
 that has no standard treatment.

 Design:

 -  Participants will be screened with medical history, physical exam, and blood and urine
 tests. They will have CT or MRI scans. For these, they will lie in a machine that takes
 pictures of their bodies.

 -  Phase 2 part of the study requests the participants to have tumor samples removed.

 -  Participants will get MEDI4636 through an IV. A small plastic tube will be inserted into
 a vein. The drug will be given every 4 weeks until disease progression.

 -  Participants will take olaparib or cediranib by mouth every day.

 -  Every 28 days will be 1 cycle. For cycle 1, participants will have 2 study visits. All
 other cycles, they will have 1 visit. At these visits, they will repeat the screening
 procedures.

 -  Patients will keep a drug and diarrhea diary.

 -  Patients on cediranib will monitor their blood pressure and keep a blood pressure diary.

 -  Participants who can become pregnant, or have a partner who can become pregnant, must
 practice an effective form of birth control.

 -  After 12 cycles, participants will have 1-3 months of follow-up.
Background:

 -  Disruption of the immune checkpoint PD-1/PD-L1 pathway yielded clinical activity in
 subsets of advanced solid tumors, such as melanoma and lung cancer.

 -  Olaparib (O), a PARP inhibitor (PARPi), has demonstrated single agent activity in
 recurrent ovarian cancer (OvCa), and subsets of prostate, triple negative breast or lung
 cancers.

 -  Our recent randomized phase 2 study showed that O and cediranib (C), a VEGFR1-3
 inhibitor was clinically superior to O alone in platinum-sensitive recurrent OvCa.

 -  We hypothesize that increased DNA damage by PARP inhibition and/or reduced angiogenesis
 by VEGFR inhibition will complement the anti-tumor activity of an immune checkpoint
 nhibitor, MEDI4736, in recurrent OvCa and other solid tumors.

 Objectives:

 -  Phase I: To determine the recommended phase II dose (RP2D) and the safety of doublet
 herapies (MEDI4736/olaparib [MEDI+O] and MEDI4736/cediranib [MEDI+C]) and triplet
 therapy (MEDI+O+C) in patients with advanced solid tumors.

 -  Phase II Cohort 1 OvCa; MEDI+O, MEDI+C and MEDI+O+C arms: To determine clinical efficacy
 as measured by overall response rate (ORR)

 -  Phase II Cohort 2 non-small cell lung cancer (NSCLC); MEDI+O and MEDI+C arms: To
 determine clinical efficacy as measured by progression-free survival (PFS)

 -  Phase II Cohort 3 small cell lung cancer (SCLC); MEDI+O arm: To determine clinical
 efficacy as measured by ORR

 -  Phase II Cohort 4 metastatic castrate-resistant prostate cancer (mCRPC); MEDI+O arm: To
 determine clinical efficacy as measured by PFS

 -  Phase II Cohort 5 triple negative breast cancer (TNBC); MEDI+O arm: To determine
 clinical efficacy as measured by ORR

 -  Phase II Cohort 6 colorectal cancer (CRC): C+MEDI arm: To determine clinical efficacy as
 measured by PFS

 Eligibility:

 -  Phase I: Advanced or recurrent solid tumors with evaluable disease.

 -  Phase II Cohort 1 MEDI+O, MEDI+C and MEDI+O+C arms: Advanced or recurrent OvCa

 -  Phase II Cohort 2 MEDI+O and MEDI+C arms: Advanced or recurrent NSCLC

 -  Phase II Cohort 3 MEDI+O arm: Advanced or recurrent SCLC

 -  Phase II Cohort 4 MEDI+O arm: mCRPC

 -  Phase II Cohort 5 MEDI+O arm: Advanced or recurrent TNBC

 -  Phase II Cohort 6 C+MEDI arm: Advanced or recurrent CRC

 -  Patients must be off prior chemotherapy, radiation therapy or biologic therapy for at
 least 3 weeks. mCPRC patients (Cohort 4) may be on hormonal therapy with GnRH
 agonists/antagonists.

 -  Adults with ECOG performance status 0-2, and adequate organ and marrow function.

 Design:

 -  Phase I: MEDI+O, MEDI+C and MEDI+O+C will dose escalate simultaneously. MEDI4736 will be
 administered once every 2 weeks or once every 4 weeks until disease progression. O
 tablets and C will be given orally on a continuous or intermittent dosing schedule. The
 DLT period will be one cycle, 28 days. Patients on the 2-week schedule greater than one
 year will be changed to the 4-week schedule until progression.

 -  MEDI+O: MEDI4736 (3 mg/kg or 10 mg/kg IV every 2 weeks, or a fixed dose of 1500 mg
 every 4 weeks) and O tablets (150 mg or 200 mg or 300 mg BID)

 -  MEDI+C: MEDI4736 (3 mg/kg or 10 mg/kg IV every 2 weeks, or a fixed dose of 1500 mg
 every 4 weeks) and C (15 mg or 20 mg or 30 mg daily or 5 days/week)

 -  MEDI+O+C: MEDI4736 (a fixed dose of 1500mg every 4 weeks) with O tablets (200 mg or
 300 mg BID) and C (15 mg or 20 mg 5 days/week)

 -  Phase II Cohort 1 OvCa MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O 300mg
 tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks).

 -  Phase II Cohort 1 OvCa MEDI+C arm: Patients will be treated with MEDI+C at RP2D (C 20mg
 once a day [5 days on/2 days off] and MEDI4736 at 1500 mg every 4 weeks).

 -  Phase II Cohort 1 OvCa MEDI+O+C arm: Patients with OvCa (Cohort 1) will be treated with
 RP2D (O tablets 300mg BID, C 20mg once a day [5 days on/2 days off] and MEDI4736 at 1500
 mg every 4 weeks).

 -  Phase II Cohort 2 NSCLC; MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O
 300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks).

 -  Phase II Cohort 2 NSCLC; MEDI+C arm: Patients will be treated with MEDI+C at RP2D (C
 20mg once a day [5 days on/2 days off] and MEDI4736 at 1500 mg every 4 weeks).

 -  Phase II Cohort 3 SCLC; MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O
 300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks).

 -  Phase II Cohort 4 mCRPC; MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O
 300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks).

 -  Phase II Cohort 5 TNBC; MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O
 300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks).

 -  Phase II Cohort 6 CRC; C+MEDI arm: Patients in the Cohort 6 will be treated with C 20mg
 daily alone for 14 days followed by the combination at RP2D (C 20mg once a day [5 days
 on/2 days off] and MEDI4736 at 1500 mg every 4 weeks).

 -  Phase II Correlative studies: Research samples including whole blood, CTCs, cell free
 DNA and plasma will be obtained at pretreatment, prior to cycle 1 day 15, prior to cycle
 3 day 1 and at progression. Mandatory baseline core biopsy and two optional biopsies
 will be obtained.

 -  Patients will be evaluated for toxicity every 4 weeks by CTCAEv4.0, and for response
 every two cycles (8 weeks) by RECIST 1.1. Patients with mCRPC (MEDI+O Cohort 4) will be
 evaluated for response initially at 8 weeks then every 12 weeks using RECIST v1.1
 criteria as per the Prostate Cancer Clinical Trials Working Group 2 (PCWG2).
-  ELIGIBILITY:

 INCLUSION CRITERIA GENERAL:

 -  Patients must be at least 18 years of age.

 -  Patients must have adequately controlled blood pressure on a maximum of three
 antihypertensive medications.

 -  Patients who have the following clinical conditions are considered to be at increased
 risk for cardiac toxicities.

 Patients with any cardiac history of the following conditions within 1 year prior to study
 enrollment are excluded from the study:

 -  Prior events including myocardial infarction, pericardial effusion, and myocarditis.

 -  Prior cardiac arrhythmia including atrial fibrillation and atrial flutter, or
 requiring concurrent use of drugs or biologics with pro-arrhythmic potential.

 -  NYHA Class II or greater heart failure.

 -  If cardiac function assessment is clinically indicated or performed, an LVEF less than
 normal per institutional guidelines, or <55%, if threshold for normal is not otherwise
 specified by institutional guidelines.

 -  QTc prolongation >470 msec or other significant ECG abnormality noted within 14 days
 of treatment.

 -  Hypertensive crisis or hypertensive encephalopathy.

 -  Clinically significant peripheral vascular disease or vascular disease, including
 rapidly growing aortic aneurysm or abdominal aortic aneurysm >5 cm or aortic
 dissection.

 -  Unstable angina.

 -  Eligibility for patients with asymptomatic and a previous diagnosis of immune or
 inflammatory colitis, or patients with chronic diarrhea > 1 month without immune
 or inflammatory colitis is a PI decision on an individual patient basis.

 -  Patients with a history of cerebrovascular accident or transient ischemic attack
 within 1 year prior to study enrollment are not eligible.

 -  Patients with a history of previous clinical diagnosis of tuberculosis are not
 eligible.

 -  Patients with a history of auto-immune disease requiring steroid maintenance, or
 history of primary immunodeficiency are not eligible.

 -  HIV-positive patients on antiretroviral therapy are ineligible because of
 potential pharmacokinetic interactions with study drugs, however, patients with
 long-standing (>5 years) HIV on antiretroviral therapy > 1 month (undetectable
 HIV viral load and CD4 count > 150 cells/microL) may be eligible if the PI
 determines no anticipated clinically significant drug-drug interactions.

 -  HBV-or HCV-positive patients are ineligible because of potential reactivation of
 hepatitis virus following steroids.

 -  Patients with a history of allergic reactions attributed to compounds of similar
 chemical or biologic composition to MEDI4736, olaparib, cediranib, or to other
 humanized monoclonal antibodies, or a history of anaphylaxis, angioedema,
 laryngeal edema, serum sickness, or uncontrolled asthma, are not eligible.

 -  Patients who have had prior immune checkpoint inhibitors, such as MEDI4736 or
 other PD1 or PD-L1 inhibitors or an anti-CTLA4 therapy are eligible.

 -  Pregnant and breastfeeding women are excluded from this study.

 -  Patients with any other concomitant or prior invasive malignancies are
 ineligible.

 PHASE II MEDI4736 PLUS OLAPARIB OR CEDIRANIB STUDY ELIGIBILITY CRITERIA - OVARIAN CANCER

 -  Patients must have histologically or cytologically confirmed persistent or recurrent
 ovarian, fallopian tube, or primary peritoneal cancer and have received at least two
 prior regimens or who are platinum resistant or refractory during or after a first
 platinum containing regimen.

 -  Patients must have at least one lesion deemed safe to biopsy and be willing to undergo
 a mandatory baseline biopsy.

 -  Patients are allowed to have received prior PARPi, and/or anti-angiogenesis therapy
 including but not limited to thalidomide, bevacizumab, sunitinib, sorafenib, or other
 anti-angiogenics. However, patients who were treated with both olaparib and cediranib,
 either in combination or sequentially are not eligible. For this study, BSI-201
 (iniparib) is not considered as PARPi.

 PHASE II STUDY MEDI4736 PLUS OLAPARIB ELIGIBILITY CRITERIA TRIPLE NEGATIVE BREAST CANCER

 -  Patients must have histologically confirmed persistent or recurrent triple-negative
 breast cancer (TNBC)

 -  ER/PR/HER2 status needs to be documented either by an outside source or at NCI.

 -  Documentation of germline BRCA1 and BRCA2 mutation (gBRCAm) status will be required
 for eligibility.

 -  Patients must have measurable disease as defined by RECIST v1.1.

 -  Patients must have at least one lesion deemed safe to biopsy and be willing to undergo
 a mandatory baseline biopsy.

 -  Patients who have received prior PARPi are ineligible.

 -  Patients must not have evidence of CNS metastasis or leptomeningeal disease within one
 year prior to enrollment.

 PHASE II MEDI4736 PLUS OLAPARIB OR CEDIRANIB STUDY ELIGIBILITY CRITERIA - NON-SMALL CELL
 LUNG CANCER

 -  Histologically or cytologically confirmed advanced NSCLC with at least one prior line
 of platinum-based chemotherapy (or treatment with EGFR, ALK, or BRAF-targeted tyrosine
 kinase inhibitors if tumors harbor an EGFR-sensitizing mutation, ALK translocation, or
 BRAF V600E mutation, respectively).

 -  Patients must have measurable disease as defined by RECIST v1.1.

 -  Patients must have at least one lesion deemed safe to biopsy and be willing to undergo
 a mandatory baseline biopsy.

 -  Patients who have received anti-angiogenesis therapy are eligible, including but not
 limited to thalidomide, bevacizumab, sunitinib, sorafenib, or other anti-angiogenics.
 However, patients who were treated with cediranib, either in combination or
 monotherapy are not eligible.

 -  Current or prior use of immunosuppressive medication within 28 days before the first
 dose of MEDI4736, with the exception 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.

 -  Patients who have had prior PARPi are not eligible.

 -  Patients with prior history of pneumonitis and/or interstitial lung disease will be
 excluded.

 PHASE II MEDI4736 PLUS OLAPARIB STUDY ELIGIBILITY CRITERIA - METASTATIC CASTRATE-RESISTANT
 PROSTATE CANCER

 -  Patients must have metastatic, progressive, castrate resistant prostate cancer
 (mCRPC).

 -  All patients must have at least one lesion deemed safe to biopsy and be willing to
 undergo a mandatory baseline biopsy.

 -  Patients must have received prior treatment with enzalutamide and/or abiraterone with
 the exception of patients who were treated with docetaxel and androgen deprivation
 therapy for metastatic castrate-sensitive prostate cancer and progressed on docetaxel
 treatment or who progress within one month of the last docetaxel dose.

 -  Patients must have undergone bilateral surgical castration or must agree to continue
 on GnRH agonists/antagonists for the duration of the study.

 -  Patients who have had progression of prostate cancer on prior docetaxel treatment for
 castrate sensitive disease are ineligible.

 -  Patients who have had prior treatment with PARPi are not eligible.

 -  Patients who have received radionuclide treatment within 6 weeks prior to the first
 dose of the study treatment are not eligible.

 -  Patients with any other concomitant or prior invasive malignancies are ineligible.