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

• 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.
• 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 not eligible.
• Pregnant and breastfeeding women are excluded from this study.
• Patients with any other concomitant or prior invasive malignancies are ineligible.

PHASE I STUDY ELIGIBILITY CRITERIA

• Patients must have histologically or cytologically confirmed advanced solid tumor that is refractory to standard treatment or for which no standard treatment exists, with evaluable disease.
• Patients are allowed to have received prior PARP inhibitors (PARPi), and/or anti-angiogenesis therapy. 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 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 platinum-containing 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 more than three lines of prior therapy in the metastatic or recurrent settings are not eligible.
• Patients who have received prior PARPi or immune checkpoint inhibitors are ineligible.

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 or ALK tyrosine kinase inhibitors if tumors harbor an EGFR-sensitizing mutation or ALK translocation 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. However, patients who were treated with cediranib, either in combination or monotherapy are not eligible.
• Patients who have had prior PARPi are not eligible.
• Patients who have received more than three lines of prior therapy in the metastatic or recurrent settings 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 - SMALL CELL LUNG CANCER

• Histologically or cytologically confirmed SCLC with at least one prior line of platinum-based chemotherapy are eligible. Patients with both platinum-sensitive and platinum-refractory disease will be eligible.
• 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. However, patients who were treated with cediranib, either in combination or monotherapy are not eligible.
• Patients who have had prior PARPi are not eligible.
• Patients who have received more than three lines of prior therapy in the metastatic or recurrent settings are not eligible.
• Patients with any other concomitant or prior invasive malignancies are ineligible. 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.
• 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 treatment with docetaxel for the treatment of metastatic castrate-sensitive prostate cancer within 6 months before the first dose of study treatment are not eligible.
• 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.

PHASE II MEDI4736 PLUS CEDIRANIB ELIGIBILITY CRITERIA - COLORECTAL CANCER

• Histologically or cytologically confirmed advanced colorectal cancer. Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and irinotecan-containing chemotherapeutic regimen, and have disease that is not amenable to potentially curative resection. Patients who have a known KRAS wild type tumor must have progressed, been intolerant of or refused cetuximab or panitumumab-based chemotherapy.
• Patients are allowed to have received prior anti-angiogenesis therapy with the exception of prior cediranib. However, patients must not have received other anti-angiogenesis therap(ies) within 6 months prior to study enrollment.
• Patients must be MSI-stable (or low).
• Patients must have at least one focus of metastatic disease that is amenable to pre-and on-treatment biopsy.
• Patients who were previously treated with cediranib are ineligible.
• Patients with any other concomitant or prior invasive malignancies are ineligible.
• Patients with prior history of pneumonitis and/or interstitial lung disease will be excluded.

Additional eligibility criteria may apply as defined per protocol.