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

• Ph I Determine the recommended phase II dose (RP2D) and the safety of doublet therapies of MEDI4736/olaparib (MEDI-O) and MEDI4736/cediranib (MEDI-C) in patients with advanced solid tumors [ Time Frame: 28 Days ]
• Ph II Determine overall response rate of MED-O and MEDI-C in patients with recurrent ovarian cancer [ Time Frame: Every 4 wks for Toxicity and every 8 wks for response ]

• Ph I Determine the recommended phase II dose (RP2D) and the safety of doublet therapies of MEDI4736/olaparib (MEDIO) and MEDI4736/cediranib (MEDI-C) in patients with advanced solid tumors [ Time Frame: 28 Days ]
• Ph II Determine overall response rate of MEDI-O and MEDI-C in patients with recurrent ovarian cancer [ Time Frame: Every 4 wks for Toxicity and every 8 wks for response ]

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 1 part of the study: To determine the safety of the combination of MEDI4736 with the drugs olaparib or cediranib.
• Phase 2 part of the study: To determine how effective this combination is in treating ovarian cancer.

Eligibility:

• Phase 1 part of the study: Adults age 18 or older with advanced or recurrent solid tumors that have no standard treatment.
• 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 2 weeks for 12 months.
• 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 inhibitor, MEDI4736, in recurrent OvCa and other solid tumors.

Objectives:

• Phase I: To determine the recommended phase II dose (RP2D) and the safety of doublet therapies of MEDI4736/olaparib (MEDI+O) and MEDI4736/cediranib (MEDI+C) and triplet therapy (MEDI+O+C) in patients with advanced solid tumors.
• Phase II MEDI+O: To determine clinical efficacy as measured by overall response rate (ORR) in patients with recurrent OvCa, triple negative breast cancer (TNBC) and small cell lung cancer (SCLC), OR as measured by progression-free survival (PFS) for patients with recurrent non-small cell lung cancer (NSCLC) and metastatic castration-resistant prostate cancer (mCRPC)
• Phase II MEDI+C: To determine clinical efficacy as measured by ORR for patients with recurrent OvCa OR by PFS for patients with recurrent NSCLC and colorectal cancer (CRC).

Eligibility:

• Phase I: Advanced or recurrent solid tumors with evaluable disease.
• Phase II MEDI+O: Advanced or recurrent OvCa (Cohort 1), NSCLC (Cohort 2), SCLC (Cohort 3), mCRPC (Cohort 4) and TNBC (Cohort 5)
• Phase II MEDI+C: Advanced or recurrent OvCa (Cohort 1), NSCLC (Cohort 2), and CRC (Cohort 3)
• Patients must be off prior chemotherapy, radiation therapy or biologic therapy for at least 3 weeks. mCPRC patients (MEDI+O, 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 MEDI+O: Patients in the Cohorts 1-5 will be treated with MEDI+O at RP2D (O 300mg tablets bid daily and MEDI4736 at 1500mg IV every 4 weeks).
• Phase II MEDI+C: Patients in the Cohorts 1-3 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 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).

• Lung Cancer
• Breast Cancer
• Ovarian Cancer
• Colorectal Cancer
• Prostate Cancer
• Triple Negative Breast Cancer

• Drug: Olaparib

  Olaparib tablets will be given orally on a continuous dosing schedule. The DLT period will be one cycle, 28 days.

  MEDI4736 (3mg/kg or 10mg/kg IV) and Olaparib tablets (200 mg or 300 mg BID)

  Ph II - MEDI4736 + Olaparib at RP2D

• Drug: Cediranib

  Cediranib will be given orally on a continuous dosing schedule. The DLT period will be one cycle, 28 days.

  MEDI4736 (10mg/kg IV) and Cediranib (15 mg or 20 mg or 30 mg daily)

  Ph II - MEDI4736 + Cediranib at RP2D

• Drug: MEDI4736
  Ph I - MEDI4736 will be administered once every 2 weeks for 12 months.

• Experimental: P1 MEDI+O
  Ph I MEDI4736 + olaparib dose escalation
  Interventions:

  • Drug: Olaparib
  • Drug: MEDI4736
• Experimental: P1 MEDI+C
  Ph I MEDI4736 + cediranib dose escalation
  Interventions:

  • Drug: Cediranib
  • Drug: MEDI4736
• Experimental: P2 MEDI+O
  Ph II MEDI4736 + olaparib at RP2D
  Interventions:

  • Drug: Olaparib
  • Drug: MEDI4736
• Experimental: P2 MEDI+C
  Ph II MEDI4736 + cediranib at RP2D
  Interventions:

  • Drug: Cediranib
  • Drug: MEDI4736
• Experimental: P1 MEDI+O+C
  Ph I MEDI4736 + olaparib + cediranib dose escalation
  Interventions:

  • Drug: Olaparib
  • Drug: Cediranib
  • Drug: MEDI4736

• 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.