Patient case: 64-year-old female with melanoma; genetic feature: BRAF (E586K)

Clinical trial: 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

Summary: 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.

Detailed description: 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.
  -  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, 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. 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.

Relevance to patient case: not relevant