MITO 27 Randomized Phase II study on Pembrolizumab plus chemotherapy versus chemotherapy alone in recurrent, platinum-resistant ovarian cancer (a MITO Group Study)

Study design Random1.1 MITO 27 N= 138 II line chemotherapy (physician choice): - PLD 40 mg/mq d1 q28; - Weekly Paclitaxel 80 mg/mq d1,8,15 q28 Gemcitabine 1000 mg/mq gg1,8,15 q28 N= 138 R A N D O M I Z T - Recurrent, platinum resistant (no refractory) epithelial ovarian, Fallopian tube, primary Peritoneal cancer - No more than 2 previous CHT lines Evaluable or - Measurable disease II line chemotherapy (physician choice): - PLD 40 mg/mq d1 q28; - Weekly Paclitaxel 80 mg/mq d1,8,15 q28 Gemcitabine 1000 mg/mq gg1,8,15 q28 + Pembrolizumab 200 mg every 3 weeks flat dose Random1.1 MITO 27

Study design Safety: Due to the absence of phase I trial on Pembro-CHT combinations a rapid reporting, monitoring and analysis of all Significant Safety Events (SSEs) (defined below) will be performed during the first three treatment cycles of the first 45 patients randomized in the combination arms (15 for each cohort). Information regarding the occurrence of all SSEs will be reported by the Investigator to the Coordinator Centre and to the IDMC within 48 hours from the time the event becomes evident to the investigator. A SSE is defined as any of the following: • Any form of Grade 3-4 Toxicity (NCI-CTC AE, v4.03) including hospitalization; • A patient death (grade 5). MITO 27

Objectives Primary: Overall survival (OS) The combination of pembrolizumab and chemotherapy is expected to increase overall survival with respect to chemotherapy alone MITO 27

Objectives Secondary: - Progression-free survival (PFS) - Toxicity - Response rate - QoL - Correlation between PD1-PDL1 as evaluated in immuno-istochemistry and Pembrolizumab response MITO 27

Inclusion Criteria MITO 27 Cytologic / histologic diagnosis of stage IC-IV ovarian cancer, primary peritoneal or Fallopian tube cancer · Disease progressed during first line chemotherapy or disease relapsed within 6 months after the last platinum treatment (refractory patients recurring during platinum treatment of 4 weeks after the last platinum treatment are excluded) Disease evaluable by RECIST version 1.1 or Ca 125 GCIG criteria · No residual peripheral neurotoxicity > Grade 1 from previous chemotherapy treatment · PS 0-2 · Age ³ 18 and < 80 years. · Life expectancy of at least 3 months   · Written informed consent prior to performance of study specific procedures or assessments · Ability and willingness to comply with treatment and follow up assessments and procedures Adequate organ functions Hematopoietic: Leukocytes > 2,500/mm3; Absolute neutrophil count >1,500/mm3; Platelets count >100,000/mm3; Hemoglobin >9 g/dL Hepatic: AST and ALT <2.5 times upper limit of normal (ULN)*; Alkaline phosphatase <3 times ULN*; Bilirubin <1.5 times ULN *: <5 times ULN if liver metastases are present Renal: Creatinine clearance >45 mL/min International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants No other invasive malignancy within the past 3 years except non-melanoma skin cancer or in situ cervical cancer Absence of any psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. MITO 27

Exclusion Criteria MITO 27 More than two previous chemotherapy line. Patients with diagnosis of immunodeficiency or patients receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjøgren’s syndrome will not be excluded from the study Serious heart disease, including heart failure, atrioventricular block of any degree, serious arrhythmia or history of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina, symptomatic peripheral vascular disease, coronary artery by-pass graft surgery, class II, III or IV congestive heart failure as defined by the New York Heart Association (NYHA) Active infection requiring antibiotics. History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months History of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C. Patients who had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or atbaseline) from adverse events due to a previously administered agent. Note: Subjects with < Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study. Patients with evidence of interstitial lung disease. History of (non infectious) pneumonitis that required steroids or current pneumonitis Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to beginning therapy, or anticipation of the need for a major surgical procedure during the course of the study; minor surgical procedures such as fine needle aspiration or core biopsy within 1 week prior to beginning therapy are also excluded. Patients should not be breast-feeding during treatment and for 120 days following the end of treatment. Known hypersensitivity to the study drugs or to drugs with similar chemical structures. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study screening. MITO 27

Statistical consideration This is a phase II randomized multicenter trial, aiming at evaluating activity of Pembrolizumab in combination to chemotherapy versus chemotherapy alone in recurrent, platinum resistant ovarian cancer. Approximately 138 patients will be randomized in a 1:1 ratio to chemotherapy or chemotherapy-Pembrolizumab combination to ensure a sample size comprising 98 events ( 69 evaluable patients per treatment arm). The trial will provide 80% power to detect a significant improvement in the primary endpoint (median OS) for the addition of pembrolizumab to chemotherapy from 13 months to 20 months (HR 0.65, one tail alpha level of 0.1%). 46 patients will be enrolled in each cohort (weekly paclitaxel, gemcitabine, pegylated liposomal doxorubicin). With a possible accrual rate of 6 patients/month, 138 patients will be enrolled in about 24 months. MITO 27

Administrative Information Academic trial NCI of Milan sponsor Data center: NCI of Milan (MITO center) Planned study start: May 2017 Assurance and Pembrolizumab provided Merck support: Pembrolizumab and financial support for data management, insurance and drug management To participate please contact: domenica.lorusso@istitutotumori.mi.it elisa.grassi@istitutotumori.mi.it MITO 27