A Study to Evaluate the Safety and Antitumor Activity in Subjects With Advanced Solid Tumor

• Pharmacokinetic Assessment [ Time Frame: 21 - 105 days ] [ Designated as safety issue: No ]
  Determine AUC, Cmax, CL, half-life (t1/2) of MEDI3617
• Immunogenicity Assessment [ Time Frame: 21 - 105 days ] [ Designated as safety issue: No ]
  Assess antidrug antibodies
• Efficacy Assessments [ Time Frame: 21 - 105 days ] [ Designated as safety issue: Yes ]
  Assess objective response rate (ORR), time to progression (TTP), duration of response (DR), time to response (TTR), progression-free survival (PFS), overall survival (OS) of MEDI3617
• Pharmacodynamic Assessments [ Time Frame: 21 - 105 days ] [ Designated as safety issue: No ]
  Evaluate the profiles of both circulating levels of Ang2 and Ang1 post MEDI3617 administration

To determine the maximum tolerated dose or optimal biological dose, and the safety profile of MEDI3617 when given as a single-agent or in combination with other chemotherapeutic agents in subjects with advanced solid malignancies resistant to standard therapy.

• Advanced Solid Tumors
• Advanced Recurrent Ovarian Tumors

• Drug: MEDI3617
  1 of 7 doses of MEDI3617 given (ex: Dose 1, 2, 3, etc) every 21 days in order to determine two safe and tolerated doses that will be used in the dose expansion phase as both Dose Level A and Dose Level B
• Drug: MEDI3617 + Bev Q3W Dose Escalation
  1 of 4 doses MEDI3617 + bev at 15mg/kg every 21 days
• Drug: MEDI3617 + Bev Q2W Dose Escalation
  1 of 4 doses MEDI3617 + bev at 10mg/kg every 28 days
• Drug: MEDI3617 + Bev Optional Dose Expansion
  Up to 2 tumor types, based on signal of antitumoral activity, may be selected for dose-expansion with combination of MEDI3617 + bev. from the single-agent dose escalation arm. Subjects will each receive MEDI3617 (MTD) + bev 15mg/kg or 10mg/kg via IV infusion every 21 or 28 days, respectively.
• Drug: MEDI3617 + Weekly Pax Dose Escalation
  IV infusions of MEDI3617 at MTD/OBD-1 or MTD/OBD Q2W (Days 1, 15) + 80 mg/m2 weekly paclitaxel (Days 1, 8, 15) every 28 days
• Drug: MEDI3617 + Pax & Carbo Q3W Dos Esc
  IV infusions of MEDI3617 at MTD/OBD-1 or MTD/OBD Q3W (Day 1) + AUC5 carboplatin (Day 1) + 175 mg/m2 paclitaxel (Day 1) evey 21 days
• Drug: MEDI3617 + Gem & Carbo Q3W Dos Esc
  IV infusions of MEDI3617 at MTD/OBD-1 or MTD/OBD Q3W (Day 1) + 1000 mg/m2 gemcitabine (Days 1, 8) + AUC4 carboplatin (Day 1) evey 21 days
• Drug: Advanced Recurrent Ovarian Tumors
  25 subjects to receive MEDI3617 at the MTD/OBD dose tested as a single-agent via IV infusion every 21 days

• Experimental: MEDI3617-Dose Escalation All SolidTumors
  1 of 7 doses of MEDI3617 (ex: Dose 1, 2, 3, etc) given as IV infusions q 21 days until unacceptable toxicity, documented disease progression, or other reasons. This arm could enroll 24-42 subjects.
  Intervention: Drug: MEDI3617
• Experimental: MEDI3617 + Bev Q3W Dose Escalation
  1 of 4 doses of MEDI3617 with bevacizumab (15mg/kg) via IV infusion every 21 days until unacceptable toxicity, documented disease progression, or other reasons. This arm could enroll 12-24 subjects.
  Intervention: Drug: MEDI3617 + Bev Q3W Dose Escalation
• Experimental: MEDI3617 + Bev Q2W Dose Escalation
  1 of 4 doses of MEDI3617 with bevacizumab (10mg/kg) via IV infusion every 28 days until unacceptable toxicity, documented disease progression, or other reasons. This arm could enroll 12-24 subjects.
  Intervention: Drug: MEDI3617 + Bev Q2W Dose Escalation
• Experimental: MEDI3617 + Bev Optional Dose Expansion
  Up to 2 tumor types, based on a signal of antitumor activity observed with MEDI3617 + bevacizumab at either 15mg/kg (Q3W) or 10mg/kg (Q2W) via IV infusion every 21 or 14 days, respectively until unacceptable toxicity, documentation of disease progression or other reasons. Each arm could enroll up to 16 subjects per arm for an overall total of 32 subjects.
  Intervention: Drug: MEDI3617 + Bev Optional Dose Expansion
• Experimental: MEDI3617 + Weekly Pax Dose Escalation
  Cohorts of 3 to 6 evaluable subjects will each receive 1 of 2 doses of MEDI3617 on Days 1 and 15 and paclitaxel 80 mg/m2 on Days 1, 8, and 15 via IV infusion every 28 days until unacceptable toxicity, documentation of disease progression, or other reasons. Enrollment of 6 to 12 subjects.
  Intervention: Drug: MEDI3617 + Weekly Pax Dose Escalation
• Experimental: MEDI3617 + Pax & Carbo Q3W Dos Esc
  Cohorts of 3 to 6 evaluable subjects will each receive 1 of 2 doses of MEDI3617 (MTD/OBD-1 or MTD/OBD), carboplatin (AUC 5 by Calvert formula), and paclitaxel (175 mg/m2) on Day 1 via IV infusion every 21 days for up to 6 cycles (cycle length = 21 days) or until unacceptable toxicity, documentation of disease progression, or other reasons. Enrollment of 6-12 subjects.
  Intervention: Drug: MEDI3617 + Pax & Carbo Q3W Dos Esc
• Experimental: MEDI3617 + Gem & Carbo Q3W Dos Esc
  Cohorts of 3 to 6 evaluable subjects will each receive 1 of 2 doses of MEDI3617 (MTD/OBD-1 or MTD/OBD) on Day 1, gemcitabine (1000 mg/m2) on Days 1 and 8, and carboplatin (AUC 4 by Calvert formula) on Day 1 via IV infusion every 21 days for up to 6 cycles (cycle length = 21 days) or until unacceptable toxicity, documentation of disease progression, or other reasons. Enrollment of 6-12 subjects.
  Intervention: Drug: MEDI3617 + Gem & Carbo Q3W Dos Esc
• Experimental: Advanced Recurrent Ovarian Tumors
  Upon completion of the single-agent dose-escalation phase, 25 subjects with advanced recurrent ovarian cancer will receive MEDI3617 at the MTD/OBD dose level tested as a single-agent
  Intervention: Drug: Advanced Recurrent Ovarian Tumors

Inclusion Criteria:

• Patients with confirmed diagnosis of advanced solid tumors (dose-escalation phase) or another solid tumor type based on antitumoral activity (dose-expansion phase) that are not responsive to standard therapy or for which no standard therapy exists
• Patients must be 18 years of age or older
• Karnofsky Performance Status ≥ 70
• Toxicities from previous cancer therapies must have recovered to CTCAE Grade = or < 2
• Adequate organ and marrow function
• Using adequate contraceptive measures, be surgically sterile or post-menopausal

Exclusion Criteria:

• Concurrently enrolled in another clinical study, except for non-interventiona observational studies, or if in a follow up period from a previous study
• Receipt of any investigational anticancer therapy within 30 days prior to the first dose of MEDI3617, or in the case of monoclonal antibodies (eg, bevacizumab), 42 days prior to the first dose of MEDI3617
• Current or previous treatment with angiopoietin inhibitors, or inhibitors of Tie1 or Tie2 including, but not limited to, AMG386, CVX-060, XL880, and XL820
• Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment
• Use of immunosuppressive medication or systemic steroids within 7 days prior to first dose of MEDI3617
• Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results
• Known bleeding diathesis
• Pulmonary hemorrhage or gross hemoptysis within 6 months prior to enrollment
• Therapeutic or palliative radiation therapy within 2 weeks prior to enrollment