A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI0639 in Advanced Solid Tumors

• Anti-Tumor [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  Assessments of antitumor activity will be based on the objective response rate, disease control rate, duration of response, progression-free survival, and overall survival.
• Immunogenicity [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  Immunogenicity The immunogenic potential of MEDI0639 will be assessed by summarizing the number and percentage of subjects who develop detectable antidrug antibody (ADA).

This is a first-time-in-human, Phase 1, multicenter, open-label, single-arm, dose-escalation (3+3) study to evaluate the safety, tolerability, antitumor activity, PK and immunogenicity of MEDI0639.

This is a first-time-in-human, Phase 1, multicenter, open-label, single-arm, dose-escalation (3+3) study to evaluate the safety, tolerability, antitumor activity, PK, and immunogenicity of MEDI0639 in adult subjects with advanced solid tumors refractory to standard therapy or for which no standard therapy exist. Up to 63 subjects will be enrolled at approximately 3 to 5 study centers in North America.

Inclusion Criteria:

• Histologically or cytologically confirmed solid tumors that are refractory to standard therapy or for which no standard therapy exist
• Age ≥ 18 years
• ECOG Performance Status of 0 or 1
• LVEF (measured by Echocardiogram) > 50%
• No gastrointestinal bleeding within 1 year of study entry.

• Adequate organ and marrow function:

  • Hemoglobin ≥ 10g/dL
  • Absolute Neutrophil Count ≥ 1500/mm3
  • Platelet Count ≥ 100,000/mm3
  • AST & ALT ≤ 2.5 x ULN
  • Bilirubin ≤ 1.5 x ULN
  • Cr Cl ≥ 50 mL/min (as determined by the Cockcroft-Gault equation or by 24-hour urine collection)
• Prior therapy against VEGF or VEGFRs including, but not limited to bevacizumab, sunitinib, sorafenib, pazopanib, motesanib (AMG706), or cediranib (AZD2171), is permitted so long as the agent does not have any known activity against DLL4 and the last dose received s at least 6 weeks prior to first dose of MEDI0639.
• Life expectancy ≥ 12 weeks
• Females of childbearing potential must be surgically sterile, have a sterile male partner, be premenarchal or at least 2 years postmenopausal, practice abstinence or otherwise must use 2 effective methods of contraception from the time of initiation of investigational product.
• Males, unless surgically sterile, must use 2 effective methods of contraception with a female partner and must agree to continue using such contraception for 90 days after the last dose of MEDI0639

Exclusion Criteria:

• Concurrent enrollment in another investigational clinical study
• Receipt of any investigational anticancer therapy within 4 weeks prior to the first dose of MEDI0639 or in the case of monoclonal antibodies, 6 weeks prior to the first dose of MEDI0639
• Concurrent or previous treatment with inhibitors of DLL4
• Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment
• Known bleeding diathesis, esophageal varices, or angioplasty
• Pulmonary hemorrhage or gross hemoptysis within 12 months
• Known arterial or venous thrombosis or pulmonary embolism within 2 years
• Concurrent use of systemic low molecular weight heparin or low dose warfarin
• Presence of brain metastases
• Cerebrovascular accident or transient ischemic attack within 2 years
• Cardiovascular events, such as myocardial infarction, unstable/severe angina, coronary/peripheral artery bypass graft, unstable cardiac arrhythmia requiring medication, congestive heart failure (NYHA > class II), within 2 years
• Tumors with squamous cell histology
• Major surgical procedure within 90 days
• Pregnancy or lactation
• Known HIV positive or Hepatitis A, B, or C infection