A Study to Test the Safety and Effectiveness of the Experimental Drug, CNTO 328, in Patients With Solid Tumors

The purpose of this study is to determine the recommended dose of CNTO 328 monotherapy, in patients with solid malignant solid tumors and to estimate the clinical benefit of CNTO 328 monotherapy in patients with ovarian cancer and with KRAS mutant tumors.

CNTO 328 is an antibody. An antibody is an important substance made by the body to fight infection. IL-6 is found naturally in the body and it can promote the growth of cancer (CA) cells. By blocking the activity of IL-6 in your body, CNTO 328 may slow down cancer growth. This study is being conducted because the sponsor changed the production process of CNTO 328. This is the first time that this new CNTO 328 will be given to patients. The study consists of two parts. In part 1, groups of patients are treated with different dose levels. In part 2, the selected dose and schedule will be further explored in patients with specific tumor types. The study tests the safety and effectiveness of the experimental drug, CNTO 328 in patients with advanced cancer. This study also tests how CNTO328 is cleared from your body and how your body reacts to it. For this reason blood tests will be performed and some characteristics of the tumor are analyzed. In Part 1, patients will be treated with different dose levels. Dose Cohort 1: 2.8 mg/kg, once every 2 weeks (1 patient); Dose Cohort 2: 5.5 mg/kg, once every 2 weeks (3 patients); Dose Cohort 3: 11 mg/kg, once every 3 weeks (6 patients); Dose Cohort 4: 15 or 8.3 mg/kg, once every 3 weeks (6 patients). Patients will be evaluated for the occurrence of dose limiting toxicities (DLTs). Dose Cohort 5: up to 20 patients with ovarian cancer or KRAS mutant tumors will be treated with the dose level that is chosen based on the experience in cohort 1-4. Patients enrolling in Part 1 (Cohorts 1-4) will receive 4 administrations of CNTO 328 over a 10-13 week period. Patients enrolling in Cohort 5 will receive 12 administrations over a 33 week period. The purpose of Part 1 of the study is to determine the recommended dose of CNTO 328 in patients with malignant solid tumors. The main purpose of the part 2 study is to estimate the clinical benefit of CNTO 328 monotherapy in patients with ovarian cancer and with KRAS mutant tumors. In Part 2, the selected dose determined by Part 1 will be further explored in patients with specific tumor types. Patients participating in Part 2 of the study will be administered the recommended dose of CNTO 328 for 12 administrations over a 33 week period. Study participation for each patient will continue for a maximum of 12 weeks after the last CNTO 328 administration. To monitor the safety of the patients participating in this study, patients will be monitored for adverse events (AEs) at every visit, and the following assessments will be performed periodically: physical exam, vital signs (before and after CNTO328 administration), ECG recording (before and after CNTO328 administration), blood draw to monitor organ function and hematological parameters, urine analysis. The assessments will be performed weekly during the first 4 weeks of the study and every 2-3 weeks thereafter. Once a patient discontinues study treatment, follow up visits up to 12 weeks after last dose are scheduled. Patients may then be contacted for up to one year after the last dose for follow-up survival and disease status information. CNTO 328 is given by intravenous (IV) infusion; through a tube directly into your vein over 1 hour. In Phase 1, cohorts 1-4, doses will be administered in a range of 2.8-15 mg/kg. In Phase 2, cohort 5 will receive the recommended dose and schedule as determined from cohorts 1-4. Patients enrolling in Phase 1 (Cohorts 1-4) will receive 4 administrations of CNTO 328 over a 10-13 week period, while patients enrolling in Cohort 5 and Phase 2 will receive 12 administrations over a 33 week period.

• Ovarian Neoplasms
• Pancreatic Neoplasms
• Colorectal Neoplasms
• Head and Neck Neoplasms
• Lung Neoplasms

Inclusion Criteria:

• Histologic or cytologic documentation of malignancy as follows: solid tumors (cohorts 1-4 only)
• Cohorts 5 and phase 2: epithelial ovarian cancers that have progressed on or after standard therapy, or for which there is no effective therapy or platinum resistant and taxane resistant, defined as progression on or within 6 months of completing therapy with taxane and platinum either alone or in combination (unless contraindications for taxane or platinum exist), and for which there is no effective therapy, or patients with known KRAS mutant tumors or pancreatic cancer, or NSCLC, CRC or head and neck (H&N) cancer that are refractory or resistant to anit-EGFR therapy
• All patients must have received at least 1 line of standard chemotherapy
• Eastern Cooperative Oncology Group (ECOG) performance status score <= 2
• Patients must have recovered from reversible toxicity of previous treatment to <= Grade 1 or an acceptable baseline
• Adequate bone marrow, liver, and renal function: hemoglobin >=9.0 g/dL, absolute neutrophil count >=1.5x10^9/L, platelets >=75x10^9/L, CrCL >20mL/min, aspartate transaminase [AST], alanine transaminase [ALT] <=2.5 x upper limit of normal [ULN] if no liver metastasis, <=5 x ULN with liver metastasis total bilirubin <= 1.5 x ULN or <=3 x ULN if due to tumor obstruction alkaline phosphatase <= 3 x ULN if no liver metastasis or bone involvement, and <=5 x ULN with liver metastasis or bone involvement, coagulation prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT) within 1.5 x ULN.

Exclusion Criteria:

• Received any prior systemic therapy or had major surgery for the cancer under study within 4 weeks (in the case of nitrosoureas and mitomycin C within 6 weeks) prior to first CNTO 328 administration
• Prior anti-IL-6 targeted therapy
• Concomitant us of immunotherapy, biotherapy, radiotherapy, chemotherapy, investigative therapy, immunosuppressive therapy, or IL-6 modulating agents is prohibited during the study except for stable low-dose steroids or luteinizing hormone-release hormone (LHRH) agonists in prostate cancer patients
• Serious concurrent illness or history of uncontrolled heart disease such as: unstable angina, congestive heart failure, myocardial infarction within preceding 12 months, clinically significant rhythm or conduction abnormality
• Patients with known allergies or clinically significant reactions to murine, chimeric, or human proteins
• Any uncontrolled medical condition, including the presence of laboratory abnormalities, that places the patient at unacceptable risk by participating in the study or confounds the ability to interpret data from the study
• Clinically significant active infection within 2 weeks prior to the first CNTO 328 administration
• Known infection with human immunodeficiency virus (HIV), known hepatitis C infection or known to be hepatitis B surface antigen positive
• Known central nervous system (CNS) metastases.