Study With IMC-A12 (Cixutumumab) in Patients Who Have Not Previously Been Treated With Chemotherapy With Metastatic Prostate Cancer

• Composite time to disease progression for patients treated with IMC-A12 every other week [ Time Frame: Approximately 42 months ] [ Designated as safety issue: No ]
• Area Under the Curve (AUC) of IMC-A12 administered at a dose of 20mg/kg every 3 weeks [ Time Frame: Approximately 42 months ] [ Designated as safety issue: No ]
  Samples will be taken prior to infusion and 1 hour after infusion, in every cycle
• Maximum Concentration (Cmax) of IMC-A12 administered at a dose of 20mg/kg every 3 weeks [ Time Frame: Approximately 42 months ] [ Designated as safety issue: No ]
  Samples will be taken prior to infusion and 1 hour after infusion, in every cycle

• Number of Participants with Adverse Events [ Time Frame: Approximately 42 months ] [ Designated as safety issue: Yes ]
• Time to radiographically evident disease progression [ Time Frame: Approximately 42 months ] [ Designated as safety issue: No ]
• Tumor response rate for all patients and the subset of patients with measurable disease [ Time Frame: Approximately 42 months ] [ Designated as safety issue: No ]
  Radiographic evaluation of response will be performed every 8 weeks for the patients treated with I.V. IMC-A12 at 10 mg/kg and every 9 weeks for the patients treated with I.V. IMC-A12 at 20 mg/kg.
• PSA Response Rate [ Time Frame: Approximately 42 months ] [ Designated as safety issue: No ]
  Proportion of participants with a decrease in PSA >= 50% from baseline PSA
• 6-month Progression-Free Survival (PFS) rate [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Proportion of participants who did not progress (had Stable Disease, Partial Response or Complete Response) and were alive 6 months after receiving their first dose of study medication

This single arm, multicenter, open-label, phase II study will enroll chemotherapy-naive patients with metastatic, histologically-confirmed adenocarcinoma of the prostate (stage M1 D2). Treatment will continue until there evidence of disease progression, intolerable toxicity, or other withdrawal criteria are met. Non-surgically castrated patients must continue the use of LHRH agonists during protocol treatment.

Thirty-one chemotherapy-naїve patients with asymptomatic metastatic androgen-independent prostate cancer will be enrolled and treated with I.V. IMC-A12 (Cixutumumab) at 10 mg.kg administered over 1 hour every 2 weeks. An additional 10 patients will be enrolled and treated with IMC-A12 at a dose of 20 mg/kg every three weeks. Treatment will continue until evidence of disease progression or intolerable toxicity. Radiographic evaluation of response will be performed every 8 weeks for the patients treated with I.V. IMC-A12 at 20 mg/kg.

Inclusion Criteria

• The patient is male and at least 18 years of age
• The patient has histologically-confirmed adenocarcinoma of the prostate
• The patient has radiographic evidence of metastatic prostate cancer (stage M1 [D2])
• The patient has prostate cancer unresponsive or refractory to hormone therapy

• The patient must have evidence of progressive disease defined as at least one of the following:

  • a. Progressive measurable disease: using conventional solid tumor criteria.
  • b. Bone scan progression: at least one new lesion on bone scan.
  • c. Increasing PSA: at least two consecutive rising PSA values over a reference value (PSA #1) taken at least 1 week apart. A third PSA (PSA #3) is required to be greater than PSA #2; if not, a fourth PSA (PSA #4) is required to be greater than PSA #2
• The patient has a PSA ≥ 2 ng/mL
• The patient has not received prior chemotherapy for metastatic prostate cancer
• The patient had prior surgical or medical castration with a serum testosterone level of < 50 ng/mL. If the method of castration is luteinizing hormone-releasing hormone (LHRH) agonists, the patient must be willing to continue the use of LHRH agonists during protocol treatment
• All clinically significant toxic effects (excluding alopecia) of prior surgery, radiotherapy, or hormonal therapy have resolved to grade ≤ 1 based on National Cancer Institute - Common Terminology Criteria for Adverse Events, Version 3.0 (NCI-CTCAE)
• The patient has not received antiandrogen therapy for at least 6 weeks (4 weeks for flutamide) prior to study entry and is without evidence of an antiandrogen withdrawal response. For patients whose progression is documented solely by PSA increase, the most recent PSA value enabling study entry must be drawn after the required antiandrogen washout period
• The patient has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1
• The patient has adequate organ function including: absolute neutrophil count ≥ 1500/μL; platelets ≥ 100,000/μL; hemoglobin ≥ 9.0 g/dL; bilirubin ≤ 1.5 times the institutional upper limit of normal (ULN); aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 3 times ULN (< 5x ULN if liver metastases are present); creatinine ≤ 1.5 x ULN (or calculated creatinine clearance > 60 mL/min); and urine protein ≤ 1+ (if urine protein is ≥ 2+, a 24-hour urine collection must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study)
• The patient has fasting serum glucose < 120 mg/dL or below the ULN
• The patient has adequate coagulation function as defined by an international normalized ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 1.5 ULN (unless on oral anticoagulant therapy). Patients receiving full-dose anticoagulation therapy are eligible provided they meet all other criteria, are on a stable dose of oral anticoagulant or low molecular weight heparin (and if on warfarin have a therapeutic INR between 2 and 3)
• The patient is asymptomatic from prostate cancer. Patients with minimal, infrequent cancer-related symptoms are eligible. Criteria regarding pain and analgesic use are detailed below
• The patient has a life expectancy > 6 months
• The patient, if sexually active, agrees to use contraceptives while on study
• The patient has provided signed informed consent

Exclusion Criteria

• The patient has any active malignancy (other than adequately treated nonmelanomatous skin cancer or other noninvasive or in situ neoplasms), or has an adequately-treated prior cancer but has been disease free for < 3 years
• The patient has an ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia (well-controlled atrial fibrillation is permitted), psychiatric illness/social situations, active bleeding or pathological condition that carries a high risk of bleeding (eg, tumor involving major vessels, tumor invading to rectal lumen, or known varices), or any other serious uncontrolled medical disorder in the opinion of the investigator
• The patient has a known hypersensitivity to therapeutic protein products
• The patient has known or suspected brain or leptomeningeal metastases
• The patient has received radiotherapy ≤ 21 days prior to first dose of IMC-A12
• The patient has received prior radiation therapy to > 30% of the bone marrow or prior strontium-89, rhenium-186, rhenium-188, or samarium-153 (patients who have received standard dose radiation to the pelvis for prostate cancer and no additional radiotherapy are eligible)
• The patient has a known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness
• The patient has received more than one course of radiotherapy to a single site of metastatic bony disease
• The patient has a bone scan that indicates "superscan" (ie, extensive metastasis to bone in numerous areas, too numerous to count or define)
• The patient is receiving corticosteroids (dexamethasone, prednisone, or others) for anorexia, weight loss, analgesia or other cancer-related symptoms(Corticosteroids may not be instituted once a patient has begun therapy on-study
• The patient requires ongoing, regularly scheduled opiate analgesic therapy for cancer related pain. Intermittent, infrequent low-potency opiate-use (eg, oxycodone, codeine) is permitted
• The patient has a history of prior treatment with other agents that specifically target the IGF receptor