Study of Adding AMG 479 to First Line Chemotherapy in Patients With Optimally Debulked Epithelial Ovarian Cancer

Study Overview
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Brief Summary
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This study will determine the value of adding AMG 479 (fully human monoclonal antibody against IGF-1R) to paclitaxel and carboplatin first line chemotherapy in patients with optimally debulked (<1 cm) FIGO stage III and IV (positive pleural cytology only) ovarian epithelial (including fallopian tube and primary peritoneal) carcinoma.

Official Title
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A Randomized, Double-blind, Placebo Controlled, Multi-center, Phase II Study of Adding AMG 479, a Fully Human Monoclonal Antibody Against Insulin-like Growth Factor Type 1 Receptor (IGF-1R) to First Line Chemotherapy in Patients With Optimally Debulked ( < 1 cm ) Epithelial Ovarian Cancer

Conditions
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Ovarian Neoplasms

Intervention / Treatment
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* Drug: AMG 479
* Drug: AMG 479 Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed optimally debulked (< 1 cm) FIGO stage III or stage IV (positive pleural cytology only) ovarian epithelial (including fallopian tube and primary peritoneal) carcinoma. Patients should have undergone surgical debulking, by a surgeon experienced in the management of ovarian cancer, with the aim of maximal surgical cytoreduction. All patients must be optimally debulked as defined as having no residual tumor of greater than 1 cm in the post surgical setting. Patients with stage IV disease will be eligible if a positive pleural cytology is the only extra peritoneal disease. Paraffin block (or 10 - 20 unstained slides) and fresh frozen surgical/biopsy specimens of the primary tumor are required at baseline. No prior systemic treatment in the primary disease treatment setting. Female ≥ 18 years of age or legal age. ECOG performance status ≤ 2. Adequate organ and bone marrow function Non diabetic patients or Type 1 or 2 Diabetic Patients: • Diabetes must be controlled with HgbA1c < 8% and fasting blood glucose level <160 mg/dL. Patient must be willing and able to comply with scheduled visits, and all study procedures. Informed consent obtained. Patients should be able to commence systemic therapy within 6 weeks of cytoreductive surgery. Life expectancy > 12 weeks. Adequate coagulation parameters (within 14 days prior to randomization), International Normalized Ratio (INR) ≤1.5; Activated Prothrombin Time (APTT) ≤ 1.5 x ULN Exclusion Criteria: Non-epithelial ovarian cancer, including malignant mixed Mullerian tumors. Borderline tumors (tumors of low malignant potential). Planned intraperitoneal cytotoxic chemotherapy. Prior systemic anticancer therapy for ovarian cancer. Any previous radiotherapy to the abdomen or pelvis. Patients with synchronous primary endometrial carcinoma, or a past history of primary endometrial carcinoma, are excluded unless ALL of the following criteria for describing the endometrial carcinoma are met: Stage ≤ Ib, no more than superficial myometrial invasion, no lymphovascular invasion, not poorly differentiated (i.e., not Grade 3 or papillary serous or clear cell). Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri or curatively treated DCIS/LCIS, or non-melanoma or in situ melanoma skin cancer. Prior treatment with a humanized monoclonal antibody anticancer therapeutic. Prior treatment with investigational treatment targeted to IGF axis including, but not limited to, CP 751,871, IM-A12, RO4858696. Previous exposure to AMG 479. Anticipation of a need for a major surgical procedure or radiation therapy during the study. History of hypersensitivity to recombinant proteins. Treatment with radiotherapy, surgery, or an investigational agent within 4 weeks of randomization. Any of the following within 6 months prior to study enrollment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA class III or IV congestive heart failure, cerebrovascular accident or transient ischemic attack, grade > 2 peripheral neuropathy, pulmonary embolism, deep vein thrombosis, or other thromboembolic event. History of brain metastases, spinal cord compression, or carcinomatous meningitis. Patient of child-bearing potential is pregnant (eg, positive human chorionic gonadotropin test) or is breast feeding. Patient of child-bearing potential is not willing to use adequate contraceptive precautions. Known active infection, or on antiretroviral therapy for HIV disease. Known positive test for chronic hepatitis B or C infection. Any other underlying physical or mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study. Refusal or inability to give informed consent to participate in the study. Other severe acute or chronic medical or psychiatric condition, or significant laboratory abnormality requiring further investigation that may cause undue risk for the patient's safety, inhibit protocol participation, or interfere with interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: A<br>Placebo plus paclitaxel/carboplatin chemotherapy administered on Day 1 of each 21-day cycle for 6 cycles - then 6 additional cycles of placebo administered on Day 1 of each 21-day cycle. | Drug: AMG 479 Placebo<br>* Matching placebo administered Day 1 of each 21 day cycle.<br>|
| Experimental: B<br>AMG 479 plus paclitaxel/carboplatin chemotherapy administered on Day 1 of each 21-day cycle for 6 cycles - then 6 additional cycles of AMG 479 single agent administered on Day 1 of each 21-day cycle. | Drug: AMG 479<br>* Solution for infusion - 18 mg/kg on day 1 of each 21-day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS): Time From Randomization Until Date of Progression or Death. | A patient may have been declared to have progressive disease on the basis of radiological measuremt of tumor lesions assessmt or CA125 evaluation (tumor measuremts taking precedence).Radiological progression was defined as per the RECIST guidelines (Therasse et al, JNCI2000) as at least 20% increase in the sum of the longest diameters of target lesions(ref the smallest sum of the longest diam recorded since the treatmt started or since the appearance of at least 1 new lesion).Serum CA125 progression was defined, according to the 2005 GCIG def: pts with: Elevated CA125 pretreatmt and normalization of CA125 has to show evidence of CA125≥ 2 times the upper normal limit on 2 occasions at least 1 wk apart OR Elevated CA125 pretreatmt which never normalized must show evidence of CA125≥ 2 times the nadir value on 2 occasions at least 1 wk apart OR CA125 in the normal range pretreatmt had to show evidence of CA125 ≥ 2 times the upper normal limit on 2 occasions at least 1 wk apart | Radiological tumor assessment: every 12(+/- 1) weeks for 3 years after randomization + CA 125: day 1 of each cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To Progression (TTP): Interval From the Date of Randomization to the Date of Disease Progression | A patient may have been declared to have progressive disease on the basis of radiological measuremt of tumor lesions assessmt or CA125 evaluation (tumor measuremts taking precedence).Radiological progression was defined as per the RECIST guidelines (Therasse et al, JNCI2000) as at least 20% increase in the sum of the longest diameters of target lesions(ref the smallest sum of the longest diam recorded since the treatmt started or since the appearance of at least 1 new lesion).Serum CA125 progression was defined, according to the 2005 GCIG def: pts with: Elevated CA125 pretreatmt and normalization of CA125 has to show evidence of CA125≥ 2 times the upper normal limit on 2 occasions at least 1 wk apart OR Elevated CA125 pretreatmt which never normalized must show evidence of CA125≥ 2 times the nadir value on 2 occasions at least 1 wk apart OR CA125 in the normal range pretreatmt had to show evidence of CA125 ≥ 2 times the upper normal limit on 2 occasions at least 1 wk apart | Radiological tumor assessment: every 12 (+/- 1) weeks for 3 years after randomization + CA125: day 1 of each cycle | 
| Overall Survival (OS) | Interval between the date from randomization to death from any cause whichever came first. | Day 1 of each cycle up to 4 years after randomization |