Study of AMG 479 as Second Line Therapy in Patients With Recurrent Platinum-sensitive Ovarian Cancer

Study Overview
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Brief Summary
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The purpose of this study is to obtain an estimate of the objective response rate (ORR) of AMG 479 in patients with recurrent platinum-sensitive ovarian epithelial (including fallopian tube and primary peritoneal) carcinoma failing frontline chemotherapy.

Official Title
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A Multicenter Open Label Phase II Study of the Efficacy and Safety of AMG 479, a Fully Human Monoclonal Antibody Against Insulin-like Growth Factor Type 1 Receptor (IGF-1R) as Second Line Therapy in Patients With Recurrent Platinum Sensitive Ovarian Cancer

Conditions
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Ovarian Neoplasms

Intervention / Treatment
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* Biological: AMG 479


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed ovarian epithelial (including fallopian tube and primary peritoneal) carcinoma. Baseline paraffin embedded tissue from the patient's primary diagnosis is requested before study enrollment and should be forwarded to the designated central laboratory. In patients with measurable disease or sufficient ascites, fresh frozen tissue or ascites fluid should be obtained by needle biopsy and submitted to the designated central laboratory. Prior treatment with at most 1 treatment regimen in the primary treatment setting. Platinum-sensitive disease defined by recurrence or progression of disease > 6 months AND < 24 months after completion of prior platinum based chemotherapy. Female > 18 years of age or legal age. ECOG performance status ≤ 1. Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Subjects with non-measurable disease with a biochemical recurrence are eligible provided the CA 125 is elevated by more than 2 times the upper limits of normal, confirmed in two successive samples, drawn at least one week apart. Resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE v.3.0 Grade ≤ 1 and to baseline laboratory values as defined in the inclusion criterion immediately below. Adequate organ and bone marrow function Nondiabetic patients or Type 1 or 2 Diabetic Patients controlled with HgbA1c < 8% and fasting blood glucose level <160 mg/dL Adequate coagulation parameters (within 21 days prior to registration), International Normalized Ratio (INR) ≤1.5; Activated ProThrombin Time (APTT) ≤ 1.5 x ULN. Exclusion Criteria: More than 1 prior chemotherapy regimen in the treatment of ovarian cancer. Platinum-resistant disease as defined by a recurrence or progression less or equal to six months after completion of the frontline platinum based chemotherapy. Anticipation of a need for a major surgical procedure (e.g., impending bowel obstruction, gastrointestinal perforation) or radiation therapy during the trial. Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or for in situ carcinoma of the cervix uteri. 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. History of hypersensitivity to recombinant proteins. Prior treatment with a humanized monoclonal antibody. Treatment with chemotherapy, radiotherapy, surgery, blood products, or an investigational agent within 3 weeks of trial enrolment. Any of the following within 6 months prior to trial registration: 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, 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 evidently 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. Mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the trial. Refusal or inability to give informed consent to participate in the trial. 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 trial results, and in the judgment of the investigator would make the patient inappropriate for entry into this trial.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMG 479<br>AMG 479 administered on day 1 of each 21-day cycle up to disease progression, unacceptable toxicity, withdrawal of consent or sponsor decision to stop the study. | Biological: 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 |
| --- | --- | --- |
| Objective Response Rate (ORR) Investigator Assessment: % of Patients in the Group Who Achieve a Complete Response(CR) or Partial Response(PR) According to RECIST Criteria and GCIG CA125 Response Criteria. - Assessments of the Response by the Investigators | RECIST(v1.0):CR:disappearance of all target lesions or disappearance of all nontarget lesions & normalization of tumor marker level/•PR:at least 30% decrease in the sum of the longest diam(LD) of target les° taking as ref the baseline sum LD OR CR for target les° & incomplete response/SD for nontarget les°. CR & PR to be confirmed no less than 4 wks after initial doc of response.The def of the resp acc to serum CA125 level was as per GCIGCA125 criteria: PR:elevated CA125 at baseline PR considered if a ≥ 50% decrease compared to baseline value was observed on 2 consecutive assessmts drawn at least 1 wk apart CR:elevated CA125 at baseline CR was def with 2 CA125 values below ULN observed on 2 consecutive assessmts drawn at least 1 wk apart A pt was considered to have a best overall resp of:CR:if CR as per RECIST & CA125 /-PR: if CR as per RECIST & PR as per CA125 OR CR as per RECIST and SD as per CA125 with elevated CA125 at baseline OR PR as per RECIST & CR/PR or SD as per CA125 | Radiological Tumor assessment: Every 9 (+/- 1 ) weeks during study treatment until documentation of progression or end of study treatment + confirmation PR or CR no less than 4 weeks after initial documentation of response + CA 125: Day 1 of each cycle | 
| Objective Response Rate (ORR) Independent Radiology Committee % of Patients in the Group Who Achieve a Complete or Partial Response According to RECIST Criteria and GCIG CA 125 Response Criteria. | RECIST(v1.0):CR:disappearance of all target lesions or disappearance of all nontarget lesions & normalization of tumor marker level/•PR:at least 30% decrease in the sum of the longest diam(LD) of target les° taking as ref the baseline sum LD OR CR for target les° & incomplete response/SD for nontarget les°. CR & PR to be confirmed no less than 4 wks after initial doc of response.The def of the resp acc to serum CA125 level was as per GCIGCA125 criteria: PR:elevated CA125 at baseline PR considered if a ≥ 50% decrease compared to baseline value was observed on 2 consecutive assessmts drawn at least 1 wk apart CR:elevated CA125 at baseline CR was def with 2 CA125 values below ULN observed on 2 consecutive assessmts drawn at least 1 wk apart A pt was considered to have a best overall resp of:CR:if CR as per RECIST & CA125 /-PR: if CR as per RECIST & PR as per CA125 OR CR as per RECIST and SD as per CA125 with elevated CA125 at baseline OR PR as per RECIST & CR/PR or SD as per CA125 | Radiological Tumor assessment: Every 9 (+/- 1 ) weeks during study treatment until documentation of progression or end of study treatment + confirmation PR or CR no less than 4 weeks after initial documentation of response + CA 125: Day 1 of each cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To Progression (TTP) Investigator Assessment | Interval from the date of registration to the date of disease progression Investigator assessment As per RECIST (v1.0), disease progression represented an increase of at least 20% in the sum of the longest diameter (SLD) of target lesions, taking as reference the smallest SLD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. | Every 9 (+/- 1 ) weeks during study treatment until documentation of progression or end of study treatment + confirmation PR or CR no less than 4 weeks after initial documentation of response | 
| Clinical Benefit Rate (CBR) Investigator Assessmt % of Patients in the gp Who Achieve a Complete Response-CR,Partial Response-PR or Stable Disease-SD for 16wks From Registrat° Considering the Global Response Combining RECIST Criteria and CA125 Assessmts | RECIST(v1.0): CR:disappearance of all target les°&non-target les°&normalization of tumor marker level PR:at least 30% decrease in the sum of the LD of target les°-ref the baseline sum LD OR CR for target les°&incomplete resp/SD for non target les° SD:insufficient shrinkage for PR or increase for PD-ref the smallest sum LD since ttmt started or Persistence of one/more non-target les°or/&maintenance of tumor marker level above the normal CA125 level: PR:elev of CA125 at baseline PR if a ≥ 50% decrease compared to baseline value observed on 2 consec assessmts drawn at least 1 wk apart CR:elev of CA125 at baseline CR 2 CA125 below ULN observed on 2 consec assessmts drawn at least 1 wk apart SD:neither CR/PR nor PD Best overall resp of : CR:if CR per RECIST & per CA125 PR:if CR per RECIST & PR per CA125 OR CR per RECIST and SD per CA125 with elev CA125 at baseline OR PR per RECIST & CR/PR or SD per CA125 SD:other cases not qualifying for progression-at least 24 wks | At 16 weeks from registration | 
| Overall Survival (OS) Investigator Assessment | Interval between the date of registration and the date of death | Day 1 of each cycle during study treatment + follow-up every 6 months for the first 3 years in the study or until death whichever occurs first | 
| Time To Marker Progression (TTMP) Investigator Assessment - Interval Form the Date of Registration to the Date of Disease Progression as Per GCIG 2005 Definition of CA 125 Progression. | The GCIG criteria (November 2005) were used to define progressive disease, based on serum CA 125 levels, as follows: Patients with elevated CA 125 pretreatment and normalization of CA 125 needed to show evidence of CA 125 greater than, or equal to, two times the ULN on two occasions at least 1 week apart or Patients with elevated CA 125 pretreatment, which never normalizes needed to show evidence of CA 125 greater than, or equal to, two times the nadir value on two occasions at least 1 week apart or Patients with CA 125 in the normal range pretreatment needed to show evidence of CA 125 greater than, or equal to, two times the ULN on two occasions at least 1 week apart. | Day 1 of each cycle | 
| Progression-free Survival (PFS) Investigator Assessment - Interval From Registration to Disease Progression or Death Due to Any Cause - According to RECIST and CA 125 | 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 | Every 9 (+/- 1 ) weeks during study treatment until documentation of progression or end of study treatment + confirmation PR or CR no less than 4 weeks after initial documentation of response |