AMG386 Comb w. Either Pegylated Liposomal Doxorubicin or Topotecan Subjects w. Advanced Recurrent Epithelial Ovarian CR

Study Overview
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Brief Summary
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This study is a 2 part, 2 cohort, open-label, dose escalation/de escalation study of AMG 386 in combination with either pegylated liposomal doxorubicin or topotecan in subjects with recurrent ovarian cancer. Up to 100 subjects will be enrolled to receive AMG 386 in combination with either pegylated liposomal doxorubicin every 4 weeks (cohort A) or topotecan weekly on days 1, 8, and 15 of a 28 day dosing schedule (cohort B). Subject enrollment and assignment to either cohort will be based on eligibility and the investigator's discretion. It is hypothesized that AMG 386, in combination with each of the chemotherapy regimens: either pegylated liposomal doxorubicin or topotecan will be safe and well tolerated in subjects with recurrent ovarian cancer.

Detailed Description
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The purpose of this study is to evaluate the effectiveness and safety of AMG 386 when used with pegylated liposomal doxorubicin or topotecan in subjects with advanced recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer

Official Title
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A Phase 1b Study of AMG 386 in Combination With Either Pegylated Liposomal Doxorubicin or Topotecan in Subjects With Advanced Recurrent Epithelial Ovarian Cancer

Conditions
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Cancer, Carcinoma, Fallopian Tube Cancer, Gynecological Malignancies, Metastases, Oncology, Ovarian Cancer, Solid Tumors, Tumors

Intervention / Treatment
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* Drug: A1: AMG 386 10 mg/kg + Liposomal doxorubicin
* Drug: A3: AMG 386 15mg/kg + Liposomal doxorubicin
* Drug: B1: AMG 386 10 mg/kg + Topotecan
* Drug: B3: AMG 386 15mg/kg + Topotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically documented recurrent invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer Subjects must have received at least one platinum containing regimen Radiographically documented progression per RECIST criteria with modifications or progression of CA 125 as adopted by GCIG during or subsequent to the last chemotherapy regimen Subjects may include those with measurable or non measurable disease All scans and x-rays used to document measurable or non measurable disease must be done within 28 days prior to enrollment Female 18 years of age or older at the time the written informed consent is obtained GOG Performance Status of 0 or 1 Left Ventricular Ejection Fraction (LVEF) >= institutional lower limit of normal for subjects assigned to cohort A only Adequate organ function as assessed by laboratory studies (hematological and chemistries) Life expectancy >= 3 months (per investigator opinion) Subjects of child bearing potential who have not undergone a bilateral salpingo oophorectomy and are sexually active must consent to use an accepted and effective double barrier non hormonal method of contraception from signing the informed consent through 6 months after last dose of study drug Exclusion Criteria: Subjects believed to be a higher than average risk of bowel perforation. This includes symptoms of partial or complete bowel obstruction, recent (within 6 months) history of fistula or bowel perforation, subjects requiring total parenteral nutrition and continuous hydration Previous abdominal /or pelvic external beam radiotherapy Known history of central nervous system metastases Subjects with a history of prior malignancy, except: Malignancy treated with curative intent and with no known active disease present for >= 3 years before study day 1 and felt to be at low risk for recurrence by treating physician Adequately treated non melanomatous skin cancer or lentigo maligna without evidence of disease Adequately treated cervical carcinoma in situ without evidence of disease Prior myeloablative high dose chemotherapy with allogeneic or autologous stem cell (or bone marrow) transplant History of arterial or deep venous thromboembolism within 12 months prior to enrollment Clinically significant cardiac disease within 12 months prior to enrollment Prior treatment with doxorubicin or pegylated liposomal doxorubicin (cohort A subjects) and topotecan (cohort B subjects) Current or within 30 days prior to enrollment treatment with immune modulators such as systemic cyclosporine and tacrolimus

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1<br>In part 1, six subjects will be assigned to each cohort A or B. This is a dose escalation/de escalation study with a 6 + 3 design based on the incidence of DLTs (dose limiting toxicities) during the first 4 weeks of combined therapy [(cohort A: AMG 386 and pegylated liposomal doxorubicin) or (cohort B: AMG 386 and topotecan)]. | Drug: A1: AMG 386 10 mg/kg + Liposomal doxorubicin<br>* Liposomal doxorubicin 50 mg/m2 IV Q4W in combination with AMG 386 10 mg/kg IV QW<br>* Other names: AMG 386;Drug: A3: AMG 386 15mg/kg + Liposomal doxorubicin<br>* A3: AMG 386 15 mg/kg IV QW + Liposomal doxorubicin 50 mg/m2 IV Q4W<br>* Other names: Liposomal doxorubicin;Drug: B1: AMG 386 10 mg/kg + Topotecan<br>* B1: AMG 386 10 mg/kg IV QW + Topotecan 4 mg/m2 IV days 1, 8, 15, of a 28 day dosing schedule<br>* Other names: AMG 386;Drug: B3: AMG 386 15mg/kg + Topotecan<br>* AMG 386 15mg/kg IV QW + Topotecan 4mg/m2 IV days 1, 8, 15 of a 28 day dosing schedule<br>* Other names: Topotecan;|
| Experimental: Part 2<br>The decision on declaration of a safe and tolerable dose during part 1 will lead to part 2 (cohort A: liposomal doxorubicin + AMG 386 MTD (max tolerated dose) of part 1, cohort B: Topotecan + AMG 386 MTD (max tolerated dose) of part 1 | Drug: A1: AMG 386 10 mg/kg + Liposomal doxorubicin<br>* Liposomal doxorubicin 50 mg/m2 IV Q4W in combination with AMG 386 10 mg/kg IV QW<br>* Other names: AMG 386;Drug: A3: AMG 386 15mg/kg + Liposomal doxorubicin<br>* A3: AMG 386 15 mg/kg IV QW + Liposomal doxorubicin 50 mg/m2 IV Q4W<br>* Other names: Liposomal doxorubicin;Drug: B1: AMG 386 10 mg/kg + Topotecan<br>* B1: AMG 386 10 mg/kg IV QW + Topotecan 4 mg/m2 IV days 1, 8, 15, of a 28 day dosing schedule<br>* Other names: AMG 386;Drug: B3: AMG 386 15mg/kg + Topotecan<br>* AMG 386 15mg/kg IV QW + Topotecan 4mg/m2 IV days 1, 8, 15 of a 28 day dosing schedule<br>* Other names: Topotecan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective is to identify the incidence of adverse events and clinical laboratory abnormalities defined as dose limiting toxicity in subjects treated with AMG 386 + pegylated liposomal doxorubicin (cohort A) and with AMG 386 + topotecan |  | first 4 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the treatment effect as measured by: objective response rate (ORR), duration of response (DOR), PFS, change in tumor burden, CA 125 Response and Progression by GCIG and CA-125 duration of response |  | Treatment and follow-up phase of study | 
| To evaluate the incidence of adverse events and clinical laboratory abnormalities not defined as DLTs. |  | first 4 weeks of treatment | 
| To determine the pharmacokinetics of pegylated liposomal doxorubicin (and its metabolite, doxorubicinol), topotecan and AMG 386 (Cmax, AUC, and Cmin for intensive assessment; Cmax and Cmin for sparse assessment). |  | Treatment and follow-up phase of study | 
| To estimate the incidence of anti AMG 386 antibody formation. |  | Treatment and follow-up phase of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fallopian tube cancer, Gynecological Malignancy, primary peritoneal cancer of predominantly epithelial origin, Stage II to IV ovarian cancer