| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Recurrent Epithelial Ovarian or Primary Peritoneal Cance |
|
| E.1.1.1 | Medical condition in easily understood language |
Ovarian Cancer
Fallopian Tube Cancer
Primary Peritoneal Cancer
|
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To estimate the treatment effect as measured by progression free survival (PFS) of subjects with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer receiving AMG 386 (either 3 mg/kg or 10 mg/kg IV QW) in combination with paclitaxel (80 mg/m2 IV QW; 3 on/1 off) compared to subjects receiving paclitaxel (80 mg/m2 IV QW; 3 on/1 off) plus placebo. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of the combination regimen of
AMG 386/paclitaxel
• To estimate other measures of treatment effect (by parameters other than PFS) of subjects receiving AMG 386 in combination with paclitaxel compared to subjects receiving paclitaxel plus placebo
• To estimate the incidence of occurrence of anti-AMG 386 antibody formation
• To evaluate the AMG 386 pharmacokinetics parameters (Cmax and Cmin) when administered with paclitaxel in subjects with recurrent ovarian cancer
• To estimate the change and duration of change on blood levels of CA-125
• To evaluate the clinical benefit among subjects receiving AMG 386 10.0 mg/kg monotherapy after disease progression on paclitaxel
• To estimate the impact of AMG 386 on patient reported ovarian cancer specific symptoms using the FACT-O, the FACT-O ovarian cancer subscale (OCS) and the FACT-O 3-item (O1, O2, O3) cancer symptom specific subscale (OCS 3-item subscale) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
4.1.1 Disease related
• Subjects must have histologically or cytologically documented epithelial ovarian
(FIGO Stage II-IV), fallopian tube or primary peritoneal cancer.
• Subjects with pseudomyxoma or mesothelioma are excluded
• Radiographically documented progression per RECIST criteria with modifications or progression of CA-125 as defined by the Rustin, et al. [Appendix H] during or subsequent to the last chemotherapy regimen.
• May include subjects with measurable or non-measurable disease
• All scans and x-rays used to document measurable or non-measurable disease must be done within 4 weeks (28 days) prior to randomization
• No more than 3 previous regimens of anti-cancer therapy. Subjects must have received at least one platinum containing regimen.
4.1.2 Demographic
• Female 18 years of age or older at the time the written informed consent is obtained.
• Subjects of child-bearing potential who have not undergone a bilateral
salpingo-oophrectomy and are sexually active must consent to use an accepted and effective non-hormonal method of contraception (ie, double barrier method (eg, condom plus diaphragm)) from signing the informed consent through 6 months after last dose of study drug.
4.1.3 General
• GOG Performance Status of 0 or 1
• Subject plans to begin protocol directed therapy within 7 days of randomization
4.1.4 Laboratory
• Adequate organ and hematological function as evidenced by the following laboratory studies within 2 weeks (14 days) of randomization:
• Hematological function, as follows:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L and ≤ 850 x 109/L
• Hemoglobin ≥ 9 g/dL
• PTT or aPTT ≤ 1.5 x ULN per institutional laboratory range and INR ≤ 1.5 per institutional laboratory range
• Renal function, as follows:
• Creatinine ≤ 2.0 mg/dL
• Calculated creatinine clearance > 40 cc/min according to the Cockcroft-Gault formula
CrCl (140-age) x actual body weight (kg)
(mL/min 72 x serum creatinine (mg/dL)
(x 0.85 for females)
• Urinary protein quantitative value of < 30 mg/dl in urinalysis or
< 1+ on dipstick, unless quantitative protein is < 1000 mg in a
24 hour urine sample
• Hepatic function, as follows:
• Total bilirubin ≤ 2.0 x ULN per institutional normal laboratory range
• SGOT (AST) and SGPT (ALT) ≤ 2.5 x ULN per institutional normal
laboratory range (≤ 5 x ULN if liver metastases are present)
• Nutritional
• Albumin ≥ 2.8 mg/dL |
|
| E.4 | Principal exclusion criteria |
4.2.1 Disease Related
• Subjects believed to be a higher than average risk for 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
• Known ongoing small bowel dysfunction (ie, persistent nausea, vomiting)
• Radiotherapy ≤ 14 days prior to randomization. Subjects must have recovered from all radiotherapy-related toxicities
• If all sites of disease have been irradiated, documented progression must have occurred in at least one site of disease subsequent to the radiation therapy.
• Previous abdominal radiotherapy
• Has not yet completed a 21 day washout period for any previous anti-cancer systemic therapies (60 days for bevacizumab or any molecule of long half-life).
• Enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s), or is receiving other investigational agent(s)
• Current or prior history of central nervous system metastasis
• Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 peripheral neuropathy ≥ grade 2
• Concurrent or prior (within 1 week before study day 1) anticoagulation therapy, excluding aspirin and anti-platelet agents. The concurrent use of low molecular weight heparin or low dose warfarin (ie, ≤ 1 mg daily) for prophylaxis against thrombosis is acceptable while on study
• History of bleeding diathesis or clinically significant bleeding within 14 days of randomization
• Major surgical procedure within 4 weeks (28 days) prior to Study Day 1
• Minor surgical procedure, or placement of central venous access device, within 7 days of Study Day 1
• Paracentesis and/or thoracentesis are permitted prior to and while on study at the discretion of the investigator as clinically indicated. Investigators should document the frequency of paracenteses and/or thoracentesis that occurred prior to the enrollment of the subject in this study on the appropriate eCRFs. Investigators should also document each paracentesis and/or thoracentesis that occurs while a subject is on study on the appropriate eCRFs.
• Subjects with a history of prior malignancy, except:
• Malignancy treated with curative intent and with no known active
disease present for ≥ 3 years before enrollment 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
• Clinically significant cardiac disease within 12 months of study enrollment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent
• Non-healing wound, ulcer or fracture
• Ongoing or active infection
• Unacceptable hypersensitivity to paclitaxel or drugs containing cremophor
• Known positive test for human immunodeficiency virus (HIV), hepatitis C, or hepatitis B surface antigen
• Known active or chronic hepatitis
• History of arterial or venous thrombosis within 12 months prior to randomization
4.2.2 Medications
• Currently or previously treated with angiopoietin inhibitors, or inhibitors of TIE-1 or TIE-2 including, but not limited to, AMG 386, XL880, XL820
• Prior therapy against vascular endothelial growth factor or the vascular endothelial growth factor receptors including, but not limited to, bevacizumab, sunitinib, sorafenib, motesanib (AMG 706) or cediranib (AZD-2171), is permitted so long as the agent does not have any known activity against angiopoietin 1 or 2, or the receptors TIE-1 or TIE-2
• Current or within 30 days of randomization treatment with immune modulators such as cyclosporine and tacrolimus
4.2.3 General
• Any condition which in the investigator’s opinion makes the subject unsuitable for study participation
• Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast feeding
• Previously enrolled into this study
• Subject will not be available for follow-up assessments |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Objective Response Rate (ORR): The incidence of either a confirmed complete response (CR) or partial response (PR) per modified RECIST criteria (responder). A confirmed CR requires 2 assessments of CR at least 28 days apart. A confirmed PR requires 2 assessments at least 28 days apart of PR or CR. All subjects that do not meet the criteria for an objective response by the analysis cutoff date will be considered non-responders.
• Duration of response (DOR): (calculated only for those subjects with a confirmed objective response) time from first confirmed objective response to disease progression per the modified RECIST criteria or death. Subjects not meeting criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.
• Modified-RECIST / CA-125 Progression Free Survival (mR/CA-125 PFS): time from randomization to disease progression per the modified RECIST criteria, confirmed CA-125 progression, or death from any cause, whichever is earlier. Subjects not meeting the criteria for modified RECIST or CA-125 progression at the time of the analysis data cutoff will be censored at their last evaluable disease assessment date.
• CA-125 response rate: The incidence of a confirmed CA-125 response. All subjects evaluable for CA-125 response that do not meet the criteria for a CA-125 response will be considered nonresponders.
• Estimate of reduction in tumor burden as measured by maximum percent change from baseline in the sum of the longest diameters (sum of the longest diameters of target lesions by conventional CT).
• AMG 386 pharmacokinetic parameters (Cmax and Cmin)
• Incidence of AEs and significant laboratory changes
• Incidence of the occurrence of anti-AMG 386 antibody formation
• Overall survival: time from randomization date to date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date.
• Time to progression (TTP): time from randomization to date of disease progression per the modified RECIST criteria. Subjects not meeting criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.
• Time to response: time from randomization to date of first objective response for confirmed responders.
• Change from baseline in blood levels of CA-125
• Change in cancer-related symptoms as assessed by the Functional Assessment of Cancer Therapy – Ovarian Cancer (FACT-O) ovarian cancer specific subscale |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Safety and Tolerability:2 years
• Objective Response Rate: 2 years
•Duration of Response: 2 years
• Modified RECIST/CA-125 Progression Free Survival: 2 years
• CA-125 Response Rate: 2 years
• Estimate of reduction in tumor burden: 2 years
• Incidence of AEs and significant laboratory changes: 2 years
• Overall Survival: 2 years
• Time to Progression: 2 years
• Time to Response: 2 years
• Change from baseline in blood levels of CA-125: 2 years
• Time-adjusted area under the curve for PROs: 2 years
• AMG 386 Pharmacokinetic parameters: 2 years
• Incidence of the occurence of AMG 386 Antibody formation: 2 years
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| India |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
When all subjects have completed the treatment period or long-term
follow-up, whichever is later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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