A Phase 1b Study of Sevacizumab in Combination With Chemotherapy in Chinese Patients With Platinum-Resistant Recurrent Ovarian Cancer.

Study Overview
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Brief Summary
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This is an open-label, multicenter, dose-escalation study designed to assess the safety, tolerability, and pharmacokinetics of Humanized Anti-VEGF Monoclonal Antibody (Sevacizumab) Injection in combination with Chemotherapy in Chinese patients with Platinum-Resistant Recurrent Ovarian Cancer. This study includes two stages. Stage 1 is the dose-escalation stage. Once the maximum tolerated dose (MTD of Sevacizumab has been established, additional patients will be enrolled in the cohort-expansion stage (Stage 2).

Detailed Description
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This is an open-label, multicenter, dose-escalation study designed to assess the safety, tolerability, and pharmacokinetics of Humanized Anti-VEGF Monoclonal Antibody (Sevacizumab) Injection in combination with Chemotherapy in Chinese patients with Platinum-Resistant Recurrent Ovarian Cancer. This study includes two stages. Stage 1 is the dose-escalation stage. Once the maximum tolerated dose (MTD of Sevacizumab has been established, additional patients will be enrolled in the cohort-expansion stage (Stage 2).

Official Title
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A Phase Ib, Dose Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of Humanized Anti-VEGF Monoclonal Antibody(Sevacizumab) Injection Plus Chemotherapy in Chinese Patients With Platinum-Resistant Recurrent Ovarian Cancer.

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Sevacizumab
* Drug: Paclitaxel
* Drug: Topotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age≥18 years Histologically documented platinum resistant EOC, FTC, or PPC of the following types: adenocarcinoma not otherwise specified (NOS), clear cell adenocarcinoma, endometriod adenocarcinoma, malignant Brenner's tumor, mixed epithelial carcinoma, mucinous adenocarcinoma, serous adenocarcinoma, transitional cell carcinoma and undifferentiated carcinoma. At least one measurable leision. (according to RECIST 1.1 ) Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1. Adequate hematologic function: ANC ≥ 1.5 × 10^9 /L, HB ≥ 90 g /L (blood transfusion allowed), PLT ≥ 100 ×10^9 /L; Adequate hepatic function: ALT ≤ 2.5 × ULN, AST ≤ 2.5 × ULN, TBIL ≤ 1.5 × ULN (patients with liver metastases ALT ≤ 5 × ULN, AST ≤ 5 × ULN); Adequate renal function: creatinine ≤ 1 × ULN; Coagulation function: INR ≤ 1.5 × ULN, APTT ≤ 1.5 × ULN Progression within 6 months from completion of a minimum of 4 platinum therapy cycles. Life expectancy ≥12 weeks. At least 4 weeks from the last chemotherapy. If patients received anti-tumor biological products, at least four t1/2 of washout period is needed Toxicity from previous treatment has to restore to ≤ grade 1 (NCI CTC4.0) Patients signed written inform consent. Willingness and capability to communicate with investigators and to comply with protocol requirements Exclusion Criteria: Previous treatment with > 2 anti-cancer regimens. Patients whose disease was refractory to their previous platinum treatment. (Refractory disease was defined as those patients who progressed during the preceding platinum treatment.) Ovarian tumors with low malignant potential (i.e. borderline tumors). Patients with a prior invasive malignancy (except non-melanoma skin cancer) or whose prior malignancy treatment contraindicated the current protocol therapy. Any prior radiotherapy to the pelvis or abdomen. Patients with serious non-healing wound, ulcer, or bone fracture. patients with a history of bowel obstruction (including subocclusive disease) related to underlying disease, a history of abdominal fistula, GI perforation, or intra-abdominal abscess or evidence of rectosigmoid involvement by pelvic examination, bowel involvement on computed tomography, or clinical symptoms of bowel obstruction. Serious infection requiring intravenous antibiotic therapy history or evidence of thrombotic or hemorrhagic disorder within 6 months before first study treatment untreated CNS disease unrelated to cancer or symptomatic CNS metastasis Patients with clinically significant cardiovascular disease. This included:Uncontrolled hypertension, defined as systolic > 150 mmHg or diastolic > 90 mmHg;Myocardial infarction or unstable angina > 6 months prior to registration;New York Heart Association (NYHA) Grade II or greater congestive heart failure;Serious cardiac arrhythmia requiring medication. This did not include asymptomatic, atrial fibrillation with controlled ventricular rate. left ventricular ejection fraction below the institutional lower limit of normal pre-existing neuropathy ≥ CTC Grade 2 for those in the paclitaxel group Known allergies to any excipient in the study drug Pregnant and lactating women Patients with proteinuria (urine protein >1+ at screening, or urine protein 1+, not recover to normal value within 24h) Previously received anti-VEGF protein drugs, such as Bevacizumab, Sevacizumab Patients with or with anticipation of invasive procedures as defined below:Major surgical procedure or significant traumatic injury within 28 days prior to the first date of sevacizumab therapy;Major surgical procedure anticipated during the course of the study. This included, but was not limited to abdominal surgery (laparotomy or laparoscopy) prior to disease progression;Core biopsy, within 7 days prior to randomization. Participation in other clinical trials within 4 weeks before enrollment The investigators consider the patients are not suitable for 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: Sevacizumab +Chemotherapy Combined chemotherapy drug including<br>Investigators selected single-agent chemotherapy on an individual patient basis from the following options, with appropriate premedication according to local standards: paclitaxel 80mg/m2 intravenously (IV)on days 1, 8, 15, and 22 every 4 weeks; or topotecan 4 mg/m2 IV on days 1, 8, and 15 every 4 weeks. | Drug: Sevacizumab<br>* Drug: Sevacizumab escalating doses of Sevacizumab : 0.5mg/kg，1mg/kg，1.5mg/kg and 2mg/kg<br>Drug: Paclitaxel<br>* paclitaxel 80mg/m2 as a > 3-hour IV infusion on days 1, 8,15, and 22 every 4 weeks;<br>Drug: Topotecan<br>* topotecan 4 mg/m2 as a >30 minute IV infusion on days 1, 8, and 15 every 4 weeks ;<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) |  | 3 years | 
| The ratio of adverse of event |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration [Cmax] | Maximum Plasma Concentration [Cmax] | 3 years | 
| Area Under the Curve [AUC], | Area Under the Curve [AUC] | 3 years | 
| Tmax | Tmax for Cmax of sevacizumab | 3 years | 
| Objective Response Rate (ORR) |  | 3 years | 
| Disease Control Rate (DCR) |  | 3 years | 
| Overall Survival (OS) |  | 3 years | 
| Progression Free Survival (PFS) |  | 3 years |