A Study of Anti-VEGF Monoclonal Antibody hPV19 in Patients With Solid Tumors

Study Overview
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Brief Summary
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hPV19 is a monoclonal antibody (mAb) directed against vascular endothelial growth factor (VEGF). hPV19 binds to human VEGF with unique binding site on VEGF different from that of Bevacizumab(Avastin) and inhibits the binding of VEGF to it's receptors, VEGF-R1 and VEGF-R2. By preventing VEGF binding to its receptors, growth of tumor blood vessels are inhibited and tumor growth prevented or slowed. In this study we are investigating the tolerability, safety, pharmacokinetics and anti-tumor activity of hPV19 in combination with chemotherapy in patients with solid tumors. hPV19 will give to patients by intravenous(i.v.) infusion with a single and multiple doses.

Official Title
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A Phase Ib Study of hPV19, a Novel Humanized Monoclonal Antibody Against Vascular Endothelial Growth Factor (VEGF),in Combination With Chemotherapy in Patients With Advanced Solid Tumors Refractory to Standard Therapy.

Conditions
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Solid Tumors

Intervention / Treatment
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* Biological: hPV19 mAb
* Biological: hPV19 mAb
* Drug: 5-Fluorouracil
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Gemcitabine
* Drug: Carboplatin
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed malignity Measurable disease Performance status 2 or less(ECOG) Life expectancy ≥3 months Exclusion Criteria: hepatitis C virus (HCV), or HIV antibody positive Previously received anti-VEGF mAb or fusion-protein drugs within 28 days nearly Evidence of serious infection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

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: group 1<br>hPV19 mAb plus FOLFOX(5-Fluorouracil,Oxaliplatin,Leucovorin) | Biological: hPV19 mAb<br>* Intravenous (IV) infusions, 4 and 6 milligrams per kilogram (mg/kg) every 2 weeks<br>* Other names: anti-VEGF mAb;Drug: 5-Fluorouracil<br>* 400 mg/m2 bolus followed by a 2400 mg/m2 continuous infusion, every 2 weeks<br>Drug: Oxaliplatin<br>* IV Infusion, 85 milligrams per square meter (mg/m2) every 2 weeks<br>Drug: Leucovorin<br>* IV infusion, 400 mg/m2 every 2 weeks<br>|
| Experimental: group 2<br>hPV19 mAb plus paclitaxel/carboplatin | Biological: hPV19 mAb<br>* Intravenous (IV) infusions, 6 milligrams per kilogram (mg/kg) every 3 weeks<br>* Other names: anti-VEGF mAb;Drug: Paclitaxel<br>* IV infusion, 175 mg/m2 every 3 weeks<br>Drug: Carboplatin<br>* IV infusion, AUC=6 every 3 weeks<br>|
| Experimental: group 3<br>hPV19 mAb plus gemcitabine/carboplatin | Biological: hPV19 mAb<br>* Intravenous (IV) infusions, 6 milligrams per kilogram (mg/kg) every 3 weeks<br>* Other names: anti-VEGF mAb;Drug: Gemcitabine<br>* IV infusion, 1000 mg/m2 at day1 and day 8 every 3 weeks<br>Drug: Carboplatin<br>* IV infusion, AUC=4 every 3 weeks<br>|
| Experimental: group 4<br>hPV19 mAb plus FOLFIRI(5-Fluorouracil,Irinotecan, Leucovorin) | Biological: hPV19 mAb<br>* Intravenous (IV) infusions, 4 and 6 milligrams per kilogram (mg/kg) every 2 weeks<br>* Other names: anti-VEGF mAb;Drug: 5-Fluorouracil<br>* 400 mg/m2 bolus followed by a 2400 mg/m2 continuous infusion, every 2 weeks<br>Drug: Leucovorin<br>* IV infusion, 400 mg/m2 every 2 weeks<br>Drug: Irinotecan<br>* IV Infusion,180 milligrams per square meter (mg/m2) every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Experienced Any Dose-Limiting Toxicities (DLT) During the DLT Assessment Period | DLTs were adverse events (AEs) possibly related to study drug that met the National Cancer Institute's Common Terminology Criteria for AEs (NCI CTCAE, version 4.03) with any one of the following: Grade 4 neutropenia ≥7 days; febrile neutropenia; grade 4 anemia; grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding; ≥ grade 3 nonhematologic toxicity with the exception of nausea, vomiting, diarrhea, dehydration or electrolyte abnormalities that resolved to a lower grade with maximum supportive treatment within 3 days; ≥Grade 3 hypertension that cannot resolved to a lower grade with supportive treatment within 2 weeks or uncontrolled hypertension; Urine protein ≥3.5 grams/24 hours and cannot resolved to < 1.0 grams/24 hours within 2 weeks; Gastrointestinal perforation: symptoms, signs and imaging evidence of abdominal pain require surgical treatment; Grade 3 or 4 arterial thromboembolism, including stroke and myocardial infarction; | during the first 21 days | 
| Number of Participants With hPV19 Drug-Related Adverse Events or Serious Adverse Events | Data are presented for the number of participants who experienced treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), Grade ≥3 TEAEs, or adverse events (AEs) leading to discontinuation of treatment that were considered to be related to hPV19. Events related to chemotherapy were reported separately. | Baseline to the last dose plus 28 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serum Anti-hPV19 Antibodies (Immunogenicity) |  | before Single dose; Day 21 of 21-day DLT assessment period; Every 8 or 9 weeks after 21-day DLT assessment period. | 
| Maximum Concentration (Cmax) of hPV19 |  | Single dose(Cycle 1)：2h before administered; after administered 10min±5min、4h±30min、24h±1h、168h±1h、336h±1h. Other cycles: 2h before administered and after administration 10min±5min. | 
| Area Under the Curve (AUC) of hPV19 |  | Single dose(Cycle 1)：2h before administered, after administered 10min±5min、4h±30min、24h±1h、168h±1h、336h±1h. Other cycles: 2h before administered and after administration 10min±5min. | 
| Half Life (t1/2) of hPV19 | t1/2 is the time required for the plasma/serum concentration to decrease 50% | Single dose(Cycle 1)：2h before administered, after administered 10min±5min、4h±30min、24h±1h、168h±1h、336h±1h. Other cycles: 2h before administered and after administration 10min±5min. | 
| Clearance (CL) of hPV19 |  | Single dose(Cycle 1)：2h before administered, after administered 10min±5min、4h±30min、24h±1h、168h±1h、336h±1h. Other cycles: 2h before administered and after administration 10min±5min. | 
| Steady State Volume of Distribution (Vss) of hPV19 | Vss is the theoretical volume in which the total amount of study drug would need to be uniformly distributed during steady state to produce the same concentration as it is in plasma/serum | Single dose(Cycle 1)：2h before administered; after administered 10min±5min、4h±30min、24h±1h、168h±1h、336h±1h. Other cycles: 2h before administered and after administration 10min±5min. | 
| Best Overall Response [Anti-Tumor Activity of hPV19 Plus Chemotherapy] | Best overall response evaluated using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria. Complete Response (CR): disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to <10 millimeters (mm). Partial Response (PR): at least a 30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. Progressive Disease (PD): an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if that was the smallest on study). In addition, the sum must have demonstrated an absolute increase of at least 5 mm (the appearance of 1 or more new lesions was considered progression). Stable Disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD, taking as reference the smallest sum diameter since treatment started. | Up to six months after 1st treatment or until progression of disease (PD) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mAb, phase1, VEGF, antibody