Phase II Study of NGR-hTNF in Combination With Doxorubicin in Platinum-resistant Ovarian Cancer

Study Overview
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Brief Summary
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The primary objective of this randomized phase II trial is to compare progression-free survival (PFS) in patients randomized to NGR-hTNF plus an anthracycline versus patients randomized to an anthracycline alone

Detailed Description
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Considering the safety/toxicity profile of NGR-hTNF characterized by mild-to-moderate constitutional symptoms, the reversibility of these adverse events generally occurring only during the infusion time; the absence of overlapping toxicities with chemotherapeutic agents; the safety and preliminary antitumor activity observed in previous trial with doxorubicin; and the objective response rate (RR) registered in a phase II trial in previously treated ovarian cancer patients seems justified to evaluate in a randomized phase II trial the efficacy of NGR-hTNF against a doxorubicin-based option in advanced ovarian cancer patients progressing or recurrent after a standard platinum/taxane-based chemotherapy.

Official Title
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NGR018: Randomized Phase II Study of NGR-hTNF Plus an Anthracycline Versus an Anthracycline Alone in Platinum-resistant Ovarian Cancer

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: NGR-hTNF
* Drug: Pegylated liposomal doxorubicin
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Histologically-proven ovarian cancer, fallopian tube and primary peritoneal cancer in advanced or metastatic stage Patients previously treated with a maximum of two platinum-based regimen plus paclitaxel and with documented progressive disease on treatment (refractory patient population) or within 6 months from last chemotherapy cycle (resistant patient population) ECOG Performance status 0 - 2 Life expectancy of 12 weeks or more Normal cardiac function Adequate baseline bone marrow, hepatic and renal function defined as follows: Neutrophils ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL Bilirubin ≤ 1.5 x ULN AST and/or ALT ≤ 2.5 x ULN in absence of liver metastasis or ≤ 5 x ULN in presence of liver metastasis Serum creatinine < 1.5 x ULN At least one (not previously irradiated) target lesion or non-measurable disease only, according to RECIST criteria Patients may have had prior therapy providing the following conditions are met: Surgery and radiation therapy: wash-out period of 14 days Systemic anti-tumor therapy: wash-out period of 21 days Patients must give written informed consent to participate in the study Exclusion Criteria: Patients must not receive any other investigational agents while on study More than two previous chemotherapy lines and previous treatment with anthracycline Patients with myocardial infarction within the last six months, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication Prolonged QTc interval (congenital or acquired) > 450 ms History or evidence upon physical examination of CNS disease unless adequately treated Patients with active or uncontrolled systemic disease/infections or with serious illness or medical conditions, which is incompatible with the protocol Known hypersensitivity/allergic reaction to human albumin preparations or to any of the excipients Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol Pregnancy or lactation.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: NGR-hTNF+ anthracycline<br>NGR-hTNF+Pegylated Liposomal Doxorubicin or Doxorubicin | Drug: NGR-hTNF<br>* NGR-hTNF: 0.8 mcg/m² as 60 minutes intravenous infusion weekly or every 3 or 4 weeks until confirmed evidence of disease progression or unacceptable toxicity occurs<br>Drug: Pegylated liposomal doxorubicin<br>* 50 mg/m² iv every 4 weeks until confirmed evidence of disease progression<br>Drug: Doxorubicin<br>* 60 mg/m² iv every 3 weeks for a maximum of 8 cycles<br>|
| Active Comparator: Arm B: anthracycline<br>Pegylated Liposomal Doxorubicin or Doxorubicin | Drug: Pegylated liposomal doxorubicin<br>* 50 mg/m² iv every 4 weeks until confirmed evidence of disease progression<br>Drug: Doxorubicin<br>* 60 mg/m² iv every 3 weeks for a maximum of 8 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Defined as the time from the date of randomization until disease progression, or death | from the date of randomization, every 6 and 8 weeks based on type of chemotherapy during treatment and every 12 weeks during the follow-up until PD or death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | defined as the time from the date of randomization until death due to any cause. | from the date of randomization, every 6 and 8 weeks based on type of chemotherapy during treatment and every 12 weeks during follow-up until death | 
| Response Rate (RR) | defined as the percentage of patients who have a best-response rating of complete or partial response, according to standard RECIST criteria. | from the date of randomization, every 6 and 8 weeks based on type of chemotherapy during treatment and every 12 weeks during the follow-up until PD or death | 
| Disease Control Rate (DCR) | defined as the percentage of patients who have a best-response rating of complete response, partial response, or stable disease, according to standard RECIST criteria. | from the date of randomization, every 6 and 8 weeks based on type of chemotherapy during treatment and every 12 weeks during the follow-up until PD or death | 
| Duration of Disease Control | measured from the date of randomization until disease progression, or death due to any cause. | from the date of randomization, every 6 and 8 weeks based on type of chemotherapy during treatment and every 12 weeks during the follow-up until PD or death | 
| Safety and Toxicity according to NCI-CTCAE criteria (version 4.03) | To evaluate safety and toxicity profile related to NGR-hTNF | from the start of treatment until 28 days after last treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NGR-hTNF, Pegylated liposomal doxorubicin, Doxorubicin, Platinum-resistant, Progression or recurrence Ovarian Cancer, Ovarian Cancer, Advanced or metastatic