Phase I Study to Evaluate Safety, Tolerability, Anti-Tumour Activity and PK Profiles of Foxy-5 in Metastatic Breast, Colon or Prostate Cancer

Study Overview
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Brief Summary
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The Wnt proteins belong to a family of proteins that have been demonstrated to play a role in the formation and dissemination of tumours. The present project focuses on the critical role of the Wnt-5a protein in the pathobiological processes that lead to metastatic cancer disease. WntResearch has identified a formylated 6 amino acid peptide fragment, named Foxy-5, which mimick the effects of Wnt-5a to impair migration of epithelial cancer cells and thereby acting anti-metastatic. The aim of the present clinical phase 1 trial is to establish the recommended dose for a clinical phase 2 study and thereby further develop Foxy-5 as a first in class anti-metastatic cancer drug. Foxy-5 is designed to inhibit the development of metastasis by reducing the motility of cancer cells and should thereby increase the survival rates of patients with solid malignant tumours.

Official Title
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Phase I Dose Escalating Study to Evaluate the Safety, Tolerability, Anti-Tumour Activity and Pharmacokinetic and Pharmacodynamic Profiles of Foxy-5 in Patients With Metastatic Breast, Colon or Prostate Cancer

Conditions
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Metastatic Breast Cancer, Colorectal Cancer, Prostate Cancer

Intervention / Treatment
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* Drug: Foxy-5


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females of at least 18 years of age Histologically/cytologically documented diagnosis of metastatic breast, colon or prostate cancer, refractory to standard therapy or for which no curative therapy exists Loss of or reduced Wnt-5a protein expression in primary or metastatic tumour cells, characterised by IHC analysis Eastern Cooperative Oncology Group (ECOG) performance status of <= 1 Life expectancy of at least 3 months Unresectable disease, i.e. the metastases cannot be surgically removed with a curative intent >= 4 weeks must have elapsed since the patient has received any other IMP >=4 weeks must have elapsed since the patient has received any anti cancer treatment; including radiotherapy (except for single dose of palliative radiotherapy), cytotoxic chemotherapy, biologic agents or targeted therapy >= 2 weeks must have elapsed since any prior surgery or therapy with bone marrow stimulating factors Adequate haematological functions as defined by: Absolute neutrophil count >= 1.5 10E9/L Platelets >= 100 10E9/L Hemoglobin >= 5.6 mmol/L Adequate hepatic function as defined by: Total bilirubin <= 1.5 x the upper limit of normal (ULN) Aspartate aminotransferase (AST) <= 2.5 x ULN* Alanine aminotransferase (ALT) <= 2.5 x ULN* * For patients with liver metastasis adequate hepatic function is defined by AST <= 5 x ULN and ALT <= 5 ULN. Adequate renal function as defined by Serum creatinine <= 1,5 x ULN Provision of written informed consent Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures Sexually active males and females of child-producing potential, must use adequate contraception (intrauterine devices, hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release) or diaphragm always with spermicidal jelly and a male condom) for the study duration and at least six months afterwards Exclusion Criteria: Active uncontrolled bleeding or bleeding diathesis (e.g., active peptic ulcer disease) Any active infection requiring antibiotic treatment Known infection with human immunodeficiency virus (HIV) or hepatitis virus Active heart disease including myocardial infarction or congestive heart failure within the previous 6 months, symptomatic coronary artery disease, or symptomatic arrhythmias currently requiring medication Known or suspected active central nervous system (CNS) metastasis. (Patients stable 8 weeks after completion of treatment for CNS metastasis are eligible) Impending or symptomatic spinal cord compression or carcinomatous meningitis Requiring immediate palliative surgery and/or radiotherapy Pre-existing neuropathy, i.e., Grade >2 neuromotor or neurosensory toxicity Participation in other clinical studies within 4 weeks of first dose of study treatment History of severe allergic or hypersensitive reactions to excipients Pregnant or breastfeeding women Chronic immunosuppressant use (e.g. systemic steroids for treatment of autoimmune disease) History of second malignancy, including histologically confirmed diagnosis of malignant melanoma except for carcinoma in situ or basal cell carcinoma Severe or uncontrolled chronic or uncontrolled systemic disease (e. g. severe respiratory or cardiovascular disease) Other medications or conditions that in the Investigator's opinion would contraindicate study participation of safety reasons or interfere with the interpretation of study results

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Foxy-5<br>Slow infusion of lyophilised and reconstituted Foxy-5 three times weekly on Monday, Wednesday and Friday for three weeks. | Drug: Foxy-5<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of Foxy-5 | Assessment of adverse events and laboratory abnormalities | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Profile for the biomarker NGAL and the amount of circulating tumour cells before and after treatment with Foxy-5 |  | samples at pre-dose at day 1, pre-dose at day 12 and pre-dose at day 26 | 
| Profile for the biomarker 15-PGHD and the amount of circulating tumour cells before and after treatment with Foxy-5 |  | samples at pre-dose at day 1, pre-dose at day 12 and pre-dose at day 26 | 
| Maximum tolerated dose (MTD) | To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of Foxy-5. Assessment of adverse events and laboratory abnormalities | 1 year | 
| Area under the plasma concentration curve (AUC) of Foxy-5 | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). | Plasma immediately prior to treatment, instantly after infusion, at 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. In the Multiple dosing cycles on days 1+3+5 and 15+29 | 
| Maximum observed plasma drug concentration (Cmax) of Foxy-5 | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). | Plasma immediately prior to treatment, instantly after infusion, at 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. In the Multiple dosing cycles on days 1+3+5 and 15+29 | 
| Time to maximum observed plasma drug concentration (tmax) of Foxy-5 | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). | Plasma immediately prior to treatment, instantly after infusion, at 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. In the Multiple dosing cycles on days 1+3+5 and 15+29 | 
| Terminal elimination half-life (t½) of Foxy-5 | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). | Plasma immediately prior to treatment, instantly after infusion, at 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. In the Multiple dosing cycles on days 1+3+5 and 15+29 | 
| Total plasma clearance (CL) of Foxy-5 | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). | Plasma immediately prior to treatment, instantly after infusion, at 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. In the Multiple dosing cycles on days 1+3+5 and 15+29 | 
| Volume of distribution (V) of Foxy-5 | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). | Plasma immediately prior to treatment, instantly after infusion, at 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion | 
| Plasma concentration at steady state (Css) of Foxy-5 | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). | Plasma immediately prior to treatment, instantly after infusion, at 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. In the Multiple dosing cycles on days 1+3+5 and 15+29 | 
| Drug accumulation ratio of Foxy-5 | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). | Plasma immediately prior to treatment, instantly after infusion, at 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion | 
| mRNA expression and protein expression of Wnt-5a |  | Tumour biopsies obtained prior to day 1 and on day 12 | 
| Anti-tumour activity of Foxy-5 | Voluntary tumour biopsies | Prior to Day 1 (-14 days is allowed) and at Day 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Foxy-5, Wnt-5A