Dose Escalating Study of Foxy-5 in Breast-, Colon- or Prostate Cancer Patients

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 first clinical phase I study was to establish the recommended dose for a clinical phase II study and enable further development of Foxy-5 as a first in class anti-metastatic cancer drug. The study did not see any DLTs and therefore failed to reach maximum tolerated dose (MTD); no recommended phase II dose (RP2D) could therefore be established based on toxicity. The aim of this study is to continue to establish the safety profile of Foxy-5 in higher doses, and determine the RP2D for later stage development based on any observed DLT's/MTD and further analysis of the pharmacodynamic profile of Foxy-5 to determine the biological response dose (BRD).

Official Title
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Phase Ib Dose Escalating Study to Evaluate the Safety, Tolerability and Pharmacodynamic Response of Foxy-5 in Patients With Metastatic Breast-, Colon- or Prostate Cancer

Conditions
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Metastatic Breast Cancer, Metastatic Colon Cancer, Metastatic 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 Must have an evaluable tumour appropriate for biopsy as determined by the Investigator. 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 Patients in active anti-coagulating treatment must be evaluated according to local standards on the discretion of the Investigator.. 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(except for a single dose of palliative 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 Previous exposure to Foxy-5 History of severe allergic or hypersensitive reactions to excipients Pregnant or breastfeeding women Active and/or within the last 5 years histologically confirmed diagnosis of malignant melanoma, gastric cancer, pancreatic cancer, lung cancer or nasopharyngeal cancer 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 for three weeks. There will be a maximum of 8 dose cohorts. Cohorts 1-4 will be conducted in the United Kingdom and Denmark whereas cohorts 5-8 will only be conducted in Denmark. As doses in cohort 1 and 2 have been investigated in the previous phase I study, cohorts 1+2 and 3 can be run in parallel with dose escalation approved by the DSMB at all times. DK+UK: Cohort 1: 0.8 mg/kg DK+UK: Cohort 2: 1.3 mg/kg DK+UK: Cohort 3: 1.8 mg/kg DK+UK: Cohort 4: 2.3 mg/kg DK only: Cohort 5: 3.0 mg/kg DK only: Cohort 6: 4.0 mg/kg DK only: Cohort 7: 5.3 mg/kg DK only: Cohort 8: 7.0 mg/kg | Drug: Foxy-5<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of Dose Limiting Toxicities (DLTs). | The number of adverse events along with the results of vital sign measurements, physical examinations, and clinical laboratory tests will be used to determine the safety and tolerability profile of Foxy-5 | 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Genome wide mRNA gene expression in tumour biopsies and blood (buffy coat) | Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5 | Tumour biopsies obtained prior to day 1 and on day 12 and 19 | 
| Wnt-5a protein expression and hematoxylin-eosin (HE) staining of tumour biopsies | Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5 | Tumour biopsies obtained prior to day 1 and on day 12 and 19 | 
| Numbers of circulating tumour cells (CTCs) in blood | Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5 | Blood sample obtained prior to day 1 and on day 12 and 19 | 
| Maximum tolerated dose (MTD) | Determined as the dose preceding the dose at which two or more patients have experienced DLTs. Assessment of adverse events and laboratory abnormalities | 6 month | 
| 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) | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | 
| Bioavailability (F) 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) | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | 
| 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) | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | 
| Absorption rate Constant (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) | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | 
| 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) | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | 
| Clearance (C) 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) | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | 
| Extraction Ratio (E) 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) | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | 
| Hepatic and Renal Clearance 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) | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. |