Metastatic Breast Cancer, Metastatic Colon Cancer, Metastatic Prostate Cancer
Conditions
Brief summary
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).
Interventions
DRUGFoxy-5
Sponsors
WntResearch AB
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Presence of Dose Limiting Toxicities (DLTs). | 6 month | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Wnt-5a protein expression and hematoxylin-eosin (HE) staining of tumour biopsies | Tumour biopsies obtained prior to day 1 and on day 12 and 19 | Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5 |
| Numbers of circulating tumour cells (CTCs) in blood | Blood sample obtained prior to day 1 and on day 12 and 19 | Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5 |
| Maximum tolerated dose (MTD) | 6 month | Determined as the dose preceding the dose at which two or more patients have experienced DLTs. Assessment of adverse events and laboratory abnormalities |
| Area under the plasma concentration curve (AUC) of Foxy-5 | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) |
| Bioavailability (F) of Foxy-5 | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) |
| Genome wide mRNA gene expression in tumour biopsies and blood (buffy coat) | Tumour biopsies obtained prior to day 1 and on day 12 and 19 | Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5 |
| Absorption rate Constant (tmax) of Foxy-5 | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) |
| Volume of distribution (V) of Foxy-5 | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) |
| Clearance (C) of Foxy-5 | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) |
| Extraction Ratio (E) of Foxy-5 | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) |
| Hepatic and Renal Clearance of Foxy-5 | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) |
| Half life (T½) of Foxy-5 | immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion. | The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) |
Countries
Denmark, United Kingdom
Outcome results
None listed