Clinical trial NCT02655952: Dose Escalating Study of Foxy-5 in Breast-, Colon- or Prostate Cancer Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Metastatic Breast Cancer
Metastatic Colon Cancer
Metastatic Prostate Cancer
Lead sponsor: WntResearch AB
Sponsor class: INDUSTRY
First posted: 2016-01-14
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: Presence of Dose Limiting Toxicities (DLTs).
timeFrame: 6 month
Secondary outcomes:
measure: Genome wide mRNA gene expression in tumour biopsies and blood (buffy coat)
timeFrame: Tumour biopsies obtained prior to day 1 and on day 12 and 19
measure: Wnt-5a protein expression and hematoxylin-eosin (HE) staining of tumour biopsies
timeFrame: Tumour biopsies obtained prior to day 1 and on day 12 and 19
measure: Numbers of circulating tumour cells (CTCs) in blood
timeFrame: Blood sample obtained prior to day 1 and on day 12 and 19
measure: Maximum tolerated dose (MTD)
timeFrame: 6 month
measure: Area under the plasma concentration curve (AUC) of Foxy-5
timeFrame: immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion.
measure: Bioavailability (F) of Foxy-5
timeFrame: immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion.
measure: Half life (T½) of Foxy-5
timeFrame: immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion.
measure: Absorption rate Constant (tmax) of Foxy-5
timeFrame: immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion.
measure: Volume of distribution (V) of Foxy-5
timeFrame: immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion.
measure: Clearance (C) of Foxy-5
timeFrame: immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion.
measure: Extraction Ratio (E) of Foxy-5
timeFrame: immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion.
measure: Hepatic and Renal Clearance of Foxy-5
timeFrame: immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion.
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Clinical Research Department, Oncology, Rigshospitalet
city: Herlev
country: Denmark
facility: Onkologisk Afdeling R, Herlev Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Newcastle
country: United Kingdom
facility: NCCC, Freeman Hospital
state: Newcastle Upon Tyne
Study officials:
affiliation: Smerud Medical Research Denmark
name: Tine Mølvadgaard, M.Sc.Pharm
role: STUDY_DIRECTOR
References: