Primary Objectives* To assess the safety and tolerability of Foxy-5 in subjects with colon cancer.* To assess circulating tumour DNA (ctDNA) in plasma as a surrogate parameter for disease recurrences in subjects with Wnt-5a low colon cancer treated…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* The incidence of adverse events (AEs) related to Foxy-5 administration of
Grade 3 and higher according to the National Cancer Institute * Common
Terminology Criteria for Adverse Events (CTCAE, version 5.0) and the
Clavien-Dindo classification of surgical complications.
* The level of ctDNA in plasma of subjects with Wnt-5a low colon cancer as a
surrogate parameter for disease recurrence in subjects with Wnt-5a low colon
cancer treated with Foxy-5 compared to subjects with Wnt-5a low colon cancer
who are in the Control Arm.
Secondary outcome
* OS at 2 years after resection of the colon cancer;
* DFS at 2 years after resection of the colon cancer;
* RFI
* The level of ctDNA in plasma of subjects with Wnt-5a high colon cancer.
exploratory endpoint:
* The level of thymidine kinase activity in serum in relationship to Wnt-5a
expression in the tumour
Background summary
Wnt-5a protein belongs to the Wnt family of secreted glycoproteins and it has
been demonstrated to play an important role in cell adhesion and cell
migration. There is a correlation between low/no expression of Wnt-5a protein
in epithelial cancer cells and high risk of recurrence in metastatic disease,
and shortened survival in cancer patients (Anastas & Moon, 2013). Low-level
expression of Wnt-5a protein has been correlated to higher histological grade
(poor differentiation) and shortened recurrence free survival in patients with
primary invasive breast carcinomas. A similar association between low Wnt-5a
protein expression in cancer cells and disease outcome has been described for
both colon and prostate cancer (Dejmek, 2005; Khaja, 2011; Khaja, 2012). In
addition to these, investigations on Wnt-5 expression in cancer cells from
patients with epithelial ovarian cancer have also shown that high expression of
Wnt-5a in ovarian cancer is correlated to a significantly prolonged overall
survival for epithelial ovarian cancer patients (Bitler, 2011).
Professor Tommy Andersson (Chief Scientific Officer of WntResearch AB) has
developed a peptide that mimicked the effect of the intact Wnt-5a molecule on
breast cancer cell migration. Based on sequence analysis of Wnt-5a, structural
bioinformatics and computational chemistry design (performed through a
collaboration with Dr. Villoutreix, INSERM, Paris), a short list of molecules
were rationally proposed for in vitro assays. Two bioactive molecules were
identified and the smallest of these (12 amino acids long) was step-wise
shortened from the N-terminal side. It was found that when this peptide only
contained 6 amino acids it had lost its bioactivity properties. However, a
chemical modification (formylation) of the N-terminal side restored and
increased its bioactive properties and made it more resistant to degradation in
vivo. Thus, through a combined in silico-in vitro-in vivo work, Dr. Andersson's
research group found that this chemically modified 6-amino-acid peptide
molecule could mimic the effects of Wnt-5a on intracellular signalling and
breast cancer cell migration (Säfholm et al., 2006). This small compound was
named Foxy-5. Foxy-5 is a synthetic hexapeptide with a formylated N-terminus,
derived from the protein sequence of the Wnt-5a protein.
The metastatic process, resulting in the formation of distant metastases in
other organs, is strongly associated with cancer related mortality, and a
medical treatment that specifically targets this process would be an important
therapeutic step in the treatment of cancer.
Study objective
Primary Objectives
* To assess the safety and tolerability of Foxy-5 in subjects with colon cancer.
* To assess circulating tumour DNA (ctDNA) in plasma as a surrogate parameter
for disease recurrences in subjects with Wnt-5a low colon cancer treated with
Foxy-5 compared to subjects with Wnt-5a low colon cancer who are in the Control
Arm.
Secondary Objectives
To determine the preliminary efficacy of Foxy-5 in subjects with colon cancer
by assessing:
* Overall survival (OS) defined as the time from surgery until death due to any
cause, assessed at two years after surgery.
* Disease-free survival (DFS) defined as the time from surgery to tumour
recurrence or death due to any cause, assessed at two years after surgery.
* Recurrence-free interval (RFI) defined as the time from randomization to
tumour recurrence.
* Circulating tumour DNA (ctDNA) in plasma as a surrogate for disease
recurrence in subjects with Wnt-5a high colon cancer treated with Foxy-5
compared to subject with Wnt-5a high colon cancer who are in the Control Arm.
Exploratory Objective
* To assess the correlation between thymidine kinase activity in serum and
Wnt-5a expression in the tumour.
Study design
A Randomized, Multicentre, Open-Label Controlled Phase II Trial
Intervention
Up to 180 subjects will be randomized as 1:1 in the trial. From which up to 90
subjects will be treated with Foxy-5 throughout the entire treatment period and
up to 90 subjects will serve as control (no placebo treatment).
Study burden and risks
Burden: Each patient will undergo assessments as specified in the Schedule of
Assessments. This includes for all patients: Informed consent, physical
examination, height and weight, vital signs and ECGs. The frequency of
assessments is limited for the patients in the control group.
Patients will receive a maximum of 39 administrations of Foxy-5 (the control
group will not receive Foxy-5 administrations).
Risks: Foxy-5 appeared to be safe and well tolerated in patients in previous
studies, with no dose limiting toxicities observed at any dose.
There are risks of trial related procedures such as blood sampling, IV
injections and diagnostic procedures. Blood draws and IV injections may cause
pain, bleeding, bruising, nerve injury and/or infections at the site of cannula
insertion.
Together, the positive outcome of the preclinical studies and the Phase I
clinical trial of Foxy-5, warrant further clinical trials to evaluate Foxy-5*s
clinical efficacy in relevant clinical settings, such as for the treatment of
colon cancer (especially in subject with Wnt-5a negative).
Benefit: Foxy-5 is expected to decrease migration of cancer cells and hence
result in lower recurrence and have a better overall survival.
Medeon Science Park, Per Albin Hanssons Väg 41
Malmö SE-205-12
SE
Medeon Science Park, Per Albin Hanssons Väg 41
Malmö SE-205-12
SE
Listed location countries
Age
Inclusion criteria
1. Ability to understand and willingness to provide written informed consent before any trial-related activities.
2. Age *18 years.
3. Male or female subjects with adenocarcinoma of the colon, judged by CT or MRI as either one of the following stages per TNM classification of colon cancer (8th edition, 2017):
T1-4, N1-2, M0 or
T4, N0, M0
and who are considered to fulfil the local criteria for adjuvant post-operative chemotherapy after scheduled surgery.
4. Scheduling of surgery according to local practice allows at least 9 pre-surgery administrations of Foxy-5 for the subject. (Please note: surgery should not be postponed for trial purposes).
5. Sexually active women of childbearing potential (WOCBP) and males with WOCBP partners who are randomized to the Foxy-5 Arm must use a highly effective method of contraception for the treatment duration and for 28 days after last Foxy-5.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
7. Clinical laboratory values at screening:
a. Absolute neutrophil count *1.5 x 109/L
b. Haemoglobin * 9 g/dL
c. Platelets * 100 x 109/L
d. Aspartate Transaminase (AST) and Alanine Transaminase (ALT) *1.5x Upper Limit of Normal (ULN)
e. Serum bilirubin *1.5 x the ULN
f. Creatinine clearance >60 mL/min (determined by Cockcroft-Gault Equation).
Exclusion criteria
Candidates will be excluded from trial entry if any of the following exclusion criteria is met:
1. Assessed as not suitable or unable to tolerate adjuvant chemotherapy.
2. Evidence of distant metastatic (M1) disease at Screening (N1-2 is allowed).
3. Any surgery (except tumour biopsy) or therapy with immune suppressive agents or bone marrow stimulating factors within the last two weeks prior to randomization.
4. Any active infection requiring IV antibiotic treatment at the time of screening.
5. History of hematologic or primary solid tumour malignancy. Subjects in complete remission for at least 5 years or judged as cured by the Investigator may be included. Subjects with any prior non-invasive basal and squamous skin cell carcinoma, cervical carcinoma of Stage 1B or less, and non-invasive superficial bladder cancer may be included.
6. Pregnant or breastfeeding women.
7. Currently participating in another trial and receiving trial therapy or received investigational therapy within 4 weeks of the first dose of Foxy-5.
8. Any other condition or treatment that, in the opinion of the Investigator, might interfere with the trial or current drug or substance abuse.
9. Inability to understand the protocol requirements, instructions and trial-related restrictions, the nature, scope, and possible consequences of the trial.
10. Unlikely to comply with the protocol requirements, instructions and trial-related restrictions; e.g., uncooperative attitude, inability to return for follow-up visits, and improbability of completing the trial.
11. Legal incapacity or limited legal capacity.
12. Any condition, which results in an undue risk for the subject during the trial participation according to the Investigator.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-003074-27-NL |
| ClinicalTrials.gov | NCT02020291,NCT02655952 |
| CCMO | NL67224.100.18 |