Clinical Trials /

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

NCT02655952

Description:

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).

Related Conditions:
  • Breast Carcinoma
  • Colon Carcinoma
  • Prostate Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: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

Clinical Trial IDs

  • ORG STUDY ID: SMR-3164
  • NCT ID: NCT02655952

Trial Conditions

  • Metastatic Breast Cancer
  • Metastatic Colon Cancer
  • Metastatic Prostate Cancer

Trial Interventions

DrugSynonymsArms
Foxy-5Foxy-5

Trial Purpose

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).

Detailed Description

Trial Arms

NameTypeDescriptionInterventions
Foxy-5ExperimentalSlow infusion of lyophilised and reconstituted Foxy-5 three times weekly for three weeks. The last cohort will include up to a total of 18 evaluable patients. The patients will be divided into 2 sub-cohorts: The first cohort will contain patients receiving IMP administration three times a week in line with the previous cohorts. A minimum of 6 and a maximum of 12 evaluable patients will be included in this cohort. The second cohort will contain patients receiving IMP administration two times a week. Between 6 and 12 patients will be included in this sub-cohort depending on the number of patients in the first sub-cohort.
  • Foxy-5

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

- 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

- Adequate blood clotting function as defined by the International Normalized Ratio (INR) < 1.20.

- Must have an evaluable tumour appropriate for biopsy as determined by the Investigator

- >=1 week must have elapsed since last treatment with any non steroidal anti-inflammatory drugs (NSAID); both COX-1 and COX-2 inhibitors

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

- History of severe allergic or hypersensitive reactions to excipients

- Pregnant or breastfeeding women

- Patients in active anticoagulant treatment.

- Previous exposure to Foxy-5

- 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

Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Both
Healthy Volunteers:No

Primary Outcome Measures

Measure:Presence of Dose Limiting Toxicities (DLTs).
Time Frame:6 month
Safety Issue:Yes
Description: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 Outcome Measures

Measure:Genome wide mRNA gene expression in tumour biopsies and blood (buffy coat)
Time Frame:Tumour biopsies obtained prior to day 1 and on day 12 and 19
Safety Issue:No
Description:Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5
Measure:Neutrophil gelatinase-associated lipocalin (NGAL)
Time Frame:Tumour biopsies and blood obtained prior to day 1 and on day 12 and 19
Safety Issue:No
Description:Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5
Measure:15-hydroxyprostaglandin dehydrogenase (15-PGDH)
Time Frame:Tumour biopsies and blood obtained prior to day 1 and on day 12 and 19
Safety Issue:No
Description:Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5
Measure:prostaglandin E2 (PGE2)
Time Frame:Tumour biopsies and blood obtained prior to day 1 and on day 12 and 19
Safety Issue:No
Description:Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5
Measure:15-keto-prostaglandin E2 (15-keto-PGE2)
Time Frame:Tumour biopsies and blood obtained prior to day 1 and on day 12 and 19
Safety Issue:No
Description:Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5
Measure:13,-14-dihydro-15-keto-prostaglandin E2 (13,-14-dihydro-15-keto-PGE2)
Time Frame:Tumour biopsies and blood obtained prior to day 1 and on day 12 and 19
Safety Issue:No
Description:Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5
Measure:Wnt-5a protein expression and hematoxylin-eosin (HE) staining of tumour biopsies
Time Frame:Tumour biopsies obtained prior to day 1 and on day 12 and 19
Safety Issue:No
Description:Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5
Measure:Numbers of cancer stem cells in tumour biopsies
Time Frame:Tumour biopsies obtained prior to day 1 and on day 12 and 19
Safety Issue:No
Description:Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5
Measure:Numbers of circulating tumour cells (CTCs) in blood
Time Frame:Blood sample obtained prior to day 1 and on day 12 and 19
Safety Issue:No
Description:Determination of the biological response dose (BRD) based on the alterations in the exploratory biomarkers during treatment with Foxy-5
Measure:Maximum tolerated dose (MTD)
Time Frame:6 month
Safety Issue:Yes
Description:Determined as the dose preceding the dose at which two or more patients have experienced DLTs. Assessment of adverse events and laboratory abnormalities
Measure:Area under the plasma concentration curve (AUC) of Foxy-5
Time Frame:immediately prior to treatment, at 0, 5, 15, 30, minutes 1, 3, 6, 8, 24, 48, 72 and 96 hours after infusion.
Safety Issue:No
Description:The concentration of Foxy-5 in human biological samples will be measured with liquid chromatography with tandem mass spectrometry detection (LC-MS/MS)

Trial Keywords