Radiolabelled CCK-2/Gastrin Receptor Analogue for Personalized Theranostic Strategy in Advanced MTC

Study Overview
=================
Brief Summary
-----------------
The study is a phase I multicentre randomized, open, parallel-arm clinical trial conducted to investigate the IMP, namely 111In-CP04. The study consists of preclinical (to establish a clinically useful formulation for the radiolabelled peptide CP04), and a clinical step. The main objective of the clinical part of the project is to establish the safety of i.v. administration of a high peptide amount and to assess the tracer biodistribution and dosimetry in MTC and normal tissues and to determine critical organs as well as the evaluation of the potential of CCK2 receptor scintigraphy to detect cancer lesions for both low (10ug) and high (50ug) peptide amount and the decrease of kidney dose after co-administration of gelofusine /gelaspan as a nephroprotective agent. To achieve this, the following study design has been accepted: the first 4 patients will receive 2 peptide amount of CP04: low peptide amount (for diagnostic purpose) and high peptide amount (for therapeutic purpose) of CP04. If no SAE is present, the remaining pts will be randomized for 2 arms: high peptide amount of 111In-CP04 with and without gelofusine/gelaspan infusion. It is expected that CCK-2/gastrin receptor imaging will become a valid diagnostic method for a specific non-invasive staging and follow-up of patients with MTC, and treatment of recurrent and disseminated disease will be more efficient with minimized nephro- and myelotoxicity (if 111In labelled).

Detailed Description
-----------------
The main goal of the study is to expand cancer preclinical research results on the usefulness of CCK-2/gastrin receptor in clinical practice. On the basis of last few years preclinical research outcome on new biomarkers, conjugate CP04 was chosen on the basis of its good stability and affinity to CCK-2/gastrin receptor in vitro, as well as its favourable biodistribution and pharmacodynamic properties in vivo, preclinically. Within this project the tracer may get a chance to be introduced to clinical practice as a more selective and efficient tool for the diagnosis, early detection and therapy of recurrent and metastatic MTC. Furthermore, the project may become the first step to establish a new, more effective strategy for the treatment of MTC patients leading to reduction of incidence and mortality as well as improvement of quality of life. CCK-2/gastrin receptors may become viable targets for radionuclide scintigraphy and radionuclide therapy, similarly to somatostatin receptors which have been instrumental to establish nuclear medicine efficacy in clinical practice. Achieving key project objectives (i.e. investigation of patients after administration of high peptide amount of the CCK-2/gastrin receptor labelled compound, performing complete patient peptide assessment and research nephrotoxicity in patients with or without administration for nephroprotective agent gelofusine/gelaspan), we will be able to define the exact molecular profile of an individual patient and tumour. Eventually, safe and efficacious personalized treatment will be planned using radiolabelled CCK-2/gastrin ligands of higher therapeutic efficacy.

Official Title
-----------------
Phase I Clinical Trial Using a Novel CCK-2/Gastrin Receptor-localizing Radiolabelled Peptide Probe for Personalized Diagnosis and Therapy of Patients With Progressive or Metastatic Medullary Thyroid Carcinoma

Conditions
-----------------
Medullary Thyroid Carcinoma

Intervention / Treatment
-----------------
* Drug: 111In-CP04
* Drug: 111In-CP04 with co-administration of gelofusine/gelaspan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Related to the medullary cancer of the thyroid: Histologically documented medullary cancer of the thyroid. Presence of more than one distant or nodal, surgically untreatable metastases confirmed with either 18F-FDG PET/CT or enhanced-CT or MRI OR Doubling time (DT) of serum calcitonin level less than two years prior to study entry and negative imaging. Karnofsky performance status > 50%. Life expectancy of more than 6 months. Related to the patient: Male or female patients aged >18 years without upper age limit. Ability to understand and willingness to sign a written informed consent document. Written informed consent obtained according to international guidelines and local laws. Exclusion Criteria: Related to the MTC: Patients with surgically treatable medullary thyroid cancer. Patients with history of second malignancy other than basal cell carcinoma of the skin. Related to previous or concomitant therapies : Participation in any other investigational trial within 3 months of study entry. Previous external beam radiation therapy within two years. Organ allograft requiring immunosuppressive therapy. Related to the patient: Pregnancy, breast-feeding. Known hypersensitivity to gastrin analogues. Patients with concurrent illnesses that might preclude study completion or interfere with study results. Patients with bladder outflow obstruction or unmanageable urinary incontinence. Clinical diagnosis of disseminated intravascular coagulation. Serum creatinine >170 μmol/L, GFR < 40 mL/min Known history of hypersensitivity to gelofusine /gelaspan or any other contraindications to gelofusine/gelaspan infusion

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: arm 1<br>111In-CP04 | Drug: 111In-CP04<br>* Radiopharmaceutical preparation<br>* Other names: 111In-CP04 (DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2;|
| Experimental: arm 2<br>111In-CP04 with co-administration of gelofusine/gelaspan | Drug: 111In-CP04 with co-administration of gelofusine/gelaspan<br>* Radiopharmaceutical preparation with co-administration of gelofusine/gelaspan<br>* Other names: 111In-CP04 (DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of CP04 | Safety of intravenous administration of CP04 at low peptide amount (for diagnostic purpose) and high peptide amount (for therapeutic purpose) radiolabelled with 200±10% MBq of 111In will be assessed by type, frequency, severity, timing and relation to the studied radiopharmaceutical Safety of intravenous administration of CP04 at low peptide amount (for diagnostic purpose) and high peptide amount (for therapeutic purpose) radiolabelled with 200±10% MBq of 111In will be assessed by type, frequency, severity, timing and relation to the studied radiopharmaceutical administration of adverse events and laboratory abnormalities based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 | 4 months | 
| Uptake of 111In-CP04 in tumor and other tissues | The radioactivity uptake of 111In-CP04 will be assessed in the tumor lesions and in other tissues naturally expressing CCK2 receptors, based on the planar and SPECT/CT images (expressed as the ratio of counts over the region of interest (ROI) selected over the target tissue compared to the counts over the equivalent region in patient's body which is not taking up the 111In-CP04), otherwise described as target to non target ratio T/N | 72 hours from 111In-CP04 injection | 
| Pharmacokinetics of 111In-CP04 | Area under the selected organs concentration versus time curve | 72 hours from 111In-CP04 injection | 
| Pharmacokinetics of 111In-CP04 | Area under the blood concentration versus time curve | 72 hours from 111In-CP04 injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic sensitivity/specificity of 111In-CP04 to detect cancer lesions | Diagnostic sensitivity/specificity of 111In-CP04 to detect cancer lesions for both diagnostic and therapeutic peptide amount by Qualitative Visual Analysis (number of patients with uptake at site of lesion, the number of lesions with abnormal tracer uptake at scintigraphy, the number and site of lesions with pathological uptake detected per verifiable organ or body region relative to those detected | 3 years | 
| Comparison of pharmacokinetic/imaging effect of low and high peptide amount | To evaluate the influence of a low amount of CP04 peptide on the high amount of peptide vs. the high amount of peptide alone on tumour and organ uptake | 3 years | 
| Gelofusine/gelaspan injection and CP04 kidney uptake | To investigate the relative decrease of kidney dose after co-administration of nephroprotective agent - gelofusine/gelaspan | 3 years | 
| Dosimetry | Pharmacokinetics data for the assessment of organ and tissue radiation absorbed doses.. | 72 hours from 111In-CP04 injection | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
theranostics, medullary thyroid carcinoma, MTC, new gastrin analog, 111In-CP04, CP04 indium, personalised diagnostics, personalised therapy, advanced MTC, CCK-2/gastrin receptor