Evaluation of a Promising New Combination of Protein Kinase Inhibitors on Organotypic Cultures of Human Renal Tumors (COMBOREIN)
Primary Purpose
Kidney Cancer
Status
Recruiting
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
CK2 and ATM inhibitors serine/ threonin Kinase combination
Sunitinib
Pazopanib
Temsirolimus
Sponsored by
About this trial
This is an interventional treatment trial for Kidney Cancer
Eligibility Criteria
Inclusion Criteria:
- major patient treated at the University Hospital of Grenoble for a renal tumor with suspected or confirmed malignancy.This includes non-metastatic patients undergoing renal lumpectomy, partial nephrectomy or total nephrectomy, as well as metastatic or locally advanced cancer patients undergoing cytoreductive surgery who are eligible for medical treatment at the same time
Exclusion Criteria:
- Contaminated patients with HIV and /or HBV (hepatitis B virus) and / or HCV (hepatitis C virus) positive serology.
- Absence or withdrawal of the informed consent of the patient.
- Tumors smaller than 2 cm on preoperative imaging
Sites / Locations
- Grenoble Alps HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Active Comparator
Active Comparator
Active Comparator
Arm Label
CK2(CX4945) and ATM(Ku 60019)
Sunitinib
Pazopanib
Temsirolimus
Arm Description
Treatment of cell culture with a combination of CK2 and ATM inhibitors serine/ threonin Kinase combination
Treatment of cell culture with Sunitinib
Treatment of cell culture with Pazopanib
Treatment of cell culture with Temsirolimus
Outcomes
Primary Outcome Measures
Incidence of cell death on organotypic cultures of human renal tumors (Efficacy)
Death cell rate on organotypic cultures of human renal tumors.
Secondary Outcome Measures
Full Information
NCT ID
NCT03571438
First Posted
June 15, 2018
Last Updated
January 16, 2020
Sponsor
University Hospital, Grenoble
1. Study Identification
Unique Protocol Identification Number
NCT03571438
Brief Title
Evaluation of a Promising New Combination of Protein Kinase Inhibitors on Organotypic Cultures of Human Renal Tumors
Acronym
COMBOREIN
Official Title
Evaluation of a Promising New Combination of Protein Kinase Inhibitors on Organotypic Cultures of Human Renal Tumors
Study Type
Interventional
2. Study Status
Record Verification Date
January 2020
Overall Recruitment Status
Recruiting
Study Start Date
October 16, 2017 (Actual)
Primary Completion Date
September 30, 2022 (Anticipated)
Study Completion Date
September 30, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Grenoble
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
The investigators objective is to test the combination directly on organotypic cultures of tumors from patients after their excision in the Department of Urology and Renal Transplantation of the University Hospital of Grenoble and to compare their efficacy with that of currently selected treatments in the clinic.
The population targeted by the combination for use in clinical practice is patients with metastatic clear cell renal cell carcinoma.
Current treatments for these patients are Sunitinib, Pazopanib and Temsirolimus.
Detailed Description
Given the failure of conventional therapies in kidney cancer, both chemo and radio resistant, it was necessary to seek therapeutic alternatives.
Thus, in 2005, the first targeted therapies in kidney cancer came with protein kinase inhibitors including mTOR (mammilian target of rapamycin) inhibitors (Temsirolimus and Everolimus) and VEGFR inhibitors (Sunitinib, Sorafenib, Pazopanib and Axitinib).
Nevertheless resistance to these treatments appeared with their prolonged use as monotherapy in all cases. One of the main mechanisms of this therapeutic escape is the adaptation of the tumor cell via the use of an alternative pathway of deregulation of cell signaling.
Thus emerged the idea of simultaneously treating multiple targets to prevent the tumor cell from adapting. Phase I / II therapeutic trials have already been initiated with the combination of anti-BRAF (proto-oncogene B-Raf) and anti-MEK (MAP-ERK kinase) in metastatic melanoma or with the combination of anti-EGFR (epidermal growth factor receptor) and anti-MET in lung and breast cancer. The results are very promising since we observe a synergistic effect of two targeted therapies combined.
In kidney cancer, this escape phenomenon is also observed (example of the mTORC2 (mammilian target of rapamycin complex 2) crosstalk on AKT which limits the effect of mTORC1 (mammilian target of rapamycin complex 1) inhibitors at the level of the PI3 kinase signaling pathway).
It is therefore time to check if this strategy is applicable in kidney cancer. The investigators have, through a chemo-genomic screening of a hundred molecules stored in the CEA (French Alternative Energies and Atomic Energy Commission) chemical bank, found a combination of inhibitors targeting the kinases CK2 and ATM very effective on a human cell line of renal cell carcinoma clear. This combination has been tested on conventional cultures as well as on more innovative 3D cultures, better reproducing the tumor environment. The preliminary results obtained show that the combination is clearly more efficient in a 3D model as well as on the VHL-line (von Hippel-Lindau) in hypoxic condition, which is very encouraging.
In the context of preclinical validation, it is now essential to evaluate the therapeutic potential of these molecules by comparing their efficiency with those currently selected.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Kidney Cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
100 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
CK2(CX4945) and ATM(Ku 60019)
Arm Type
Experimental
Arm Description
Treatment of cell culture with a combination of CK2 and ATM inhibitors serine/ threonin Kinase combination
Arm Title
Sunitinib
Arm Type
Active Comparator
Arm Description
Treatment of cell culture with Sunitinib
Arm Title
Pazopanib
Arm Type
Active Comparator
Arm Description
Treatment of cell culture with Pazopanib
Arm Title
Temsirolimus
Arm Type
Active Comparator
Arm Description
Treatment of cell culture with Temsirolimus
Intervention Type
Combination Product
Intervention Name(s)
CK2 and ATM inhibitors serine/ threonin Kinase combination
Intervention Description
Treatment of cell culture with CK2 and ATM inhibitors serine/ threonin Kinase combination
Intervention Type
Drug
Intervention Name(s)
Sunitinib
Intervention Description
Treatment of cell culture with Sunitinib
Intervention Type
Drug
Intervention Name(s)
Pazopanib
Intervention Description
Treatment of cell culture with Pazopanib
Intervention Type
Drug
Intervention Name(s)
Temsirolimus
Intervention Description
Treatment of cell culture with Temsirolimus
Primary Outcome Measure Information:
Title
Incidence of cell death on organotypic cultures of human renal tumors (Efficacy)
Description
Death cell rate on organotypic cultures of human renal tumors.
Time Frame
after the treatment period (between 48 and 96 hours)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
major patient treated at the University Hospital of Grenoble for a renal tumor with suspected or confirmed malignancy.This includes non-metastatic patients undergoing renal lumpectomy, partial nephrectomy or total nephrectomy, as well as metastatic or locally advanced cancer patients undergoing cytoreductive surgery who are eligible for medical treatment at the same time
Exclusion Criteria:
Contaminated patients with HIV and /or HBV (hepatitis B virus) and / or HCV (hepatitis C virus) positive serology.
Absence or withdrawal of the informed consent of the patient.
Tumors smaller than 2 cm on preoperative imaging
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jean-Luc Descotes, PU-PH
Phone
+33 (0)4 76 76 59 22
Email
jldescotes@chu-grenoble.fr
Facility Information:
Facility Name
Grenoble Alps Hospital
City
Grenoble
ZIP/Postal Code
38043
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jean-Luc Descotes, PU-PH
12. IPD Sharing Statement
Learn more about this trial
Evaluation of a Promising New Combination of Protein Kinase Inhibitors on Organotypic Cultures of Human Renal Tumors
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