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Evaluation of a Promising New Combination of Protein Kinase Inhibitors on Organotypic Cultures of Human Renal Tumors (COMBOREIN)

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ClinicalTrials.gov Identifier: NCT03571438
Recruitment Status : Recruiting
First Posted : June 27, 2018
Last Update Posted : January 18, 2020
Sponsor:
Information provided by (Responsible Party):
University Hospital, Grenoble

Study Description
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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.


Condition or disease Intervention/treatment Phase
Kidney Cancer Combination Product: CK2 and ATM inhibitors serine/ threonin Kinase combination Drug: Sunitinib Drug: Pazopanib Drug: Temsirolimus Not Applicable

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluation of a Promising New Combination of Protein Kinase Inhibitors on Organotypic Cultures of Human Renal Tumors
Actual Study Start Date : October 16, 2017
Estimated Primary Completion Date : September 30, 2022
Estimated Study Completion Date : September 30, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: CK2(CX4945) and ATM(Ku 60019)
Treatment of cell culture with a combination of CK2 and ATM inhibitors serine/ threonin Kinase combination
 Combination Product: CK2 and ATM inhibitors serine/ threonin Kinase combination
Treatment of cell culture with CK2 and ATM inhibitors serine/ threonin Kinase combination
Active Comparator: Sunitinib
Treatment of cell culture with Sunitinib
 Drug: Sunitinib
Treatment of cell culture with Sunitinib
Active Comparator: Pazopanib
Treatment of cell culture with Pazopanib
 Drug: Pazopanib
Treatment of cell culture with Pazopanib
Active Comparator: Temsirolimus
Treatment of cell culture with Temsirolimus
 Drug: Temsirolimus
Treatment of cell culture with Temsirolimus


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of cell death on organotypic cultures of human renal tumors (Efficacy) [ Time Frame: after the treatment period (between 48 and 96 hours) ]
    Death cell rate on organotypic cultures of human renal tumors.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03571438


Contacts
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Contact: Jean-Luc Descotes, PU-PH +33 (0)4 76 76 59 22 jldescotes@chu-grenoble.fr

Locations
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France
Grenoble Alps Hospital Recruiting
Grenoble, France, 38043
Contact: Jean-Luc Descotes, PU-PH         
Sponsors and Collaborators
University Hospital, Grenoble
More Information
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Responsible Party: University Hospital, Grenoble
ClinicalTrials.gov Identifier: NCT03571438    
Other Study ID Numbers: 38RC17.063
First Posted: June 27, 2018    Key Record Dates
Last Update Posted: January 18, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Kidney Diseases
Urologic Diseases
Male Urogenital Diseases
Sirolimus
Sunitinib
Temsirolimus
MTOR Inhibitors
 Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents