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

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

Tracking Information

• First Submitted Date: June 15, 2018
• First Posted Date: June 27, 2018
• Last Update Posted Date: January 18, 2020
• Actual Study Start Date: October 16, 2017
• Estimated Primary Completion Date: September 30, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 26, 2018)

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.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of a Promising New Combination of Protein Kinase Inhibitors on Organotypic Cultures of Human Renal Tumors
• Official Title: Evaluation of a Promising New Combination of Protein Kinase Inhibitors on Organotypic Cultures of Human Renal Tumors

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.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Kidney Cancer

Intervention

• Combination Product: CK2 and ATM inhibitors serine/ threonin Kinase combination
  Treatment of cell culture with CK2 and ATM inhibitors serine/ threonin Kinase combination
• Drug: Sunitinib
  Treatment of cell culture with Sunitinib
• Drug: Pazopanib
  Treatment of cell culture with Pazopanib
• Drug: Temsirolimus
  Treatment of cell culture with Temsirolimus

Study Arms

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 26, 2018): 100
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 30, 2024
• Estimated Primary Completion Date: September 30, 2022 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: France

Administrative Information

• NCT Number: NCT03571438
• Other Study ID Numbers: 38RC17.063
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: University Hospital, Grenoble
• Original Responsible Party: Same as current
• Current Study Sponsor: University Hospital, Grenoble
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: University Hospital, Grenoble
• Verification Date: January 2020