EVESOR: a Phase 1 Trial of Everolimus and Sorafenib

Study Overview
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Brief Summary
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EVESOR multiparameter phase I trial aims at determining the safety of different doses and dosing schedules of everolimus in combination with sorafenib as well as the recommended doses & dosing schedules for phase 2 trials in adult patients with advanced solid tumors.

Detailed Description
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The present phase I trial aims at determining the safety of different doses and dosing schedules of everolimus in combination with sorafenib as well as the recommended doses & dosing schedules for phase 2 trials in adult patients with advanced solid tumors.

Official Title
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EVESOR: a Phase 1 Trial of Everolimus and Sorafenib to Assess the Impact of Doses and Administration Sequences on Pharmacokinetic and Pharmacodynamic Effects of the Combination

Conditions
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Metastatic or Locally Advanced Solid Tumors

Intervention / Treatment
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* Drug: Everolimus and sorafenib
* Drug: Everolimus and sorafenib
* Drug: Everolimus and sorafenib
* Drug: Everolimus and sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with solid tumors (breast adenocarcinomas, colorectal adenocarcinomas, renal cell carcinomas, gastric and oesophageal adenocarcinomas, pancreatic cancers, hepatocellular carcinoma, ovarian and Fallopian tube adenocarcinomas, primary peritoneal carcinoma, endometrial and cervix cancers, non-small cell lung carcinoma, melanoma, thyroid carcinomas) resistant or not amenable to standard treatments Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. Patients must have assessable primary or metastatic lesion using dynamic contrast enhanced ultrasound Patients must be willing to have two tumor biopsies performed (one before study start and one during study treatment), unless medically contraindicated. No previous treatment with sorafenib and everolimus. Patients may have been previously treated with one experimental drug: sorafenib or everolimus. No other limitation on prior therapy. However, there must be at least a 4 week interval between initiation of study treatment and any prior radiotherapy or systemic therapy, 6 weeks if the last regimen included BCNU or mitomycin C. Males and females aged >18 years. Life expectancy of greater than 12 weeks. ECOG performance status ≤ 2 (Karnofsky > 70%; see Appendix A). Patients must have normal organ and marrow function. Patients must be able to swallow medication. Pregnancy Testing. Women of childbearing potential are required to have a negative serum pregnancy test within 10-14 days and within 24 hours prior to the first dose of either drug (serum or urine). Ability to understand and the willingness to sign a written informed consent document. Patient without any legal protection measure and having health coverage. Exclusion Criteria: Previous treatment with sorafenib and everolimus. Patients may not be receiving any other investigational agents. Patients with known brain metastases should be excluded from this clinical trial. History of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus or sorafenib or other agents used in the study. Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible. Patients who are taking concurrent medications that are strong inducers/inhibitors of CYP3A4 should be switched to alternative medications to minimize any potential risk. If such patients cannot be switched to alternative medications, they will be ineligible to participate in this study. A list of prohibited CYP3A4 inducers and inhibitors is provided in Appendix D. Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption. Patients who are serologically positive for Hepatitis A, B or C, or have other forms of hepatitis or cirrhosis are ineligible, except for patients with hepatocellular carcinoma. Patients with hepatocellular carcinoma with Child Pugh B or C score. Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia other than chronic, stable atrial fibrillation, or psychiatric illness/social situations that would limit compliance with study requirements. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with everolimus. Cardiovascular: Patients with QTc ≥ 470 mSec, as measured by ECG using Bazett's formula for both male and female are ineligible. Patients who have not recovered from side effects of previous systemic anticancer therapy to ≤ CTCAE Grade 2 prior to the first dose of combination.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Schedule A<br>Everolimus run-in period followed by continuous administration of everolimus and sorafenib | Drug: Everolimus and sorafenib<br>* Everolimus will be given alone during a 2 week run-in period before starting sorafenib. Subsequently sorafenib will be administered twice a day while everolimus will be given once a day continuously.<br>Drug: Everolimus and sorafenib<br>* Sorafenib will be given alone during a 2 week run-in period before starting everolimus. Subsequently sorafenib will be administered twice a day while everolimus will be given once a day continuously.<br>Drug: Everolimus and sorafenib<br>* Bid sorafenib will be given every other week alternating with 1 week qd everolimus. Doses will be escalated.<br>Drug: Everolimus and sorafenib<br>* Sorafenib will be given twice a day for 3 days-on 4 days-off while everolimus will be administered continuously on a daily basis. Doses will be escalated.<br>|
| Active Comparator: Schedule B<br>Sorafenib run-in period followed by continuous administration of everolimus and sorafenib | Drug: Everolimus and sorafenib<br>* Everolimus will be given alone during a 2 week run-in period before starting sorafenib. Subsequently sorafenib will be administered twice a day while everolimus will be given once a day continuously.<br>Drug: Everolimus and sorafenib<br>* Sorafenib will be given alone during a 2 week run-in period before starting everolimus. Subsequently sorafenib will be administered twice a day while everolimus will be given once a day continuously.<br>Drug: Everolimus and sorafenib<br>* Bid sorafenib will be given every other week alternating with 1 week qd everolimus. Doses will be escalated.<br>Drug: Everolimus and sorafenib<br>* Sorafenib will be given twice a day for 3 days-on 4 days-off while everolimus will be administered continuously on a daily basis. Doses will be escalated.<br>|
| Experimental: Schedule C<br>Everolimus and sorafenib in alternance | Drug: Everolimus and sorafenib<br>* Everolimus will be given alone during a 2 week run-in period before starting sorafenib. Subsequently sorafenib will be administered twice a day while everolimus will be given once a day continuously.<br>Drug: Everolimus and sorafenib<br>* Sorafenib will be given alone during a 2 week run-in period before starting everolimus. Subsequently sorafenib will be administered twice a day while everolimus will be given once a day continuously.<br>Drug: Everolimus and sorafenib<br>* Bid sorafenib will be given every other week alternating with 1 week qd everolimus. Doses will be escalated.<br>Drug: Everolimus and sorafenib<br>* Sorafenib will be given twice a day for 3 days-on 4 days-off while everolimus will be administered continuously on a daily basis. Doses will be escalated.<br>|
| Experimental: Schedule D<br>Continuous administration of everolimus and intermittent administration of sorafenib | Drug: Everolimus and sorafenib<br>* Everolimus will be given alone during a 2 week run-in period before starting sorafenib. Subsequently sorafenib will be administered twice a day while everolimus will be given once a day continuously.<br>Drug: Everolimus and sorafenib<br>* Sorafenib will be given alone during a 2 week run-in period before starting everolimus. Subsequently sorafenib will be administered twice a day while everolimus will be given once a day continuously.<br>Drug: Everolimus and sorafenib<br>* Bid sorafenib will be given every other week alternating with 1 week qd everolimus. Doses will be escalated.<br>Drug: Everolimus and sorafenib<br>* Sorafenib will be given twice a day for 3 days-on 4 days-off while everolimus will be administered continuously on a daily basis. Doses will be escalated.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (dose limiting toxicities) as well as the recommended doses & dosing schedules for phase 2 trials in adult patients with advanced solid tumors. |  | Patients will be evaluated for dose limiting toxicities during the first 28-day cycle. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) parameters of everolimus in combination with sorafenib | Search for interactions | During the first 28-day cycle | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Everolimus ; Sorafenib ; Phase 1 trial ; Solid tumor