Safety and Pharmacokinetics of Regorafenib and Cetuximab in Combination

Study Overview
=================
Brief Summary
-----------------
To establish safety, tolerability and pharmacokinetics of regorafenib and cetuximab in combination, and to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D)

Official Title
-----------------
A Phase 1b, Multi-center, Non-randomized, Open Label, Dose Escalation Design Study of Regorafenib (BAY73-4506) in Combination With Cetuximab in Subjects With Locally Advanced or Metastatic Solid Tumors Who Are Not Candidates for Standard Therapy or in Whom Regorafenib or Cetuximab is Considered as a Standard Treatment

Conditions
-----------------
Neoplasms

Intervention / Treatment
-----------------
* Drug: Regorafenib (Stivarga, BAY73-4506)
* Drug: Cetuximab (ERBITUX)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with histologically or cytologically confirmed, locally advanced or metastatic solid tumors who are not candidates for standard therapy or in whom regorafenib or cetuximab is considered a standard treatment. Patients with metastatic colorectal cancer (mCRC) must have a record of K-ras gene mutational analysis available and no K-ras mutation is present. Male or female patients ≥ 18 years of age Women of childbearing potential must have a blood or urine pregnancy test performed a maximum of 7 days before start of study treatment, and a negative result must be documented before start of study treatment Life expectancy of at least 3 months Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days of starting the study treatment: Platelet count ≥ 100,000/cubic millimeters (mm3), hemoglobin (Hb) ≥ 8.5 g/dl, leukocyte count > 3,000/mm3, absolute neutrophil count (ANC) ≥ 1,000/mm3 Total bilirubin ≤ 1.5 x the upper limit of normal (ULN). Mildly elevated total bilirubin (< 6 mg/dL) is allowed if Gilbert's syndrome is documented. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects whose cancer involves their liver). Amylase and lipase ≤ 1.5 x ULN Serum creatinine ≤ 1.5 times ULN and creatinine clearance (CLcr) ≥ 30 mL/min according to the Cockroft-Gault formula Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Exclusion Criteria: Prior treatment with Regorafenib Prior discontinuation of cetuximab treatment due to toxicity or intolerance of cetuximab Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication Non-healing wound, ulcer, or bone fracture Systemic anticancer therapy within 28 days Patients unable to swallow and retain oral medications

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regorafenib<br>Regorafenib will be administered once daily on Days 1-21 of each 28-day Cycle (3 weeks on / 1 week off). The starting dose of regorafenib is 120 mg q.d., if this is tolerable in combination with cetuximab the dose will be escalated to 160 mg q.d.; if it is not tolerated the dose will be de-escalated to 80 mg q.d. Subjects will receive an initial i.v. infusion of cetuximab (loading dose of 400 mg/ m2 BSA) on Pre-cycle Day -7. The treatment of regorafenib in combination with cetuximab maintenance dose (250 mg/m2 BSA) starts on Cycle 1 Day 1. Cetuximab infusions will be given in a once-weekly dosing-regimen as approved. | Drug: Regorafenib (Stivarga, BAY73-4506)<br> <br> Drug: Cetuximab (ERBITUX)<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of regorafenib in combination with cetuximab | MTD is defined as the maximum dose at which the incidence of dose-limiting toxicities (DLTs) during Cycle 1 is below 20 %, or as the maximum dose administered, whichever is achieved first during dose escalation | 1 month | 
| Number of participants with Adverse Events as a measure of safety and tolerability |  | Up to 2 years or longer | 
| Cmax,md (Cmax after multiple dose) for regorafenib and cetuximab |  | Multiple time points on Day 15 | 
| AUC(0-24)md (AUC from time zero to 24 hours after multiple-dose administration) for regorafenib |  | Multiple time points on Day 15 | 
| AUC(0-26)md (AUC from time zero to 26 hours after multiple-dose administration) for cetuximab |  | Multiple time points on Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response according to RECIST 1.1 |  | Up to 2 years or longer | 
| tmax,md (tmax after multiple-dose administration) for regorafenib, its metabolites M-2 (BAY75-7495) and M-5 (BAY81-8752) and cetuximab |  | Multiple time points on Day 15 | 
| tlast,md (tlast after multiple dosing) for regorafenib, its metabolites M-2 (BAY75-7495) and M-5 (BAY81-8752) and cetuximab |  | Multiple time points on Day 15 | 
| Cmax,md for metabolites M-2 (BAY75-7495) and M-5 (BAY81-8752) |  | Multiple time points on Day 15 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Regorafenib, Cetuximab, Solid tumors, Cancer, Safety, Tolerability, Pharmacokinetics