Safety and Pharmacokinetics of Regorafenib and Cetuximab in Combination

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

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)

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: Regorafenib (Stivarga, BAY73-4506); Drug: Cetuximab (ERBITUX)

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Regorafenib; 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); Drug: Cetuximab (ERBITUX)

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	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

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Weekes C, Lockhart AC, Lee JJ, Sturm I, Cleton A, Huang F, Lenz HJ. A phase 1b study evaluating the safety and pharmacokinetics of regorafenib in combination with cetuximab in patients with advanced solid tumors. Int J Cancer. 2019 Nov 1;145(9):2450-2458. doi: 10.1002/ijc.32317. Epub 2019 Jun 14.

Helpful Links

• Click here to find results for studies related to Bayer products.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 21, 2013
• Primary Completion (ACTUAL): January 31, 2017
• Study Completion (ACTUAL): April 3, 2018

Study Registration Dates

• First Submitted: October 28, 2013
• First Submitted That Met QC Criteria: October 28, 2013
• First Posted (ESTIMATE): November 1, 2013

Study Record Updates

• Last Update Posted (ACTUAL): April 9, 2019
• Last Update Submitted That Met QC Criteria: April 5, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Safety; Cancer; Solid tumors; Pharmacokinetics; Cetuximab; Tolerability; Regorafenib
• Additional Relevant MeSH Terms: Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: 16547

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No