Clinical Trials /

Safety and Pharmacokinetics of Regorafenib and Cetuximab in Combination

NCT01973868

Description:

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)

Related Conditions:
  • Colorectal Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Safety and Pharmacokinetics of <span class="go-doc-concept go-doc-intervention">Regorafenib</span> and <span class="go-doc-concept go-doc-intervention">Cetuximab</span> in Combination

Title

  • Brief Title: Safety and Pharmacokinetics of Regorafenib and Cetuximab in Combination
  • 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
  • Clinical Trial IDs

    NCT ID: NCT01973868

    ORG ID: 16547

    Trial Conditions

    Neoplasms

    Trial Interventions

    Drug Synonyms Arms
    Regorafenib (Stivarga, BAY73-4506) Regorafenib (intermittent), Regorafenib (continuous)
    Cetuximab (ERBITUX) Regorafenib (intermittent), Regorafenib (continuous)

    Trial Purpose

    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)

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Regorafenib (intermittent) Experimental In the Intermittent-Regorafenib arm, 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 in each cohort first receive a single dose of regorafenib (at the assigned dose level) on Pre-cycle Day -14 (2 days) and 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. Regorafenib (Stivarga, BAY73-4506), Cetuximab (ERBITUX)
    Regorafenib (continuous) Experimental In the Continuous-Regorafenib arm, regorafenib will be administered once daily on Days 1-28 of each 28-day Cycle with no break between the cycles. If the starting dose of intermittent-Regorafenib arm in combination with cetuximab was tolerated, the continuous-Regorafenib arm will start with the dose of 100 mg q.d; if the starting dose of the intermittent arm was not tolerated, the dose will start with 60 mg q.d. Subjects in each cohort first receive a single dose of regorafenib (at the assigned dose level) on Pre-cycle Day -14 (2 days) and 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. Regorafenib (Stivarga, BAY73-4506), Cetuximab (ERBITUX)

    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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum tolerated dose (MTD) of regorafenib in combination with cetuximab

    Number of participants with Adverse Events as a measure of safety and tolerability

    Cmax (maximum drug concentration in blood) for regorafenib and cetuximab

    Cmax,md (Cmax after multiple dose) for regorafenib and cetuximab

    AUC (area under the blood concentration vs time curve from zero to infinity after single (first) dose) for regorafenib and cetuximab

    AUC(0-24) (AUC from time zero to 24 hours after first-dose administration) for regorafenib

    AUC(0-24)md (AUC from time zero to 24 hours after multiple-dose administration) for regorafenib

    AUC(0-26)md (AUC from time zero to 26 hours after multiple-dose administration) for cetuximab

    Secondary Outcome Measures

    Tumor response according to RECIST 1.1

    tmax (time to reach maximum drug concentration in blood) for regorafenib, its metabolites M-2 (BAY75-7495) and M-5 (BAY81-8752) and cetuximab

    tlast (time of last quantifiable drug concentration) for regorafenib, its metabolites M-2 (BAY75-7495) and M-5 (BAY81-8752) and cetuximab

    tmax,md (tmax after multiple-dose administration) for regorafenib, its metabolites M-2 (BAY75-7495) and M-5 (BAY81-8752) and cetuximab

    tlast,md (tlast after multiple dosing) for regorafenib, its metabolites M-2 (BAY75-7495) and M-5 (BAY81-8752) and cetuximab

    AUC(0-tlast) (AUC from time zero to the last data point > lower limit of quantification) for regorafenib, its metabolites M-2 (BAY75-7495) and M-5 (BAY81-8752) and cetuximab

    AUC(0-tlast)md (AUC(0-tlast) after multiple dosing) for regorafenib, its metabolites M-2 (BAY75-7495) and M-5 (BAY81-8752) and cetuximab

    AUC(0-24)md (AUC from time zero to 24 hours after multiple-dose administration) for regorafenib and its metabolites M-2 (BAY75-7495) and M-5 (BAY81-8752)

    Cmax for metabolites M-2 (BAY75-7495) and M-5 (BAY81-8752)

    Cmax,md for metabolites M-2 (BAY75-7495) and M-5 (BAY81-8752)

    AUC(0-1)md (AUC from time zero to 1 hours after multiple-dose administration) for cetuximab

    Trial Keywords

    Regorafenib

    Cetuximab

    Solid tumors

    Cancer

    Safety

    Tolerability

    Pharmacokinetics