Dose-Finding Study of Cabozantinib (XL184) in Japanese Subjects With Advanced Cancer

Phase 1 Multiple Ascending Dose Study of XL184 Monotherapy in Japanese Subjects With Advanced or Metastatic Solid Tumors

The purpose of this study is to evaluate the safety profile, tolerability, pharmacokinetics (PK), pharmacodynamics, pharmacogenomic (PGX) and preliminary efficacy following daily oral doses of cabozantinib (XL184) in Japanese patients with advanced or metastatic solid tumors. Also, the effect of XL184 in the treatment of non-small cell lung cancer (NSCLC) patients with various activating mutations will be evaluated at the recommended Phase 2 dose.

Study Overview

• Status: Completed
• Conditions: Cancer; NSCLC; Solid Tumors
• Intervention / Treatment: Drug: cabozantinib capsules; Drug: cabozantinib tablets

• Study Type: Interventional
• Enrollment (Anticipated): 85
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Koto
    • Ariake, Koto, Japan, 135-8550
      • The Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR)
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0045
      • National Cancer Center Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Select Inclusion Criteria:

• Subjects with advanced or metastatic solid tumors for whom the standard of care is ineffective or inappropriate.
• NSCLC expansion cohort subjects must have confirmed NSCLC (Stage IIIb or IV) and documented activating mutations.
• At least 4 weeks must have elapsed from the last anti-cancer therapy. At least 6 weeks for nitrosoureas, mitomycin C and liposomal doxorubicin.
• Have adequate bone marrow function, adequate liver function, and adequate renal function.
• Sexually active subjects (men and women of child-bearing potential (WOCBP)) must agree to use medically accepted barrier methods of contraception (eg, male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control. Women of childbearing potential (WOCBP) must have a negative pregnancy test at screening.

Select Exclusion Criteria:

• Symptomatic central nervous system (CNS) metastasis, or active CNS metastasis requiring medication.
• WOCBP who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for the entire study period and for 4 months after the last dose of investigational product.
• Women who are pregnant or breastfeeding.
• Sexually active fertile men not using effective birth control for the entire study period and for 4 months after the last dose of investigational product if their partners are WOCBP.
• Subjects who have uncontrolled intercurrent illness including, but not limited to, infection requiring systemic therapy, symptomatic congestive heart failure, uncontrolled hypertension, uncontrolled angina pectoris, uncontrolled peptic ulcer, cardiac arrhythmia requiring medication.
• Subjects who are HIV antibody positive, HBs antigen positive, and/or HCV antibody positive.
• Subjects with body cavity fluid retention which requires drainage.
• Subjects with any major surgery within 8 weeks prior to study enrollment.
• Subjects with major unhealed wounds or fracture.
• Subjects with a history or concurrent diagnosis of gastrointestinal perforation.
• Subjects with evidence of bleeding tendency or coagulopathy.
• Subjects with a history of thromboembolism.
• Subjects with a history of or concurrent pancreatitis.
• Exposure to any investigational drug within 30 days of enrollment.
• Subjects receiving radiation therapy or treatment with radionuclides within 6 to 2 weeks before first dose of XL184.
• NSCLC expansion cohorts: subjects must not be diagnosed with another malignancy within 2 years before first dose of XL184.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cabozantinib capsules and tablets; Subjects will be enrolled in cohorts at different dose levels in order to determine the maximum tolerated dose of cabozantinib. Initially, subjects enrolled will receive the capsule formulation; other subjects will receive the tablet formulation.	Drug: cabozantinib capsules; cabozantinib capsules administered as 25-mg and 100-mg strengths once-daily until disease progression; Other Names: XL184; Drug: cabozantinib tablets; cabozantinib tablets administered as 20-mg and 60-mg strengths once-daily until disease progression; Other Names: XL184

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose	To establish the MTD and recommended Phase 2 dose (or dose range as appropriate) of XL184 when administered orally on a once daily schedule in subjects with advanced or metastatic solid tumors.	Assessed in the clinic on Days 1 through 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of XL184	Safety and tolerability of multiple doses of XL184 administered orally on a daily basis. Assessed from informed consent until at least 30 days after discontinuation.	From study start to October 2014
Plasma Pharmacokinetics	Assess plasma pharmacokinetics of daily oral administration of XL184 from Treatment Day 1 to Day 29.	Assessed in the clinic from Day 1 through Day 29
Tumor response (preliminary anti-tumor activity)	Assess tumor response after repeated administration of XL184 from screening until discontinuation. Assessed as best overall response by cohort by radiological response defined by RECIST criteria.	Study start to October 2014

Collaborators and Investigators

• Sponsor: Exelixis

Publications and helpful links

General Publications

• Nokihara H, Nishio M, Yamamoto N, Fujiwara Y, Horinouchi H, Kanda S, Horiike A, Ohyanagi F, Yanagitani N, Nguyen L, Yaron Y, Borgman A, Tamura T. Phase 1 Study of Cabozantinib in Japanese Patients With Expansion Cohorts in Non-Small-Cell Lung Cancer. Clin Lung Cancer. 2019 May;20(3):e317-e328. doi: 10.1016/j.cllc.2018.12.018. Epub 2018 Dec 31.

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: March 9, 2012
• First Submitted That Met QC Criteria: March 12, 2012
• First Posted (Estimate): March 14, 2012

Study Record Updates

• Last Update Posted (Estimate): August 20, 2015
• Last Update Submitted That Met QC Criteria: August 19, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: NSCLC; Advanced cancer; Metastatic
• Other Study ID Numbers: XL184-014