Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib (CELESTIAL)

• ClinicalTrials.gov Identifier: NCT01908426
• Recruitment Status: Completed
• First Posted: July 25, 2013
• Results First Posted: March 1, 2019
• Last Update Posted: May 6, 2021
• Sponsor: Exelixis
• Information provided by (Responsible Party): Exelixis

Tracking Information

• First Submitted Date: July 23, 2013
• First Posted Date: July 25, 2013
• Results First Submitted Date: October 16, 2018
• Results First Posted Date: March 1, 2019
• Last Update Posted Date: May 6, 2021
• Study Start Date: September 26, 2013
• Actual Primary Completion Date: October 16, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 27, 2019)

Overall Survival (OS) [ Time Frame: Up to 45 months ]

The primary analysis of OS is defined as the time from randomization to death from any cause. The analysis was based on a second planned interim analysis prespecified to be performed at approximately the 75% information fraction (ie, at approximately 466 deaths). The data cutoff date for this event-driven analysis in the Intent to Treat (ITT) population was 01 June 2017. Median OS was calculated using the Kaplan-Meier estimates.

Original Primary Outcome Measures (submitted: July 24, 2013)

Overall Survival (OS) [ Time Frame: Up to 38 months ]

OS is defined as the time from randomization to death from any cause.

Current Secondary Outcome Measures (submitted: February 27, 2019)

• Progression-Free Survival (PFS) [ Time Frame: Up to 45 months ]
  Duration of PFS is defined as the time of randomization to the earlier of the following events, progressive disease as determined by Investigator (per RECIST 1.0, which is defined by a ≥ 20% increase in the sum of the longest diameter of target lesions from baseline) or death due to any cause. A Kaplan- Meier analysis was performed to estimate the median duration.
• Objective Response Rate (ORR) [ Time Frame: ORR is measured by radiologic assessment every 8 weeks after randomization until disease progression or discontinuation of study treatment (up to 45 months) ]
  Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Original Secondary Outcome Measures (submitted: July 24, 2013)

• Progression-Free Survival (PFS) [ Time Frame: Up to 38 months ]
  Duration of PFS is defined as the time of randomization to the earlier of the following events: progressive disease or death due to any cause.
• Objective Response Rate (ORR) [ Time Frame: Up to 38 months ]
  ORR is measured by radiologic assessment every 8 weeks after randomization until disease progression or discontinuation of study treatment. ORR is the proportion of subjects experiencing a confirmed complete response(CR) or confirmed partial response (PR).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib
• Official Title: A Phase 3, Randomized, Double-blind, Controlled Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib
• Brief Summary: The purpose of this study is to evaluate the effect of Cabozantinib (XL184) compared with placebo on overall survival in subjects with advanced hepatocellular carcinoma who have received prior sorafenib.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Hepatocellular Carcinoma

Intervention

• Drug: Cabozantinib tablets
  Other Name: XL184
• Drug: Placebo tablets

Study Arms

• Experimental: Cabozantinib (XL184)
  Cabozantinib (XL184) 60 mg tablet once daily
  Intervention: Drug: Cabozantinib tablets
• Placebo Comparator: Placebo
  Oral cabozantinib-matched placebo tablet once daily
  Intervention: Drug: Placebo tablets

Publications *

• Freemantle N, Mollon P, Meyer T, Cheng AL, El-Khoueiry AB, Kelley RK, Baron AD, Benzaghou F, Mangeshkar M, Abou-Alfa GK. Quality of life assessment of cabozantinib in patients with advanced hepatocellular carcinoma in the CELESTIAL trial. Eur J Cancer. 2022 Jun;168:91-98. doi: 10.1016/j.ejca.2022.03.021. Epub 2022 Apr 26.
• El-Khoueiry AB, Meyer T, Cheng AL, Rimassa L, Sen S, Milwee S, Kelley RK, Abou-Alfa GK. Safety and efficacy of cabozantinib for patients with advanced hepatocellular carcinoma who advanced to Child-Pugh B liver function at study week 8: a retrospective analysis of the CELESTIAL randomised controlled trial. BMC Cancer. 2022 Apr 9;22(1):377. doi: 10.1186/s12885-022-09453-z.
• Kelley RK, Miksad R, Cicin I, Chen Y, Klumpen HJ, Kim S, Lin ZZ, Youkstetter J, Hazra S, Sen S, Cheng AL, El-Khoueiry AB, Meyer T, Abou-Alfa GK. Efficacy and safety of cabozantinib for patients with advanced hepatocellular carcinoma based on albumin-bilirubin grade. Br J Cancer. 2022 Mar;126(4):569-575. doi: 10.1038/s41416-021-01532-5. Epub 2021 Oct 7.
• Trojan J, Mollon P, Daniele B, Marteau F, Martin L, Li Y, Xu Q, Piscaglia F, Zaucha R, Sarker D, Lim HY, Venerito M. Comparative Efficacy of Cabozantinib and Ramucirumab After Sorafenib for Patients with Hepatocellular Carcinoma and Alpha-fetoprotein >/= 400 ng/mL: A Matching-Adjusted Indirect Comparison. Adv Ther. 2021 May;38(5):2472-2490. doi: 10.1007/s12325-021-01700-2. Epub 2021 Apr 6.
• Kelley RK, Ryoo BY, Merle P, Park JW, Bolondi L, Chan SL, Lim HY, Baron AD, Parnis F, Knox J, Cattan S, Yau T, Lougheed JC, Milwee S, El-Khoueiry AB, Cheng AL, Meyer T, Abou-Alfa GK. Second-line cabozantinib after sorafenib treatment for advanced hepatocellular carcinoma: a subgroup analysis of the phase 3 CELESTIAL trial. ESMO Open. 2020 Aug;5(4):e000714. doi: 10.1136/esmoopen-2020-000714.
• Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klumpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 2018 Jul 5;379(1):54-63. doi: 10.1056/NEJMoa1717002.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 27, 2019): 707
• Original Estimated Enrollment (submitted: July 24, 2013): 760
• Actual Study Completion Date: January 12, 2021
• Actual Primary Completion Date: October 16, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Select Inclusion Criteria:

1. Histological or cytological diagnosis of HCC.
2. The subject has disease that is not amenable to a curative treatment approach.
3. Received prior sorafenib.
4. Progression following at least 1 prior systemic treatment for HCC.
5. Recovery to from toxicities related to any prior treatments.
6. ECOG performance status of 0 or 1.
7. Adequate hematologic and renal function, based upon meeting protocol defined laboratory criteria within 7 days before randomization.
8. Child-Pugh Score of A.
9. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection.
10. Sexually active fertile subjects(male and female)must agree to use medically accepted methods of contraception during the course of the study and for 4 months after the last dose of study treatment.
11. Female subjects of childbearing potential must not be pregnant at screening.

Select Exclusion Criteria:

1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
2. Receipt of more than 2 prior systemic therapies for advanced HCC.
3. Any type of anticancer agent (including investigational) within 2 weeks before randomization.
4. Radiation therapy within 4 weeks (2 weeks for radiation for bone metastases) or radionuclide treatment within 6 weeks of randomization.
5. Prior cabozantinib treatment.
6. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before randomization.
7. Concomitant anticoagulation, at therapeutic doses, with anticoagulants.
8. Serious illness other than cancer that would preclude safe participation in the study.
9. Subjects with untreated or incompletely treated varices with bleeding or high risk for bleeding.
10. Moderate or severe ascites.
11. Pregnant or lactating females.
12. Diagnosis of another malignancy within 2 years before randomization, except for superficial skin cancers, or localized, low-grade tumors.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, France, Germany, Hong Kong, Ireland, Italy, Korea, Republic of, Netherlands, New Zealand, Poland, Romania, Singapore, Spain, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Brazil, Georgia, Mexico

Administrative Information

• NCT Number: NCT01908426
• Other Study ID Numbers: XL184-309
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Exelixis
• Original Responsible Party: Same as current
• Current Study Sponsor: Exelixis
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Exelixis
• Verification Date: April 2021