Study of Cabozantinib (XL184) in Adults With Advanced Malignancies

• ClinicalTrials.gov Identifier: NCT00940225
• Recruitment Status: Completed
• First Posted: July 15, 2009
• Results First Posted: April 25, 2024
• Last Update Posted: April 25, 2024
• Sponsor: Exelixis
• Information provided by (Responsible Party): Exelixis

Tracking Information

• First Submitted Date: July 12, 2009
• First Posted Date: July 15, 2009
• Results First Submitted Date: December 6, 2023
• Results First Posted Date: April 25, 2024
• Last Update Posted Date: April 25, 2024
• Actual Study Start Date: September 2009
• Actual Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 28, 2024)

• Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only [ Time Frame: From initial dose through final study visit up to 44 months ]
  Objective response rate (ORR) per modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.0 per investigator The analysis of ORR in the RDT Cohorts were defined as the proportion of subjects with a best overall response of confirmed complete response (CR) or partial response (PR) per mRECIST 1.0 during the 12-week Lead-In Stage. In the NRE Ovarian Cohort, mRECIST 1.1 was used. ORR for the NRE CRPC Cohorts was not a primary objective and is therefore not captured in the table below.
• Bone Scan Response (BSR) - NRE, CRPC [ Time Frame: From initial dose through final study visit up to 15 months ]
  The reduction of bone scan lesion area (BSLA) by > 30% was used as the quantitative measure of BSR. BSR was a primary outcome measure for only the NRE CRPC Cohorts.
• Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only [ Time Frame: From initial dose through final study visit up to 44 months ]
  Progression Free Survival during the Randomized Stage (Randomized Population)

• Original Primary Outcome Measures (submitted: July 13, 2009): To evaluate the efficacy of XL184 in subjects with advanced solid tumors [ Time Frame: Assessed approximately every 6 weeks using MRI, CT, and/or bone scans ]

Current Secondary Outcome Measures (submitted: March 28, 2024)

• Duration of Objective Response (OR) - Responders From Lead-in Stage [ Time Frame: From initial dose through final study visit up to 44 months ]
  Duration of objective response was defined as the time from the tumor assessment that first documented PR or CR that was subsequently confirmed at least 28 days later until the date of documented progression. There were either few or no responders in the Gastric/GEJ, SCLC, and pancreatic cohorts so these cohorts are excluded.
• Progression Free Survival (PFS) - Throughout the Study [ Time Frame: From initial dose through final study visit up to 44 months ]
  Progression-free survival (PFS) from first dose throughout the study was estimated for all subjects (safety population) using a piecewise method.
• Duration of Bone Scan Response - NRE Cohorts, CRPC Only [ Time Frame: From initial dose through final study visit up to 15 months ]
  The duration of BSR per IRF was calculated for CRPC subjects with an objective response (CR or PR) during the study.
• Overall Survival (OS) - NRE Cohorts, CRPC and Ovarian Only [ Time Frame: From initial dose through final study visit up to 15 months ]

Original Secondary Outcome Measures (submitted: July 13, 2009)

• Safety and tolerability of XL184 in subjects with advanced solid tumors [ Time Frame: Assessed approximately every 3 weeks, during study visits ]
• To correlate the pathway dysfunction of disease-related genes or proteins such as MET and downstream signaling molecules with clinical outcome [ Time Frame: Assessed approximately every 6 weeks through blood samples and tumor biopsies ]
• To further characterize the pharmacokinetic (PK) and pharmacodynamic parameters of XL184 [ Time Frame: Assessed approximately every 6 weeks through blood samples ]

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

Descriptive Information

• Brief Title: Study of Cabozantinib (XL184) in Adults With Advanced Malignancies
• Official Title: A Randomized Discontinuation Study of XL184 in Subjects With Advanced Solid Tumors
• Brief Summary: This is a Phase 2 study to evaluate the efficacy and safety of cabozantinib (XL184) in subjects with selected advanced tumor types.

Detailed Description

The goal of this clinical trial was to learn about the efficacy, safety, and tolerability of cabozantinib against a placebo in subjects with Metastatic Breast Cancer (MBC), Gastric and Gastroesophageal Junction Cancer (GEJ), Hepatocellular Carcinoma (HCC), Melanoma, Non-small Cell Lung Cancer (NSCLC), Ovarian (primary peritoneal or fallopian tube carcinoma), Pancreatic Cancer, Castration-Resistant Prostate Cancer (CRPC), or Small cell Lung Cancer (SCLC) with advanced tumors.

The main questions this study aimed to answer were:

• What is the efficacy of cabozantinib in subjects with advanced solid tumors?
• What is the safety and efficacy of cabozantinib at two starting dose levels 100 milligrams (mg) once daily (po QD) and 39.4 mg po QD? Please note: that the 39.4 mg, po QD was only used in the Non-Randomized Expansion (NRE) part of the study

There were three stages to the Randomized Discontinuation Trial (RDT):

1. The Lead in Stage: This stage enrolled eligible patients with advanced solid tumors who received open-label cabozantinib at 100 mg once daily for 12 weeks.

2. The Randomized Stage: Subjects who demonstrated stable disease (SD) at the end of 12 weeks of the Lead-in Stage were randomized to receive cabozantinib or placebo (a look-alike substance that contains no active drug) in a blinded manner.

   After randomization, when a patient developed progressive disease (PD), study treatments were discontinued and the treatment blind was broken. If the subject was on a placebo, the subject was offered the opportunity to receive cabozantinib. If the subject was already on cabozantinib, the subject entered the Post-Treatment Period where they were followed until death.

3. Open-Label Extension: Subjects who were deemed with partial response (PR) or complete response (CR) at Week 12 of the Lead-In Stage were not randomized but allowed to participate in the "Open Label Extension". Patients were given the cabozantinib treatment of 100 mg, po QD.

The emerging data supported enrollment in an open-label, Non-Randomized Expansion cohort (NRE). These cohorts targeted patients with prostate and ovarian cancers. For the patients with prostate, they were assigned to either 100 mg, po QD or 39.4 mg, po QD.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Solid Tumors
• Cancer

Intervention

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

Study Arms

• Experimental: Lead-in Stage - cabozantinib (XL184)
  Open Label, cabozantinib, 100 mg, po QD for 12 weeks.
  Intervention: Drug: Cabozantinib
• Experimental: Randomized Stage - cabozantinib (XL184)
  Blinded, cabozantinib, 100 mg, po QD until disease progression.
  Intervention: Drug: Cabozantinib
• Placebo Comparator: Randomized Stage - placebo
  Blinded, placebo, 100 mg, po QD until disease progression.
  Intervention: Drug: Placebo
• Experimental: Open-Label Extension - cabozantinib (XL184)
  Open Label, cabozantinib, for subjects that were on placebo during the randomized stage, 100 mg, po QD until disease progression or unacceptable toxicity.
  Intervention: Drug: Cabozantinib
• Experimental: Non-Randomized Expansion (NRE) Cohort - Castrate Resistant Prostate Cancer (CRPC), 100mg
  Open Label, cabozantinib, 100 mg, po QD until disease progression or unacceptable toxicity.
  Intervention: Drug: Cabozantinib
• Experimental: Non-Randomized Expansion (NRE) Cohort - Castrate Resistant Prostate Cancer (CRPC), 39.4mg
  Open Label, cabozantinib, 39.4, po QD until disease progression or unacceptable toxicity.
  Intervention: Drug: Cabozantinib
• Experimental: A. Non-Randomized Expansion (NRE) Cohort - Ovarian
  Open Label, cabozantinib, 100 mg, po QD until disease progression or unacceptable toxicity.
  Intervention: Drug: Cabozantinib

Publications *

• Schoffski P, Gordon M, Smith DC, Kurzrock R, Daud A, Vogelzang NJ, Lee Y, Scheffold C, Shapiro GI. Phase II randomised discontinuation trial of cabozantinib in patients with advanced solid tumours. Eur J Cancer. 2017 Nov;86:296-304. doi: 10.1016/j.ejca.2017.09.011. Epub 2017 Oct 20.
• Vergote IB, Smith DC, Berger R, Kurzrock R, Vogelzang NJ, Sella A, Wheler J, Lee Y, Foster PG, Weitzman R, Buckanovich RJ. A phase 2 randomised discontinuation trial of cabozantinib in patients with ovarian carcinoma. Eur J Cancer. 2017 Sep;83:229-236. doi: 10.1016/j.ejca.2017.06.018. Epub 2017 Jul 26.
• Kelley RK, Verslype C, Cohn AL, Yang TS, Su WC, Burris H, Braiteh F, Vogelzang N, Spira A, Foster P, Lee Y, Van Cutsem E. Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study. Ann Oncol. 2017 Mar 1;28(3):528-534. doi: 10.1093/annonc/mdw651.
• Tolaney SM, Nechushtan H, Ron IG, Schoffski P, Awada A, Yasenchak CA, Laird AD, O'Keeffe B, Shapiro GI, Winer EP. Cabozantinib for metastatic breast carcinoma: results of a phase II placebo-controlled randomized discontinuation study. Breast Cancer Res Treat. 2016 Nov;160(2):305-312. doi: 10.1007/s10549-016-4001-y. Epub 2016 Oct 6.
• Leibowitz-Amit R, Pintilie M, Khoja L, Azad AA, Berger R, Laird AD, Aftab DT, Chi KN, Joshua AM. Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial. J Transl Med. 2016 Jan 13;14:12. doi: 10.1186/s12967-015-0747-y.
• Smith MR, Sweeney CJ, Corn PG, Rathkopf DE, Smith DC, Hussain M, George DJ, Higano CS, Harzstark AL, Sartor AO, Vogelzang NJ, Gordon MS, de Bono JS, Haas NB, Logothetis CJ, Elfiky A, Scheffold C, Laird AD, Schimmoller F, Basch EM, Scher HI. Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study. J Clin Oncol. 2014 Oct 20;32(30):3391-9. doi: 10.1200/JCO.2013.54.5954. Epub 2014 Sep 15.
• Basch E, Autio KA, Smith MR, Bennett AV, Weitzman AL, Scheffold C, Sweeney C, Rathkopf DE, Smith DC, George DJ, Higano CS, Harzstark AL, Sartor AO, Gordon MS, Vogelzang NJ, de Bono JS, Haas NB, Corn PG, Schimmoller F, Scher HI. Effects of cabozantinib on pain and narcotic use in patients with castration-resistant prostate cancer: results from a phase 2 nonrandomized expansion cohort. Eur Urol. 2015 Feb;67(2):310-8. doi: 10.1016/j.eururo.2014.02.013. Epub 2014 Feb 20.
• Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, Vaishampayan UN, Haas NB, Spira AI, Lara PN Jr, Lin CC, Srinivas S, Sella A, Schoffski P, Scheffold C, Weitzman AL, Hussain M. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013 Feb 1;31(4):412-9. doi: 10.1200/JCO.2012.45.0494. Epub 2012 Nov 19.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 18, 2015): 730
• Original Estimated Enrollment (submitted: July 13, 2009): 600
• Actual Study Completion Date: June 2014
• Actual Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• The subject has a cytologically or histologically and radiologically confirmed, advanced, recurrent, or metastatic solid tumor of the nine types listed below:

  • Pancreatic Cancer
  • Castration-Resistant Prostate Cancer (CRPC)
  • Hepatocellular Carcinoma (HCC)
  • Gastric or Gastroesophageal Junction Cancer
  • Melanoma
  • Small Cell Lung Cancer (SCLC)
  • Ovarian cancer, primary peritoneal or fallopian tube carcinoma
  • Breast cancer that is one of the following subtypes: estrogen receptor positive breast cancer, estrogen receptor/progesterone receptor/HER2-negative (triple-negative), or inflammatory (regardless of receptor status) disease histology
  • Non-Small Cell Lung Cancer (NSCLC)
• Certain requirements for prior therapies may apply
• The subject has documented progressive disease at screening
• Subjects having any tumor type of other than CRPC must have at least one lesion that is not within a previously irradiated field and is measurable on CT or MRI scan
• The subject has recovered to baseline or CTCAE ≤ Grade 1 from toxicities related to prior treatment (some exceptions apply)
• The subject is ≥ 18 years old on the day of consent
• Tissue samples from archival or fresh tissue, or a tissue block of the subject's tumor
• The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• The subject has adequate organ function
• The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document
• Sexually active fertile subjects (male and female), and their partners, must agree to use medically accepted methods of contraception during the course of the study and for 3 months after the last dose of the study drug(s)
• Female subjects of childbearing potential must have a negative pregnancy test at screening

Exclusion Criteria:

• The subject has experienced clinically-significant hematemesis or hemoptysis of >0.5 teaspoon of red blood, or other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
• The subject has a cavitating pulmonary lesion(s) or a pulmonary lesion abutting or encasing a major blood vessel
• Certain restrictions on prior treatments apply
• The subject has known symptomatic or uncontrolled brain metastases or epidural disease
• The subject has prothrombin time/International Normalized Ratio (PT/INR) or partial thromboplastin time (PTT) test results that are above (1.3x)the laboratory upper limit of normal
• The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or Coumadin-related agents, heparin, thrombin or FXa inhibitors, and antiplatelet agents (low-dose aspirin (≤81 mg/day), low-dose warfarin (≤1mg/day, and prophylactic low molecular weight heparin (LMWH) are permitted)
• The subject has a corrected QT interval(QTcF)>500 ms at screening
• The subject has uncontrolled, significant intercurrent illness
• The subject is unable to swallow capsules
• The subject is pregnant or breastfeeding
• The subject has a previously-identified allergy or hypersensitivity to components of the study treatment formulation
• The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee
• The subject has had another diagnosis of malignancy requiring systemic treatment within the last two years, unless non-melanoma skin cancer, in-situ carcinoma of the cervix, or superficial bladder cancer

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: Belgium, Israel, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT00940225
• Other Study ID Numbers: XL184-203
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Exelixis
• Original Responsible Party: Christian Scheffold, MD, PhD, Director, Clinical Research, Exelixis, Inc., Exelixis, Inc.
• Current Study Sponsor: Exelixis
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Exelixis
• Verification Date: December 2023