Clinical trial NCT00940225: Study of Cabozantinib (XL184) in Adults With Advanced Malignancies
Official title: A Randomized Discontinuation Study of XL184 in Subjects With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Solid Tumors
Cancer
Keywords: Metastatic Breast Cancer (MBC)
Melanoma
Stomach or Gastroesophageal Junction Carcinoma (GEJ)
Hepatocellular Carcinoma (HCC)
Small Cell Lung Cancer (SCLC)
Non-Small Cell Lung Cancer (NSCLC)
Ovarian Cancer
Pancreatic Cancer
Prostate Cancer
Lead sponsor: Exelixis
Sponsor class: INDUSTRY
First posted: 2009-07-15
Enrollment: 730
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only
timeFrame: From initial dose through final study visit up to 44 months
measure: Bone Scan Response (BSR) - NRE, CRPC
timeFrame: From initial dose through final study visit up to 15 months
measure: Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only
timeFrame: From initial dose through final study visit up to 44 months
Secondary outcomes:
measure: Duration of Objective Response (OR) - Responders From Lead-in Stage
timeFrame: From initial dose through final study visit up to 44 months
measure: Progression Free Survival (PFS) - Throughout the Study
timeFrame: From initial dose through final study visit up to 44 months
measure: Duration of Bone Scan Response - NRE Cohorts, CRPC Only
timeFrame: From initial dose through final study visit up to 15 months
measure: Overall Survival (OS) - NRE Cohorts, CRPC and Ovarian Only
timeFrame: From initial dose through final study visit up to 15 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Pinnacle Oncology of Arizona
state: Arizona
city: Sacramento
country: United States
facility: University of California Davis Cancer Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Comprehensive Cancer Center
state: Florida
city: Augusta
country: United States
facility: Medical College of Georgia
state: Georgia
city: Indianapolis
country: United States
facility: Central Indiana Cancer Centers
state: Indiana
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Boston
country: United States
facility: Dana Farber Cancer Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Columbia
country: United States
facility: University of Missouri Health Care
state: Missouri
city: Lee's Summit
country: United States
facility: Kansas City Cancer Center
state: Missouri
city: Saint Louis
country: United States
facility: Midwest Hematology Oncology Consultants
state: Missouri
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: New York
country: United States
facility: NYU Clinical Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Hilliard
country: United States
facility: Ohio State University GYN Oncology
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Tulsa
country: United States
facility: Cancer Care Associates
state: Oklahoma
city: Tualatin
country: United States
facility: Northwest Cancer Specialists
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Greenville
country: United States
facility: Cancer Centers of the Carolinas, ITOR
state: South Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Austin
country: United States
facility: Texas Oncology - Central Austin Cancer Center
state: Texas
city: Dallas
country: United States
facility: Mary Crowley Medical Research Center
state: Texas
city: Houston
country: United States
facility: University of Texas, M. D., Anderson Cancer Center
state: Texas
city: Tyler
country: United States
facility: Tyler Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Fairfax Northern Virginia Hematology Oncology
state: Virginia
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Brussels
country: Belgium
facility: One Study Location
city: Jette
country: Belgium
facility: One Study Location
city: Leuven
country: Belgium
facility: Multiple Study Locations
city: Liege
country: Belgium
city: Mons
country: Belgium
facility: One Study Location
city: Jerusalem
country: Israel
facility: One Study Location
city: Tel Aviv
country: Israel
facility: One Study Location
city: Tel-Hashomer
country: Israel
facility: One Study Location
city: Zerifin
country: Israel
facility: One Study Location
city: Tainan City
country: Taiwan
facility: Multiple Study Locations
city: Taipei
country: Taiwan
facility: Chang Gung Medical Foundation, Taoyuan County
city: Taipei
country: Taiwan
city: London
country: United Kingdom
facility: One Study Location
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.