Study of Cabozantinib (XL184) in Adults With Advanced Malignancies

Cancer Clinical Trial

Official title:

A Randomized Discontinuation Study of XL184 in Subjects With Advanced Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00940225
• Other study ID #: XL184-203
• Status: Completed
• Phase: Phase 2
• Start date: September 2009
• Est. completion date: June 2014

Study information

• Verified date: December 2023
• Source: Exelixis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 2 study to evaluate the efficacy and safety of cabozantinib (XL184) in subjects with selected advanced tumor types.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 730
• Est. completion date: June 2014
• Est. primary completion date: May 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cancer
• Solid Tumors

Intervention

Drug:
• Cabozantinib

• Placebo

Locations

Country	Name	City	State
Belgium	One Study Location	Brussels
Belgium	One Study Location	Jette
Belgium	Multiple Study Locations	Leuven
Belgium	One Study Location	Mons
Israel	One Study Location	Jerusalem
Israel	One Study Location	Tel Aviv
Israel	One Study Location	Tel-Hashomer
Israel	One Study Location	Zerifin
Taiwan	Multiple Study Locations	Tainan City
Taiwan	Chang Gung Medical Foundation, Taoyuan County	Taipei
United Kingdom	One Study Location	London
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	Medical College of Georgia	Augusta	Georgia
United States	Texas Oncology - Central Austin Cancer Center	Austin	Texas
United States	Dana Farber Cancer Center	Boston	Massachusetts
United States	University of Missouri Health Care	Columbia	Missouri
United States	Mary Crowley Medical Research Center	Dallas	Texas
United States	Rocky Mountain Cancer Centers	Denver	Colorado
United States	Wayne State University	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Fairfax Northern Virginia Hematology Oncology	Fairfax	Virginia
United States	Florida Cancer Specialists	Fort Myers	Florida
United States	Cancer Centers of the Carolinas, ITOR	Greenville	South Carolina
United States	Ohio State University GYN Oncology	Hilliard	Ohio
United States	University of Texas, M. D., Anderson Cancer Center	Houston	Texas
United States	Central Indiana Cancer Centers	Indianapolis	Indiana
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Kansas City Cancer Center	Lee's Summit	Missouri
United States	Mount Sinai Comprehensive Cancer Center	Miami Beach	Florida
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYU Clinical Cancer Center	New York	New York
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of California Davis Cancer Center	Sacramento	California
United States	Midwest Hematology Oncology Consultants	Saint Louis	Missouri
United States	University of California, San Francisco	San Francisco	California
United States	Pinnacle Oncology of Arizona	Scottsdale	Arizona
United States	University of Washington	Seattle	Washington
United States	Stanford University Medical Center	Stanford	California
United States	Northwest Cancer Specialists	Tualatin	Oregon
United States	Cancer Care Associates	Tulsa	Oklahoma
United States	Tyler Cancer Center	Tyler	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Exelixis

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only	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.	From initial dose through final study visit up to 44 months
Primary	Bone Scan Response (BSR) - NRE, CRPC	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.	From initial dose through final study visit up to 15 months
Primary	Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only	Progression Free Survival during the Randomized Stage (Randomized Population)	From initial dose through final study visit up to 44 months
Secondary	Duration of Objective Response (OR) - Responders From Lead-in Stage	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.	From initial dose through final study visit up to 44 months
Secondary	Progression Free Survival (PFS) - Throughout the Study	Progression-free survival (PFS) from first dose throughout the study was estimated for all subjects (safety population) using a piecewise method.	From initial dose through final study visit up to 44 months
Secondary	Duration of Bone Scan Response - NRE Cohorts, CRPC Only	The duration of BSR per IRF was calculated for CRPC subjects with an objective response (CR or PR) during the study.	From initial dose through final study visit up to 15 months
Secondary	Overall Survival (OS) - NRE Cohorts, CRPC and Ovarian Only		From initial dose through final study visit up to 15 months