Study of Cabozantinib (XL184) in Adults With Advanced Malignancies

Phase 2

Completed

Conditions: Solid Tumors
Cancer

Interventions: Drug: Cabozantinib
Drug: Placebo

Registration Number: NCT00940225

Lead Sponsor: Exelixis

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 730

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Bone Scan Response (BSR) - NRE, CRPC	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	From initial dose through final study visit up to 44 months	Progression Free Survival during the Randomized Stage (Randomized Population)
Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only	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.

Secondary Outcome Measures

Name	Time	Method
Duration of Objective Response (OR) - Responders From Lead-in Stage	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	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	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	From initial dose through final study visit up to 15 months

Trial Locations

Locations (37): Pinnacle Oncology of Arizona
🇺🇸
Scottsdale, Arizona, United States
Cancer Centers of the Carolinas, ITOR
🇺🇸
Greenville, South Carolina, United States
Comprehensive Cancer Centers of Nevada
🇺🇸
Las Vegas, Nevada, United States
University of California, San Francisco
🇺🇸
San Francisco, California, United States
University of Missouri Health Care
🇺🇸
Columbia, Missouri, United States
Mount Sinai Comprehensive Cancer Center
🇺🇸
Miami Beach, Florida, United States
Kansas City Cancer Center
🇺🇸
Lee's Summit, Missouri, United States
Florida Cancer Specialists
🇺🇸
Fort Myers, Florida, United States
Medical College of Georgia
🇺🇸
Augusta, Georgia, United States
Central Indiana Cancer Centers
🇺🇸
Indianapolis, Indiana, United States
Dana Farber Cancer Center
🇺🇸
Boston, Massachusetts, United States
Midwest Hematology Oncology Consultants
🇺🇸
Saint Louis, Missouri, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
NYU Clinical Cancer Center
🇺🇸
New York, New York, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Cancer Care Associates
🇺🇸
Tulsa, Oklahoma, United States
Ohio State University GYN Oncology
🇺🇸
Hilliard, Ohio, United States
Northwest Cancer Specialists
🇺🇸
Tualatin, Oregon, United States
University of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States
University of Texas, M. D., Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Sarah Cannon Research Institute
🇺🇸
Nashville, Tennessee, United States
Mary Crowley Medical Research Center
🇺🇸
Dallas, Texas, United States
Fairfax Northern Virginia Hematology Oncology
🇺🇸
Fairfax, Virginia, United States
Tyler Cancer Center
🇺🇸
Tyler, Texas, United States
University of Washington
🇺🇸
Seattle, Washington, United States
Multiple Study Locations
🇨🇳
Tainan City, Taiwan
One Study Location
🇬🇧
London, United Kingdom
Chang Gung Medical Foundation, Taoyuan County
🇨🇳
Taipei, Taiwan
University of California Davis Cancer Center
🇺🇸
Sacramento, California, United States
Rocky Mountain Cancer Centers
🇺🇸
Denver, Colorado, United States
Yale University School of Medicine
🇺🇸
New Haven, Connecticut, United States
University of Michigan Health System
🇺🇸
Ann Arbor, Michigan, United States
Wayne State University
🇺🇸
Detroit, Michigan, United States
University of Oklahoma
🇺🇸
Oklahoma City, Oklahoma, United States
Tulane University Health Sciences Center
🇺🇸
New Orleans, Louisiana, United States
Texas Oncology - Central Austin Cancer Center
🇺🇸
Austin, Texas, United States
Stanford University Medical Center
🇺🇸
Stanford, California, United States