The objective of this study is to evaluate the effect of cabozantinib compared with placebo on overall survival in subjects with advanced HCC previously treated with sorafenib.
ID
Source
Brief title
Condition
- Hepatobiliary neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint: Overall survival (OS)
Secondary outcome
Secondary endpoints:
* Objective response rate (ORR) per RECIST 1.1
* Progression-free survival (PFS) per RECIST 1.1
Additional endpoints:
* Safety and tolerability
* Pharmacokinetics (PK)
* Relationship of baseline and changes in biomarkers with treatment and/or
clinical outcome
* Health-related quality of life (HRQOL) as assessed by the EuroQol Health
questionnaire instrument (EQ-5D-5L)
Background summary
Hepatocellular carcinoma (HCC) is the second highest cause of cancer-related
deaths globally, behind only lung cancer. HCC is usually resistant to systemic
chemotherapy. Sorafenib, a small-molecule inhibitor of vascular endothelial
growth factor receptor (VEGFR) and other protein kinases, has been shown to
improve the time to progression and overall survival in patients with HCC, who
eventually progress and succumb to their disease despite treatment (Llovet
2008). At the present time, no drug has demonstrated efficacy in patients with
inoperable or metastatic HCC that has progressed after treatment with sorafenib.
MET and VEGF signaling have been implicated in tumor neo-angiogenesis,
invasion, and dissemination, and in osteoblast and osteoclast function, while
dysregulation of MET and VEGF pathway components has been associated with poor
prognosis in multiple tumor types. Resistance to VEGF-targeted therapies may
arise from the up-regulation of alternative pro-angiogenic and pro-invasive
signaling pathways, including the MET pathway. Consistent with this, combined
inhibition of the VEGF receptor (VEGFR) and MET results in efficacy enhanced
over that achieved via inhibition of either pathway alone in some tumor models.
Cabozantinib is an orally bioavailable tyrosine kinase inhibitor with potent
activity against MET and VEGFR2, as well as a number of other receptor tyrosine
kinases that have also been implicated in tumor pathobiology, including RET,
KIT, AXL, and FLT3. Cabozantinib suppresses MET and VEGFR2 signaling, rapidly
inducing apoptosis of endothelial and tumor cells, resulting in tumor
regression in a variety of xenograft
models. Cabozantinib prolonged survival in a MET-driven transgenic mouse model
of HCC. In clinical studies, cabozantinib has demonstrated promising activity
in multiple tumor types and in 2012 was approved by the US FDA for the
treatment of progressive metastatic medullary thyroid cancer.
A cohort of 41 subjects with HCC was enrolled in a Phase 2 randomized
discontinuation study evaluating cabozantinib (Study XL184-203). The majority
of subjects (80%) had received prior systemic therapy for the disease; over
half (51%) had received prior sorafenib. Extrahepatic spread was present in 73%
of subjects, consistent with a relatively poor prognosis. Within the first 12
weeks, 2 subjects had a confirmed partial response (PR) and 32 subjects had
stable disease; the Week-12 disease control rate (PR plus stable disease) was
66%. Tumor regression appeared independent of prior sorafenib exposure. Based
on the most recent survival data which included 38 deaths among the 41
subjects, the median OS from the initial cabozantinib dose as estimated by the
Kaplan-Meier method was 11.5 months (95% CI: 7.3, 15.6) (data on file). Among
sorafenib-pretreated subjects, the median OS was 12.9 months (95% CI: 10.8,
16.8). The safety profile was similar to that of other tyrosine kinase
inhibitors such as sorafenib, with manageable adverse events (AEs) during
treatment.
Study objective
The objective of this study is to evaluate the effect of cabozantinib compared
with placebo on overall survival in subjects with advanced HCC previously
treated with sorafenib.
Study design
This is a Phase 3 multicenter, randomized, double-blinded, controlled trial of
cabozantinib vs placebo, both with best supportive care.
Intervention
Subjects will take blinded study medication (tablets containing 60 mg of
cabozantinib or placebo equivalent) once daily orally at bedtime. Required dose
reductions will be in decrements of 20 mg cabozantinib or placebo equivalent.
Subjects will continue blinded study treatment as long as they continue to
experience clinical benefit in the opinion of the investigator or until
unacceptable toxicity, the need for subsequent systemic anticancer therapy or
liver-directed local anticancer therapy, or other reasons for treatment
discontinuation.
Study burden and risks
With an estimated treatment period of 4 months and a study prticipation of 1
year, patients will undergo the following study procedures, during 12-13 study
visits (incl. 2-3 phone contacts):
- 9x physical exam and vital signs
- 9x ECOG score
- 5-6x ECG
- 9x blood samples
- 4x urinalysis
- 5x serum pregnancy test (only women who can get pregnant)
- 4x CT/MRI-scan
- 1x bone scan (4x for subjects with bone lesions at screening)
- 7x questionnaire
- 1x tumor biopsy (optional and only if no archival biopsy is available)
Side Effects That Occurred in More Than 20% of Cancer Patients Treated with
Cabozantinib:
- Fatigue (tiredness)
- Diarrhea
- Loss of appetite
- Nausea
- Blisters, rash or pain in hands or feet
- Weight loss
- Vomiting
- High blood pressure
- Changes to the way things taste
- Change in voice
Harbor Bay Parkway 1851
Alameda CA 94502
US
Harbor Bay Parkway 1851
Alameda CA 94502
US
Listed location countries
Age
Inclusion criteria
1. Histologische of cytologische diagnose van HCC (resultaten van een voorafgaand biopt wordt geaccepteerd)
2. De proefpersoon heeft een ziekte die niet ontvankelijk is voor een curatieve behandelingsmethode (bv. transplantatie, operatie, radiofrequente ablatie)
3. Eerder behandeld met sorafenib
4. Progressie volgend op tenminste 1 eerdere systemische behandeling voor HCC
5. Herstel tot * graad 1 van toxische effecten van eerdere behandelingen, tenzij de bijwerkingen klinisch niet significant zijn en/of stabiel zijn bij ondersteunende behandeling
6. Leeftijd * 18 jaar op de dag van toestemming
7. ECOG-performancestatus van 0 of 1
8. Adequate hematologische functie, gebaseerd op het voldoen aan de volgende laboratoriumcriteria binnen 7 dagen voor randomisatie:
a. absolute aantal neutrofielen (ANC) * 1200/mm3 (* 1,2 x 109/l)
b. bloedplaatjes * 60.000/mm3 (* 60 x 109/l)
c. hemoglobine * 8 g/dl (* 80 g/l)
9. Adequate nierfunctie, gebaseerd op het voldoen aan de volgende laboratoriumcriteria binnen 7 dagen voor randomisatie:
a. serumcreatinine * 1,5 x de bovengrens van normaal of een berekende creatinineklaring * 40 ml/min (gebruikmakend van de Cockroft-Gault-vergelijking: (140 * leeftijd) x gewicht (kg)/(serumcreatinine × 72 [mg/dl]) voor mannen. (Voor vrouwen vermenigvuldigen met 0,85.)
EN
b. urinaire eiwit/creatinine-verhouding (*urine protein/creatinine ratio*, UPCR) * 1 mg/mg (* 113,1 mg/mmol) of eiwit in 24-uurs urine < 1 g
10. Child-pughscore A
11. Totaal bilirubine * 2 mg/dl (* 34,2 µmol/l) binnen 7 dagen voor randomisatie
12. Serumalbumine * 2,8 g/dl (* 28 g/l) binnen 7 dagen voor randomisatie
13. Alanineaminotransferase (ALAT) en aspartaataminotransferase (ASAT) < 5,0 x de bovengrens van normaal (*upper limit of normal*, ULN) binnen 7 dagen voor randomisatie
14. Hemoglobine A1c (HbA1c) * 8% binnen 7 dagen voor randomisatie
(als HbA1c resultaten niet beschikbaar zijn [bv, hemoglobine variant], een nuchtere serum glucose * 160 mg/dL)
15. Antivirale therapie volgens de plaatselijke zorgstandaard in geval van actieve infectie met hepatitis B-virus (HBV)
Exclusion criteria
1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma
2. Receipt of more than 2 prior systemic therapies for advanced HCC. Additional prior systemic therapies used as adjuvant or local therapy are allowed.
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 (eg, I-131 or Y-90) within 6 weeks of randomization. Subject is excluded if there are any clinically relevant ongoing complications from prior radiation therapy.
5. Prior cabozantinib treatment
6. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before randomization. Eligible subjects must be without corticosteroid treatment at the time of randomization.
7. Concomitant anticoagulation, at therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, low molecular weight heparin (LMWH), thrombin or coagulation factor X (FXa) inhibitors, or antiplatelet agents (eg, clopidogrel). Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (* 1 mg/day), and low-dose LMWH are permitted.
8. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
a. Cardiovascular disorders including
i. Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment
iii. Stroke (including TIA), myocardial infarction, or other ischemic event within 6 months before randomization
iv. Thromboembolic event within 3 months before randomization. Subjects with thromboses of portal/hepatic vasculature attributed to underlying liver disease and/or liver tumor are eligible
b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization,
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to randomization
c. Major surgery within 2 months before randomization. Complete healing from major surgery must have occurred 1 month before randomization. Complete healing from minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before randomization. Subjects with clinically relevant complications from prior surgery are not eligible
d. Cavitating pulmonary lesion(s) or endobronchial disease
e. Lesion invading a major blood vessel including but not limited to :
inferior vena cava, pulmonary artery, or aorta). Subjects with lesions
invading the portal vasculature are eligible.
f. Clinically significant bleeding risk including the following within 3 months of randomization: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of red blood, or other signs indicative of pulmonary hemorrhage, or history of other significant bleeding if not due to reversible external factors
g. Other clinically significant disorders such as:
i. Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)-related illness Subjects with active
hepatitis virus infection controlled with antiviral therapy are eligible.
ii. Serious non-healing wound/ulcer/bone fracture
iii. Malabsorption syndrome
iv. Uncompensated/symptomatic hypothyroidism
v. Requirement for hemodialysis or peritoneal dialysis
vi. History of solid organ transplantation
9. Subjects with untreated or incompletely treated varices with bleeding or high risk for bleeding are excluded with the following clarification: subjects with history of prior variceal bleeding must have been treated with adequate endoscopic therapy without any evidence of recurrent bleeding for at least 6 months prior to study entry and must be stable on optimal medical management (e.g. non-selective beta blocker, proton pump inhibitor) at study entry.
10. Moderate or severe ascites
11. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 7 days before randomization
Note: If the QTcF is > 500 ms in first ECG, a total of 3 ECGs should be performed. If the average of these 3 consecutive results for QTcF is * 500 ms, the subject meets eligibility in this regard.
12. Inability to swallow tablets
13. Previously identified allergy or hypersensitivity to components of the study treatment formulations
14. Pregnant or lactating females
15. Diagnosis of another malignancy within 2 years before randomization, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR201300100191-NL |
| ClinicalTrials.gov | NCT01908426 |
| CCMO | NL44658.068.13 |