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2012年11月29日，美国食品药品监督管理局FDA批准Cometriq(cabozantinib)治疗已播散至身体其他部分(转移的)甲状腺髓样癌。
甲状腺制造一种有助于维持血中钙健康水平的激素被称为降钙素[calcitonin]细胞中发生甲状腺髓样癌。这性癌自发发生或在有某些基因突变家族，导致内分泌系统1种或更多癌症，包括甲状腺。
美国国立癌症研究所估计在2012年56,460 美国人将诊断有甲状腺癌和1,780将死于此病。约4%甲状腺癌是甲状腺髓癌，为罕见甲状腺癌之一。
FDA的药物评价和研究中心血液学和肿瘤室主任Richard Pazdur，M.D.说：“在过去2年中Cometriq是第二个被批准治疗甲状腺髓样癌和反映FDA承诺发展和批准为治疗罕见病药物，”“在2011年4月批准Caprelsa，有此罕见和难治疾病患者的治疗选择有限。”
美国FDA在其优先审评程序下在6个月内完成Cometriq的申请审评。这个程序为可能提供治疗重要进展或当前没有治疗存在的药物提供一个加快6个月审评。Cometriq因为意向治疗罕见病或情况还获得孤儿产品指定。
Cometriq是激酶抑制剂阻断涉及髓样癌细胞的发育和生长的异常激酶蛋白。在服用Cometriq前至少2小时和后1小时患者不应进食。
在一项涉及330例有甲状腺髓样癌患者临床研究确定Cometriq的安全性和有效性。用Cometriq治疗增加无癌进展生存患者生存时间长度(无进展生存) 而，有些患者，肿瘤大小减小(缓解率)。
被给予Cometriq患者无肿瘤生长生存平均11.2个月与之比较接受糖丸(安慰剂)患者平均4个月。结果还显示用Cometriq治疗患者27%肿瘤大小减小平均持续接近15个月，而who 接受安慰剂患者未见减小。用Cometriq治疗不延长 患者生命。
Cometriq处方资料包括黑框警告警告患者和卫生保健专业人员严重和在有些患者中结肠内发生致命性出血和孔(穿孔和瘘管)。
最常见副作用是腹泻；炎症或口腔痛；发红，疼痛，或指趾肿胀(手足综合征)；体重减轻；食欲不振；恶心；疲乏；口疼；头发灰或色消失；难闻味；高血压新发作或恶化；腹痛和便秘。最常见实验室异常包括肝酶增加，低钙和磷，白血细胞和血小板减低。
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use COMETRIQ safely and effectively. See full prescribing information for COMETRIQ.
COMETRIQ ® (cabozantinib) capsules, for oral use
Initial U.S. Approval: 2012
WARNING: PERFORATIONS AND FISTULAS, and
HEMORRHAGE See full prescribing information for complete boxed warning.
Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1)
Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)
INDICATIONS AND USAGE
COMETRIQ is a kinase inhibitor indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). (1)
DOSAGE AND ADMINISTRATION
Recommended Dose: 140 mg orally, once daily. (2.1)
Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. (2.1)
Do NOT substitute COMETRIQ capsules with cabozantinib tablets. (2.1)
Hepatic Impairment: The recommended starting dose of COMETRIQ is 80 mg in patients with mild or moderate hepatic impairment. (2.1)
DOSAGE FORMS AND STRENGTHS
20 mg and 80 mg capsules. (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
Thrombotic Events: Discontinue COMETRIQ for myocardial infarction, cerebral infarction, or other serious arterial thromboembolic events. (5.3)
Wound Complications: Withhold COMETRIQ for dehiscence or complications requiring medical intervention. (5.4)
Hypertension: Monitor blood pressure regularly. Discontinue COMETRIQ for hypertensive crisis. (5.5)
Osteonecrosis of the jaw: Discontinue COMETRIQ. (5.6).
Palmar-plantar erythrodysesthesia syndrome (PPES): Interrupt COMETRIQ, decrease dose. (5.7)
Proteinuria: Monitor urine protein. Discontinue for nephrotic syndrome. (5.8)
Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue COMETRIQ. (5.9)
Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.10, 8.1, 8.3)
ADVERSE REACTIONS
The most commonly reported adverse drug reactions (≥ 25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥ 25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Exelixis, Inc. at 1-855-500-3935 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Strong CYP3A4 inhibitors: Reduce the COMETRIQ dosage. (2.2, 7.1)
Strong CYP3A4 inducers: Increase the COMETRIQ dosage. (2.2, 7.2)
USE IN SPECIFIC POPULATIONS
Lactation: Advise not to breastfeed while taking COMETRIQ. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 5/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
Do NOT substitute COMETRIQ capsules with cabozantinib tablets.
The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs.
Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules.
Do not take a missed dose within 12 hours of the next dose.
Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 while taking COMETRIQ.
In Patients with Hepatic Impairment: The recommended starting dose of COMETRIQ for patients with mild to moderate hepatic impairment is 80 mg [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
2.2 Dosage Modifications
For Adverse Reactions
Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions.
Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows:
If previously receiving 140 mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule)
If previously receiving 100 mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules)
If previously receiving 60 mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ
Permanently discontinue COMETRIQ for any of the following:
development of visceral perforation or fistula formation
severe hemorrhage
serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction)
nephrotic syndrome
malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management
osteonecrosis of the jaw
reversible posterior leukoencephalopathy syndrome
In Patients Concurrently Taking a Strong CYP3A4 Inhibitor
Reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
In Patients Concurrently Taking a Strong CYP3A4 Inducer
Increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg [see Drug Interactions (7.2), Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
COMETRIQ 20-mg gelatin capsules are grey with "XL184 20mg" printed in black on the body of the capsule.
COMETRIQ 80-mg gelatin capsules are Swedish orange with "XL184 80mg" printed in black on the body of the capsule.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Perforations and Fistulas
Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal.
Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula.
5.2 Hemorrhage
Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%).
Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.
5.3 Thrombotic Events
COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively).
Discontinue COMETRIQ in patients who develop an acute myocardial infarction, cerebral infarction, or any other clinically significant arterial thromboembolic complication.
5.4 Wound Complications
Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.
5.5 Hypertension
COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.
5.6 Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Discontinue COMETRIQ for ONJ. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.
5.7 Palmar-Plantar Erythrodysesthesia Syndrome
Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with COMETRIQ and was severe (Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.
5.8 Proteinuria
Proteinuria was observed in 4 (2%) of patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.
5.9 Reversible Posterior Leukoencephalopathy Syndrome
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS.
5.10 Embryo-Fetal Toxicity
Based on data from animal studies and its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib administration to pregnant animals during organogenesis resulted in embryolethality at exposures below those occurring clinically at the recommended dose, and in increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with COMETRIQ and for 4 months after the last dose [see Use in Specific Populations (8.1), (8.3), and Clinical Pharmacology (12.1)].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the label:
Perforations and Fistula [see Boxed Warning, Warnings and Precautions (5.1)]
Hemorrhage [see Boxed Warning, Warnings and Precautions (5.2)]
Thromboembolic Events [see Warnings and Precautions (5.3)]
Wound Complications [see Warnings and Precautions (5.4)]
Hypertension [see Warnings and Precautions (5.5)]
Osteonecrosis of the Jaw [see Warnings and Precautions (5.6)]
Palmar-plantar erythrodysesthesia syndrome [see Warnings and Precautions (5.7)]
Proteinuria [see Warnings and Precautions (5.8)]
Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.9)]
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of COMETRIQ was evaluated in 330 patients with progressive metastatic medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, doubleblind, controlled trial (Study 1) [see Clinical Studies (14)]. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years.
Adverse reactions which occurred in ≥ 25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2).
Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration.
The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting.
Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.
Table 1. Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in COMETRIQ-Treated Patients (Study 1) [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)]
| MedDRA System Organ Class/Preferred Terms |
COMETRIQ
(n=214) |
Placebo
(n=109) |
All
Grades |
Grades
3-4 |
All
Grades |
Grades
3-4 |
|
| GASTROINTESTINAL DISORDERS |
| Diarrhea |
63 |
16 |
33 |
2 |
| Stomatitis† |
51 |
5 |
6 |
0 |
| Nausea |
43 |
1 |
21 |
0 |
| Oral pain‡ |
36 |
2 |
6 |
0 |
| Constipation |
27 |
0 |
6 |
0 |
| Abdominal pain§ |
27 |
3 |
13 |
1 |
| Vomiting |
24 |
2 |
2 |
1 |
| Dysphagia |
13 |
4 |
6 |
1 |
| Dyspepsia |
11 |
0 |
0 |
0 |
| Hemorrhoids |
9 |
0 |
3 |
0 |
GENERAL DISORDERS AND
ADMINISTRATION SITE CONDITIONS |
| Fatigue |
41 |
9 |
28 |
3 |
| Asthenia |
21 |
6 |
15 |
1 |
| INVESTIGATIONS |
| Decreased weight |
48 |
5 |
10 |
0 |
| METABOLISM AND NUTRITION DISORDERS |
| Decreased appetite |
46 |
5 |
16 |
1 |
| Dehydration |
7 |
2 |
2 |
1 |
MUSCULOSKELETAL AND CONNECTIVE
TISSUE DISORDERS |
| Arthralgia |
14 |
1 |
7 |
0 |
| Muscle spasms |
12 |
0 |
5 |
0 |
| Musculoskeletal chest pain |
9 |
1 |
4 |
0 |
| NERVOUS SYSTEM DISORDERS |
| Dysgeusia |
34 |
0 |
6 |
0 |
| Headache |
18 |
0 |
8 |
0 |
| Dizziness |
14 |
0 |
7 |
0 |
| Paresthesia |
7 |
0 |
2 |
0 |
| Peripheral sensory neuropathy |
7 |
0 |
0 |
0 |
| Peripheral neuropathy |
5 |
0 |
0 |
0 |
| PSYCHIATRIC DISORDERS |
| Anxiety |
9 |
0 |
2 |
0 |
RESPIRATORY, THORACIC AND
MEDIASTINAL DISORDERS |
| Dysphonia |
20 |
0 |
9 |
0 |
SKIN AND SUBCUTANEOUS TISSUE
DISORDERS |
| PPES |
50 |
13 |
2 |
0 |
Hair color changes/
depigmentation, graying |
34 |
0 |
1 |
0 |
| Rash |
19 |
1 |
10 |
0 |
| Dry skin |
19 |
0 |
3 |
0 |
| Alopecia |
16 |
0 |
2 |
0 |
| Erythema |
11 |
1 |
2 |
0 |
| Hyperkeratosis |
7 |
0 |
0 |
0 |
| VASCULAR DISORDERS |
| Hypertension |
33 |
8 |
4 |
0 |
| Hypotension |
7 |
1 |
0 |
0 | National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0
Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation
Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia
Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain
Palmar-plantar erythrodysesthesia syndrome
Table 2 Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients (Study 1) [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)]
| Test |
COMETRIQ
(n=214) |
Placebo
(N=109) |
| |
All Grades |
Grade 3-4 |
All Grades |
Grade 3-4 |
| Chemistries |
|
|
|
|
| Increased AST |
86 |
3 |
35 |
2 |
| Increased ALT |
86 |
6 |
41 |
2 |
| Increased ALP |
52 |
3 |
35 |
3 |
| Hypocalcemia |
52 |
12 |
27 |
3 |
| Hypophosphatemia |
28 |
3 |
10 |
1 |
| Hyperbilirubinemia |
25 |
2 |
14 |
5 |
| Hypomagnesemia |
19 |
1 |
4 |
0 |
| Hypokalemia |
18 |
4 |
9 |
3 |
| Hyponatremia |
10 |
2 |
5 |
0 |
| Hematologic |
|
|
|
|
| Lymphopenia |
53 |
16 |
51 |
11 |
| Neutropenia |
35 |
3 |
15 |
2 |
| Thrombocytopenia |
35 |
0 |
4 |
3 |
| |
| ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase | Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.
Table 3 Per-Patient Incidence of Hypertension (Study 1)
| Hypertension, JNC* Stage |
COMETRIQ
N=211‡(%) |
Placebo
N=107‡(%) |
| Normal: Grade 0: Systolic < 120 mmHg and Diastolic < 80 mmHg |
4 |
15 |
| Pre-hypertension: Systolic ≥ 120 mmHg or Diastolic ≥ 80 mmHg |
34 |
54 |
| Stage 1: Systolic ≥ 140 mmHg or Diastolic ≥ 90 mmHg |
46 |
25 |
| Stage 2: Systolic ≥ 160 mmHg or Diastolic ≥ 100 mmHg |
15 |
5 |
| Malignant: Diastolic ≥ 120 mmHg |
0 |
0 | Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003: 289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged.
Patients classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.
Patients with at least two blood pressure measurements after the first dose
7 DRUG INTERACTIONS
7.1 Effect of CYP3A4 Inhibitors
Administration of a strong CYP3A4 inhibitor, ketoconazole to healthy subjects increased single-dose plasma cabozantinib exposure by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) while taking COMETRIQ or reduce the dosage of COMETRIQ if concomitant use with strong CYP3A4 inhibitors cannot be avoided [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
Avoid ingestion of foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 while taking COMETRIQ.
7.2 Effect of CYP3A4 Inducers
Administration of a strong CYP3A4 inducer, rifampin to healthy subjects decreased single-dose plasma cabozantinib exposure by 77%. Avoid chronic co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ or increase the dosage of COMETRIQ if concomitant use with strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
7.3 Effect of MRP2 Inhibitors
Concomitant administration of MRP2 inhibitors may increase the exposure to cabozantinib. Monitor patients for increased toxicity when MRP2 inhibitors (e.g., abacavir, adefovir, cidofovir, furosemide, lamivudine, nevirapine, ritonavir, probenecid, saquinavir, and tenofovir) are co-administered with COMETRIQ [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies administration of cabozantinib to pregnant rats and rabbits during organogenesis resulted in embryofetal lethality and structural anomalies at exposures that were below those occurring clinically at the recommended dose [see Data]. Advise pregnant women or women of childbearing potential of the potential hazard to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
In an embryo-fetal development study in pregnant rats, daily oral administration of cabozantinib throughout organogenesis caused increased embryo-fetal lethality compared to controls at a dose of 0.03 mg/kg (less than 1% of the human exposure by AUC at the 140 mg dose). Findings included delayed ossifications and skeletal variations at a dose of 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the 140 mg dose).
In pregnant rabbits, daily oral administration of cabozantinib throughout organogenesis resulted in findings of visceral malformations and variations including reduced spleen size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the 140 mg dose).
In a pre- and postnatal study in rats, cabozantinib was administered orally from gestation day 10 through postnatal day 20. Cabozantinib did not produce adverse maternal toxicity or affect pregnancy, parturition or lactation of female rats, and did not affect the survival, growth or postnatal development of the offspring at doses up to 0.3 mg/kg/day (approximately 0.02 times the recommended clinical dose of 140 mg based on body surface area).
8.2 Lactation
Risk Summary
There is no information regarding the presence of cabozantinib or its metabolites in human milk, or their effects on the breastfed infant, or milk production. Because of the potential for serious adverse reactions in a breastfed infant from COMETRIQ, advise a lactating woman not to breastfeed during treatment with COMETRIQ and for 4 months after the final dose.
8.3 Females and Males of Reproductive Potential
Contraception
Females
COMETRIQ can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with COMETRIQ and for 4 months after the final dose.
Infertility
Females and Males
Based on findings in animals, COMETRIQ may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and effectiveness of COMETRIQ in pediatric patients have not been studied.
Juvenile Animal Data
Juvenile rats were administered cabozantinib daily at doses of 1 or 2 mg/kg/day from Postnatal Day 12 (comparable to less than 2 years in humans) through Postnatal Day 35 or 70. Mortalities occurred at doses equal and greater than 1 mg/kg/day (approximately 0.07 times the clinical dose of 140 mg/day based on body surface area). Hypoactivity was observed at both doses tested on Postnatal Day 22. Targets were generally similar to those seen in adult animals, occurred at both doses, and included the kidney (nephropathy, glomerulonephritis), reproductive organs, gastrointestinal tract (cystic dilatation and hyperplasia in Brunner’s gland and inflammation of duodenum; and epithelial hyperplasia of colon and cecum), bone marrow (hypocellularity and lymphoid depletion), and liver. Tooth abnormalities and whitening as well as effects on bones including reduced bone mineral content and density, physeal hypertrophy, and decreased cortical bone also occurred at all dose levels. Recovery was not assessed at the 2 mg/kg dose level (approximately 0.14 times the clinical dose of 140 mg based on body surface area) due to high levels of mortality. At the low dose level, effects on bone parameters were partially resolved but effects on the kidney and epididymis/testis persisted after treatment ceased.
8.5 Geriatric Use
Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.
8.6 Hepatic Impairment
Increased exposure to cabozantinib has been observed in patients with mild to moderate hepatic impairment. Reduce the starting dose of COMETRIQ in patients with mild (Child-Pugh score (C-P) A) or moderate (C-P B) hepatic impairment. COMETRIQ is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].
8.7 Renal Impairment
Dosage adjustment is not required in patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE
One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.
11 DESCRIPTION
COMETRIQ is the (S)-malate salt of cabozantinib. Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular formula is C28H24FN3O5•C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib (S)-malate salt is:
Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous media.
COMETRIQ (cabozantinib) capsules are supplied as printed hard gelatin capsules containing cabozantinib (S)-malate equivalent to 20 mg or 80 mg cabozantinib and the following inactive ingredients: silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, fumed silica, and stearic acid.
The grey gelatin capsule shells contain black iron oxide and titanium dioxide and the Swedish orange gelatin capsule shells contain red iron oxide, and titanium dioxide. The printing ink contains shellac glaze, black iron oxide, N-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, ROS1, TYRO3, MER, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of orally administered COMETRIQ 140 mg on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled study in patients with MTC. A mean increase in QTcF of 10 - 15 ms was observed at 4 weeks after initiating COMETRIQ. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No COMETRIQ-treated patients had a QTcF > 500 ms [see Clinical Studies (14)].
12.3 Pharmacokinetics
A population pharmacokinetic analysis of cabozantinib was performed using data collected from 289 patients with solid tumors including MTC following oral administration of 140 mg daily doses. Repeat daily dosing of COMETRIQ at 140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state was achieved by Day 15.
Absorption
Following oral administration of COMETRIQ, median time to peak cabozantinib plasma concentrations (Tmax) ranged from 2 to 5 hours post-dose.
A 19% increase in the Cmax of the tablet formulation (CABOMETYX™) compared to the capsule formulation (COMETRIQ) was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations [see Dosage and Administration (2.1)].
Cabozantinib Cmax and AUC values increased by 41% and 57%, respectively, following a high-fat meal relative to fasted conditions in healthy subjects administered a single 140 mg oral COMETRIQ dose.
Distribution
The oral volume of distribution (V/F) of cabozantinib is approximately 349 L. Cabozantinib is highly protein bound in human plasma (≥ 99.7%).
Elimination
The predicted effective half-life is approximately 55 hours and the clearance (CL/F) at steady-state is estimated to be 4.4 L/hr.
Metbolism
Cabozantinib is a substrate of CYP3A4 in vitro.
Excretion
Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single 140 mg dose of an investigational 14C-cabozantinib formulation in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72 hour collection.
Specific Populations
The following patient characteristics did not result in a clinically relevant difference in the pharmacokinetics of cabozantinib: age (20-86 years), sex, race (Whites and non-Whites), or mild to moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m2 as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics of cabozantinib is unknown in patients with worse than moderate renal impairment (eGFR less than 29 mL/min/1.73m2) as estimated by MDRD equation or renal impairment requiring dialysis.
Hepatic Impairment
Following a single oral 60 mg COMETRIQ, mean AUC0-inf for cabozantinib increased by 81% in subjects with mild (C-P A) hepatic impairment and 63% in subjects with moderate (C-P B) hepatic impairment compared to subjects with normal hepatic function [see Dosage and Administration (2.1), Use in Specific Populations (8.6)].
The pharmacokinetics of cabozantinib has not been studied in patients with severe (C-P C) hepatic impairment [see Use in Specific Populations (8.6)].
Pediatric Population
The pharmacokinetics of cabozantinib has not been studied in the pediatric population [see Use in Specific Populations (8.4)].
Drug Interactions
CYP3A4 Inhibition on Cabozantinib
Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%.
CYP3A4 Induction on Cabozantinib
Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%.
Cabozantinib on CYP2C8 substrates
No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) was observed when co-administered with cabozantinib at steady-state plasma concentrations (≥ 100 mg/day daily for a minimum of 21 days) in patients with solid tumors.
Gastric pH modifying agents on Cabozantinib
No clinically-significant effect on plasma cabozantinib exposure (AUC) was observed following co-administration of the proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers.
In vitro Studies
Metabolic Pathways
Inhibition of CYP3A4 reduced the formation of the XL184 N-oxide metabolite by >80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation.
Although cabozantinib is an inhibitor of CYP2C8 in vitro, a clinical study of this potential interaction concluded that concurrent use did not result in a clinically relevant effect on CYP2C8 substrate exposure. Given this finding, other less sensitive substrates of pathways affected by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, and CYP3A4) were not evaluated in a clinical study because, although a clinically relevant exposure effect cannot be ruled out, it is unlikely. Cabozantinib does not inhibit CYP1A2 and CYP2D6 isozymes in vitro.
Cabozantinib is an inducer of CYP1A1 mRNA; however, the clinical relevance of this finding is unknown. Cabozantinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4.
Drug Transporter Systems
Cabozantinib is an inhibitor, but not a substrate, of P-gp transport activities and has the potential to increase plasma concentrations of co-administered substrates of P-gp. The clinical relevance of this finding is unknown.
Cabozantinib is a substrate of MRP2 in vitro and MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. The clinical relevance of this finding is unknown.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Cabozantinib was not carcinogenic in a 26-week carcinogenicity study in rasH2 transgenic mice.
Cabozantinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo mouse micronucleus assay.
Based on nonclinical findings, male and female fertility may be impaired by treatment with COMETRIQ. In a fertility study in which cabozantinib was administered to male and female rats at doses of 1, 2.5, and 5 mg/kg/day, male fertility was significantly compromised at doses equal to or greater than 2.5 mg/kg/day (approximately equal to the human exposure by AUC at the recommended dose), with a decrease in sperm counts and reproductive organ weights. In females, fertility was significantly reduced at doses equal to or greater than 1 mg/kg/day (approximately 50% of the human exposure by AUC at the recommended dose) with a significant decrease in the number of live embryos and a significant increase in pre- and post-implantation losses.
Observations of effects on reproductive tract tissues in general toxicology studies were supportive of effects noted in the dedicated fertility study and included hypospermia and absence of corpora lutea in male and female dogs in a 6-month repeat dose study at exposures equal to 6% and 3%, respectively, the human exposure by AUC at the recommended dose. In addition, female rats administered 5 mg/kg/day for 14 days (approximately equal to the human exposure by AUC at the recommended dose) exhibited ovarian necrosis.
14 CLINICAL STUDIES
The safety and efficacy of COMETRIQ was assessed in an international, multi-center, randomized, double-blind, controlled trial (Study 1) of 330 patients with metastatic medullary thyroid carcinoma (MTC). Patients were required to have evidence of actively progressive disease within 14 months prior to study entry confirmed by an Independent Radiology Review Committee (IRRC) masked to treatment assignment (89%) or the treating physician (11%). Patients were randomized (2:1) to receive COMETRIQ 140 mg (n = 219) or placebo (n = 111) orally once daily, without food, until disease progression determined by the treating physician or until intolerable toxicity. Randomization was stratified by age (≤ 65 years vs. > 65 years) and prior use of a tyrosine kinase inhibitor (TKI) (yes vs. no). No cross-over was allowed at the time of progression. The main efficacy outcome measures of progression-free survival (PFS), objective response (OR), and response duration were based on IRRC-confirmed events using modified RECIST criteria.
Of 330 patients randomized, 67% were male, the median age was 55 years, 23% were 65 years or older, 89% were white, 54% had a baseline ECOG performance status of 0, and 92% had undergone a thyroidectomy. The RET mutation status determined by a research-use assay was positive in 51%, negative in 14%, and was unknown in 35%. Twenty-five percent (25%) had two or more prior systemic therapies and 21% had been previously treated with a TKI.
A statistically significant prolongation in PFS was demonstrated among COMETRIQ-treated patients compared to those receiving placebo [HR 0.28 (95% CI: 0.19, 0.40); p<0.0001], with median PFS times of 11.2 months and 4.0 months in the COMETRIQ and placebo arms, respectively.
Partial responses were observed only among patients in the COMETRIQ arm (27% vs. 0; p<0.0001). The median duration of objective responses was 14.7 months (95% CI: 11.1, 19.3) for patients treated with COMETRIQ. There was no statistically significant difference in overall survival (median OS: 26.6 months in the COMETRIQ arm vs. 21.1 months in the placebo arm [HR = 0.85 (95% CI: 0.64, 1.12), p = 0.2409]).
Figure 1: Progression-Free Survival
16 HOW SUPPLIED/STORAGE AND HANDLING
COMETRIQ 20 mg capsules are supplied as hard gelatin capsules with grey cap and grey body, printed with "XL184 20mg" in black ink and containing cabozantinib (S)-malate salt equivalent to 20 mg cabozantinib.
COMETRIQ 80 mg capsules are supplied as hard gelatin capsules with Swedish orange cap and Swedish orange body, printed with "XL184 80mg" in black ink and containing cabozantinib (S)- malate salt equivalent to 80 mg cabozantinib.
COMETRIQ capsules are supplied as follows:
Cartons
140 mg daily-dose carton NDC#42388-011-14
Containing four 140 mg daily-dose blister cards
(each blister card contains seven 80-mg and twenty-one 20-mg capsules)
100 mg daily-dose carton NDC#42388-012-14
Containing four 100 mg daily-dose blister cards
(each blister card contains seven 80-mg and seven 20-mg capsules)
60 mg daily-dose carton NDC#42388-013-14
Containing four 60 mg daily-dose blister cards
(each blister card contains twenty-one 20-mg capsules)
Store COMETRIQ at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a0c3bea-c87b-4d25-bb44-5f0174da6b34
卡博替尼Cabozantinib(XL184)可控制多种肿瘤和骨转移
CabozantinibXL184的Ⅱ期临床试验结果显示，该试验新药对多种晚期癌症具有较高的疾病控制率，并且可缩小甚至消除骨转移病灶。美国亚利桑那州Pinnacle肿瘤血液医院的Michael S. Gordon博士将在6月份召开的美国临床肿瘤学会ASCO年会上报告上述研究结果。
该项试验设计为随机终止试验RDT，纳入398例进展性可测量性癌症患者，其中39%的患者在入组时已发生骨转移。在开放性研究阶段，所有患者每天服用100 mg 受试药物，共12周。病情进展增长≥20%患者退出试验，部分应答患者缩小≥30%继续服药，病情稳定患者随机分组接受cabozantinib或安慰剂治疗。
结果显示，cabozantinib对13种肿瘤中的12种具有抗肿瘤活性，并且骨扫描结果显著改善。虽然总应答率仅为9%，但cabozantinib单药治疗12周后，肝癌、前列腺癌和卵巢癌患者的疾病稳定率分别可达76%、71%和58%，黑色素瘤、乳腺癌和非小细胞肺癌的疾病控制率分别为45%、45%和40%。
令人惊讶的是，在68例骨转移患者中，59例骨转移缩小或消除。包括乳腺癌、前列腺癌和黑色素瘤在内的患者，骨扫描显示转移病灶部分或完全消失，并且在治疗6周后即可得到改善。其中去势耐药性前列腺癌患者效果最为明显，86%的患者表现为完全或部分骨扫描缓解。与此同时，骨疼痛也得到缓解，镇痛药物需求减少、骨重吸收标志物水平下降，贫血患者的血红蛋白持续增加。
最常见的3级或以上不良反应事件为疲劳9%、手足综合征8%和高血压5%，不良事件停药率为12%。
该研究已经扩大规模，以纳入更多的去势耐药性前列腺癌和铂类耐药或难治性卵巢癌患者，并考虑在Ⅲ期试验中进一步观察上述患者的疗效。
Cabozantinib为口服酪氨酸激酶抑制剂，同时作用于血管内皮素生长因子2VEGF2和MET。
上述结果提示，该药物对多种实体瘤有效，可能与其作用于肿瘤生长的2种信号传导途径有关。
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