凡德他尼（caprelsa）

【Function and Indications】

The indication of Vandetanib Caprelsa is medullary thyroid cancer.

1. Treatment of advanced NSCLC (non-small cell lung cancer) Study 003 compared the efficacy of Vandetanib 300 mg/d and Gefitinib 250 mg/d in 168 patients with advanced NSCLC who failed first-line or second-line chemotherapy. Compared with Gefitinib, Vandetanib significantly increased the effective rate and prolonged the progression-free survival time, which were 8% and 1%, 11.9 weeks and 8.1 weeks, respectively (P=0.011). In clinical trials, if the patient’s disease progresses or cannot tolerate toxicity, he is allowed to change the treatment plan. The results of the trial showed that the disease control rate of patients who replaced Vandetanib with Gefitinib was 14%, while the disease control rate of patients who replaced Gefitinib with Vandetanib reached 32%. The median overall survival from Vandetanib to Gefitinib was expected to be 6.1 months, and from Gefitinib to Vandetanib was 7.4 months. Study 0007 is ongoing, aiming to evaluate the efficacy of vandetanib combined with paclitaxel (200 mg/m2) + carboplatin (AUC=6) as first-line treatment for stage IIIB-IV NSCLC. Preliminary trial results show that vandetanib can be combined with traditional chemotherapy drugs to treat NSCLC without significantly increasing grade 3~4 adverse reactions.

2. 46 patients with advanced breast cancer who had previously failed paclitaxel + anthracycline chemotherapy were treated with vandetanib (100 mg or 300 mg). No objective efficacy was observed in 44 evaluable patients, and one patient in each group had stable disease (SD) for ≥24 weeks. The authors believe that the efficacy of single-agent vandetanib in the treatment of relapsed and resistant breast cancer is limited, but it is well tolerated.

3. Treatment of advanced multiple myeloma: 18 patients with multiple myeloma who had failed chemotherapy or hematopoietic stem cell transplantation took vandetanib (100 mg) orally for 3 to 29.4 weeks. There was no improvement in globulin or urine M protein. The toxicity was tolerable. Common toxicity included nausea, vomiting, diarrhea, rash, skin itching, sensory disturbance, etc., but no clear QT interval changes were observed.

4. Treatment of thyroid cancer: Medullary thyroid cancer has a low incidence and is hereditary. Whether it is radiotherapy, combined chemotherapy or endocrine therapy, the effect is poor and the prognosis is poor. Study 0008 is an ongoing, open phase II study to evaluate the efficacy and toxicity of vandetanib in the treatment of advanced hereditary medullary thyroid cancer. Among the 11 evaluable patients (receiving vandetanib 300 mg/d for at least 3 months), 2 patients achieved PR and 9 patients achieved SD. In addition, the patient’s plasma tumor markers calcitonin and carcinoembryonic antigen decreased by 72% and 25% respectively compared with the baseline values. It is currently believed that vandetanib mainly acts on the tumor cell target RET tyrosine kinase in the treatment of medullary thyroid cancer. RET can promote tumor cell growth and survival. 40% of sporadic and 100% of hereditary medullary thyroid cancer have overexpression of RET gene.

[Model and Specification]
300mg/30 tablets.

[Usage and Dosage]
(1) 300 mg once a day
(2) The dose may need to be reduced in the event of severe toxicity or prolonged QTc interval
(3) The starting dose should be reduced to 200 mg in patients with moderate and severe renal impairment.

[Clinical Studies]
(1) Pharmacodynamics: Vandetanib is a synthetic aniline quinazoline compound, an oral small molecule multi-target tyrosine kinase inhibitor (TKI), which can act on tumor cell EGFR, VEGFR and RET tyrosine kinases simultaneously, and can also selectively inhibit other tyrosine kinases, as well as serine/threonine kinases, and block signal transduction by multiple targets. Therefore, it is a multi-channel tumor signal transduction inhibitor.
(2) Pharmacokinetics: Vandetanib is slowly absorbed orally, has a prolonged and extensive distribution, binds to plasma proteins, and has a two-compartment metabolism model. The terminal half-life of healthy volunteers is 10 days, and the drug metabolism of patients is slower than that of healthy volunteers, with a terminal half-life of about 20 days. Vandetanib is eliminated slowly, mainly through feces and urine, and 69% is eliminated from the body in 21 days. Food intake has no significant effect on drug metabolism.

[Precautions]
(1) Prolonged QT interval, torsade de pointes, and sudden death have been reported. Monitor electrocardiograms and serum potassium, calcium, and TSH levels at baseline, 2-4 weeks and 8-12 weeks after starting vandetanib treatment, and every 3 months thereafter and after dose adjustment. When the dose is reduced appropriately
(2) Stevene-Johnson syndrome leading to death has been observed. Severe skin reactions may prompt permanent discontinuation of vandetanib
(3) Signs of interstitial lung disease leading to death have been reported. Discontinue vandetanib and study for unexplained dyspnea, cough, and fever. Appropriate measures should be taken for interstitial lung disease
(4) Ischemic cerebrovascular events, hemorrhage, heart failure, diarrhea, hypothyroidism, hypertension, and reversible posterior leukoencephalopathy syndrome have been observed
(5) Vandetanib may be fatal when administered to pregnant women. Women are advised to avoid pregnancy while receiving vandetanib and for 4 months after treatment
(6) Because of the risk of QT prolongation, torsade de pointes, and sudden death, vandetanib is only available through a strict distribution program called the vandetanib REMS program. Only certified prescribers and pharmacies can prescribe and dispense vandetanib.

[Adverse Reactions and Contraindications]
It is well tolerated at ≤300 mg/d, with the most common adverse reactions being diarrhea, rash, nausea, hypertension, anorexia, asymptomatic QT prolongation, and proteinuria. As the dose increases, hypophosphatemia, folliculitis, elevated transaminases, nonspecific intestinal obstruction, thrombocytopenia, congestive heart failure, deep vein thrombosis, pulmonary embolism, etc. may occur. The most common dose-limiting toxicities (DLTs) are diarrhea, hypertension, and rash.

[Contraindications]
Patients with long QT syndrome should not use vandetanib.

[Drug Interactions]
There is no pharmacokinetic interaction when combined with docetaxel. No pharmacokinetic interactions related to the CYP3A4 inhibitor itraconazole or the 5-HT3 antagonist ondansetron were found.
Currently, clinical trials of vandetanib for the treatment of NSCLC are being conducted in my country.
1. Treatment of advanced NSCLC (non-small cell lung cancer) Study 003 compared the efficacy of vandetanib 300 mg/d and gefitinib 250 mg/d in 168 patients with advanced NSCLC who had failed first-line or second-line chemotherapy. Compared with gefitinib, vandetanib significantly increased the effective rate and prolonged the progression-free survival time, which were 8% and 1%, 11.9 weeks and 8.1 weeks, respectively (P=0.011). In clinical trials, if the patient’s disease progresses or cannot tolerate toxicity, they are allowed to change the treatment plan. The results of the trial showed that the disease control rate of patients who replaced vandetanib with gefitinib was 14%, while the disease control rate of patients who replaced gefitinib with vandetanib reached 32%. The estimated median overall survival from vandetanib to gefitinib was 6.1 months, while that from gefitinib to vandetanib was 7.4 months. Study 0007 is ongoing, aiming to evaluate the efficacy of vandetanib combined with paclitaxel (200 mg/m2) + carboplatin (AUC=6) as first-line treatment for stage IIIB-IV NSCLC. Preliminary trial results show that vandetanib can be combined with traditional chemotherapy drugs to treat NSCLC without significantly increasing grade 3~4 adverse reactions.
2. 46 patients with advanced breast cancer who had previously failed paclitaxel + anthracycline chemotherapy were treated with vandetanib (100 mg or 300 mg). No objective efficacy was observed in 44 evaluable patients. One patient in each group had stable disease (SD) for ≥24 weeks. The authors believe that the efficacy of single-agent vandetanib in the treatment of relapsed and resistant breast cancer is limited, but it is well tolerated.
3. Treatment of advanced multiple myeloma: 18 patients with multiple myeloma who had failed chemotherapy or hematopoietic stem cell transplantation took vandetanib (100 mg) orally for 3 to 29.4 weeks. There was no improvement in globulin or urine M protein. The toxicity and side effects were tolerable. Common toxicity and side effects included nausea, vomiting, diarrhea, rash, skin itching, sensory disturbances, etc., but no clear QT interval changes were observed.
4. Treatment of thyroid cancer: Medullary thyroid cancer has a low incidence and is hereditary. Whether it is radiotherapy, combined chemotherapy or endocrine therapy, the effect is poor and the prognosis is poor. Study 0008 is an ongoing, open Phase II study to evaluate the efficacy and toxicity of vandetanib in the treatment of advanced hereditary medullary thyroid cancer. Among the 11 evaluable patients (receiving vandetanib 300 mg/d for at least 3 months), 2 patients achieved PR and 9 patients achieved SD. In addition, the patient’s plasma tumor markers calcitonin and carcinoembryonic antigen decreased by 72% and 25% respectively compared with the baseline values. It is currently believed that vandetanib mainly acts on the tumor cell target RET tyrosine kinase in the treatment of medullary thyroid cancer. RET can promote tumor cell growth and survival. 40% of sporadic and 100% of hereditary medullary thyroid cancer have overexpression of RET gene.

【Storage】
Store at room temperature away from light.