Clinical trial NCT04012619
Conditions: Non-squamous Non-small-cell Lung Cancer Anlotinib
Sponsor: Sichuan University
Start date: 2019-04-30; Completion date: 2020-12-30
Enrollment: 8 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
Anlotinib is a novel oral multitarget tyrosine kinase inhibitor and primary targeted to VEGFR, FGFR, PDGFR and c-Kit. The ALTER-0303 trial showed that patients with advanced non-small cell lung cancer (NSCLC) who received anlotinib as third-line or further therapy had more survival benefit. Pemetrexed plus platinum-based chemotherapy (AP) was long considered as the first line treatment in non-squamous NSCLC patients with negative driver mutation. In this dose exploration study, the primary objective is to establish the safety profile of anlotinib combined with AP in non-squamous NSCLC patients by identifying dose limiting toxicity (DLT), maximum tolerance dose (MTD), the recommended phase II dose, and schedule. Secondary objective includes the assessment of preliminary antitumor effect.

Detailed description:
Anlotinib, a new small molecule inhibitor of multiple receptor tyrosine kinases targeting the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-Kit,8,9 has been approved as a third-line treatment for refractory advanced NSCLC by the China Food and Drug Administration (CFDA) on May 9, 2018.10 Previous study in phase II (ALTER0302) trial has shown a better progression-free survival (PFS) in advanced NSCLC patients treated with anlotinib compared those with the placebo (4.8 vs 1.2 months, P\<0.0001).11 In phase III (ALTER0303) trial, both the overall survival (OS) and PFS of advanced NSCLC patients were observed to be significantly longer in the anlotinib group (median, 9.6 and 5.4 months) than the placebo group (median, 6.3 and 1.4 months).12 Moreover, anlotinib also displayed manageable toxicity, long circulation, and broad-spectrum antitumor potential.13,14 For the lack of recommended drugs with exactly therapeutic effect in the third-line treatment of SCC patients, it is worth to further analyze the efficacy and specifically clinical observation indicator of anlotinib in this subtype of NSCLC patients. In this dose exploration study, the primary objective is to establish the safety profile of anlotinib combined with AP in treatment-naive non-squamous NSCLC patients by identifying dose limiting toxicity (DLT), maximum tolerance dose (MTD), the recommended phase II dose, and schedule. Secondary objective includes the assessment of preliminary antitumor effect.

Arms: arm 1: Patients receive pemetrexed (500mg/m2) with cisplatin (75mg/m2)/carboplatin (area under the curve 5) once every 3 weeks, and anlotinib (dose escalation) once daily on days 1-14 of a 21-day cycle. Anlotinib with AP will be administrated up to 4 cycles followed by maintenance treatment with anlotinib once daily (12mg/d) on days 1-14 of a 21-day cycle until disease progression or treatment intolerance.
Interventions: intervention 1: Anlotinib Hydrochloride
Intervention descriptions: intervention 1: Patients receive pemetrexed with cisplatin/carboplatin once every 3 weeks, and anlotinib (dose escalation) once daily on days 1-14.

Protocol documents:
Prot_SAP_000.pdf: 
ALTER-L003: Anlotinib Hydrochloride Combined With AP in Stage
IIIB/IIIC/IV Non-squamous Non-small-cell Lung Cancer
NCT number: NCT04012619
Date: 2018.07.01
Version：1.0
Study population
Eligible patients had histologically or cytologically con frmed stage IIIB/IIIC/IV
nonsquamous NSCLC; were nega tive for mutations of EGFR\ALK\ROS1; were
aged 18 to 70; never received any systematic treatment (including immu notherapy);
had an Eastern Cooperative Oncology Group (ECOG) performance status 0–1; had
an expected survival time ≥3 months; and presented no major organ dysfunction.
Patients were excluded if they had active brain metastases, uncontrolled hypertension,
severe cardiovascular diseases, or coagulation abnormalities. This study was reviewed
and approved by the Institutional Review Board of West China Hospital, Sichuan
University. Written informed consent was obtained from all participants.
This study is registered with ClinicalTrials.gov, number NCT04012619.
Study design
This study employed a standard 3+3 dose reduction design and eligible patients
received anlotinib-chemotherapy regimen on 21-day cycles for 4 cycles. Pemetrexed
(500 mg/m2) and cisplatin (75 mg/m2) or carboplatin (AUC = 5) were intravenously
given on day 1 of each cycle. According to the ALTER0303 study, the initial dose of
anlotinib was set as 12 mg/day with a 2-week on/1-week off schedule, and was
reduced to 10 mg/day and 8 mg/day in sequence depending on DLTs in cycle 1.
Patients who had disease control after the combination regimen continued to receive
anlotinib maintenance until disease progression.
Assessments
The primary endpoint was the MTD of anlotinib, at which less than 33% of patients
experienced a DLT in the first treatment cycle. DLT was defined as grade 4 and above
hematological toxicity, grade 2 and above liver and kidney function injury and grade 3
and above non-hematological toxicity. The secondary endpoints included PFS and OS.
PFS was defined as the time from the date of randomization to the date of disease
progression or death. OS was defined as the time from the date of randomization to
the date of death.
Statistical analysis


Recruitment of a minimum of 3 patients and a maximum of 18 patients was planned
in accordance with the 3+3 study design. All patients who received at least one dose
of the investigational drug were included in safety assessment and those who
completed at least one cycle of the treatment were eligible for efficacy evaluation.
The baseline demographic characteristics and frequency of adverse events were
summarised with descriptive statistics. Two-sided 95% exact CIs were calculated for
ORR and DCR using the Clopper-Pearson method, and estimated time-to-event
endpoints were calculated with the Kaplan-Meier method with two-sided 95% CIs for
medians. All statistical analyses were carried out with SAS 9.1.3 software.