Nivolumab Combined With Anlotinib as Re-challenge Treatment in Advanced NSCLC

NCT04507906 | Completed Phase 1 FDA Drug

• 1 other identifier: LS2025
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase Ib/IIa, open-label, single center study, aiming to investigate safety and efficacy of nivolumab (administered intravenously) in combination with anlotinib (administered orally) in immunotherapy-treated advanced NSCLC. The study has been designed to allow an investigation of the optimal combination dose and schedule while ensuring the safety of patients with intensive safety monitoring. There are two main parts to this study; Part A, combination dose finding and Parts B, dose expansion. Part B will either be initiated if RP2D reached in Part A, or not initiated if RP2D was not reached in Part A. Part A has been designed to identify the recommended dose of combination of nivolumab plus anlotinib for further clinical evaluation based upon assessment of the safety and tolerability data collected during the first 21 days (cycle 1, 21 days per cycle). The 21-day assessment period was selected as the major toxicities leading to cessation of dose de-escalation in such Phase I oncology studies (haematological, gastrointestinal, liver enzymes) are anticipated to present within this duration. "3+3"design was used in the dose finding cohort. If RP2D was reached in Part A, eligible patients would be enrolled and receive nivolumab (360mg q3w, intravenously) plus anlotinib (RP2D, QD from day 1 to 14 of a 21-day cycle) till disease progression (PD) withdraw of consent, or unacceptable toxicity to further evaluate the safety, tolerability and efficacy in terms of ORR , DCR, DOR, PFS and OS. The tumor response will be evaluated according to RECIST Version 1.1 every 6 weeks.

Conditions

NSCLC Stage IV; Checkpoint Inhibitor

Keywords

NSCLC; Nivolumab; Anlotinib

Outcome Measures

Primary Outcomes (1)

• Objective response rate (ORR)

  Patients who were assessed as partial response or complete response

  6-9 weeks

Secondary Outcomes (3)

• Disease control rate (DCR)

  6-9 weeks

• Progression-free survival (PFS)

  5-7 months

• Overall survival (OS)

  13-15 months

Study Arms (1)

Nivolumab + Anlotinib Arm

OTHER

Drug: Nivolumab Combined with Anlotinib

Interventions

Nivolumab Combined with Anlotinib DRUG

In combination dose finding phase, Phase 1b will begin with Dose Level 1; anlotinib 12 mg/day orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360mg q3w, intravenously) will be administered to eligible subjects on a 21-day treatment cycle. Two dose de-escalation steps are included: Dose Level 2 (anlotinib 10 mg/day orally, from days 1 to 14 in a 21-day cycle) and nivolumab 360mg q3w, intravenously) and Dose Level 3 (anlotinib 8 mg/day orally, from days 1 to 14 in a 21-day cycle) and nivolumab 360mg q3w, intravenously).If RP2D was reached in Part A, eligible patients would be enrolled and receive nivolumab (360mg q3w, intravenously) plus anlotinib (RP2D, QD from day 1 to 14 of a 21-day cycle) .

Nivolumab + Anlotinib Arm

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• According to the 8th edition of the AJCC/UICC TNM staging system for NSCLC, patients with locally advanced (stage III B/III C), metastatic or recurrent (stage IV) NSCLC confirmed by histology or cytology who are unable to undergo surgery and radical concomitant radiochemotherapy and are confirmed to have at least one measurable lesion according to RECIST 1.1.
• Without active brain metastasis
• Previously treated with ICIs with progressive disease.
• Age ≥18 years and ≤75 years;
• ECOG PS score: 0 to 1
• Palliative radiotherapy must be completed 7 days before the first dose of study drugs;
• The main organs function is normal, that is, the following criteria met:
• Good hematopoietic function, defined as absolute neutrophil count ≥1.5×109 /L, platelet count≥100 ×109 /L, hemoglobin ≥90g/L \[no blood transfusion or no erythropoietin (EPO) dependence within 7 days before enrollment\]
• Biochemical test results should meet the following criteria: BIL \< 1.25 times the upper limit of normal value (ULN); ALT and AST \< 2.5 × ULN; in case of liver metastases, ALT and AST \< 5 × ULN; Cr ≤1.5×ULN or creatinine clearance (CCr) ≥60ml/min; Coagulation function is good, INR and PT ≤1.5 times ULN; if the subject is receiving anticoagulant treatment, PT should be within the prescribed range of use of anticoagulant drugs;
• Women of child-bearing age should agree to take contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study and within 6 months after the study; non-breast-feeding patients whose serum or urinary pregnancy test should be negative; male patients should agree to take contraceptive measures during the study and within 6 months after the study.
• Patients are voluntarily enrolled into the study, sign the informed consent form and have good compliance.

You may not qualify if:

• Patients who meet any of the following criteria will be excluded:
• Subjects with active CNS metastases are excluded. Subjects are eligible if CNS metastases are adequately treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to enrollment. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent).
• Small cell lung cancer (including mixed small cell and non-small cell lung cancer) or central squamous cell carcinoma with cavity;
• With obvious hemorrhage symptom
• With driver mutation (EGFR/ALK/ROS1) or mutation status are unknown
• Patients who have not received IO as frontline treatment;
• Patients who have grade 3 AEs when treated with IO
• Patients with many factors affecting oral medication, such as dysphagia, gastrointestinal resection, chronic diarrhea and intestinal obstruction;
• Patients who are known to have active brain metastases, spinal cord compression, carcinomatous meningitis, or brain or leptomeningeal disease diagnosed by CT or MRI at the time of screening;
• Patients with severe and / or uncontrolled diseases, such as: unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months before randomization, severe uncontrolled arrhythmias; uncontrolled blood pressure (systolic blood pressure \> 140 mmHg, diastolic blood pressure \> 90 mmHg);
• Active or uncontrolled serious infection;
• Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis;
• Not completely controlled eye inflammation or eye infection, or any condition that may lead to the above-mentioned ocular diseases
• Poorly controlled diabetes (fasting blood glucose (FBG) \> 10mmol/L);
• Routine urine test result indicates that urine protein ≥++, and 24-hour urine protein quantitation is confirmed to be \> 1.0 g;

Sponsors & Collaborators

• Shanghai Chest Hospital: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Shanghai Chest hospital

Shanghai, Shanghai Municipality, 200030, China

Location

Related Publications (1)

• Zhang B, Liu H, Shi C, Gao Z, Zhong R, Gu A, Chu T, Wang H, Xiong L, Zhang W, Zhang X, Yan B, Teng J, Wang W, Bai H, Qiao R, Cheng L, Kuang Y, Zhao R, Zhong H, Han B. Safety and efficacy of multi-target TKI combined with nivolumab in check-point inhibitor-refractory patients with advanced NSCLC: a prospective, single-arm, two-stage study. BMC Cancer. 2024 Jun 11;24(1):715. doi: 10.1186/s12885-024-12479-0.

  PMID: 38862908 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

anlotinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of pulmonary department of Shanghai Chest Hospital

Study Record Dates

• First Submitted: August 8, 2020
• First Posted: August 11, 2020
• Study Start: November 2, 2020
• Primary Completion: March 31, 2022
• Study Completion: March 31, 2022
• Last Updated: June 28, 2022

Record last verified: 2022-06

Locations

CN (1)