Anti-CTLA-4 Antibody Followed by Anti-PD-1 Antibody in Recurrent or Metastatic NSCLC (SEQUENCE)

A Phase I Study Evaluating the Safety and Efficacy of CTLA-4 Antibody Ipilimumab Followed by PD-1 Antibody SHR-1210 in Patients With Recurrent or Metastatic Non-small Cell Lung Cancer

Immunotherapy has made rapid progress in melanoma, Hodgkin's lymphoma, non-small cell lung cancer, and bladder cancer, etc. Preclinical data suggested that the use of anti-PD-1 antibody in combination with CTLA-4 receptor blockers may increase antitumor activity. The CheckMate-012 study showed that nivolumab and ipilimumab combination therapy achieved an overall response rate of 43% in unselected patients with non-small cell lung cancer, compared with 23% in the nivolumab monotherapy group; and in the PD-L1 positive subgroup, nivolumab in combination with ipilimumab showed a response rate of 57%, while nivolumab alone was 28%. This showed that the combination therapy of nivolumab and ipilimumab can increase the efficacy, but the adverse events of grade 3 or above of combination therapy reach 37%. The toxic side effects limit the widespread use of nivolumab in combination with ipilimumab therapy.

However, since the action of ipilimumab is limited to the initiation of the immune response (antigen presentation and immune cell activation), and its long half-time of 15.4 days, ipilimumab can used as an induction therapy, following by the PD1 monoclonal antibody. This phase I study is aimed to evaluated the safety and efficacy of CTLA-4 antibody followed by PD-1 antibody in patients with recurrent or metastatic non-small cell lung cancer.

Study Overview

• Status: Unknown
• Conditions: Non Small Cell Lung Cancer
• Intervention / Treatment: Drug: Ipilimumab; Drug: SHR-1210

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Wenfeng Fang, MD; Phone Number: 86-15322302066; Email: fangwf@sysucc.org.cn

Study Locations

• China
  • Guangdong
    • GuangZhou, Guangdong, China, 510060
      • Recruiting
      • Cancer Center of Sun-Yat Sen University (CCSYSU)
      • Contact: Li Zhang, Master; Phone Number: 86-20-8734-3458; Email: zhangli6@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age >=18 years old, male or female;
• Histologically confirmed locally advanced or metastatic non-small-cell lung cancer;
• At least one systemic chemotherapy regimen for locally advanced or metastatic disease (patients received neoadjuvant chemotherapy, concurrent chemoradiotherapy, or adjuvant chemotherapy within 6 months can be considered as first-line system therapy);
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1;
• At least one measurable lesion according to criteria RECIST v1.1;
• Life expectancy of at least 12 weeks;
• Patient has adequate bone marrow as defined by the following laboratory values:

White blood cell ≥ 3.0 × 109/L Absolute neutrophil count ≥ 1.5 × 109/L Platelets ≥ 75 × 109/L

• Patient has adequate organ function as defined by the following laboratory values:

In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be below 2.5 × ULN. If the patient has liver metastases, ALT and AST should be < 5 × ULN Total serum bilirubin < ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range of the central laboratory in patients with well documented Gilbert's Syndrome Serum creatinine ≤ 1.5 × ULN

• Provide written, informed consent to participate in the study and follow the study procedures;
• Women of childbearing potential must agree and commit to the use of a highly effective non-hormonal method of contraception, ie, intrauterine device, bilateral tubal ligation, vasectomized partner, or abstinence (only when it is the preferred lifestyle of the patient), from the time of informed consent until 28 days after the last dose of the investigational products. Men and their female partners of childbearing potential must agree and commit to use a highly effective method of contraception (ie, any of the above methods or hormonal contraception associated with inhibition of ovulation) while on treatment and for 3 months after last dose of investigational products

Exclusion Criteria:

• Driver gene EGFR, ALK and ROS were positive;
• In presence of active autoimmune disease or a history of autoimmune disease (such as the following, but not limited to: interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, vasculitis, nephritis, hyperthyroidism, hypothyroidism; Patients with hormone replacement therapy can be included; Patients with vitiligo or asthma in childhood have been completely relieved, and no intervention in adults can be included; The subjects who needed medical intervention with bronchial dilation were ineligible;
• Patients are using immunity inhibitors or systemic hormone therapy for immunosuppression purpose (such as prednisone > 10 mg/day), except for local hormone therapy.
• Patients were known to be allergic to macromolecular protein, or any components in ipilimumab or SHR-1210;
• Patients with clinical symptoms of central nervous system metastasis (e.g. brain edema, requirement of hormone intervention, or brain metastases progression);
• Another malignancy within 2 years prior to screening, with the exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer;
• Patients with congenital or acquired immunodeficiency (such as HIV infection), or active hepatitis (HBV DNA≥10⁴/ml);
• Any severe and / or uncontrolled medical conditions.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Sequential group; intravenous ipilimumab following by intravenous SHR-1210

Drug: Ipilimumab; Patients received two doses of intravenous ipilimumab (at a dose of 1 mg per kilogram of body weight) every 3 weeks, following by intravenous SHR-1210 (at a fixed dose of 200mg) every 2 weeks.; Other Names: Yervoy; Drug: SHR-1210; Patients received two doses of intravenous ipilimumab (at a dose of 1 mg per kilogram of body weight) every 3 weeks, following by intravenous SHR-1210 (at a fixed dose of 200mg) every 2 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety in the treatment of ipilimumab followed by SHR1210	Adverse events occurring up to 30 days after the last dose of ipilimumab or SHR1210 are evaluated and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1	Up to 4 weeks
Clinical Benefit Response (CBR)	CBR as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1	Up to 4 weeks
Progression-free Survival (PFS)	PFS as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1	Up to 4 weeks
Overall survival (OS)	OS as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1	Up to 4 weeks
Duration of response (DOR)	DOR as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1	Up to 4 weeks
Time To Progression (TTP)	TTP as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1	Up to 4 weeks

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2018
• Primary Completion (Anticipated): December 31, 2018
• Study Completion (Anticipated): December 31, 2019

Study Registration Dates

• First Submitted: April 28, 2018
• First Submitted That Met QC Criteria: May 15, 2018
• First Posted (Actual): May 17, 2018

Study Record Updates

• Last Update Posted (Actual): May 30, 2018
• Last Update Submitted That Met QC Criteria: May 27, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: non-small cell lung cancer; PD-1 antibody; clinical trial, phase I; CTLA-4 antibody
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Ipilimumab
• Other Study ID Numbers: 2018-FXY-032

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes