Consolidation Sintilimab After Concurrent Chemoradiation in Patients With Unresectable Stage III NSCLC (CONSIST)

CONSIST: A Phase III Randomized Control Study of Consolidation Sintilimab (IBI308) After Concurrent Chemoradiation Versus Chemoradiation Alone in Patients With Unresectable Local Advanced Stage III NSCLC

This is an open label, multi-center, randomized, control phase III trial, to compare the efficacy and safety of consolidation therapy with sintilimab (IBI308) versus best supported care (BSC), in unresectable stage III NSCLC patients who do not experience disease progression after initial concurrent chemoradiation.

Study Overview

• Status: Unknown
• Conditions: Carcinoma, Non-Small Cell Lung
• Intervention / Treatment: Drug: Consolidation Sintilimab

Detailed Description

This is an open label, multi-center, randomized, control study of sintilimab versus BSC in unresectable local advanced stage III NSCLC patients without disease progression after concurrent chemoradiation.

• Study Type: Interventional
• Enrollment (Anticipated): 162
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China
      • Recruiting
      • Shandong Cancer Hospital
      • Contact: Jinming Yu, Ph.D; Phone Number: +86-531-67626142; Email: sdyujinming@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed written informed consent before initiation of any study procedures
2. Age ≥ 18 years and ≤ 75 years
3. Histologically or cytologically confirmed NSCLC, with unresectable local advanced disease (stage III according to NSCLC staging version 8)
4. Expected survival over 3 months
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
6. At least 1 measurable disease according to RECIST 1.1
7. Pulmonary function: forced expiratory volume at one second (FEV1) > 1 liter(L)
8. Patient must not have received any anti-cancer therapy for the purpose of treating lung cancer. However, exploratory thoracotomy, mediastinoscopy, excision biopsy, and other kinds of surgery for diagnosis and staging purpose is acceptable. Patients with local or regional recurrent disease after pneumonectomy is allowed to participate if they meet other inclusion criteria (e.g. stage III, inappropriate for re-operation).
9. For all female patients of childbearing potential, a negative pregnancy test (either urine or serum) must be obtained within 3 days before the first dose (Cycle 1, Day 1) of study treatment. If a urine pregnancy test shows an unconfirmed result, a serum pregnancy test must be performed.
10. Adequate hematopoietic function, defined as: absolute neutrophil count (ANC) ≥ 1.5 x 10*9/L; platelet count ≥100 x 10*9/L; hemoglobin ≥90 g/L [no blood transfusion within 7 days or not erythropoietin (EPO) dependent]
11. Adequate liver function, defined as: total serum bilirubin ≤ 1.5 x upper limit of normal (ULN); serum alanine transaminase (ALT) and aspartic transaminase (AST) ≤ 2.5 x ULN, with no liver transplantation
12. Adequate renal function, defined as: serum creatinine ≤ 1.5 x ULN or calculated creatinine-clearance ≥ 60 ml/min (Cockcroft-Gault). Urine protein less than 2+ by urinalysis or 24-hour urinary protein quantity < 1g
13. Adequate coagulation function, defined as: international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN. For patients receiving anticoagulant therapy can be enrolled if PT is within the range defined by anticoagulant therapy.
14. Myocardial enzymes are within normal range
15. All subjects of childbearing potential must agree to use efficient contraceptive methods that result in a failure rate of < 1% per year during the study treatment period and for at least 180 days after discontinuation from study treatment.

Exclusion Criteria:

1. Being treated by other investigational drugs within an interventional study, or have received any investigational drugs or instruments within 4 weeks prior to the first dose of study treatment
2. Being enrolled in other interventional studies, unless they are observational studies or during the follow-up stage of an interventional study
3. NSCLC histology with small cell lung cancer (SCLC) components
4. Active or autoimmune disease history (within the past 2 years), or history of immune deficiency

5. Previous immune therapy including: anti PD-1, anti PD-L1, anti PD-L2 or treatment targeting other co-stimulatory or co-inhibitory T-cell receptors [e.g. cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, and CD137]

   a) Systemic therapy with Chinese patent medicine or drugs of immunoregulation effect (including thymosin, interferon, interleukin, unless local delivery for controlling pleural effusion) within 2 weeks prior to the first dose of study treatment, or major surgery within 4 weeks prior to the first dose of study treatment

6. Clinical evidence of active diverticulitis, abdominal abscess, or gastrointestinal obstruction
7. Previous organ or blood system transplantation
8. Known allergic to pemetrexed, paclitaxel, etoposide, cisplatin, carboplatin, sintilimab component and/or any excipients

9. A history of active autoimmune disease requiring systemic treatment (e.g. using drugs for disease remission, corticosteroids or immunosuppressor) within 2 years prior to the first dose of study treatment. Substitution therapy (e.g. thyroxine, insulin or physiological corticosteroids for treating adrenal or pituitary dysfunction) is not considered as a systemic treatment.

   a) Diagnosis as immunodeficiency, or being treated with systemic glucocorticoid or other kinds of immunosuppressor within 7 days prior to the first dose of study treatment. A physiological dose of glucocorticoid (≤10 mg/day prednisone or equivalent dose of other steroids) is permitted.

10. Previously diagnosis as other malignant tumors within 5 years prior to the first dose of study treatment, with the exception of: skin basal cell carcinoma or squamous cell carcinoma with radical treatment, and/or carcinoma in situ underwent radical resection
11. History of non-infectious pneumonitis requiring treatment with glucocorticoid within 1 year prior to the first dose of study treatment, or currently existed interstitial lung disease
12. Active infectious that required systemic therapy
13. Know psychiatric illness or drug abuse that would limit compliance with study requirements
14. Know human immunodeficiency virus (HIV) infection (HIV 1/2 antibody positive)

15. Untreated active viral hepatitis B (HBV)

    Patients with HBV who meet the following criteria are also eligible:

    1. HBV virus load (VL) <1000 copy/ml (200 IU/ml), and patients must continuously receive anti-HBV therapy during all through study treatment phase to prevent virus activation
    2. Patients with a result of anti-HBc(+)、HBsAg (-)、anti-HBs (-) 和 HBV VL (-) are not required to receive prophylactic anti-HBV therapy, but must be closely monitored for virus re-activation
16. Patients with active HCV infection (HCV antibody positive and HCV-RNA > the lower detection limit)
17. History or evidence of disease, treatment or laboratory abnormalities that would interfere the study outcome, prevent patients from participating entirely, or ineligible to enroll per the investigators' judgement
18. Pregnant or lactating women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sintilimab Arm; Sintilimab consolidation therapy	Drug: Consolidation Sintilimab; Sintilimab consolidation therapy after concurrent chemoradiation, 200mg IV, every 3 weeks, until progressive disease (PD, unless patients can continuously benefit from study treatment per investigators' judgement), start new anti-cancer therapy, intolerable toxicity, withdraw informed consent or other conditions that require study treatment discontinuation. Sintilimab will be given at a maximum of 12 months.
No Intervention: Observation Arm; Observation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS (per RECIST 1.1 as assessed by the investigator) will be defined as the time from the date of randomisation until the date of objective disease progression or death (by any cause in the absence of progression).	up to 24 months after enrollment or study close

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Control Rate (DCR)	DCR (per RECIST 1.1 as assessed by the investigator) is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR), or stable disease (SD).	up to 24 months after enrollment or study close
Duration of Response (DoR)	DoR (per RECIST 1.1 as assessed by the investigator) is defined as the time from the date for first documented response of complete response (CR) or partial response (PR) until the date for the first documented response of progressive disease (PD) or death in the absence of progression.	up to 24 months after enrollment or study close
Overall survival (OS)	OS (per RECIST 1.1 as assessed by the investigator) is defined as the time from the date of randomisation until death due to any cause.	up to 24 months after enrollment or study close
Objective Response Rate (ORR)	ORR (per RECIST 1.1 as assessed by the investigator) is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR).	up to 24 months after enrollment or study close
Progression Free Survival (PFS) Rate at 12/18 months	PFS rate at 12/18 months is defined as the proportion (%) of patients who are alive and progression free at 12 and 18months from the date of randomisation.	From the date of randomization until the Kaplan-Meier estimate of PFS at 12/18months
Treatment-related Adverse Events (AEs)	The grade of AEs and the number of patients with AEs are assessed by the investigator based on CTCAE v4.03 from the date of randomization to 90 days after last dose of study treatment.	From the date of randomization to 90 days after last dose of study treatment

Collaborators and Investigators

• Sponsor: Shandong Cancer Hospital and Institute

Publications and helpful links

General Publications

• Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeno J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Ozguroglu M; PACIFIC Investigators. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. doi: 10.1056/NEJMoa1709937. Epub 2017 Sep 8.
• Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR, D'Amico TA, DeCamp MM, Dilling TJ, Dobelbower M, Doebele RC, Govindan R, Gubens MA, Hennon M, Horn L, Komaki R, Lackner RP, Lanuti M, Leal TA, Leisch LJ, Lilenbaum R, Lin J, Loo BW Jr, Martins R, Otterson GA, Reckamp K, Riely GJ, Schild SE, Shapiro TA, Stevenson J, Swanson SJ, Tauer K, Yang SC, Gregory K, Hughes M. Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017 Apr;15(4):504-535. doi: 10.6004/jnccn.2017.0050.
• Auperin A, Le Pechoux C, Rolland E, Curran WJ, Furuse K, Fournel P, Belderbos J, Clamon G, Ulutin HC, Paulus R, Yamanaka T, Bozonnat MC, Uitterhoeve A, Wang X, Stewart L, Arriagada R, Burdett S, Pignon JP. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010 May 1;28(13):2181-90. doi: 10.1200/JCO.2009.26.2543. Epub 2010 Mar 29.
• Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. doi: 10.1016/S1470-2045(14)71207-0. Epub 2015 Jan 16.
• Tsujino K, Kurata T, Yamamoto S, Kawaguchi T, Kubo A, Isa S, Hasegawa Y, Ou SH, Takada M, Ando M. Is consolidation chemotherapy after concurrent chemo-radiotherapy beneficial for patients with locally advanced non-small-cell lung cancer? A pooled analysis of the literature. J Thorac Oncol. 2013 Sep;8(9):1181-9. doi: 10.1097/JTO.0b013e3182988348.
• Ahn JS, Ahn YC, Kim JH, Lee CG, Cho EK, Lee KC, Chen M, Kim DW, Kim HK, Min YJ, Kang JH, Choi JH, Kim SW, Zhu G, Wu YL, Kim SR, Lee KH, Song HS, Choi YL, Sun JM, Jung SH, Ahn MJ, Park K. Multinational Randomized Phase III Trial With or Without Consolidation Chemotherapy Using Docetaxel and Cisplatin After Concurrent Chemoradiation in Inoperable Stage III Non-Small-Cell Lung Cancer: KCSG-LU05-04. J Clin Oncol. 2015 Aug 20;33(24):2660-6. doi: 10.1200/JCO.2014.60.0130. Epub 2015 Jul 6.
• Yoon SM, Shaikh T, Hallman M. Therapeutic management options for stage III non-small cell lung cancer. World J Clin Oncol. 2017 Feb 10;8(1):1-20. doi: 10.5306/wjco.v8.i1.1.

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2018
• Primary Completion (Anticipated): December 30, 2020
• Study Completion (Anticipated): December 30, 2021

Study Registration Dates

• First Submitted: January 11, 2019
• First Submitted That Met QC Criteria: March 19, 2019
• First Posted (Actual): March 21, 2019

Study Record Updates

• Last Update Posted (Actual): March 21, 2019
• Last Update Submitted That Met QC Criteria: March 19, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: PD-1; Sintilimab; Locally advanced; Stage III Non-Small Cell Lung Cancer; Unresectable Non-Small Cell Lung Cancer; Concurrent Chemoradiation; Immune-mediated cancer therapy; IBI308
• 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
• Other Study ID Numbers: CONSIST

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No