Neoadjuvant Therapy With Toripalimab and JS004 Combined With Platinum-based Doublet Chemotherapy for Resectable or Potentially Resectable Stage III Non-small Cell Lung Cancer: A Randomised Controlled, Open-label, Phase 2 Trial

Phase 2

Not yet recruiting

• Conditions: Stage III Non-small Cell Lung Cancer
• Interventions: Drug: Toripalimab; Drug: JS004; Drug: Pemetrexed; Drug: Nab-paclitaxel; Drug: Carboplatin; Procedure: Surgery

• Registration Number: NCT05891080
• Lead Sponsor: Shanghai Pulmonary Hospital, Shanghai, China

Brief Summary

For stage III non-small cell lung cancer (NSCLC), neoadjuvant chemotherapy plus PD-1 antibody is recommended. However, most patients could not achieve complete pathological response (CPR). New immunotherapeutic strategy is needed to achieve higher CPR rate. JS004 is a new antibody targeting B and T lymphocyte attenuator (BTLA) which restrains the function of immune cells and leads to immune escape of tumor cells. The combination of PD-1 antibody and BTLA antibody has shown good therapeutic effect in solid tumors. This trial aims to investigate the efficacy and safety of the therapeutic regimen of toripalimab and JS004 plus chemotherapy in stage III NSCLC.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-05-22
• Status Verified: 2023-06
• Study First Submitted QC: 2023-06-03
• Last Update Submitted: 2023-06-03
• Study First Posted: 2023-06-06
• Last Update Posted: 2023-06-06
• Study Start: 2023-07-01
• Primary Completion: 2025-07-01
• Study Completion: 2030-07-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 124

Inclusion Criteria

1. The patient shall sign the Informed Consent Form.
2. Aged 18 ≥ years.
3. Histological or cytological diagnosis of NSCLC by needle biopsy, and stage IIIB-IIIC confirmed by imageological examinations (CT, PET-CT or EBUS).
4. Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1.
5. Life expectancy is at least 12 weeks.
6. At least 1 measurable lesion according to RECIST 1.1.
7. Patients with good function of other main organs (liver, kidney, blood system, etc.)
8. Patients with lung function can tolerate surgery;
9. Without systematic metastasis (including M1a, M1b and M1c);
10. Fertile female patients must voluntarily use effective contraceptives not less than 120 days after chemotherapy or the last dose of toripalimab (whichever is later) during the study period, and urine or serum pregnancy test results within 7 days prior to enrollment are negative.
11. Unsterilized male patients must voluntarily use effective contraception during the study period not less than 120 days after chemotherapy or the last dose of toripalimab (whichever is later).

Exclusion Criteria

1. Participants who have received any systemic anti-cancer treatment for thymic epithelial tumor, including surgical treatment, local radiotherapy, cytotoxic drug treatment, targeted drug treatment and experimental treatment;
2. Participants with any unstable systemic disease (including active infection, uncontrolled hypertension), unstable angina pectoris, angina pectoris starting in the last three months, congestive heart failure (>= NYHA) Grade II), myocardial infarction (6 months before admission), severe arrhythmia requiring drug treatment, liver, kidney or metabolic diseases;
3. With activate or suspectable autoimmune disease, or autoimmune paracancer syndrome requiring systemic treatment;
4. Participants who are allergic to the test drug or any auxiliary materials;
5. Participants with Interstitial lung disease currently;
6. Participants with active hepatitis B, hepatitis C or HIV;
7. Pregnant or lactating women;
8. Participants suffering from nervous system diseases or mental diseases that cannot cooperate;
9. Participated in another therapeutic clinical study;
10. Other factors that researchers think it is not suitable for enrollment.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Safety run-in arm	JS004	In this arm, 6 patients with resectable or potentially resectable stage III non-small cell lung cancer will receive 4 circles of neoadjuvant toripalimab and JS004 combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
JS004 arm	Nab-paclitaxel	Patients with resectable or potentially resectable stage III non-small cell lung cancer will be randomized into this arm (59 patients) and receive 4 circles of neoadjuvant toripalimab and JS004 combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
Safety run-in arm	Surgery	In this arm, 6 patients with resectable or potentially resectable stage III non-small cell lung cancer will receive 4 circles of neoadjuvant toripalimab and JS004 combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
Safety run-in arm	Nab-paclitaxel	In this arm, 6 patients with resectable or potentially resectable stage III non-small cell lung cancer will receive 4 circles of neoadjuvant toripalimab and JS004 combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
JS004 arm	JS004	Patients with resectable or potentially resectable stage III non-small cell lung cancer will be randomized into this arm (59 patients) and receive 4 circles of neoadjuvant toripalimab and JS004 combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
JS004 arm	Surgery	Patients with resectable or potentially resectable stage III non-small cell lung cancer will be randomized into this arm (59 patients) and receive 4 circles of neoadjuvant toripalimab and JS004 combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
Control arm	Nab-paclitaxel	Patients with resectable or potentially resectable stage III non-small cell lung cancer will be randomized into this arm (59 patients) and receive 4 circles of neoadjuvant toripalimab combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
Control arm	Surgery	Patients with resectable or potentially resectable stage III non-small cell lung cancer will be randomized into this arm (59 patients) and receive 4 circles of neoadjuvant toripalimab combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
Safety run-in arm	Toripalimab	In this arm, 6 patients with resectable or potentially resectable stage III non-small cell lung cancer will receive 4 circles of neoadjuvant toripalimab and JS004 combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
Safety run-in arm	Pemetrexed	In this arm, 6 patients with resectable or potentially resectable stage III non-small cell lung cancer will receive 4 circles of neoadjuvant toripalimab and JS004 combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
Safety run-in arm	Carboplatin	In this arm, 6 patients with resectable or potentially resectable stage III non-small cell lung cancer will receive 4 circles of neoadjuvant toripalimab and JS004 combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
JS004 arm	Toripalimab	Patients with resectable or potentially resectable stage III non-small cell lung cancer will be randomized into this arm (59 patients) and receive 4 circles of neoadjuvant toripalimab and JS004 combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
JS004 arm	Pemetrexed	Patients with resectable or potentially resectable stage III non-small cell lung cancer will be randomized into this arm (59 patients) and receive 4 circles of neoadjuvant toripalimab and JS004 combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
Control arm	Pemetrexed	Patients with resectable or potentially resectable stage III non-small cell lung cancer will be randomized into this arm (59 patients) and receive 4 circles of neoadjuvant toripalimab combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
JS004 arm	Carboplatin	Patients with resectable or potentially resectable stage III non-small cell lung cancer will be randomized into this arm (59 patients) and receive 4 circles of neoadjuvant toripalimab and JS004 combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
Control arm	Toripalimab	Patients with resectable or potentially resectable stage III non-small cell lung cancer will be randomized into this arm (59 patients) and receive 4 circles of neoadjuvant toripalimab combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.
Control arm	Carboplatin	Patients with resectable or potentially resectable stage III non-small cell lung cancer will be randomized into this arm (59 patients) and receive 4 circles of neoadjuvant toripalimab combined with platinum-based doublet chemotherapy and those resectable after neoadjuvant therapy will be treated with surgery.

Primary Outcome Measures

Name	Time	Method
Pathologic complete response (PCR) rate	Up to 30 months	PCR rate is defined as the proportion of participants who have achieved pathologic complete response (on routine hematoxylin and eosin staining, no tumor cell can be found in tumor bed or lymph node) in all participants.

Secondary Outcome Measures

Name	Time	Method
Treatment-related adverse event (TRAE)	Up to 30 months	TRAE is defined and classified according to NCI-CTCAE v5.0 in all participants.
Objective response rate (ORR)	up to 30 months	ORR is defined according to the RECIST v1.1 criteria.
Rate of conversion from potentially resectable to resectable	Up to 30 months	Rate of conversion from potentially resectable to resectable is defined as the proportion of participants with potentially resectable tumor conversed into resectable tumor in all participants with potentially resectable tumor.
EORTC-QLQ-L13 scale	up to 5 months	The assessment is made according to the Quality of Life Scale for Lung Cancer Patients (EORTC-QLQ-LC13). EORTC's QLQ-LC13 is a core scale for lung cancer patients, with a total of 13 items. The items are divided into 4 grades: Not at All, A Little, Quite a Bit, and Very Much, assigned with 1 to 4 scores respectively. The higher score, the worse quality.
EORTC-QLQ-C30 scale	up to 5 months	The assessment is made according to the Quality of Life Scale for Lung Cancer Patients (EORTC-QLQ-C30, Version 3). EORTC's QLQ-C30 (V3.0) is a core scale for lung cancer patients, with a total of 30 items. Among them, Item 29 and 30 are divided into seven grades, which are assigned with 1 to 7 scores according to the answer options. The other items are divided into 4 grades: Not at All, A Little, Quite a Bit, and Very Much, assigned with 1 to 4 scores respectively. The higher score, the worse quality.
R0 resection rate	Up to 30 months	R0 resection rate is defined as the proportion of participants who have achieved R0 resection (complete resection with no residual tumor cell in the resection margin) in all participants.
Event-free survival (EFS)	up to 60 months	Event-free survival (EFS) is defined as the length of time (months) from randomization to any of the following events: any progression of disease precluding surgery, progression or recurrence disease based on response evaluation criteria in solid tumors (RECIST) 1.1 after surgery, or death due to any cause. Participants who don't undergo surgery for reason other than progression will be considered to have an event at progression or death. Progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Major pathologic response (MPR) rate	Up to 30 months	MPR rate is defined as the proportion of participants who have achieved major pathologic response (on routine hematoxylin and eosin staining, tumors with no more than 10% viable tumor cells) in all participants.
Overall survival (OS)	up to 60 months	It is defined as the time (months) from enrollment to death of participant due to any cause. In the case of a patient who still survives at the time of analysis, the date of last contact will be taken as the censoring date.