Neoadjuvant LDRT Combined With Durvalumab in Potentially Resectable Stage III NSCLC

A Phase Ib Trial on the Safety and Feasibility of Neoadjuvant Low Dose Radiation, Chemotherapy and Durvalumab for Potentially Resectable Stage III Non-small Cell Lung Cancer (NSCLC)

Introduction: Although PACIFIC regimen definitive concurrent chemoradiotherapy (CRT) followed by Durvalumab consolidation therapy is considered the standard of care for most of stage III NSCLC patients, neoadjuvant immunotherapy combined with chemotherapy followed by surgery has shown the trend to be considered for some potentially resectable patients. The rationales for neoadjuvant treatment are tumor regression effect before surgery, early eradication of micrometastasis. Recently the investigators also find some clinical trials exploring the adding of 45 Gy in 25 fractions radiation to the combination of chemotherapy and immunotherapy neoadjuvant therapy and the investigators could see the safety is the most concern, especially the pneumonitis incidence. Low dose radiation could help control the toxicity induced by radiation and has synergic effect with immunotherapy. The aim of this phase Ib study is to assess the safety and feasibility of the combination of the concurrent low dose radiation, chemotherapy and Durvalumab neoadjuvant therapy, to explore which radiation dose is the best among our three-dose designs and evaluate if the combining neoadjuvant therapy could further improve MPR in the meantime no severe toxicities especially the grade 3-4 pneumonitis would happen.

Method: 9 eligible patients with histologically confirmed NSCLC (potentially resectable clinical stage III according to the American Joint Committee on Cancer 8th staging system) are enrolled. Patients receive Chemo (Day1 and 22 nanoparticle albumin-bound paclitaxel 260 mg/m2 and carboplatin AUC 5 ) and durvalumab (Day 1 and 22, 1500mg) and radiotherapy of 10 Gy in 5 fractions, 20 Gy in 10 fractions, 30 Gy in 15 fractions respectively in our three groups from Day1, followed by surgery. After surgery, patients are suggested to be treated with durvalumab for one year (every 4weeks, 1500 mg). The primary endpoints are safety and tolerability. The secondary endpoints are objective response rate (ORR), event-free survival EFS), overall survival (OS), pathologic complete response (pCR), and major pathologic response(MPR) in the primary tumor. biomarker analysis of PD-L1 using cancer tissue and LIPI, ctDNA using blood sample will be conducted pre-and post- neoadjuvant and post-surgery.

Study Overview

• Status: Recruiting
• Conditions: Stage III Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Durvalumab; Drug: nanoparticle albumin bound paclitaxel; Radiation: low dose radiation therapy

• Study Type: Interventional
• Enrollment (Anticipated): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Recruiting
      • Sichuan Cancer Hospital
      • Contact: Juan Li, Doctor; Phone Number: +86 13880276636; Email: dr.lijuan@hotmail.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. Aged 18 ≥ years.
2. Histological or cytological diagnosis of NSCLC by needle biopsy, and potentially resectable stage III confirmed by image logical examinations (CT, PET-CT or EBUS).
3. Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1.
4. Life expectancy is at least 12 weeks.
5. At least 1 measurable lesion according to RECIST 1.1.
6. With the feasibility or anticipated feasibility after neoadjuvant therapy to receive radical surgery;
7. Patients with good function of other main organs (liver, kidney, blood system, etc.):

1) ANC count ≥1.5×10^9/L, platelet count ≥100×10^9/L，hemoglobin ≥90 g/L; 2) the international standard ratio of prothrombin time (INR) and prothrombin time (PT) < 1.5 times of upper limit of normal (ULN); 3) Partial thromboplastin time (APTT) ≤1.5×ULN; 4) Total bilirubin ≤1.5×ULN; 5) Alanine aminotransferase (ALT) aspartate aminotransferase (AST) ≤2.5×ULN, or ALT and AST ≤5×ULN in the patients with liver metastatic tumor.

8. Patients with normal lung function can tolerate surgery; 9. Without systematic metastasis (including M1a, M1b and M1c); 10. The patient shall sign the Informed Consent Form.

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. Administration of any Chinese medicine against cancer before administration of the drug;
3. Participants with other cancer within five years before the start of this study;
4. 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;
5. With activate or suspectable autoimmune disease, or autoimmune para cancer syndrome requiring systemic treatment;
6. Antibiotics were used to treat the infection for 4 weeks prior to the start of the trial;
7. Participants who were systemically treated with corticosteroids (prednisone or other corticosteroids >10 mg/ day) or other immunosuppressive agents within 2 weeks prior to first administration. In the absence of active autoimmune disease, inhaled or topical corticosteroids and adrenal hormone replacement therapy with a dose of less than 10 mg/ day of prednisone are permitted;
8. Participants who are allergic to the test drug or any auxiliary materials;
9. Participants with active hepatitis B, hepatitis C or HIV;
10. The vaccine was administered within 4 weeks of the start of the trial;
11. Participants who have undergone major surgery or severe trauma in other systems within 2 months before the start of this trial;
12. Pleural effusion, pericardial effusion or ascites that are not clinically controlled and require pleural puncture or abdominal puncture drainage within 2 weeks before inclusion;
13. The patients have active pia meningioma, uncontrolled or untreated brain metastases;
14. Pregnant or lactating women;
15. Participants suffering from nervous system diseases or mental diseases that cannot cooperate;
16. Participated in another therapeutic clinical study;
17. Other factors that researchers think it is not suitable for enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm; Durvalumab 1500mg, IV, Q3W, 2 cycles Albumin paclitaxel 260 mg/m2 + Carboplatin AUC5, IV, Q3W, 2 cycles Chemoradiotherapy(CRT): Cohort 1: 2 Gy in 5 Fraction Cohort 2: 2 Gy in 10 Fraction Cohort 3: 2 Gy in 15 Fraction	Drug: Durvalumab; Day 1 and 22, 1500mg; Drug: nanoparticle albumin bound paclitaxel; Day1 and 22 nanoparticle albumin-bound paclitaxel 260 mg/m2 and carboplatin AUC 5; Radiation: low dose radiation therapy; 10 Gy in 5 fractions, 20 Gy in 10 fractions, 30 Gy in 15 fractions respectively in our three groups from Day1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-emergent adverse events	Safety is based on evaluation of adverse events (AEs) and serious adverse events (SAEs) from the time of study drug administration through the End of Study visit. AEs and SAEs will be examined with National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 4.03.	30 days after last dose up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR	Objective Response Rate determined by Response Evaluation Criteria in Solid Tumors	36 months
EFS	Event-free survival	36 months
MPR	Major pathological response rate	36 months
pCR	Pathological complete response rate	36 months

Collaborators and Investigators

• Sponsor: Juan LI, MD

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2021
• Primary Completion (Anticipated): June 10, 2023
• Study Completion (Anticipated): June 10, 2023

Study Registration Dates

• First Submitted: May 24, 2021
• First Submitted That Met QC Criteria: December 2, 2021
• First Posted (Actual): December 15, 2021

Study Record Updates

• Last Update Posted (Actual): December 15, 2021
• Last Update Submitted That Met QC Criteria: December 2, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• 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; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Paclitaxel; Durvalumab; Albumin-Bound Paclitaxel
• Other Study ID Numbers: EK2021001

Drug and device information, study documents

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