Clinical trial NCT05092412: Low-dose Radiotherapy Combined With Durvalumab, Chemotherapy(EP) in the Treatment of ES-SCLC
Official title: A First-line Multi-center, Single-arm Exploratory Study Using Low-dose Radiotherapy (LDRT) Combined With Durvalumab (MEDI4736), Etoposide, and Cisplatin/Carboplatin for Patients With Extensive-stage Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Lung Cancer
Extensive-stage Small-cell Lung Cancer
Durvalumab
Keywords: ES-SCLC
Durva
LDRT
Lead sponsor: Sichuan University
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2021-10-25
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to evaluate the efficacy of low-dose radiotherapy (LDRT) combined with durvalumab, etoposide, and cisplatin/carboplatin in the first-line treatment of extensive-stage small cell lung cancer.

Detailed description: This study will enrol 30 subjects at 3 sites in China. Subjects who fulfil all the inclusion criteria and none of the exclusion criteria will be enrolled and receive treatment with Durvalumab and EP for 4 cycles. Durvalumab will be administered at a dose of 1500 mg every 3 weeks (Q3W) with first-line chemotherapy and will continue to be administered as monotherapy every 4 weeks(Q4W) post-chemotherapy until progressive disease. The LDRT deals with primary tumour in a 15 Gy of 5 fractions over five days, starting from Day 1 in the first cycle. Subjects will attend safety follow up 12 weeks ±14 days after last dose of Durvalumab. The primary endpoint is mPFS.

Eligibility criteria: Inclusion Criteria:

* At the time of screening, male or female participants were ≥18 years old.
* Before carrying out any research program related procedures (including screening evaluation), obtain written informed consent and any locally required authorization from the participant or his legal representative.
* Extensive-stage disease confirmed by histology or cytology (American Joint Committee on Cancer (8th edition) stage IV SCLC \[any T, any N and M1a/b/c\]), or due to multiple lung nodules with a wide range Or the size of the tumor/nodule is too large to be included in a tolerable radiotherapy plan for stage T3-4 disease.

Participants with brain metastases must be asymptomatic or stable with steroids and anticonvulsants for at least 1 month before study treatment. Participants with suspected brain metastases during screening should undergo brain CT/MRI before enrollment in the study.

* The participant must be considered suitable for platinum-based chemotherapy as the first-line treatment for extensive-stage small cell lung cancer. Chemotherapy must include either cisplatin or carboplatin, combined with etoposide.
* The participant must be considered suitable for thoracic radiotherapy as the first-line treatment for extensive-stage small cell lung cancer.
* Life expectancy on the first day of study treatment was ≥12 weeks.
* At the time of enrollment, the World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) physical status score was 0 or 1.
* Weight\>30 kg.
* According to the requirements of RECIST1.1 guidelines, at least one lesion (never received radiotherapy before), accurately measured by computed tomography (CT) or magnetic resonance imaging (MRI) at baseline shows that its longest diameter is ≥10mm (except for lymph nodes, Its short axis must be ≥15 mm); and the lesion is suitable for repeated and accurate measurement.
* Have not been exposed to immune-mediated therapies in the past, including but not limited to other anti-PD-1, anti-PD-L1 and anti-programmed cell death ligand 2 (anti-PD-L2) antibodies, except for therapeutic anti-tumor vaccines.
* With sufficient organ and bone marrow function, it needs to be measured 28 days before receiving treatment, which is defined as follows:

Hemoglobin ≥9 g/dL. Absolute neutrophil count ≥ 1.5 × 109/L (granulocyte colony stimulating factor is not allowed during screening).

Platelet count ≥75 × 109/L. Serum bilirubin ≤1.5 × upper limit of normal (ULN). It is not applicable to participants diagnosed with Gilbert syndrome. These participants are allowed to enter into the group through consultation with the investigators.

For participants without liver metastasis: ALT and AST ≤2.5 × ULN. The ALT and AST of participants with liver metastases are ≤5 × ULN.

* Measured or calculated creatinine clearance rate: According to the Cockcroft-Gault formula (using actual body weight) or a 24-hour urine test, participants receiving cisplatin therapy \>60mL/min, and participants receiving carboplatin therapy \>45mL/min.
* The female participant has evidence of postmenopausal status, or the urine or serum pregnancy test result of the premenopausal female participant is negative. Women who stop menopause for 12 months without other medical reasons are considered menopausal. The specific requirements for age are as follows:

For female participants \<50 years of age who had amenorrhea for 12 months or more after discontinuing exogenous hormone therapy and whose luteinizing hormone and follicle-stimulating hormone levels were in the postmenopausal range or who had undergone sterilization (bilateral oophorectomy or hysterectomy) were considered postmenopausal.

For female participants ≥50 years of age, if all exogenous hormone treatments are stopped and the menopause is 12 months or more, or radiotherapy-induced ovariectomy and the last menstruation occurred more than 1 year ago, or chemotherapy-induced menopause and the last menstruation is more than 1 year , Or have undergone surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy), who can be considered a postmenopausal woman.

Exclusion Criteria:

* Participate in the design and execution of the study (applicable to researchers and/or members of the research center).
* Have previously received the distribution of experimental drug (IP) in this study.
* Enroll in another clinical study at the same time, unless it is an observational (non-interventional) clinical study or the follow-up phase of an interventional study.
* Etoposide-platinum (carboplatin or cisplatin)-based chemotherapy is medically contraindicated.
* Have a history of chest radiotherapy or plan to undergo intensive chest radiotherapy before systemic treatment. Radiotherapy outside the chest (eg, bone metastases) for the purpose of palliative care is allowed, but it must be completed before the first administration of the study drug.
* Simultaneously carry out any chemotherapy, biological products or hormone therapy for cancer treatment. The use of hormone therapy for non-cancer related conditions (eg, hormone replacement therapy) is acceptable.
* Major surgery (defined by the investigator) within 28 days before the first IP administration. Note: Local surgery on isolated lesions for the purpose of palliative care is acceptable.
* History of allogeneic organ transplantation.
* Paraneoplastic syndromes (PNS) with autoimmune properties requiring systemic treatment (systemic steroids or immunosuppressive agents) or clinical symptoms suggesting that PNS is aggravated.
* Active or previously recorded autoimmune diseases or inflammatory diseases (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis \[except diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, Wegener syndrome \[granulomatous vasculitis, Graves disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). For this standard, the following exceptions:

Participants with vitiligo or hair loss. Participants with hypothyroidism (eg after Hashimoto syndrome) and stable disease after receiving hormone replacement therapy.

Any chronic skin disease that does not require systemic treatment. Participants without active disease in the past 5 years can be included in the study after discussion with the investigators.

Participants with celiac disease who can be controlled by diet alone.

* Uncontrolled concurrent diseases, including but not limited to: persistent or active infections, interstitial lung disease, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina, arrhythmia, concomitant Severe chronic gastrointestinal disease with diarrhea, or psychiatric/social problem conditions that may limit compliance with research requirements, cause a significant increase in the risk of AEs, or affect the participant's ability to provide written informed consent.
* A history of another type of primary malignant tumor, except for the following conditions:

Malignant tumors that are treated for the purpose of curing, have no known active disease ≥5 years before the first administration of IP, and have a low potential for recurrence risk.

Adequately treated non-melanoma skin cancer or malignant freckle-like nevus without evidence of disease.

Carcinoma in situ with adequate treatment and no evidence of disease.

* History of leptomeningeal carcinoma.
* History of active primary immunodeficiency.
* Active infections, including tuberculosis (clinical evaluation, including clinical history, physical examination, imaging findings and tuberculosis examination in line with local clinical practice), hepatitis B (known positive for HBV surface antigen \[HbsAg\]), hepatitis C or human immunity Defective virus (HIV 1/2 antibody positive). Participants who have previously suffered from HBV infection or who have been cured (defined as the presence of hepatitis B core IgG antibodies and the absence of HBsAg) are eligible. Participants who are positive for HCV antibodies are only eligible if they are negative for HCV RNA polymerase chain reaction.
* Immunosuppressive drugs were being used when durvalumab was first administered; Or use of immunosuppressive drugs in the 14 days prior to initial use of durvalumab. There are exceptions to this criterion:

Intranasal, inhaled, topical steroid therapy or local injection of steroid drugs (eg, intra-articular injection).

Systemic corticosteroid therapy that does not exceed 10 mg of prednisone per day or its equivalent physiological dose.

Steroids used as pre-medication for allergic reactions (for example, medication before CT scan). Steroid pretherapy for chemotherapy is acceptable.

* Vaccine live attenuated vaccine within 30 days before the first dose of IP. Note: After enrollment, participants cannot receive live vaccines during IP treatment and within 30 days after the last dose of IP.
* Pregnant or lactating female participants, or male or female participants with reproductive potential who are unwilling to take effective birth control measures during screening to 90 days after the last dosing of durvalumab monotherapy.
* Known to have allergic or hypersensitivity reactions to duvalvumab, etoposide, carboplatin, cisplatin or any of its excipients.
* Have participated in the clinical research of durvalumab and/or other anti-tumor drugs in the past, regardless of the allocation of treatment groups.

Primary outcomes:
measure: Progression-free survival (PFS)
timeFrame: up to 2 years
Secondary outcomes:
measure: median overall survival（mOS）
timeFrame: up to 2 years
measure: Objective response rate (ORR)
timeFrame: up to 2 years
measure: 6-month progression-free survival rate / 12-month progression-free survival rate (PFS6/12)
timeFrame: 1 years
Other outcomes:
Locations:
city: Chongqing
country: China
facility: Chongqing University Cancer Hospital
state: Chongqing
city: Zhengzhou
country: China
facility: Henan Provincial People's Hospital
state: He Nan
city: Chengdu
country: China
facility: West China Hospital Sichuan University
state: Si Chuan
Study officials:
affiliation: West China Hospital
name: You Lu, MD
role: STUDY_CHAIR
affiliation: West China Hospital
name: Yan Zhang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Chongqing University Cancer Hospital
name: Yue Xie, MM
role: STUDY_DIRECTOR
affiliation: Chongqing University Cancer Hospital
name: Shu Jie Li, MM
role: PRINCIPAL_INVESTIGATOR
affiliation: Henan Provincial People's Hospital
name: Shun Dong Cang, MD
role: STUDY_DIRECTOR
affiliation: Henan Provincial People's Hospital
name: Lu Lu Su, MD
role: PRINCIPAL_INVESTIGATOR
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