Evaluation of Thoracic Radiotherapy Combined with Durvalumab and Chemotherapy in Extensive-Stage Small-Cell Lung Cancer: A Randomized Phase III Trial

Trial ID: 2023-505514-15-00
Sponsor: Norwegian University Of Science And Technolology

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Diseases & Conditions

Small cell lung cancer extensive stage

Objectives

The primary objective of this randomized phase III trial is to evaluate whether the addition of **thoracic radiotherapy** (TRT) to durvalumab (MEDI4736) plus chemotherapy enhances 1-year survival in patients with extensive stage small-cell lung cancer. This is clinically relevant as improving survival rates in this aggressive cancer type can significantly impact patient outcomes and treatment strategies.

Secondary objectives include:

Investigating whether adding TRT improves 2-, 3-, 4-, and 5-year overall survival.
Assessing improvements in overall response rates, response rates in non-irradiated lesions, and progression-free survival (PFS) with TRT.
Evaluating the impact of TRT on local control.
Comparing the frequency and severity of adverse events between treatment arms.
Comparing health-related quality of life between treatment arms.
Comparing the duration of severe adverse events between treatment arms.
Comparing the frequency and timing of brain metastases between treatment arms.
Assessing cognitive function in the study cohort and comparing cognitive function between those receiving prophylactic cranial irradiation (PCI) and those who do not.
Investigating associations between treatment outcomes and biomarkers in tissue, blood, and stool, such as circulating tumor DNA (ctDNA) in blood, microRNA (miRNA), and gut microbiome.

Participants

The clinical trial involves participants diagnosed with **small-cell lung cancer, extensive stage**. The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have adequate organ and marrow function and a body weight greater than 30 kg. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria ensure that participants have a life expectancy of at least 3 months and at least one thoracic lesion suitable for irradiation. Lifestyle considerations such as diet and physical activity are not specified. Participants must be capable of providing informed consent and comply with the study protocol, including treatment and follow-up visits. The trial does not specifically target any particular lifestyle habits or conditions beyond the medical criteria outlined.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the survival benefit of adding thoracic radiotherapy to **durvalumab** immunotherapy plus chemotherapy in patients with extensive stage small-cell lung cancer. The trial aims to assess whether this combination improves 1-year overall survival, with secondary endpoints including 2-year to 5-year overall survival, overall response rates, progression-free survival, and health-related quality of life. The trial is expected to run until December 31, 2035, with recruitment starting on August 1, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as stage IV disease, adequate pulmonary function, and an ECOG performance status of 0 or 1. Following randomization, participants will receive treatment and attend scheduled follow-up visits to monitor response and adverse events. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 60 months, depending on individual response and tolerance to treatment.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The study protocol requires compliance with all scheduled visits and examinations, including follow-up assessments. The trial's methodology ensures rigorous data collection and analysis to determine the efficacy and safety of the treatment regimen, contributing valuable insights into the management of extensive stage small-cell lung cancer.

Treatment

The clinical trial involves the administration of **IMFINZI** (durvalumab), a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 50 mg/mL and is administered via the **intravenous** route. The maximum daily dose is 1500 mg, with a total maximum dose of 130,000 mg over the course of the treatment period, which spans up to 60 days. Durvalumab is a monoclonal antibody, classified under the ATC code L01XC28, and is produced by AstraZeneca AB. The active substance, durvalumab, is derived from a protein of other origin and is also known by the synonym MEDI4736.

In addition to the experimental treatment, the study includes the administration of standard chemotherapy as part of the treatment regimen. The trial aims to evaluate the survival benefit of adding thoracic radiotherapy to the combination of durvalumab and chemotherapy in patients with extensive-stage small-cell lung cancer. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy

Efficacy in the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the **1-year overall survival** rate, which will be used to determine the survival benefit of adding thoracic radiotherapy to durvalumab (MEDI4736) immunotherapy plus chemotherapy in patients with extensive stage small-cell lung cancer. Secondary endpoints include 2-year, 3-year, 4-year, and 5-year overall survival rates, overall response rates, response rates in non-irradiated lesions, progression-free survival, progression-free survival in non-irradiated lesions, local control rates in the thorax, frequency and severity of adverse events, and health-related quality of life.

The efficacy parameters will be measured and collected at specified timepoints throughout the trial. Tumor assessments will be conducted using computed tomography (CT) scans or magnetic resonance imaging (MRI) within 28 days prior to randomization to identify target lesions according to RECIST 1.1 criteria. The trial will monitor patients' health-related quality of life and adverse events to evaluate the treatment's impact on overall well-being and safety. The data collected will be analyzed to determine the efficacy of the treatment regimen in improving survival and disease control in the target patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g. Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocolrelated procedures, including screening evaluations.
Age at least 18 years at time of study entry.
ECOG performance status of 0 or 1.
Body weight >30 kg.
Adequate organ and marrow function.
Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.
Life expectancy of at least 3 months.
At least 1 lesion in the thorax, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline and is possible to irradiate to 30 Gy in 10 fractions. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to randomization.
Histologically or cytologically confirmed SCLC. Mixed histology may be acceptable as long as the SCLC component accounts for more than 90%.
Stage IV disease according to the TNM v8. Patients with stage III disease are eligible if the disease is too widespread to be treated as limited stage SCLC.
Pulmonary function: FEV1 >1 L or >30 % of predicted value and DLCO >30 % of predicted value.
Female patients of childbearing potential (postmenarcheal, not postmenopausal [>12 continuous months of amenorrhea with no identified cause other than menopause], and no surgical sterilization) should use highly effective contraception and take active measures to avoid pregnancy while undergoing systemic study therapy and for at least 5 months after the last dose.
Patients with brain metastases are eligible provided they are asymptomatic or treated and stable on steroids and/or anticonvulsants prior to the start of treatment.

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Exclusion Criteria

Participation in another clinical study with an investigational product during the last 30 days.
Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
Previous chemo- or radiotherapy for SCLC. Patients who have undergone surgery, but no adjuvant therapy are eligible.
Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Chief Investigator.
Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Chief Investigator.
Any concurrent chemotherapy, investigational product or biologic cancer therapy.
Any prior checkpoint inhibitor therapy, including durvalumab.
Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drugs.
Immediate need for thoracic radiotherapy or bulky disease outside the thorax, or need for such radiotherapy before completion of chemo-immunotherapy.
Major surgical procedure within 28 days prior to the first dose of study drugs. Note: Local surgery of isolated lesions for palliative intent is acceptable.
History of allogenic organ transplantation.
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia or QTcF value >470 ms on ECG, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
History of another primary malignancy.
Leptomeningeal carcinomatosis.
Untreated, symptomatic central nervous system (CNS) metastases. Any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on steroids and/or anticonvulsants prior to the start of treatment.
History of active primary immunodeficiency.
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.
Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.
Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Estonia	Not Recruiting	01 Aug 2023	40
Iceland	Not Recruiting	01 Aug 2023	5
The Netherlands	Not Recruiting	01 Aug 2023	—
Norway	Not Recruiting	01 Aug 2023	120
Sweden	Not Recruiting	01 Aug 2023	50
Netherlands	—	—	95