Study of Durvalumab or Durvalumab and Tremelimumab, and Placebo in Stage I-III Limited Disease Small-Cell Lung Cancer Patients

Phase 3

Active, not recruiting

• Conditions: Malignant neoplasm of unspecifiedpart of bronchus or lung,

• Registration Number: CTRI/2019/01/017034
• Lead Sponsor: AstraZeneca AB

Brief Summary

This is a Phase III, randomized, double-blind, placebo-controlled, multi-center study assessing the efficacy and safety of durvalumab or durvalumab and tremelimumab combination therapy versus placebo as consolidation treatment in patients with LD-SCLC who have not progressed following definitive, platinum-based, concurrent CRT.

 To be eligible for this study, patients must have achieved CR, PR, or SD and have not progressed following definitive, platinum-based, concurrent CRT. This CRT treatment, and PCI treatment if received per local standard of care, must be completed within 1 to 42 days prior to randomization and the first dose of investigational product (IP; ie, durvalumab, tremelimumab,or placebo) in this study.In addition,the baseline efficacy assessment must be performed post-CRT as part of the screening procedures within 42 days before randomization and the first dose of IP.

 Approximately 750 patients will be recruited in order to enroll and randomize approximately 600 patients in a 1:1:1 ratio to 1 of 3 treatment groups: durvalumab monotherapy, durvalumab and tremelimumab combination therapy, or placebo.  Randomization will be stratified by TNM stage (I/II versus III) and receipt of PCI (yes versus no). Recruitment for patients with TNM Stage III disease will be limited to up to 85% of the targeted global population. Patients will receive their assigned treatment until clinical/RECIST 1.1-defined radiological progression, until intolerable toxicity, or for a maximum of 24 months (26 doses/cycles), whichever occurs first.

Detailed Description

Not available

Study Timeline

• Study Start: 2019-01-18
• Last Update Posted: 2024-06-17

Recruitment & Eligibility

• Status: Closed to Recruitment of Participants
• Sex: All
• Target Recruitment: 600

Inclusion Criteria

• Informed consent 1.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.
• 2.Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses.
• 3.Provision of signed and dated written genetic informed consent prior to collection of sample for genetic analysis.
• 4.Age 18 to 75 years at the time of screening.
• For patients aged <20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
• Type of patient and disease characteristics 5.
• Histologically or cytologically documented limited-stage SCLC (Stage I-III SCLC [T any, N any, M0] according to the American Joint Committee on Cancer Staging Manual [AJCC Cancer Staging Manual, 8th Edition] or the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology 2016]), ie, patients whose disease can be encompassed within a radical radiation portal.
• Patients who are Stage I or II must be medically inoperable.
• 6.World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at enrollment and randomization.
• 7.Received 4 cycles of platinum-based chemotherapy concurrent with RT, which must be completed within 1 to 42 days prior to randomization and the first dose of IP.
• i.The chemotherapy regimen must contain platinum and etoposide, as per local standard-of-care regimens.
• ii.For patients who are recovering from toxicities associated with initial treatment or for whom PCI is indicated by local standard of care, the first dose of IP may be delayed by up to 42 days from the end of the CRT.
• iii.Radiotherapy must have commenced no later than the end of Cycle 2 of chemotherapy.
• Receipt of 3 cycles of platinum-based chemotherapy concurrent with RT will be permitted if the patient achieved disease control and Investigators judge no additional benefit will be expected with additional cycle of chemotherapy.
• 9.Received a total dose of radiation of 60 to 66 Gy for standard QD radiation schedules or 45 Gy for hyperfractionated BID radiation schedules.
• Sites are encouraged to adhere to mean organ radiation dosing as follows: i.
• Mean lung dose <20 Gy and/or V20 must be <35% ii.Heart V50 <25% 10.Tumor sample requirements: i.
• Provision of an archived tumor tissue block (or at least 15 newly cut unstained slides, where available) ≤3 years old, where such samples exist in a quantity sufficient to allow for analysis (refer to the Laboratory Manual for details) ii.
• A recent (≤3 months) tumor biopsy (taken following completion of the most recent therapy) is an optional requirement, provided that a biopsy procedure is technically feasible, and the procedure is not associated with unacceptable clinical risk.
• Adequate organ and marrow function independent of transfusion, infusion, or growth factor support for at least 14 days prior to screening, defined as below: i.
• Hemoglobin ≥9.0 g/dL ii.
• Absolute neutrophil count ≥1.5 × 109 /L iii.
• Platelet count ≥100 × 109/L iv.
• Serum bilirubin ≤1.5 × the upper limit of normal (ULN).
• This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician.
• ALT and AST ≤2.5 × ULN vi.
• Measured creatinine clearance (CL) >40 mL/min or calculated CL >40 mL/min as determined by Cockcroft-Gault (using actual body weight) 12.
• Must have a life expectancy of at least 12 weeks Weight 13.
• Body weight >30 kg Sex 14.
• Male or female.

Exclusion Criteria

• Patients are eligible to be included in the study only if none of the following exclusion criteria apply: Medical conditions 1.
• Mixed SCLC and NSCLC histology 2.
• Extensive-stage SCLC 3.
• Patients with Grade ≥2 pneumonitis from prior CRT 4.
• History of allogeneic organ transplantation 5.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, 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]).
• The following are exceptions to this criterion: i.
• Patients with vitiligo or alopecia ii.
• Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement iii.
• Any chronic skin condition that does not require systemic therapy iv.
• Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician v.
• Patients with celiac disease controlled by diet alone 6.
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent 7.
• History of another primary malignancy except for: i.
• Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence ii.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease iii.
• Adequately treated carcinoma in situ without evidence of disease 8.
• History of leptomeningeal carcinomatosis 9.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C (HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies).
• Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible.
• Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Any unresolved toxicity NCI Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 from previous CRT with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria i.
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician 12.
• Brain metastases or spinal cord compression.
• All patients will have an MRI (preferred) or CT, preferably with IV contrast of the brain, prior to study entry.
• 13.Mean QT interval corrected for heart rate using fridericia formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• Patients who received sequential CRT for LD-SCLC (no overlap of RT with chemotherapy) 16.
• Receipt of consolidation chemotherapy after radiation.
• (Treatment with etoposide and platinum after radiation is acceptable as 1 regimen for 1 to 2 cycles; chemotherapy regimens other than etoposide and platinum as consolidation are not permitted.) 18.
• Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
• Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
• 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 drug.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
• Major surgical procedure (as defined by the Investigator) within 42 days prior to the first dose of IP.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab.
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent ii.
• Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) Prior/concurrent clinical study experience 24.
• Participation in another clinical study with an investigational product administered in the last 4 weeks.
• Previous IP assignment in the present study 26.
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional Study.
• Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment group assignment.
• Female patients who are pregnant or breastfeeding and male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of IP.
• Judgment by the Investigator that the patient should not participate in the study because the patient is unlikely to comply with study procedures, restrictions, and requirements.
• Genetics research study (optional): Exclusion criteria for participation in the optional (DNA) genetics research component of the study include: i.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To assess the efficacy of durvalumab in combination with tremelimumab therapy	During the Treatment period and Follow up period (Time frame-Approximately | 4 years)
•OS	During the Treatment period and Follow up period (Time frame-Approximately | 4 years)
•PFS using BICR assessments according to RECIST 1.1	During the Treatment period and Follow up period (Time frame-Approximately | 4 years)
compared to placebo in terms of OS	During the Treatment period and Follow up period (Time frame-Approximately | 4 years)
combination with tremelimumab therapy compared to placebo in terms of PFS	During the Treatment period and Follow up period (Time frame-Approximately | 4 years)
To assess the efficacy of durvalumab monotherapy as well as durvalumab in	During the Treatment period and Follow up period (Time frame-Approximately | 4 years)

Secondary Outcome Measures

Name	Time	Method
•To assess the efficacy of durvalumab and tremelimumab combination therapy compared to durvalumab monotherapy in terms of PFS, OS,and ORR	•To assess disease-related symptoms and HRQoL in patients treated with durvalumab monotherapy or durvalumab and tremelimumab combination therapy compared to placebo using the EORTC, QLQ-C30 v3 and QLQ-LC13
Exploratory objectives:	•To assess treatment-related side effects in patients treated with durvalumab monotherapy and durvalumab and tremelimumab combination therapy compared to placebo using PRO-CTCAE
To explore the relationship(s) between patient biomarker status and durvalumab PK exposure and clinical outcomes before and after treatment.	•To explore irRECIST as assessment methodologies for clinical benefit of durvalumab monotherapy and durvalumab and tremelimumab combination therapy compared to placebo with assessment by BICR.
•To assess the efficacy of durvalumab monotherapy compared to placebo in terms of OS	•To assess the efficacy of durvalumab monotherapy and durvalumab and tremelimumab combination therapy compared to placebo in terms of ORR, PFS18a, PFS24a, TTDM, OS24, OS36, and PFS2
•To collect blood and tissue samples, or leverage residual samples, for analysis of peripheral and tumoral biomarkers	•To investigate the relationship between a patient’s PD-L1 expression and spatial distribution within the tumor microenvironment and clinical
Safety objectives:	•To assess the safety and tolerability profile of durvalumab monotherapy and durvalumab and tremelimumab combination therapy compared to
•To investigate the immunogenicity of durvalumab monotherapy and durvalumab and tremelimumab combination therapy	•To investigate the relationship between a patient’s tumor mutational burden (TMB) measured in tumor and/or blood and efficacy outcomes with
•To assess the patients’ overall impression of the severity of their cancer symptoms using PGIS	•To describe and evaluate health resource use associated with durvalumab monotherapy and durvalumab and tremelimumab combination therapy and underlying disease
•To collect and store DNA from tissue and/or blood according to each country’s local and ethical procedures for future exploratory research	into genes/genetic variation that may influence response (ie, distribution, safety, tolerability, and efficacy) to IPs and/or susceptibility to disease

Trial Locations

Locations (8)

Action Cancer Hospital; 🇮🇳 North, DELHI, India

Apollo Speciality Hospital; 🇮🇳 Chennai, TAMIL NADU, India

Artemis Hospitals; 🇮🇳 Gurgaon, HARYANA, India

Manibhai Shivabhai Patel Cancer Centre, Shree Krishna Hospital and Medical Research Centre; 🇮🇳 Anand, GUJARAT, India

Rajiv Gandhi Cancer Institute and Research Centre; 🇮🇳 Delhi, DELHI, India

Shettys Hospital; 🇮🇳 Bangalore, KARNATAKA, India

Sri Venkateshwara Hospital; 🇮🇳 Bangalore, KARNATAKA, India

Tata Medical Centre; 🇮🇳 Kolkata, WEST BENGAL, India

Action Cancer Hospital

🇮🇳North, DELHI, India

Dr Samit Purohit

Principal investigator

01149222222

samitmedonc@gmail.com