A Phase II Study Assessing the Efficacy of Etoposide Free Chemotherapy Plus Durvalumab (MEDI4736) in First Line Extensive Disease Small Cell Lung Cancer (SCLC)

Study Overview
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Brief Summary
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The current study is intended to be a proof of concept to evaluate the potential value of synergy between paclitaxel carboplatin and immunotherapy. If a signal clearly shows superiority over the CASPIAN data , we will have arguments to think that the combination of paclitaxel and carboplatin is more suitable for synergy with immunotherapy than the standard etoposide and carboplatin.

Official Title
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A Phase II Study Assessing the Efficacy of Etoposide Free Chemotherapy Plus Durvalumab (MEDI4736) in First Line Extensive Disease Small Cell Lung Cancer (SCLC)

Conditions
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Small Cell Lung Cancer Extensive Stage

Intervention / Treatment
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* Drug: Carboplatin + Paclitaxel + Durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed consent. Patients diagnosed with histologically confirmed SCLC Extended-Stage Disease at time of accrual according to the criteria of the Veteran's Administration Lung Cancer Group (VALG). At least one measurable target lesion according to RECIST v1.1 per investigator assessment. The radiological assessment has to be done within the timelines indicated. Age ≥ 18 years. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 (see Appendix 1). Body weight >30 kg. Adequate biological functions. Woman patients who are no longer likely to procreate (physiologically unfit to carry a pregnancy), which includes: Hysterectomy, Ovariectomy, Bilateral tubal ligation, Postmenopausal women. Woman patients who are of childbearing potential are eligible: They must have a negative serum pregnancy test within the week preceding the first dose of treatment and preferably as close as possible to the first dose. They must agree to use methods of contraception acceptable for IFCT. Contraceptive methods should be used throughout the course of treatment and should be maintained for 6 months after the end of treatment. Male subjects who are sexually active with a woman of childbearing potential are eligible if an efficacious contraception method should be used during the treatment and during the 6 months following the last dose. Patient must have a life expectancy of at least 12 weeks. Patient covered by a national health insurance. Exclusion Criteria: Non-small cell lung cancer (NSCLC) or combined SCLC and NSCLC. Prior systemic anticancer therapy for SCLC. Radiotherapy needed at initiation of treatment. Major surgical procedure (as defined by the Investigator) within 28 days prior initiation of treatment. Symptomatic brain metastasis. History of leptomeningeal carcinomatosis. Symptomatic congestive heart failure, uncontrolled hypertension, unstable angina, cardiac arrhythmia or clinically uncontrolled heart disease. Mean QT interval corrected (QTc) ≥470 ms. Corticosteroid therapy at a dose greater than 10 mg per day of prednisolone or equivalent for more than 10 days within 14 days prior initiation of treatment. Serum sodium <125 mmol/L unless corrective treatment prior to initiation of study treatment. Hypercalcemia despite corrective treatment (corrected calcemia = Calcium (mmol) + [(40-albumin (g)) x 0.025]). History of allogenic organ transplantation. Immunosuppressive systemic therapy (cyclophosphamide, aziathioprine, methotrexate, thalidomide and TNF inhibitor) within 28 days prior to inclusion. Active or prior documented autoimmune disease or inflammatory disorders including but is not limited to inflammatory bowel disease (colitis or Crohn's disease), diverticulitis (with the exception of diverticulosis), sarcoidosis syndrome, myasthenia gravis, lupus erythematosus, rheumatoid arthritis, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain Barré's syndrome, multiple sclerosis, vasculitis and glomerulonephritis. Note: The following are exceptions are listed below: patients with vitiligo or alopecia, patients with history of autoimmune hypothyroidism treated with a stable dose of hormone replacement therapy, any chronic skin condition that does not require systemic therapy, patients without active disease in the last 5 years may be included but only after consultation with the investigator, patients with celiac disease controlled by diet alone, patients with diabetes treated with insulin. Serious chronic gastrointestinal conditions associated with diarrhea History of idiopathic pulmonary fibrosis, organized pneumonia (i.e., bronchiolitis obliterans), drug-induced pulmonary pathology or active signs of pneumonia, interstitial lung disease (whatever the cause) detected on the pulmonary CT-scan. History of cancer Note: Patients with a history of cancer for more than 3 years are eligible if they have been treated and considered cured. Patients with a history of basal cell carcinoma of the skin or in situ carcinoma of the cervix are eligible. Concomitant anti-cancer treatment or within 3 years prior to the start of study treatment, including chemotherapy, immunotherapy, hormone therapy, biotherapy or anti-angiogenic treatment (VEGF inhibitors or VEGFR inhibitors). Any medical or personal that would make the patient unable to comply with study procedures and/or could interfere with the patient safety. Receipt of live, attenuated vaccine within 30 days prior to the first dose of study drugs. Note: Patients, if enrolled, should not receive live vaccine whilst receiving study drugs and up to 30 days after the last dose of study drugs. Nucleic acid vaccines, inactivated vaccines against COVID-19 are allowed. Ongoing or active infection including: COVID-19. Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice). Hepatitis B virus (known positive HBV surface antigen [HbsAg] result). 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. Positive hepatitis C virus (HCV). Human immunodeficiency virus (positive HIV 1 / 2 antibodies). Note: patients with severe psoriasis (10% of your body's surface area) are not eligible. Paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemic treatment (systemic steroids or immunosuppressive agents) or clinical symptomatology suggesting worsening of PNS. Pregnant or lactating woman. Known allergy or hypersensitivity to study treatment or any excipient. Concomitant treatment with another experimental treatment or participation in another clinical trial. Patient who is subject to legal protection or who is unable to express his will.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carboplatin + Paclitaxel + Durvalumab<br>Carboplatin AUC 6, day 1 of three-week cycle for four cycles Paclitaxel 200 mg/m² day 1 of a three-week cycle for four cycles Durvalumab 1500 mg every 3 weeks for 4 cycles followed by 1500 mg maintenance every 4 weeks until progression, unacceptable toxicity, or consent withdrawal | Drug: Carboplatin + Paclitaxel + Durvalumab<br>* Carboplatin AUC 6, day 1 of three-week cycle for four cycles Paclitaxel 200 mg/m² day 1 of a three-week cycle for four cycles Durvalumab 1500 mg every 3 weeks for 4 cycles followed by 1500 mg maintenance every 4 weeks until progression, unacceptable toxicity, or consent withdrawal<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall Survival (OS) defined as the time from the date of first dose of study drug to the date of death due to any cause | At 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best response rate (RECIST 1.1) | Best response rate (RECIST 1.1) which is defined as the percentage of subjects with a complete response (CR) or partial response (PR) determined by Investigator review and by independent reviewer as per RECIST v1.1 criteria. | About 48 months | 
| Overall Survival (OS) | Overall Survival (OS) defined as the time from the date of first dose of study drug to the date of death due to any cause | About 48 months | 
| Overall Survival (OS) | Overall Survival (OS) defined as the time from the date of first dose of study drug to the date of death due to any cause | At 24 months | 
| Overall Survival (OS) | Overall Survival (OS) defined as the time from the date of first dose of study drug to the date of death due to any cause | At 36 months | 
| Progression free survival (PFS) | Progression free survival (PFS) defined as the time from the date of inclusion to the earliest date of disease progression, as determined by Investigator review and by independent reviewer of radiographic disease assessments per RECIST v1.1, or death due to any cause | About 48 months | 
| Safety and tolerability of paclitaxel carboplatin and durvalumab. | Incidence, nature, and severity of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) | About 48 months | 
| Quality of life of patients | Change from baseline of Quality of life assessment using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30 LC13) at all scheduled time points. | About 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IFCT, SCLC, SCLC Extensive Stage