Atezolizumab and Rechallenge Chemotherapy in Relapsed Patients With Extensive-stage Small Cell Lung Cancer (ES-SCLC).

Prior treatment

• More than 1 line of prior treatment for ES-SCLC.
• First-line chemotherapy other than platinum-etoposide.
• Symptomatic brain metastases or spinal cord compression (CT or MRI of the head is required within 4 weeks prior to randomization)requiring immediate radiotherapy for palliation. Patients with treated brain metastases (or untreated but asymptomatic) and off steroids or on a stable dose of steroids (≤10 mg of prednisone-equivalent) are also eligible provided that all of the following criteria are met:
  • If treated, at least 14 days between the end of stereotactic radiotherapy or whole brain radiotherapy and initiation of study treatment and recovery from AEs related to radiotherapy to ≤ grade 1 (except alopecia), or at least 28 days between neurosurgical resection and initiation of study treatment;
  • Anticonvulsant therapy at a stable dose is permitted;
  • Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla or spinal cord);
  • There is no evidence of interim intracranial progression between completion of CNS directed therapy (if administered) and initiation of study treatment.
• Patient has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines and COVID vaccines that do not contain live virus are permitted. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 \[IL-2\]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment except for PD-L1 inhibitor maintenance as part of first-line treatment.
• Any condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of registration . The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection);
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent;
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• Diagnosed with or treated for another malignancy within 3 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type may be enrolled in the study if they have undergone complete resection and no evidence of active disease is present.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment other than those in the present study. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• Treatment with any other investigational agent within 30 days prior to starting study treatment, or 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.
• Infection requiring intravenous antibiotic therapy or other serious infection within 14 days before the first dose of study drug.
• Prior allogeneic stem cell or solid organ transplantation.
• Surgery within 4 weeks (or 2 weeks for a minor surgery) before study enrolment and not fully recovered to baseline or to a stable clinical status. Insertion of a vascular device is allowed.
• Patients who experienced medically significant or NCI CTCAE Grade 3 or higher toxicities in response to first-line immunotherapy

Other illness

• Presence of resistant relapse (progressive disease within 60 days from the end of first-line chemotherapy) or refractory disease (progressive disease during the first 4 cycles of first-line chemoimmunotherapy).
• Evidence of leptomeningeal disease.
• Any comorbid condition or unresolved toxicity that would preclude administration of second-line chemotherapy.

Lab values

• For female subjects: positive serum pregnancy test, pregnancy, or breastfeeding.

Other

• First-line treatment without either atezolizumab or durvalumab.
• Less than 4 cycles of first-line platinum-etoposide.
• Unwilling or unable to comply with the protocol or cooperate fully with the investigator and site personnel.

• Diagnosis of small-cell lung cancer (SCLC) (according to WHO classification 2015) confirmed at pathology (histology or cytology).
• Male or female and ≥ 18 years of age.
• Life expectancy ≥ 12 weeks.
• Disease progression at least 60 days after the completion of first-line chemotherapy consisting of at least 4 cycles of platinum-etoposide plus either atezolizumab or durvalumab and have not received any other treatment (except for immunotherapy as maintenance treatment); the 60 day-interval is calculated from the date of the last chemotherapy administration to the date of the first radiologically documented progressive disease.
• No previous radiotherapy on the only one site disease progression, unless that site had subsequent evidence of progressive disease.
• Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2.
• Patients with treated brain metastases (or untreated but asymptomatic) and off steroids or on a stable dose of steroids (≤10 mg of prednisone-equivalent) are also eligible. Radiotherapy must have been completed a minimum of 14 days prior to registration, and patients must have recovered from AEs related to radiotherapy to \< grade 1 (except alopecia)
• For Females: must be postmenopausal (defined as occurring 12 months after last menstrual period) before the screening visit, or are surgically sterile. If they are of childbearing potential, a negative serum pregnancy test prior to study entry has to be documented; furthermore, they agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form (ICF) through 5 months after the last dose of study drug,or agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
• For Males: even if surgically sterilized (i.e., post-vasectomy status) agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, or practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
• Normal baseline laboratory values as specified below:
  • Absolute neutrophil count (ANC) ≥1500/mm3
  • Platelet count ≥ 100 x 109/L (≥100,000/μL) without transfusion
  • Hemoglobin ≥ 90 g/L (≥ 9 g/dL); patients may be transfused to meet this criterion.
  • Total bilirubin \< 1.5x the institutional upper limit of normal (ULN)
  • Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \< 2.5x the institutional ULN (\< 5x if liver function test elevations are due to liver metastases)
  • Creatinine \< 1.5x institutional ULN or estimated creatinine clearance using the Cockcroft-Gault formula ≥ 30 mL/minute for patients with creatinine levels above institutional limits
  • For patients not receiving therapeutic anticoagulation: INR and aPTT ≤ 1.5 x ULN
  • Negative HIV test at screening {with the following exception: patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ≥ 200/μL, and have an undetectable viral load}
  • Negative hepatitis B surface antigen (HBsAg) test at screening
  • Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening accompanied by either of the following:
  • Negative total hepatitis B core antibody (HBcAb)
  • Positive total HBcAb test followed by a negative (per local laboratory definition) hepatitis B virus (HBV) DNA testNegative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening The HCV RNA test must be performed for patients who have a positive HCV antibody test.
• Stable medical condition, including the absence of acute exacerbations of chronic illnesses, serious infections, or major surgery within 4 weeks before registration, and otherwise noted in other inclusion/exclusion criteria.
• Recovered (i.e., ≤ grade 1 toxicity) from effects of prior anticancer therapy, except alopecia.
• Prior radiotherapy is allowed provided that it has been completed more than 2 weeks before starting protocol treatment and patients have recovered from AEs related to radiotherapy to \< grade 1
• Ability to comply with protocol requirements.
• The patient or the patient's legal representative has to be able to provide written informed consent. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.