LB-100, Carboplatin, Etoposide, and Atezolizumab for the Treatment of Extensive-Stage Small Cell Lung Cancer and Unresectable or Metastatic Extrapulmonary Small Cell or High-Grade Neuroendocrine Carcinoma

Inclusion Criteria

• All subjects must have the ability to understand and the willingness to sign a written informed consent
• Histologically or cytologically confirmed extensive-stage disease small cell lung carcinoma per the Veterans Administration Lung Study Group (VALG) staging system, or in the dose-escalation portion of the trial only: unresectable/metastatic extrapulmonary small cell carcinoma or high-grade neuroendocrine carcinoma
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST guideline (version 1.1)
• At least 18 years old at the time of screening
• Estimated life expectancy of at least 12 weeks
• For women: Must be surgically sterile (surgical procedure: bilateral tubal ligation), post-menopausal (at least 12 consecutive months of amenorrhea) or have a negative pregnancy test. Women of childbearing potential must be compliant with a medically approved contraceptive regimen (intrauterine device [IUD], birth control pills, or barrier device) during and for 3 months after the treatment period; must have a negative serum or urine pregnancy test within 14 days before study drug treatment and must not be breastfeeding
• For men: agreement to remain abstinent or use medically approved contraceptive measures, as defined below: * With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during study therapy and for at least 6 months after the last dose of study therapy to avoid exposing the embryo
• A performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) scale
• Absolute neutrophil (segmented and bands) count (ANC) >= 1.5 x 10/L
• Platelets >= 100 x 10/L
• Hemoglobin >= 9 g/dL
• Bilirubin =< 1.5 times upper limits of normal (ULN) may be enrolled
• Alkaline phosphatase (AP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 times ULN (AP, AST, and ALT =< 5 times ULN are acceptable if the liver has tumor involvement)
• Calculated creatinine clearance (CrCl) >= 60 mL/min based on the Cockcroft and Gault formula
• Up to one prior cycle of prior systemic chemotherapy, immunotherapy, biological, hormonal, or investigational therapy for SCLC, extrapulmonary small cell or high-grade neuroendocrine

Exclusion Criteria

• Currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
• Diagnosis of non-small cell lung cancer (NSCLC) or mixed NSCLC and small cell lung cancer (SCLC) or low-grade neuroendocrine carcinoma
• No prior malignancy other than SCLC, extrapulmonary small cell carcinoma, high-grade neuroendocrine carcinoma, carcinoma in situ of the cervix, or nonmelanoma skin cancer, unless that prior malignancy was diagnosed and definitively treated 5 or more years prior to study entry with no subsequent evidence of recurrence. Patients with a history of low grade (Gleason score =< 6 = Gleason group 1) localized prostate cancer will be eligible even if diagnosed less than 5 years prior to study entry
• Serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the patient’s ability to adhere to the protocol
• Active or ongoing infection during screening requiring the use of systemic antibiotics
• Serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease as defined by the New York Heart Association class III or IV
• Clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have 1) previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroid medication for 1 week prior to the first dose of study drug and have completed radiation 2 weeks prior to the first dose of study drug OR 2) untreated brain metastases that are asymptomatic and stable
• Known or suspected allergy to any agent given in association with this trial
• Pregnant or lactating women
• History of autoimmune disease, including minor/mild autoimmune disease not requiring immunosuppressants (such as eczema on less than 10% of the body surface area and long term diabetes mellitus type 1 on stable insulin)
• Known hepatitis B or hepatitis C
• Known human immunodeficiency virus (HIV) positive
• Treatment with systemic corticosteroid or other immunosuppressive medication other than corticosteroids equivalent to < 10 mg prednisone/day. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are also allowed
• Administration of a live, attenuated vaccine within 28 days prior to study
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters are allowed
• Uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL or corrected serum calcium > ULN). Patients who are receiving denosumab prior to study entry must be willing and eligible to discontinue its use and replace it with a bisphosphonate while in the study
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Prior allogeneic bone marrow transplantation or solid organ transplant
• QTcF (Fridericia Correction Formula) > 470 on 2 out of 3 electrocardiograms (EKG’s)
• Diagnosis of congenital long QT syndrome
• Treatment, within 7 days prior to first dose of study drug, with medications that are known to prolong the QT interval and/or are associated with a risk of torsades de pointes
• Treatment with CYP450 substrates within 7 days prior to first dose of study drug
• Treatment with nephrotoxic compounds within 7 days prior to first dose of study drug
• Treatment with warfarin within 7 days prior to first dose of study drug
• Treatment with antiepileptic medications that may increase etoposide clearance (including but not limited to phenytoin, phenobarbital, carbamazepine, and valproic acid) within 7 days prior to first dose of study drug
• Treatment with strong P-glycoprotein inhibitors within 7 days prior to first dose of study drug
• Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study