Temozolomide and Atezolizumab as Second or Third Line for the Treatment of Metastatic or Recurrent Small Cell Lung Cancer

Inclusion Criteria:

• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information

• NOTE: HIPAA authorization may be included in the informed consent or obtainedseparately

• Age >= 18 years at the time of consent

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 2 within 28days prior to registration

• Have histologically or cytologically-documented diagnosis of extensive stage (i.e.metastatic and/or recurrent) small cell lung cancer and have progressed or recurredafter platinum-based chemotherapy with immunotherapy. Eligible patients will bedefined as follows:

• "Sensitive" Disease: Patients who had one previous line of chemotherapy andrelapsed after > 90 days of completion of treatment

• "Resistant" Disease: Patients with no response to first-linechemo-immunotherapy or progression < 90 days after completing treatment

• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 within 28 days prior to registration

• Maximum of 3 prior lines of systemic therapy is allowed in the setting of metastaticdisease. Patients who recur after treatment for limited state disease, and whoreceive first line metastatic treatment with chemo-immunotherapy would be consideredeligible upon progression on chemo-IO in the metastatic setting

• Absolute neutrophil count (ANC) >= 1.5 K/mm^3 (obtained within 28 days prior toregistration)

• Platelets >= 100,000 / mcL (obtained within 28 days prior to registration)

• Serum creatinine =< 2.0 X upper limit of normal (ULN) OR measured or calculatedcreatinine clearance (glomerular filtration rate [GFR] can also be used in place ofcreatinine or creatinine clearance [CrCl]) >= 50 mL/min as estimated by Cockcroftand Gault formula for subject with creatinine levels > 2 x institutional ULN (obtained within 28 days prior to registration)

• Bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubinlevels > 1.5 ULN

• Patients with known Gilbert disease: serum bilirubin =< 3 x ULN) (obtainedwithin 28 days prior to registration)

• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) =< 3 X ULN OR =< 5 X ULN for subjects with liver metastases (obtained within 28 days prior toregistration)

• Albumin > 2.5 g/dL (obtained within 28 days prior to registration)

• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN forpatients not receiving therapeutic anticoagulation (obtained within 28 days prior toregistration)

• For patients receiving therapeutic anticoagulation: stable anticoagulantregimen

• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN for patients not receivingtherapeutic anticoagulation (obtained within 28 days prior to registration)

• For patients receiving therapeutic anticoagulation: stable anticoagulantregimen

• Females of childbearing potential must have a negative serum or urine pregnancy testwithin 14 days prior to registration

• For women of childbearing potential: agreement to remain abstinent (refrain fromvaginal intercourse) or use contraceptive methods and agreement to refrain fromdonating eggs, as defined below:

• Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the final doseof atezolizumab or temozolomide. Women must refrain from donating eggs duringthis same period

• Examples of contraceptive methods with a failure rate of < 1% per year includebilateral tubal ligation, male sterilization, hormonal contraceptives thatinhibit ovulation, hormone releasing intrauterine devices, and copperintrauterine devices

• The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, orpost ovulation methods) and withdrawal are not adequate methods ofcontraception

• For men able to father a child: agreement to remain abstinent (refrain from vaginalintercourse) or use a condom, and agreement to refrain from donating sperm, asdefined below:

• With a female partner of childbearing potential or pregnant female partner, menmust remain abstinent or use a condom during the treatment period and for 3months after the final dose of temozolomide to avoid exposing the embryo. Menmust refrain from donating sperm during this same period

• The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not adequate methods of contraception

• As determined by the enrolling physician or protocol designee, ability of thesubject to understand and comply with study procedures for the entire length of thestudy

• Availability of archival tissue, preferably a recent formalin-fixed,paraffin-embedded (FFPE) tumor tissue block. A recently obtained archival FFPE tumortissue block from a primary or metastatic tumor resection or biopsy can be providedif it was obtained within 1 year of trial screening. Patients with tumor specimensolder than 1 year, or who do not have biopsy specimen may still be eligible ifdeemed so by the sponsor-investigator.

• Be willing to provide peripheral blood samples at specified time-points during thestudy

• Life expectancy greater than 3 months as determined by the enrolling physician orprotocol designee

• Ability to swallow and retain oral medication

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in astudy of an investigational agent and received study therapy or used aninvestigational device within 4 weeks of the first dose of treatment

• Has received prior temozolomide therapy

• Patients with a prior or concurrent malignancy whose natural history or treatmenthas the potential to interfere with the safety or efficacy assessment of theinvestigational regimen are not eligible for this trial

• Symptomatic central nervous system (CNS) metastases or untreated or activelyprogressing CNS metastases. Subjects with asymptomatic CNS metastases (treated oruntreated) will be eligible provided all of the following criteria are met.

1. Measurable disease, per RECIST v1.1, must be present outside the CNS.

2. The patient has no history of intracranial hemorrhage or spinal cordhemorrhage.

3. The patient has not undergone stereotactic radiotherapy within 7 days prior toinitiation of study treatment, whole-brain radiotherapy within 14 days prior toinitiation of study treatment, or neurosurgical resection within 28 days priorto initiation of study treatment.

4. The patient has no ongoing requirement for corticosteroids as therapy for CNSdisease at the time of study treatment.

5. If the patient is receiving anti-convulsant therapy, the dose is consideredstable and appropriate by the treating physician.

6. Metastases are limited to the cerebellum or the supratentorial region (i.e., nometastases to the midbrain, pons, medulla, or spinal cord).

• NOTE: Subjects who are symptomatic and have not undergone prior brainimaging must undergo a head computed tomography (CT) scan or brain MRIwithin 28 days prior to registration to exclude brain metastases

• NOTE: A subject with previously treated brain metastasis may be consideredif they have completed their treatment for brain metastasis at least 2weeks prior to study registration and all of the above criteria are met.

• Clinically significant acute infection requiring systemic antibacterial, antifungal,or antiviral therapy including:

• Tuberculosis (clinical evaluation that includes clinical history, physicalexamination, and radiographic findings, and TB testing in line with localpractice)

• Hepatitis B (known positive HBV surface antigen [HBsAg] result)

• Hepatitis C, or

• Human immunodeficiency virus (positive HIV 1/2 antibodies)

• NOTES: Patients with a past or resolved HBV infection (defined as the presenceof hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Inpatients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated. Patientspositive for hepatitis C (HCV) antibody are eligible only if polymerase chainreaction is negative for HCV ribonucleic acid (RNA). Subjects with HIV/acquiredimmunodeficiency syndrome (AIDS) with adequate antiviral therapy to controlviral load (i.e undetectable) would be allowed if they are stable and have beenon treatment for >= 4 weeks prior to first dose of study drug(s). Subjects withviral hepatitis with controlled viral load would be allowed while onsuppressive antiviral therapy. Testing not required

• Has had prior chemotherapy, immunotherapy, targeted small molecule therapy, orradiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previouslyadministered agent

• Note: Subjects with =< grade 2 neuropathy or alopecia due to chemotherapy arean exception to this criterion and may qualify for the study

• Note: If subject received major surgery, they must have recovered adequatelyfrom the toxicity and/or complications from the intervention prior to startingtherapy

• Note: Subjects with irreversible toxicity that in the opinion of the treatingphysician is not reasonably expected to be exacerbated by the investigationalproduct may be included (e.g., hearing loss, hormone deficiency requiringreplacement therapy)

• Active or history of autoimmune disease or immune deficiency, including, but notlimited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipidantibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barresyndrome, or multiple sclerosis, with the following exceptions:

• Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is notconsidered a form of systemic treatment

• Patients with controlled type 1 diabetes mellitus who are on an insulin regimenare eligible for the study

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are eligible for the study provided all of following conditions aremet:

• Rash must cover =< 10% of body surface area

• Disease is well controlled at baseline and requires only low-potencytopical corticosteroids

• No occurrence of acute exacerbations of the underlying condition requiringpsoralen plus ultraviolet A radiation, methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high-potency or oralcorticosteroids within the previous 12 months

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest computed tomography (CT) scan. History ofradiation pneumonitis in the radiation field (fibrosis) is permitted

• Significant cardiovascular disease (such as New York Heart Association Class II orgreater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstableangina

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial

• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation ofstudy treatment

• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use whilethe mother is being treated on study)

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator

• History of severe allergic anaphylactic reactions to chimeric or humanizedantibodies or fusion proteins

• Known hypersensitivity to Chinese hamster ovary cell products or to any component ofthe atezolizumab formulation

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (more than once monthly). Patients with indwelling catheters (e.g., PleurX) are allowed.

• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium >12mg/dL or corrected serum calcium > ULN)

• History of leptomeningeal disease