Testing the Combination of an Anti-cancer Drug, Iadademstat, With Other Anti-cancer Drugs (Atezolizumab or Durvalumab) at Improving Outcomes for Small Cell Lung Cancer

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed small cell lung cancer (SCLC)

• Patients must have measurable disease, defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded fornon-nodal lesions) as ≥ 20 mm (≥ 2 cm) by chest x-ray or as ≥ 10 mm (≥ 1 cm) with CTscan, MRI, or calipers by clinical exam or the shortest axis for nodal lesions as ≥ 15 mm (≥ 1.5 cm) with CT scan

• Patients who have been treated with platinum etoposide chemotherapy plus eitheratezolizumab or durvalumab immunotherapy for 4 cycles with either a radiographicresponse or stable disease

• Age ≥ 18 years. Because no dosing or adverse event data are currently available onthe use of iadademstat in combination with atezolizumab and durvalumab in patients <18 years of age, children are excluded from this study

• Body weight ≥ 50 kg

• Patient is able to swallow oral medications

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%).This assessment for eligibility will take place after patients have received 4cycles of standard of care (SOC) chemotherapy-ICI

• Leukocytes ≥ 2,000/mcL

• Lymphocyte count ≥ 500/mcL

• Absolute neutrophil count ≥ 1,500/mcL

• Hemoglobin ≥ 9 g/dL

• Platelets ≥ 100,000/mcL

• Albumin ≥ 3 g/dL

• Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 ×institutional ULN unless liver metastases are present, in which case it must be ≤ 5 × ULN

• Glomerular filtration rate (GFR) ≥ 60 mL/min

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Evidence of post-menopausal status or negative urinary or serum pregnancy test forfemale pre-menopausal patients. Pregnant women are excluded from this study becauseatezolizumab and durvalumab are monoclonal antibody agents with the potential forteratogenic or abortifacient effects. Women will be considered post-menopausal ifthey have been amenorrheic for 12 months without an alternative medical cause. Thefollowing age-specific requirements apply:

• Women < 50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulatinghormone levels in the post-menopausal range for the institution or underwentsurgical sterilization (bilateral oophorectomy or hysterectomy).

• Women ≥ 50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses >1 year ago, hadchemotherapy-induced menopause with last menses > 1 year ago, or underwentsurgical sterilization (bilateral oophorectomy, bilateral salpingectomy orhysterectomy)

• The effects of iadademstat, atezolizumab, and durvalumab on the developing humanfetus are unknown. For this reason and because monoclonal antibody agents are knownto be teratogenic, women of child-bearing potential and males with females ofchild-bearing potential must agree to use adequate contraception (hormonal orbarrier method of birth control; abstinence) prior to study entry, for the durationof study participation, and for 150 days after the last dose of study medication.Should a woman become pregnant or suspect she is pregnant while she or her partneris participating in this study, she should inform her treating physicianimmediately.

• Females of childbearing potential must agree to:

• Use effective contraception during the trial and 150 days after the end oftreatment.

• Practice true abstinence during the trial and 150 days after the end oftreatment.

• Have a negative urine pregnancy test at screening.

• Not to donate or freeze egg(s) during the course of this study or within 150 days after receiving their last dose of study drug.

• Male patients even if surgically sterilized (i.e., status post-vasectomy) mustagree to:

• Use effective contraception during the entire study treatment period andthrough 150 days after the last dose of study drug.

• Not to donate or freeze sperm during the course of this study or within 150 days after receiving their last dose of study drug.

• Because there is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with atezolizumab and durvalumab, femaleparticipants who are breastfeeding must agree to discontinue breastfeeding. Thesepotential risks may also apply to iadademstat

• Ability to understand and the willingness to sign a written informed consentdocument. Legally authorized representatives may sign and give informed consent onbehalf of study participants

Exclusion Criteria:

• Patients medicated with anti-depressants reported to have KDM1A/LSD1 inhibitoryactivity: Tranylcypromine or phenelzine

• Patients who have not recovered from grade ≥2 adverse events (AEs) due to prioranti-cancer therapy with the exception of alopecia, vitiligo, and the laboratoryvalues defined in the inclusion criteria.

• Patients with grade ≥ 2 neuropathy will be evaluated on a case-by-case basisafter consultation with the study physician

• Patients who are receiving any other investigational agents or any other agentadministered for the treatment of the patient's cancer within four half-lives or 4weeks prior to cycle 1, day 1, whichever is shorter

• Treatment with systemic immunostimulatory agents (including, but not limited to,interferon [IFN]-α or interleukin [IL]-2) within 4 weeks or five half-lives of thedrug (whichever is longer) prior to cycle 1, day 1

• Treatment with systemic immunosuppressive medications (including, but not limitedto, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1or anticipation of need for systemic immunosuppressive medication during studytreatment, with the following exceptions:

• Patients who have received acute, low dose, systemic immunosuppressantmedications or one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible afterPrincipal Investigator confirmation has been obtained.

• Patients who have received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, orlow-dose corticosteroids for orthostatic hypotension or adrenocorticalinsufficiency are eligible

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to iadademstat, atezolizumab, or durvalumab. In particular, ahistory of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric antibodies, fusion proteins, or Chinese hamster ovary cell products or toany component of the atezolizumab formulation

• Atezolizumab Concomitant Medication Considerations: Patients are not allowed toreceive immunostimulatory agents, immunosuppressive medications, or herbal andnatural remedies

• Durvalumab Concomitant Medication Considerations: Patients are not allowed toreceive immunosuppressive medications, EGFR TKIs, or herbal and natural remedies

• Iadademstat Concomitant Medication Considerations: Patients are not allowed toreceive prophylactic hematopoietic colony stimulating factors, any complementary oralternative medicine [any of various systems of healing or treating disease (asnon-prescription drugs, herbal medicine and homeopathy)]. Use of these types oftreatments must be terminated 1 week prior to start of study treatment

• History of allogenic organ transplantation

• Patients with active tuberculosis (TB)

• Patients with uncontrolled intercurrent illness or any other significantcondition(s) that would make participation in this protocol unreasonably hazardous

• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizingpneumonia, etc.), or evidence of active pneumonitis on screening chest computedtomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted

• Unstable angina, symptomatic or otherwise uncontrolled arrhythmia (does not includestable, lone atrial fibrillation), Fridericia's correction (QTcF) > 480 ms based onscreening electrocardiogram (ECG), myocardial infarction ≤ 3 months prior to firststudy treatment, cerebrovascular accidents ≤ 3 months before study treatment start.Patient has congestive heart failure New York Heart Association (NYHA) class 2, 3 or 4 or patients with a history of congestive heart failure NYHA class 2, 3 or 4 in thepast, unless a screening echocardiogram performed within 1 month prior to studyentry demonstrates a left ventricular ejection fraction that is ≥ 45%

• History or risk of autoimmune disease, including, but not limited to, myastheniagravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoidarthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegenergranulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis,with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism on a stable doseof thyroid replacement hormone may be eligible.

• Patients with controlled Type 1 diabetes mellitus (HbA1c < 8%) on a stableinsulin regimen may be eligible.

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis wouldbe excluded) are permitted provided all of the following conditions are met:

• Rash must cover less than 10% of body surface area (BSA).

• Disease is well controlled at baseline and only requiring low potencytopical steroids.

• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,retinoids, biologic agents, oral calcineurin inhibitors; high potency ororal steroids) within the previous 12 months.

• Any chronic skin condition that does not require systemic therapy.

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician.

• Patients with celiac disease controlled by diet alone

• Patients should not receive vaccines 30 days prior and through 30 days after thelast dose of study treatment with the exception of seasonal influenza vaccines andvaccines intended to prevent SARS-CoV-2, pneumococcal infection and coronavirusdisease 2019 (COVID-19). If a patient had received a live attenuated vaccine within 30 days of the first dose of trial treatment, eligibility should be discussed withthe investigator

• Patient has had major surgery within 4 weeks prior to the first study dose

• Patient has radiation therapy within 4 weeks prior to the first study dose excludingpalliative and central nervous system (CNS) radiation

• Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GIdisease, or for an unknown reason that may alter the absorption of iadademstat. Inaddition, patients with enteric stomata are also excluded

• Patients with history of clinically significant bleeding, specifically any historyof intracranial hemorrhage / hemorrhagic cardiovascular accident (CVA), or patientswith gastrointestinal bleeding within the 3 months prior to study entry

• Patients with known irreversible bleeding disorders or receiving antiplatelettherapy for other indications

• Patients with uncontrolled disseminated intravascular coagulation

• Patients who refuse or are unable to potentially receive blood products