Testing of Tazemetostat in Combination With Topotecan and Pembrolizumab in Patients With Recurrent Small Cell Lung Cancer

Inclusion Criteria:

• Patients enrolled to the primary cohort must have limited- or extensive-disease SCLCat diagnosis, with relapse at study entry with measurable disease per ResponseEvaluation Criteria in Solid Tumors (RECIST) 1.1, and with prior therapy withplatinum doublet. Patients with extensive stage disease should have receivedchemo-immunotherapy. Both platinum-sensitive and platinum-resistant patients will beincluded

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of pembrolizumab in combination with tazemetostat and topotecan in patients < 18 years of age, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 70%)

• Leukocytes >= 3000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L

• Total bilirubin =< 1.5 institutional upper limit of normal (ULN) OR direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 × ULN

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN

• Creatinine =< 1.5 institutional ULN OR glomerular filtration rate (GFR) >= 60mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney functionvalues, no lower than 30 mL/min/1.73 m^2

• Note: Creatinine clearance (CrCl) should be calculated per institutionalstandard. Glomerular filtration rate (GFR) can also be used in place ofcreatinine or CrCl

• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 × ULN unlesspatient is receiving anticoagulant therapy as long as PT or partial thromboplastintime (PTT) is within therapeutic range of intended use of anticoagulants

• Activated (a)PTT =< 1.5 × ULN unless patient is receiving anticoagulant therapy aslong as PT or PTT is within therapeutic range of intended use of anticoagulants

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load (CD4 count of greater than 250 cells/mcL)within 6 months are eligible for this trial. They must not be receiving prophylactictherapy for an opportunistic infection

• 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 they are symptomaticallystable while off steroid therapy for a minimum of 7 days

• Patients should be class 2B or better on the New York Heart Association FunctionalClassification

• Ability to understand and the willingness to sign a written informed consentdocument

• The effects of pembrolizumab and tazemetostat on the developing human fetus areunknown. For this reason and because monoclonal antibodies, EZH2 inhibitors as wellas other therapeutic agents used in this trial are known to be teratogenic, women ofchild-bearing potential and men must agree to use adequate contraception (hormonalor barrier method of birth control; abstinence) prior to study entry and for theduration of study treatment and for 6 months after the last dose of study treatment.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. Men treated or enrolled on this protocol must also agree to useadequate contraception prior to the study, for the duration of study participation,and 3 months after completion of study treatment administration

Exclusion Criteria:

• Patients who have had chemotherapy, immune checkpoint inhibitors, or radiotherapywithin 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering thestudy.

• Note: Patients who have had palliative radiotherapy may be included as long asthey have recovered from any radiotherapy related adverse events (allow atleast 3 days between radiotherapy completion and study treatment)

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1).

• Note: Patients with =< grade 2 neuropathy or =< grade 2 alopecia are anexception to this criterion and may qualify for the study

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

• Untreated immunodeficiency or receiving systemic steroid therapy or any other formof immunosuppressive therapy within 7 days prior to the first dose of trialtreatment. The use of physiologic doses of corticosteroids may be approved afterconsultation with the study principal investigator (PI)

• Patients who are receiving any other investigational agents

• Patients with symptomatic brain metastasis are not eligible due to their extremelypoor prognosis and since it is unclear whether the investigational agent penetratesthe blood-brain barrier. However, subjects who have had treatment for their brainmetastasis and are symptomatically stable while off steroid therapy for a minimum of 7 days may be enrolled. The use of physiologic doses of corticosteroids may beapproved after consultation with the study PI

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to pembrolizumab and tazemetostat or other agents used in study

• Has an active autoimmune disease that has required systemic treatment in the past 2years (i.e., with use of disease modifying agents, corticosteroids, orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment

• Has a history of (non-infectious) pneumonitis that required steroids or currentpneumonitis

• Patients with uncontrolled intercurrent illness but not limited to, ongoing oractive infection, interstitial lung disease or active, non-infectious pneumonitis,symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia,or psychiatric illness/social situations that would limit compliance with studyrequirements

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Pregnant women are excluded from this study because pembrolizumab as a monoclonalantibody, and tazemetostat as a EZH2 inhibitor may have the potential forteratogenic or abortifacient effects. Because there is an unknown but potential riskfor adverse events in nursing infants secondary to treatment of the mother withpembrolizumab or tazemetostat, breastfeeding should be discontinued if the mother istreated with these agents and for 1 week after the last dose of tazemetostat. Thesepotential risks may also apply to other agents used in this study

• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) orhepatitis C

• Has received a live vaccine within 30 days of planned treatment start. Seasonal fluvaccines that do not contain live virus are permitted

• Has thrombocytopenia, neutropenia, or anemia of grade >= 3 (per Common TerminologyCriteria for Adverse Events [CTCAE] 5.0 criteria) or any prior history of myeloidmalignancies, including myelodysplastic syndrome (MDS)

• Has abnormalities known to be associated with MDS (e.g. del 5q, chromosome [chr] 7abnormality [abn]) and myeloproliferative neoplasm (MPN) (e.g. JAK2 V617F) observedin cytogenetic testing and DNA sequencing

• Has a prior history of T-cell lymphoblastic lymphoma (T-LBL), T-cell acute leukemia (T-ALL) or B-cell acute lymphoblastic leukemia (B-ALL)