Testing Low-Dose Common Chemotherapy (Liposomal Doxorubicin) in Combination With an Anti-Cancer Drug, Peposertib, in Advanced Sarcoma

Inclusion Criteria:

• Patients must have histologically confirmed sarcoma that is metastatic orunresectable and for which there is no known curative treatment

• Dose escalation cohort: Patients must have histologic diagnosis of leiomyosarcoma (LMS) or selected soft tissue sarcomas (myxofibrosarcoma [MFS], undifferentiatedpleomorphic sarcoma [UPS], synovial sarcoma, or dedifferentiated liposarcoma [DDLPS]). Pathology review and confirmation of diagnosis will occur at the siteenrolling the patient on this study

• Dose expansion cohort: Patients must have histology diagnosis of LMS. Pathologyreview and confirmation of diagnosis will occur at the site enrolling the patient onthis study

• Dose escalation cohort: Patients must have evaluable disease that is amenable tobiopsy

• Dose expansion cohort: Patients must have disease which is measurable at study entryaccording to RECIST 1.1 criteria and amenable to biopsy

• Patients must have been treated with at least 1 prior line of therapy. Prioranthracycline use is permitted as long as the cumulative dose prior to enrollmentdoes not exceed 300 mg/m^2

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of peposertib (M3814) in combination with liposomal doxorubicin in patients < 18 years of age, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)for both dose escalation and dose expansion

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN

• Hemoglobin >= 8 g/dL

• Glomerular filtration rate (GFR) >= 51 mL/min/1.73 m^2 (per institutional estimatebased on creatinine level)

• 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 whileoff steroid support

• 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

• Patients with known history of clinically significant cardiac disease, or currentsymptoms of cardiac disease, or history of treatment with cardiotoxic agents shouldhave a clinical risk assessment of cardiac function using the New York HeartAssociation Functional Classification. To be eligible for this trial, patientsshould be class 2B or better and have an left ventricular ejection fraction (LVEF)above the institutional upper limit of normal if LVEF measurement is available

• Female patients of childbearing potential must have a negative urine or serumpregnancy test within 72 hours prior to receiving the first dose of studymedication. If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required

• Female patients of childbearing potential must be willing to use an adequatemethod of contraception for the course of the study through 3 months after thelast dose of peposertib (M3814) and 6 months after the last dose of liposomaldoxorubicin

• Male patients of reproductive potential must agree to avoid impregnating a partnerwhile receiving study drug and for 3 months after the last dose of peposertib (M3814) and 6 months after the last dose of liposomal doxorubicin by complying withadequate methods of contraception

• Note: Abstinence is acceptable if this is the usual lifestyle and preferredcontraception for the patient

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

Exclusion Criteria:

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

• Prior palliative radiotherapy within 14 days of cycle 1 day 1 and prior definitiveradiotherapy within 42 days of cycle 1 day 1. Adverse effects of radiation therapymust resolve to baseline prior to cycle 1 day 1

• Patients who are receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to peposertib (M3814) or other agents used in study

• Patients who cannot discontinue concomitant medications or herbal supplements thatare strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymesCYP3A4/5, CYP2C9, and CYP2C19. Concomitant use of CYP3A4/5 substrates with a narrowtherapeutic index are also excluded. Patients may confer with the study doctor todetermine if alternative medications can be used. The following categories ofmedications and herbal supplements must be discontinued for at least the specifiedperiod of time before the patient can be treated:

• Strong inducers of CYP3A4/5 and CYP2C19: >= 3 weeks prior to study treatment

• Strong inhibitors of CYP3A4/5 and CYP2C19: >= 1 week prior to study treatment

• Substrates of CYP3A4/5 with a narrow therapeutic index: >= 1 day prior to studytreatment

• Strong inhibitors of CYP2C9: >= 1 week prior to study treatment

• Patients who cannot discontinue concomitant proton-pump inhibitors (PPIs). Patientsmay confer with the study doctor to determine if such medications can bediscontinued. These must be discontinued >= 5 days prior to study treatment.Patients do not need to discontinue calcium carbonate

• LVEF measurement and baseline electrocardiogram (ECG) should be performed asclinically indicated based on cardiac risk assessment of the investigator; patientswith known LVEF < the institutional lower limit of normal (LLN) are excluded

• Patients with uncontrolled intercurrent illness

• Patients who cannot swallow tablets whole

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate CNS specific treatment is not required and is unlikely to be requiredduring the first cycle of therapy

• Pregnant women are excluded from this study because peposertib (M3814) is anadenosine triphosphate (ATP)-competitive inhibitor of DNA-protein kinase catalyticsubunit (PKcs) with the potential for teratogenic or abortifacient effects. Becausethere is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with peposertib (M3814), breastfeeding shouldbe discontinued if the mother is treated with peposertib (M3814). These potentialrisks may also apply to other agents used in this study

• Patients may not have received prior treatment with a DNA-protein kinase (PK)inhibitor