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

This phase I trial tests the safety, side effects, and best dose of a new of liposomal doxorubicin and peposertib in treating patients with sarcoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Chemotherapy drugs, such as liposomal doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Peposertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving liposomal doxorubicin and peposertib may shrink or stabilize sarcoma.

Inclusion Criteria:Patients must have histologically confirmed sarcoma that is metastatic or unresectable and for which there is no known curative treatmentDose escalation cohort: Patients must have histologic diagnosis of leiomyosarcoma (LMS) or selected soft tissue sarcomas (myxofibrosarcoma [MFS], undifferentiated pleomorphic sarcoma [UPS], synovial sarcoma, or dedifferentiated liposarcoma [DDLPS]). Pathology review and confirmation of diagnosis will occur at the site enrolling the patient on this studyDose expansion cohort: Patients must have histology diagnosis of LMS. Pathology review and confirmation of diagnosis will occur at the site enrolling the patient on this studyDose escalation cohort: Patients must have evaluable disease that is amenable to biopsyDose expansion cohort: Patients must have disease which is measurable at study entry according to RECIST 1.1 criteria and amenable to biopsyPatients must have been treated with at least 1 prior line of therapy. Prior anthracycline use is permitted as long as the cumulative dose prior to enrollment does not exceed 300 mg/m^2Age >= 18 years. Because no dosing or adverse event data are currently available on the use of peposertib (M3814) in combination with liposomal doxorubicin in patients < 18 years of age, children are excluded from this studyEastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) for both dose escalation and dose expansionAbsolute neutrophil count >= 1,500/mcLPlatelets >= 100,000/mcLTotal 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 ULNHemoglobin >= 8 g/dLCreatinine =< 1.5 x ULN AND (only if above 1.5 x ULN)Glomerular filtration rate (GFR) >= 51 mL/min/1.73 m^2Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trialFor patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicatedPatients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral loadPatients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression while off steroid supportPatients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trialPatients with known history of clinically significant cardiac disease, or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better and have an left ventricular ejection fraction (LVEF) above the institutional upper limit of normal if LVEF measurement is availableFemale patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be requiredFemale patients of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 3 months after the last dose of peposertib (M3814) and 6 months after the last dose of liposomal doxorubicinMale patients of reproductive potential must agree to avoid impregnating a partner while 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 with adequate methods of contraceptionNote: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patientAbility to understand and the willingness to sign a written informed consent documentExclusion 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 alopeciaPrior palliative radiotherapy within 14 days of Cycle 1 Day 1 and prior definitive radiotherapy within 42 days of Cycle 1 Day 1. Adverse effects of radiation therapy must resolve to baseline prior to Cycle 1 Day 1Patients who are receiving any other investigational agentsHistory of allergic reactions attributed to compounds of similar chemical or biologic composition to peposertib (M3814) or other agents used in studyPatients who cannot discontinue concomitant medications or herbal supplements that are strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5, CYP2C9, and CYP2C19. Concomitant use of CYP3A4/5 substrates with a narrow therapeutic index are also excluded. Patients may confer with the study doctor to determine if alternative medications can be used. The following categories of medications and herbal supplements must be discontinued for at least the specified period of time before the patient can be treated:Strong inducers of CYP3A4/5 and CYP2C19: >= 3 weeks prior to study treatmentStrong inhibitors of CYP3A4/5 and CYP2C19: >= 1 week prior to study treatmentSubstrates of CYP3A4/5 with a narrow therapeutic index: >= 1 day prior to study treatmentStrong inhibitors of CYP2C9: >= 1 week prior to study treatmentPatients who cannot discontinue concomitant proton-pump inhibitors (PPIs). Patients may confer with the study doctor to determine if such medications can be discontinued. These must be discontinued >= 5 days prior to study treatment. Patients do not need to discontinue calcium carbonateLVEF measurement and baseline electrocardiogram (ECG) should be performed as clinically indicated based on cardiac risk assessment of the investigator; patients with known LVEF < the institutional lower limit of normal (LLN) are excludedPatients with uncontrolled intercurrent illnessPatients who cannot swallow tablets wholePatients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required during the first cycle of therapyPregnant women are excluded from this study because peposertib (M3814) is an ATP-competitive inhibitor of DNA-PKcs with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with peposertib (M3814), breastfeeding should be discontinued if the mother is treated with peposertib (M3814). These potential risks may also apply to other agents used in this studyPatients may not have received prior treatment with a DNA-PK inhibitor