Study of All-Trans Retinoic Acid (ATRA) and Cemiplimab in Patients With Advanced Leiomyosarcoma

Inclusion Criteria:

• Age ≥18 years

• Confirmed metastatic or locally advanced - unresectable Leiomyosarcoma (LMS)

• Measurable disease based on RECIST 1.1. (At least one target lesion)

• Patients must have received standard of care chemotherapy. No limits to prior linesof therapy.

• Prior PD-1 and/or PD-L1 directed therapies are permitted. Minimal wash out period of 3 weeks for Pembrolizumab, Nivolumab , Durvalumab, 4 weeks for Ipilimumab.

• ECOG performance status of 0-2.

• Adequate organ function, as defined below.

• Absolute neutrophil count (ANC) ≥ 1,500 /mcL, hemoglobin ≥9 g/dL (patients maybe transfused to meet this criterion), lymphocytes ≥ 500/mcL, platelets ≥ 100,000/mcL

• Serum creatinine ≤ 1.5 X upper limit of normal (ULN) or measured or calculatedcreatinine clearance (CrCl) ≥ 60 mL/min for patients with creatinine levels > 1.5 X ULN (glomerular filtration rate [GFR] can also be used in place ofcreatinine or CrCl)

• Serum total bilirubin ≤ 1.5 X ULN or direct bilirubin ≤ ULN for patients withtotal bilirubin levels > 1.5 X ULN. FOr patients with known Gilbert disease,serum bilirubin ≤ 3 X ULN

• Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 X ULN or ≤ 5 X ULN for patients with liver metastases

• albumin ≥ 2.5 g/dL

• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unlesspatients is receiving anticoagulant therapy as long as PT or PTT is withintherapeutic range of intended use of anticoagulants

• Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless the patients isreceiving anticoagulant therapy as long as PT or PTT is within therapeuticrange of intended use of anticoagulants

• Anticipated life expectancy of ≥ 6 months.

• Willing to comply with study procedures

• Female patients of childbearing potential should have a negative urine or serumpregnancy within 14 days prior to receiving the first dose of study medication. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required.

• Be willing and able to understand and sign the written informed consent document.

• Ability to swallow and retain oral medication.

• HIV-infected patients on effective anti-retroviral therapy with undetectable viralload within 6 months are eligible for this trial. Testing not indicated for patientswithout known history of HIV.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated. Testing notindicated for patients without known history of HBV.

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. Testing not indicated for patients without known history of HCV.

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.

• 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, Sjögren syndrome, Guillain-Barrésyndrome, or multiple sclerosis with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are stable onthyroid-replacement hormone are eligible for the study

• 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

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy atdoses > 10 mg prednisone or equivalent or other form of immunosuppressive therapywithin 14 days prior to the first dose of trial treatment.

• Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepaticencephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinicallymeaningful ascites is defined as ascites from cirrhosis requiring increasing dosageof diuretics or paracentesis.

• Has symptomatic central nervous system (CNS) metastases and/or carcinomatousmeningitis. Patients with asymptomatic CNS lesions will be eligible if consideredappropriate by the treating physician. Patients with previously treated brainmetastases may participate provided they have had a stable neurological status forat least 2 weeks after completion of definitive therapy. Patients may be oncorticosteroids (≤ 10 mg of prednisone-equivalent) to control brain metastases ifthey have been on a stable dose for 2 weeks (14 days) prior to the start of studytreatment and are clinically asymptomatic. This exception does not includecarcinomatous meningitis which is excluded regardless of clinical stability.

• Pregnancy or breastfeeding or intention of becoming pregnant during study treatmentor within 180 days for Cemiplimab after the final dose of study treatment

• Women of childbearing potential must have a negative serum pregnancy testresult within 14 days prior to initiation of study treatment.

• Highly effective contraception should be used in women of childbearingpotential during treatment with Cemiplimab and for at least 6 months followingthe last dose of Cemiplimab.

• Any patient who has experienced unacceptable toxicity on prior checkpoint inhibitortherapy as detailed below:

1. ≥ Grade 3 AE related to checkpoint inhibitor.

2. Ongoing ≥ Grade 2 immune-related AE associated with checkpoint inhibitor withthe exception of endocrine toxicities as detailed below.

3. CNS, ocular or cardiac AE of any grade related to checkpoint inhibitor. * NOTE:Patients with a prior or ongoing endocrine AE are permitted to enroll if theyare stably maintained on appropriate replacement therapy and are asymptomatic.

• History of migraines requiring treatment within 3 months of study entry.

• 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 of radiation pneumonitis in the radiation field (fibrosis) ispermitted.

• Significant cardiovascular disease (such as New York Heart Association Class II orgreater cardiac disease, myocardial infarction, or cerebrovascular accident) within 6 months prior to initiation of study treatment, unstable arrhythmia, or unstableangina

• Major surgical procedure, other than for diagnosis, within 8 weeks prior toinitiation of study treatment, or anticipation of need for a major surgicalprocedure during the study

• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiationof study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent aurinary tract infection or chronic obstructive pulmonary disease exacerbation) areeligible for the study.

• Prior allogeneic stem cell or solid organ transplantation

• Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior toinitiation of study treatment, during treatment with Cemiplimab, and for 5 monthsafter the last dose of Cemiplimab.

• Current treatment with anti-viral therapy for HBV

• Has had prior chemotherapy, immunotherapy, targeted small molecule therapy, orradiation therapy within 2 weeks prior to study Day 1

• History of severe allergic anaphylactic reactions to human antibodies.

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

• Known allergy or hypersensitivity to any component of ATRA

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