Dostarlimab before Chemoradiotherapy and Surgery for the Treatment of Locally Advanced Mismatch Repair Deficiency or Microsatellite Instability Solid Tumors

Inclusion Criteria

• Willing and able to provide written informed consent for the trial
• Be >= 18 years of age on the date of signing informed consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Histologically confirmed locally advanced solid tumor
• Solid tumors that in standard practice would be treated with neoadjuvant therapy or surgery (depending on tumor type)
• No evidence of distant metastases
• Tumor specimen that demonstrates mismatch repair deficiency by immunohistochemistry or microsatellite instability as demonstrated by next generation sequencing (NGS) or polymerase chain reaction (PCR)
• Negative pregnancy test done 72 hours prior to beginning treatment, for women of childbearing potential only. Subjects of childbearing potential must be willing to use a highly effective method of contraception (with a failure rate of <1% per year). Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives, or double barrier method (diaphragm plus condom). Contraception, for the course of the study starting with the first dose of study medication through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Nonchildbearing potential is defined as follows (by other than medical reasons): * >= 45 years of age and has not had menses for > 1 year * Patients who have been amenorrhoeic for < 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation * Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use 2 adequate barrier methods throughout the study
• Participant receiving corticosteroids may continue if their dose is stable for least 4 weeks prior to initiating protocol therapy
• Has corrected QT interval by Fridericia (QTcF) =< 450 msec, or =< 480 msec for participants with bundle branch block
• Absolute neutrophil count (ANC) >= 1,500 /mm^3 (within 14 days of cycle 1 day 1)
• Platelets >= 100,000 / mcL (within 14 days of cycle 1 day 1)
• Hemoglobin > 8 g/dL (within 14 days of cycle 1 day 1)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (within 14 days of cycle 1 day 1) * Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 14 days of cycle 1 day 1)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (within 14 days of cycle 1 day 1)
• For patients not taking warfarin: international normalized ratio (INR) =< 1.5 or prothrombin time (PT) < 1.5 x ULN; and either partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN. Patients on warfarin may be included on a stable dose with a therapeutic INR < 3.5 (within 14 days of cycle 1 day 1)

Exclusion Criteria

• Presence of metastatic or recurrent disease
• Prior radiation therapy, chemotherapy, or surgery for tumor
• For patients with colorectal primary - Tumor is causing symptomatic bowel obstruction (patients who have a temporary diverting ostomy are eligible)
• COHORT 1 ONLY: Other invasive malignancy =< 5 years prior to registration. Exceptions are non-melanoma skin cancer that has undergone potentially curative therapy and in situ cervical carcinoma
• Diagnosis of immunodeficiency or receiving systemic steroid therapy (> 10 mg daily prednisone or equivalent) or any other form of non- physiologic dose immunosuppressive therapy within 7 days prior to first dose of trial treatment. Use of inhaled steroids, local injection of steroids, topical steroids, and steroidal eye drops are allowed
• Active autoimmune disease requiring systemic treatment within the past 2 years or documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents at non-physiologic doses
• Active infection requiring systemic therapy
• COHORT 1 ONLY: Received prior therapy with an antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
• Has experienced any of the following with prior immunotherapy: any immune-related adverse event (AE) >= grade 3, immune-related severe neurologic events of any-grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain-Barre Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (Stevens-Johnson Syndrome, toxic epidermal necrolysis, or Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS] syndrome), or myocarditis of any grade. Non- clinically significant laboratory abnormalities are not exclusionary
• Other anticancer or experimental therapy. No other experimental therapies (including chemotherapy, radiation, hormonal treatment, antibody therapy, immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, matrix metalloprotease inhibitors, thalidomide, anti-VEGF/Flk-1 monoclonal antibody or other experimental drugs) of any kind are permitted while the patient is receiving study treatment
• Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Women who are pregnant or breastfeeding, or men expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening visit through 150 days after the last dose of study medication
• Concurrent medical or psychiatric condition or disease which, in the investigator’s judgement, would make them inappropriate candidates for entry into the study. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, chronic obstructive pulmonary disease, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent
• Received a live vaccine within 30 days of planned start of study medication
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment
• History of interstitial lung disease or pneumonitis
• Known hypersensitivity to dostarlimab components or excipients
• Has a history of or evidence of cardiac abnormalities such as serious, uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities within the 6 months prior to enrollment, including: Second degree (Type II) or third degree atrioventricular block. Cardiomyopathy, myocarditis, myocardial infraction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting. Symptomatic pericarditis