Study of Induction PD-1 Blockade in Subjects With Locally Advanced Mismatch Repair Deficient 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.

• 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

• No evidence of distant metastases.

• Radiologically measurable or clinically evaluable disease

• Tumor specimen that demonstrates mismatch repair deficiency by Immunohistochemistryor microsatellite instability as demonstrated by NGS or PCR.

• Negative pregnancy test done 72 hours prior to beginning treatment, for women ofchildbearing potential only. Subjects of childbearing potential must be willing touse an adequate method of contraception. Appropriate methods of birth controlinclude abstinence, oral contraceptives, implantable hormonal contraceptives, ordouble barrier method (diaphragm plus condom). Contraception, for the course of thestudy starting with the first dose of study medication through 150 days after thelast dose of study medication. Note: Abstinence is acceptable if this is the usuallifestyle 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 hysterectomyand oophorectomy must have a follicle stimulating hormone value in thepostmenopausal range upon screening evaluation

• Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documentedhysterectomy or oophorectomy must be confirmed with medical records of the actualprocedure or confirmed by an ultrasound. Tubal ligation must be confirmed withmedical records of the actual procedure, otherwise the patient must be willing touse 2 adequate barrier methods throughout the study.

• Participant receiving corticosteroids may continue if their dose is stable forleast 4 weeks prior to initiating protocol therapy.

• Has QTcF ≤ 450 msec, or ≤ 480 msec for participants with bundle branch block.

• Demonstrate adequate organ function as defined below within 14 days of Cycle 1,Day 1, all screening labs should be performed within 14 days of treatmentinitiation.

• Hematological

• Absolute neutrophil count (ANC) ≥1,500 /mcL

• Platelets ≥100,000 / mcL

• Hemoglobin >9 g/dL or ≥5.6 mmol/L

• Renal

• Serum creatinine OR Measured or calculated(a) creatinine clearance (GFR can also beused in place of creatinine or CrCl) ≤1.5 × upper limit of normal (ULN) OR ≥60mL/min for subject with creatinine levels > 1.5 × institutional ULN

• Hepatic

• Serum total bilirubin ≤ 1.5 × ULN OR Direct bilirubin ≤ ULN for subjects with totalbilirubin levels > 1.5 ULN

• AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN

• Coagulation

• International Normalized Ratio (INR) or Prothrombin Time (PT) Activated PartialThromboplastin Time (aPTT) ≤1.5 × ULN unless subject is receiving anticoagulanttherapy as long as PT or PTT is within therapeutic range of intended use ofanticoagulants ≤1.5 × ULN unless subject is receiving anticoagulant therapy as longas PT or PTT is within therapeutic range of intended (a) Creatinine clearance shouldbe calculated per institutional standard.

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. Exceptionsare non-melanoma skin cancer that has undergone potentially curative therapy and insitu cervical carcinoma.

• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any otherform of non- physiologic dose immunosuppressive therapy within 7 days prior to firstdose of trial treatment.

• Active autoimmune disease requiring systemic treatment within the past 2 years ordocumented history of clinically severe autoimmune disease, or a syndrome thatrequires 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 specificallytargeting T- cell co-stimulation or checkpoint pathways.

• Experienced ≥ Grade 3 immune-related AE with prior immunotherapy, except fornon-clinically significant lab abnormalities.

• Other Anticancer or Experimental Therapy. No other experimental therapies (includingchemotherapy, radiation, hormonal treatment, antibody therapy, immunotherapy, genetherapy, vaccine therapy, angiogenesis inhibitors, matrix metalloproteaseinhibitors, thalidomide, anti-VEGF/Flk-1 monoclonal antibody or other experimentaldrugs) 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., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

• Women who are pregnant or breastfeeding, or men expecting to conceive or fatherchildren within the projected duration of the trial, starting with the pre-screeningvisit through 150 days after the last dose of study medication.

• Concurrent medical or psychiatric condition or disease which, in the investigator'sjudgement, 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 pulmonarydisease, uncontrolled major seizure disorder, unstable spinal cord compression,superior vena cava syndrome, or any psychiatric disorder that prohibits obtaininginformed consent.

• Received a live vaccine within 30 days of planned start of study medication.

• Major surgical procedure, open biopsy, or significant traumatic injury within 28days prior to enrollment.

• History of interstitial lung disease.

• Known hypersensitivity to TSR-042 components or excipients.