RECRUITING

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

Conditions

Rectal Adenocarcinoma Clinical Stage: Stage II (T3-4, N-)Stage III (Any T, N+)Solid Tumor Solid Tumor, Adult PD1 blockade TSR-042 Radiation Capecitabine 5-FU 19-288 Dostarlimab

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

The purpose of this study is to find out whether the study drug, TSR-042, followed by standard chemoradiotherapy (the chemotherapy drug capecitabine + radiation therapy) and standard surgery is an effective treatment for advanced dMMR solid tumors. The study will also look at the safety of the study drug.

Official Title

A Phase II Study of Induction PD-1 Blockade in Subjects With Locally Advanced Mismatch Repair Deficient Solid Tumors

Quick Facts

Study Start:2019-12-11

Study Completion:2026-11-30

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT04165772

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion 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 Immunohistochemistry or microsatellite instability as demonstrated by NGS or 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 an adequate method of contraception. 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 150 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. * ≥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 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 treatment initiation. * 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 be used in place of creatinine or CrCl) ≤1.5 × upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \> 1.5 × institutional ULN * Hepatic * Serum total bilirubin ≤ 1.5 × ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN * AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN * Coagulation * International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended (a) Creatinine clearance should be calculated per institutional standard.	* 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 or any other form of non- physiologic dose immunosuppressive therapy within 7 days prior to first dose of trial treatment. * 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. * Experienced ≥ Grade 3 immune-related AE with prior immunotherapy, except for non-clinically significant lab abnormalities. * 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., HBsAg reactive) or Hepatitis C (e.g., HCV 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. * Known hypersensitivity to TSR-042 components or excipients.

Inclusion Criteria

Exclusion 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 Immunohistochemistry or microsatellite instability as demonstrated by NGS or 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 an adequate method of contraception. 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 150 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
* ≥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 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 treatment initiation.
* 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 be used in place of creatinine or CrCl) ≤1.5 × upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \> 1.5 × institutional ULN
* Hepatic
* Serum total bilirubin ≤ 1.5 × ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN
* AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN
* Coagulation
* International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended (a) Creatinine clearance should be calculated per institutional standard.

* 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 or any other form of non- physiologic dose immunosuppressive therapy within 7 days prior to first dose of trial treatment.
* 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.
* Experienced ≥ Grade 3 immune-related AE with prior immunotherapy, except for non-clinically significant lab abnormalities.
* 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., HBsAg reactive) or Hepatitis C (e.g., HCV 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.
* Known hypersensitivity to TSR-042 components or excipients.

Contacts and Locations

Study Contact

Andrea Cercek, MD

CONTACT

646-888-4189

cerceka@mskcc.org

Neil Segal, MD, PhD

CONTACT

646-888-4187

Principal Investigator

Andrea Cercek, MD

PRINCIPAL_INVESTIGATOR

Memorial Sloan Kettering Cancer Center

Study Locations (Sites)

Hartford Healthcare (Data Collection)

Hartford, Connecticut, 06102

United States

Baptist Alliance MCI (Data Collection Only)

Miami, Florida, 33143

United States

Memorial Sloan Kettering Basking Ridge - Limited Protocol Activities

Basking Ridge, New Jersey, 07920

United States

Memorial Sloan Kettering Monmouth - Limited Protocol Activities

Middletown, New Jersey, 07748

United States

Memorial Sloan Kettering Bergen - Limited Protocol Activities

Montvale, New Jersey, 07645

United States

New York Cancer and Blood Specialists

Babylon, New York, 11702

United States

Memorial Sloan Kettering Commack - Limited Protocol Activities

Commack, New York, 11725

United States

Memorial Sloan Kettering Westchester - Limited Protocol Activities

Harrison, New York, 10604

United States

Memorial Sloan Kettering Cancer Center

New York, New York, 10065

United States

Memorial Sloan Kettering Nassau - Limited Protocol Activities

Uniondale, New York, 11553

United States

Lehigh Valley Health Network (Data Collection Only)

Allentown, Pennsylvania, 18103

United States

Collaborators and Investigators

Sponsor: Memorial Sloan Kettering Cancer Center

Andrea Cercek, MD, PRINCIPAL_INVESTIGATOR, Memorial Sloan Kettering Cancer Center

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2019-12-11

Study Completion Date2026-11-30

Study Record Updates

Study Start Date2019-12-11

Study Completion Date2026-11-30

Terms related to this study

Keywords Provided by Researchers

PD1 blockade
TSR-042
Radiation
Capecitabine
5-FU
19-288
Solid tumor
Dostarlimab

Additional Relevant MeSH Terms

Rectal Adenocarcinoma
Clinical Stage: Stage II (T3-4, N-)
Stage III (Any T, N+)
Solid Tumor
Solid Tumor, Adult