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

NCT04165772 | Recruiting Phase 2 FDA Drug

• 1 other identifier: 19-288
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Pathologic complete response (pCR) or complete clinical response (cCR) at 12 months

  To determine the pathologic complete response rate (pCR) or complete clinical response (cCR) rate at 12 months, after PD-1 blockade and with or without chemoradiation in subjects with mismatch repair deficient locally advanced adenocarcinoma.

  12 months

Study Arms (2)

Cohort 1

EXPERIMENTAL

Patients with clinical Stage II or Stage III MRI-staged, MSI-H or dMMR, solid tumors will receive up to 6 months (9, 21-day cycles) of PD-1 blockade followed by radiological and surgical restaging of the tumor. If subject exhibits complete clinical response, non-operative management will be followed. If a complete clinical response is not reached after 6 months of PD-1 blockade, the participant will proceed with standard chemoradiation. After completing chemoradiation participant will be assessed for response if complete CR is not obtained then the participant will proceed with disease specific surgical resection or standard of care therapy.

Drug: TSR-042 or Dostarlimab; Drug: capecitabine or 5-FU; Radiation: Intensity Modulated Radiation Therapy (IMRT)

Cohort 2

OTHER

The plan is to enroll six patients with MSI, regardless of their primary cancer diagnosis. This cohort will serve to generate hypothesis and initial data to plan a larger study. All analyses from this cohort will be exploratory

Drug: TSR-042 or Dostarlimab

Interventions

TSR-042 or Dostarlimab DRUG

Patients will be given TSR-042/Dostarlimab at a dose of 500mg IV, over 30 minutes Q 3 weeks.

Also known as: Dostarlimab

Cohort 1; Cohort 2

capecitabine or 5-FU DRUG

Capecitabine 825mg/m2 BID concurrently with radiation per standard radiation guidelines. If patient is unable to tolerate oral medication, infusional 5-FU is an acceptable alternative.

Cohort 1

Intensity Modulated Radiation Therapy (IMRT) RADIATION

The radiation dose is 5400 cGy to the tumor and surrounding nodes 4700 cGy to the pelvis, with an integrated boost to the primary tumor and involved nodes of receiving 5400cGy in 27fx.

Cohort 1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead
• Tesaro, Inc.: collaborator

Study Sites (10)

Hartford Healthcare (Data Collection)

Hartford, Connecticut, 06102, United States

RECRUITING

Baptist Alliance MCI (Data Collection Only)

Miami, Florida, 33143, United States

RECRUITING

Memorial Sloan Kettering Basking Ridge - Limited Protocol Activities

Basking Ridge, New Jersey, 07920, United States

RECRUITING

Memorial Sloan Kettering Monmouth - Limited Protocol Activities

Middletown, New Jersey, 07748, United States

RECRUITING

Memorial Sloan Kettering Bergen - Limited Protocol Activities

Montvale, New Jersey, 07645, United States

RECRUITING

Memorial Sloan Kettering Commack - Limited Protocol Activities

Commack, New York, 11725, United States

RECRUITING

Memorial Sloan Kettering Westchester - Limited Protocol Activities

Harrison, New York, 10604, United States

RECRUITING

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

RECRUITING

Memorial Sloan Kettering Nassau - Limited Protocol Activities

Uniondale, New York, 11553, United States

RECRUITING

Lehigh Valley Health Network (Data Collection Only)

Allentown, Pennsylvania, 18103, United States

RECRUITING

Related Publications (4)

• Cercek A, Foote MB, Rousseau B, Smith JJ, Shia J, Sinopoli J, Weiss J, Lumish M, Temple L, Patel M, Wilde C, Saltz LB, Argiles G, Stadler Z, Artz O, Maron S, Ku G, Gu P, Janjigian YY, Molena D, Iyer G, Coleman J, Abida W, Cohen S, Soares K, Schattner M, Strong VE, Yaeger R, Paty P, Shcherba M, Sugarman R, Romesser PB, Zervoudakis A, Desai A, Segal NH, El Dika I, Widmar M, Wei I, Pappou E, Fumo G, Aparo S, Gonen M, Gollub M, Jayaprakasam VS, Kim TH, Garcia Aguilar J, Weiser M, Diaz LA Jr. Nonoperative Management of Mismatch Repair-Deficient Tumors. N Engl J Med. 2025 Jun 19;392(23):2297-2308. doi: 10.1056/NEJMoa2404512. Epub 2025 Apr 27.

  PMID: 40293177 DERIVED

• Saude-Conde R, Nguyen D, Hendlisz A. Immunotherapies in non-metastatic gastrointestinal cancers. Curr Opin Oncol. 2023 Jul 1;35(4):334-346. doi: 10.1097/CCO.0000000000000956. Epub 2023 May 9.

  PMID: 37222204 DERIVED

• Costa B, Vale N. Dostarlimab: A Review. Biomolecules. 2022 Jul 26;12(8):1031. doi: 10.3390/biom12081031.

  PMID: 35892341 DERIVED

• Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, El Dika IH, Segal N, Shcherba M, Sugarman R, Stadler Z, Yaeger R, Smith JJ, Rousseau B, Argiles G, Patel M, Desai A, Saltz LB, Widmar M, Iyer K, Zhang J, Gianino N, Crane C, Romesser PB, Pappou EP, Paty P, Garcia-Aguilar J, Gonen M, Gollub M, Weiser MR, Schalper KA, Diaz LA Jr. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N Engl J Med. 2022 Jun 23;386(25):2363-2376. doi: 10.1056/NEJMoa2201445. Epub 2022 Jun 5.

  PMID: 35660797 DERIVED

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

dostarlimab; Capecitabine; Fluorouracil; Radiotherapy, Intensity-Modulated

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Radiotherapy; Therapeutics

Study Officials

• Andrea Cercek, MD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Andrea Cercek, MD

CONTACT

646-888-4189; cerceka@mskcc.org

Neil Segal, MD, PhD

CONTACT

646-888-4187

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a Phase II study investigating the efficacy of PD1 blockade with TSR-042 in patients with locally advanced MMRd or MSI rectal adenocarcinoma.

Study Record Dates

• First Submitted: November 13, 2019
• First Posted: November 18, 2019
• Study Start: December 11, 2019
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): November 30, 2026
• Last Updated: January 23, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share

Locations

US (10)