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

• ClinicalTrials.gov Identifier: NCT04165772
• Recruitment Status: Recruiting
• First Posted: November 18, 2019
• Last Update Posted: March 29, 2023
• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborator: Tesaro, Inc.
• Information provided by (Responsible Party): Memorial Sloan Kettering Cancer Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Rectal Adenocarcinoma; Clinical Stage: Stage II (T3-4, N-); Stage III (Any T, N+); Solid Tumor; Solid Tumor, Adult	Drug: TSR-042 or Dostarlimab; Drug: capecitabine or 5-FU; Radiation: Intensity Modulated Radiation Therapy (IMRT)	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 200 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 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.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Induction PD-1 Blockade in Subjects With Locally Advanced Mismatch Repair Deficient Solid Tumors
• Actual Study Start Date: December 11, 2019
• Estimated Primary Completion Date: November 30, 2023
• Estimated Study Completion Date: November 30, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; 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; Patients will be given TSR-042/Dostarlimab at a dose of 500mg IV, over 30 minutes Q 3 weeks.; Other Name: Dostarlimab; Drug: capecitabine or 5-FU; 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.; Radiation: Intensity Modulated Radiation Therapy (IMRT); 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 2; 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; Patients will be given TSR-042/Dostarlimab at a dose of 500mg IV, over 30 minutes Q 3 weeks.; Other Name: Dostarlimab

Outcome Measures

Primary Outcome Measures :

1. Pathologic complete response (pCR) or complete clinical response (cCR) at 12 months [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 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.
  • 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.

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 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

Contacts

Contact: Andrea Cercek, MD; 646-888-4189; cerceka@mskcc.org

Contact: Neil Segal, MD, PhD; 646-888-4187

Locations

United States, Connecticut

Hartford Healthcare (Data Collection); Recruiting

Hartford, Connecticut, United States, 06102

Contact: Gerard Fumo, DO 860-972-4700

United States, Florida

Baptist Alliance MCI (Data Collection Only); Recruiting

Miami, Florida, United States, 33143

Contact: Antonio Ucar, MD 786-373-3436

United States, New Jersey

Memorial Sloan Kettering Basking Ridge - Limited Protocol Activities; Recruiting

Basking Ridge, New Jersey, United States, 07920

Contact: Andrea Cercek, MD 646-888-4189

Principal Investigator: Andrea Cercek, MD

Memorial Sloan Kettering Monmouth - Limited Protocol Activities; Recruiting

Middletown, New Jersey, United States, 07748

Contact: Andrea Cercek, MD 646-888-4189

Memorial Sloan Kettering Bergen - Limited Protocol Activities; Recruiting

Montvale, New Jersey, United States, 07645

Contact: Andrea Cercek, MD 646-888-4189

United States, New York

New York Cancer and Blood Specialists; Recruiting

Babylon, New York, United States, 11702

Contact: Richard Zuniga, MD 631-751-3000

Memorial Sloan Kettering Commack - Limited Protocol Activities; Recruiting

Commack, New York, United States, 11725

Contact: Andrea Cercek, MD 646-888-4189

Principal Investigator: Andera Cercek, MD

Memorial Sloan Kettering Westchester - Limited Protocol Activities; Recruiting

Harrison, New York, United States, 10604

Contact: Andrea Cercek, MD 646-888-4189

Memorial Sloan Kettering Cancer Center; Recruiting

New York, New York, United States, 10065

Contact: Andrea Cercek, MD 646-888-4189

Contact: Leonard Saltz, MD 646-888-4181

Principal Investigator: Andrea Cercek, MD

Memorial Sloan Kettering Nassau - Limited Protocol Activities; Recruiting

Uniondale, New York, United States, 11553

Contact: Andrea Cercek, MD 646-888-4189

United States, Pennsylvania

Lehigh Valley Health Network (Data Collection Only); Recruiting

Allentown, Pennsylvania, United States, 18103

Contact: Maged Khalil, MD 610-402-7880

Sponsors and Collaborators

Memorial Sloan Kettering Cancer Center

Tesaro, Inc.

Investigators

• Principal Investigator: Andrea Cercek, MD; Memorial Sloan Kettering Cancer Center

More Information

Additional Information:

Memorial Sloan Kettering Cancer Center 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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

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.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT04165772
• Other Study ID Numbers: 19-288
• First Posted: November 18, 2019
• Last Update Posted: March 29, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Memorial Sloan Kettering Cancer Center:

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

Additional relevant MeSH terms:

Neoplasms; Capecitabine; Dostarlimab; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents