Clinical Trials /

TSR-042 in People With Locally Advanced Mismatch Repair Deficient Rectal Cancer

NCT04165772

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 rectal cancer. The study will also look at the safety of the study drug.

Related Conditions:
  • Rectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: TSR-042 in People With Locally Advanced Mismatch Repair Deficient Rectal Cancer
  • Official Title: A Phase II Study of Induction PD-1 Blockade in Subjects With Locally Advanced Mismatch Repair Deficient Rectal Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: 19-288
  • NCT ID: NCT04165772

Conditions

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

Interventions

DrugSynonymsArms
TSR-042Patients with rectal adenocarcinoma
capecitabinePatients with rectal adenocarcinoma

Purpose

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 rectal cancer. The study will also look at the safety of the study drug.

Trial Arms

NameTypeDescriptionInterventions
Patients with rectal adenocarcinomaExperimentalPatients with clinical Stage II (T3-4, N-) or Stage III (any T, N+) MRI-staged, MSI-H or dMMR, rectal cancer will receive up to 6 months (8, 3-week cycles) of PD-1 blockade followed by standard chemoradiation (with concurrent capecitabine) and then TME (total mesorectal excision). Patients will be given TSR-042 500mg flat dose Q3 weeks. Patients will be evaluated initially 6 weeks and 3 month intervals on anti-PD1 therapy with rectal MRI, CT chest abdomen and pelvis and DRE (digital rectal exam)/endoscopic rectal ultrasound evaluation. Patients with tumor progression at any point will be treated with standard chemoradiation.
  • TSR-042
  • capecitabine

Eligibility 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 rectal adenocarcinoma.

          -  Clinical stage: Stage II (T3-4, N-) or Stage III (any T, N+)

          -  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 registration, 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 as long as their dose is
                  stable for least 4 weeks prior to initiating protocol therapy.

               -  Demonstrate adequate organ function as defined below, all screening labs should
                  be performed within 8 days of treatment initiation.

        Exclusion Criteria:

          -  Recurrent rectal cancer.

          -  Prior pelvic radiation therapy, chemotherapy, or surgery for rectal cancer.

          -  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.

          -  Tumor is causing symptomatic bowel obstruction (patients who have a temporary
             diverting ostomy are eligible).

          -  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.

          -  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, with the exception
             of 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:pathologic complete response (pCR)
Time Frame:1 year
Safety Issue:
Description:pCR is defined as complete absence of tumor determined pathologically post neoadjuvant therapy.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • PD1 blockade
  • TSR-042
  • Radiation
  • Capecitabine
  • 5-FU
  • 19-288

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