Dostarlimab before Chemoradiotherapy and Surgery for the Treatment of Locally Advanced Mismatch Repair Deficiency or Microsatellite Instability Rectal Cancer
- Willing and able to provide written informed consent for the trial
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Histologically confirmed rectal adenocarcinoma
- Rectal cancer 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 next generation sequencing (NGS) or polymerase chain reaction (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
- Absolute neutrophil count (ANC) >= 1,500 /mm^3 (within 14 days of cycle 1 day 1)
- Platelets >= 100,000 / mcL (within 14 days of cycle 1 day 1)
- Hemoglobin > 9 g/dL or >= 5.6 mmol/L (within 14 days of cycle 1 day 1)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (within 14 days of cycle 1 day 1) * Creatinine clearance should be calculated per institutional standard
- Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 14 days of cycle 1 day 1)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (within 14 days of cycle 1 day 1)
- For patients not taking warfarin: international normalized ratio (INR) =< 1.5 or prothrombin time (PT) < 1.5 x ULN; and either partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN. Patients on warfarin may be included on a stable dose with a therapeutic INR < 3.5 (within 14 days of cycle 1 day 1)
- Recurrent rectal cancer
- Prior pelvic radiation therapy, chemotherapy, or surgery for rectal cancer
- 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 adverse event (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., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [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
I. To determine the pathologic complete response rate (pCR) or complete clinical response (cCR) rate at 12 months, after PD-1 blockade with or without chemoradiation in subjects with mismatch repair deficient locally advanced rectal adenocarcinoma.
I. Determine the objective response rate (ORR) after PD-1 blockade.
II. Determine the safety and tolerability of PD-1 blockade in subjects with mismatch repair deficient locally advanced rectal cancer.
I. To investigate the relationship between candidate efficacy/resistance biomarkers (from blood and tumor) and anti-tumor activity of PD-1 blockade using pre-treatment tumor biopsies, as well as tumor specimens from responder patients.
II. To evaluate the feasibility of using circulating tumor deoxyribonucleic acid (DNA) in plasma to monitor tumor response in rectal cancer patients.
III. To determine the molecular characteristics of response and resistance to PD-1 blockade in mismatch repair (MMR) deficient tumors.
Patients receive dostarlimab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Beginning 6-8 weeks after completion of dostarlimab, patients who do not have a complete clinical response receive standard of care capecitabine orally (PO) twice daily (BID) or fluorouracil IV continuously for 5 days per week, and concurrently undergo standard of care intensity-modulated radiation therapy (IMRT) 5 days per week for 5.5 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery.
After completion of study treatment, patients are followed up every 4 months for up to 5 years.
Trial Phase Phase II
Trial Type Treatment
Memorial Sloan Kettering Cancer Center
- Primary ID 19-288
- Secondary IDs NCI-2019-08450
- Clinicaltrials.gov ID NCT04165772