Tislelizumab for the Treatment of Patients with Mismatch Repair Deficient Metastatic Colorectal Cancer or Stage II or III Rectal Cancer
This phase II trial tests how well tislelizumab works in treating patients with mismatch repair deficient colorectal cancer that has spread from where it first started (primary site) to other places in the body (metastatic) or stage II or III rectal cancer. Tislelizumab is a type of drug called a PD-1 inhibitor. It is designed to block a protein called programmed cell death protein 1, which acts as a “brake” on the immune system. Blocking this protein is like releasing the brakes, so the immune system can target tumor cells and destroy them.
Inclusion Criteria
- ALL SUBJECTS: Age 18 years or older on date of signing informed consent
- ALL SUBJECTS: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- ALL SUBJECTS: Negative pregnancy test done within 72 hours prior to start of treatment for women of childbearing potential * Women of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study and for >= 120 days after the last dose of tislelizumab. They must also have a negative urine or serum pregnancy test result =< 7 days before first dose of study drug ** The Clinical Trials Facilitation Group recommendations related to contraception and pregnancy testing in clinical studies include the use of highly effective forms of birth control (Clinical Trials Facilitation Group 2014). These methods include the following: *** Oral, intravaginal, or transdermal combined (estrogen- and progestogen-containing) hormonal contraception associated with the inhibition of ovulation *** Oral, injectable, implantable progestogen-only hormonal contraception associated with the inhibition of ovulation **** Note: Oral birth control pills are not considered a highly effective form of birth control, and if they are selected, they must be used with a second, barrier method of contraception such as condoms with or without spermicide *** An intrauterine device *** Intrauterine hormone-releasing system *** Bilateral tubal occlusion *** Vasectomized partner **** Note: This is only considered a highly effective form of birth control when the vasectomized partner is the sole partner of the study participant and there has been a medical assessment confirming surgical success *** A sterile male is one for whom azoospermia, in a semen sample, has been demonstrated as definitive evidence of infertility *** Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment) **** Note: Total sexual abstinence should only be used as a contraceptive method if it is in line with the patients’ usual and preferred lifestyle. Periodic abstinence (eg, calendar, ovulation, sympto-thermal, postovulation methods), declaration of abstinence for the duration of exposure to study drug, and withdrawal are not acceptable methods of contraception ** Of note, barrier contraception (including male and female condoms with or without spermicide) is not considered a highly effective method of contraception; if used, this method must be used in combination with one of the highly effective forms of birth control listed above * “Women of non-childbearing potential” are defined as female patients meeting any of the following criteria: ** Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or hysterectomy) ** Postmenopausal, defined as: *** >= 55 years of age with no spontaneous menses for >= 12 months OR *** < 55 years of age with no spontaneous menses for >= 12 months AND with postmenopausal follicle-stimulating hormone (FSH) concentration > 30 IU/mL and all alternative medical causes for the lack of spontaneous menses for >= 12 months have been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, etc *** If an FSH measurement is required to confirm postmenopausal state, concomitant use of hormonal contraception or hormonal replacement therapy should be excluded (adapted from Clinical Trials Facilitation Group [CTFG] 2014.) * Nonsterile males must be willing to use a highly effective method of birth control for the duration of the study and for >= 120 days after the last dose of tislelizumab ** A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility ** Males with known "low sperm counts" (consistent with "subfertility") are not to be considered sterile
- ALL SUBJECTS: The ability to adhere to the study protocol and willingness to provide informed consent
- ALL SUBJECTS: Absolute neutrophil count (ANC) >= 1,500 /mm^3 (within 14 days of cycle 1 day 1)
- ALL SUBJECTS: Platelets >= 100,000/mcL (within 14 days of cycle 1 day 1)
- ALL SUBJECTS: Hemoglobin > 9 g/dL or >= 5.6 mmol/L (within 14 days of cycle 1 day 1)
- ALL SUBJECTS: Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 30 mL/min for subjects with creatinine levels > 1.5 x institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) (within 14 days of cycle 1 day 1)
- ALL SUBJECTS: 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)
- ALL SUBJECTS: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (< 5 x ULN if hepatic metastases are present in cohort 1) (within 14 days of cycle 1 day 1)
- ALL SUBJECTS: International normalized ratio (INR) =< 1.5 or prothrombin time (PT) =< 1.5 x ULN (within 14 days of cycle 1 day 1) * Patients on warfarin may be included on a stable dose with a therapeutic INR < 3.5
- ALL SUBJECTS: Either partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN (within 14 days of cycle 1 day 1)
- COHORT 1: Histological confirmation of colorectal adenocarcinoma
- COHORT 1: Confirmation of dMMR by immunohistochemistry
- COHORT 1: Radiologically measurable metastatic disease as per RECIST 1.1, not eligible for potentially curative surgery
- COHORT 2: Histological confirmation of rectal adenocarcinoma
- COHORT 2: Confirmation of dMMR by immunohistochemistry
- COHORT 2: Rectal cancer stage II or III per American Joint Committee on Cancer (AJCC) 8th edition criteria
- COHORT 2: No evidence of distant metastases
- The ability to adhere to the study protocol and willingness to provide informed consent
Exclusion Criteria
- ALL SUBJECTS: Presence of other active malignancy
- ALL SUBJECTS: Diagnosis of immunodeficiency or receiving systemic steroid therapy or other immunosuppressive therapy within 7 days prior to first dose of treatment * Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication =< 14 days before first dose of study drug. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of an active autoimmune disease. Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded: ** Adrenal replacement steroid (dose =< 10 mg daily of prednisone or equivalent) ** Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption ** Short course (=< 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen
- ALL SUBJECTS: Active autoimmune disease requiring systemic therapy within the 2 years prior to treatment initiation * Well controlled hypothyroidism, diabetes, and skin conditions allowed
- ALL SUBJECTS: Untreated active hepatitis B or hepatitis C * Patients actively on therapy with disease under control are allowed
- ALL SUBJECTS: Untreated acquired immunodeficiency syndrome (AIDS) * Patients with human immunodeficiency virus (HIV) well controlled on anti-retroviral therapy are allowed
- ALL SUBJECTS: Infection (including tuberculosis infection, etc.) requiring systemic (oral or intravenous) antibacterial, antifungal, or antiviral therapy =< 14 days before first dose of study drug
- ALL SUBJECTS: History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases including pulmonary fibrosis * Patients with significantly impaired pulmonary function or who require supplemental oxygen at baseline must undergo an assessment of pulmonary function at screening
- ALL SUBJECTS: Currently receiving other anticancer or experimental therapy
- ALL SUBJECTS: Has received prior therapy with an immune checkpoint inhibitor
- ALL SUBJECTS: Prior >= grade 3 immune-related adverse event (AE) from previous immunotherapy
- ALL SUBJECTS: Pregnant women, women who are breast-feeding, or men expecting to conceive or father children during the trial period, through 120 days after last dose of medication
- ALL SUBJECTS: Receipt of live vaccine within 30 days of planned treatment start
- ALL SUBJECTS: Major surgical procedure or significant traumatic injury within 28 days prior to enrollment
- ALL SUBJECTS: Known hypersensitivity to tislelizumab
- ALL SUBJECTS: Prior allogeneic stem cell or organ transplantation
- ALL SUBJECTS: Any of the following cardiovascular risk factors: * Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, =< 28 days before first dose of study drug * Pulmonary embolism =< 28 days before first dose of study drug * Any history of acute myocardial infarction =< 6 months before first dose of study drug * Any history of heart failure meeting New York Heart Association Classification III or IV =< 6 months before first dose of study drug * Any event of ventricular arrhythmia >= grade 2 in severity =< 6 months before first dose of study drug * Any history of cerebrovascular accident =< 6 months before first dose of study drug * Uncontrolled hypertension that cannot be managed by standard antihypertension medications =< 28 days before first dose of study drug * Any episode of syncope or seizure =< 28 days before first dose of study drug
- COHORT 1: Prior immunotherapy, chemotherapy, radiation therapy, or surgery for metastatic colorectal cancer * Treatment with adjuvant therapy of prior localized tumor is allowable as long as it was completed at least 6 months prior to cycle 1 day 1
- COHORT 1: Known active central nervous system (CNS) metastasis and/or carcinomatous meningitis * Patients with previously treated brain metastases may participate if the brain metastases are stable via MRI assessment, performed >= 4 weeks after treatment
- COHORT 2: Prior immunotherapy, chemotherapy, radiation therapy, or surgery for localized rectal cancer
- COHORT 2: Presence of metastatic or recurrent disease
Additional locations may be listed on ClinicalTrials.gov for NCT06529523.
Locations matching your search criteria
United States
New York
New York
PRIMARY OBJECTIVE:
I. To estimate the overall response rate (ORR; defined as complete response, CR or partial response, PR) by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria separately in patients with treatment naive metastatic mismatch repair deficient (dMMR) colorectal cancer (cohort 1) and treatment naive localized dMMR rectal cancer (cohort 2) to PD-1 blockade therapy with tislelizumab in Nigeria.
SECONDARY OBJECTIVES:
I. To estimate progression free survival (PFS), overall survival (OS), and duration of response (DOR) in cohort 1 and 2, separately.
II. To estimate the screening rate (defined as proportion of colorectal cancer [CRC] patients with dMMR tumors approached who agreed to be screened for the study) and the rate of treatment initiation for enrolled patients (defined as proportion of enrolled patients that initiated at least one dose of tislelizumab).
III. To estimate the feasibility of assessment by magnetic resonance imaging (MRI) and colonoscopy in cohort 2 (defined as the proportion of patients enrolled in cohort 2 that completed their per protocol MRI and colonoscopy, separately).
IV. To estimate adverse events from PD-1 blockade with tislelizumab in cohort 1 and 2, separately.
V. To describe changes in global health status from baseline.
EXPLORATORY OBJECTIVES:
I. To investigate the relationship between pre-treatment tumor-derived biomarkers and antitumor activity of PD-1 blockade.
II. To investigate the relationship between serial circulating tumor deoxyribonucleic acid (DNA) in plasma and the feasibility of using it to monitor treatment response.
III. To study the molecular characteristics of response and resistance to PD-1 blockade therapy in dMMR CRC.
OUTLINE: Patients with dMMR metastatic colorectal cancer are assigned to Cohort 1 and patients with dMMR localized rectal cancer are assigned to Cohort 2.
COHORT 1: Patients receive tislelizumab intravenously (IV) once every 3 weeks (Q3W). Treatment repeats every 3 weeks for up to 104 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) throughout the study and undergo collection of blood samples at screening and on study. Patients may undergo colonoscopy at screening and may undergo biopsy at screening and optionally on study.
COHORT 2: Patients receive tislelizumab IV Q3W. Treatment repeats every 3 weeks for up to 27 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, and collection of blood samples throughout the study and undergo colonoscopy and biopsy at screening and on study.
After completion of study treatment, patients are followed up at 21 days and then every 26 weeks for up to 4 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorFiyinfolu Balogun
- Primary ID24-063
- Secondary IDsNCI-2024-06531
- ClinicalTrials.gov IDNCT06529523