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A Study of Tucatinib and Trastuzumab in Patients with HER2-Positive Locally Advanced Rectal Cancer
Trial Status: active
This phase II trial tests how well tucatinib and trastuzumab with standard chemotherapy works in treating patients with HER2-positive, KRAS wild-type rectal cancer that has spread to nearby tissue or lymph nodes (locally advanced). HER2 (human epidermal growth factor 2) protein is involved in normal cell growth. HER2 may be made in larger than normal amounts by some types of cancer cells such as rectal cancer which would be referred to as HER2 positive. KRAS gene makes a protein that is involved in cell signaling pathways that control cell growth, cell maturation, and cell death. The natural, unchanged (unmutated) form of the gene is called wild-type KRAS. Tucatinib and trastuzumab both work by targeting and blocking HER2. When HER2 is blocked, the cancer may stop growing, or it may grow more slowly, and the cancer cells may shrink. In other research studies, the study drugs have been shown to work better when used to treat colorectal cancer with KRAS wild-type compared to KRAS mutated tumors. CAPOX is a combination of two drugs (capecitabine and oxaliplatin) and used as standard chemotherapy in treatment of locally advanced rectal cancer. CAPOX works by damaging the deoxyribonucleic acid (DNA) in cancer cells, and may cause the cells to stop growing and die. FOLFOX is a combination of three drugs (fluorouracil, oxaliplatin, and leucovorin) also works by damaging the deoxyribonucleic acid (DNA) in cancer cells, and may cause the cells to stop growing and die. CAPOX and FOLFOX are considered standard care. Giving trastuzumab and tucatinib before standard CAPOX chemotherapy may help shrink or stabilize cancer in patients with rectal cancer.
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
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Histologically confirmed rectal adenocarcinoma
Adenocarcinoma with distal margin of 15 cm or less from the anal verge on endoscopy, staged with endorectal ultrasound (ERUS) or magnetic resonance imaging (MRI) as cT3/cT4 N0 or cT(any) cN1/2
No evidence of distant metastases
Radiologically measurable or clinically evaluable disease
Have confirmed HER2-positive rectal adenocarcinoma, as defined by having tumor tissue tested at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, meeting at least one of the following criteria:
* HER2+ overexpression (3+ immunohistochemistry [IHC]) by an Food and Drug Administration (FDA)-approved HER2 IHC test following the package insert’s interpretational manual for gastric cancer
* HER2 2+ IHC is eligible if the tumor is amplified by an FDA-approved HER2 in situ hybridization assay (fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization [CISH]) following the package insert’s interpretational manual for gastric cancer
* HER2 (ERBB2) amplification by CLIA-certified next generation sequencing (NGS) sequencing assay
Tumor specimen that demonstrates intact mismatch repair enzymes by immunohistochemistry or microsatellite stability as demonstrated by NGS or polymerase chain reaction (PCR)
Tumor specimen that indicates RAS wild-type based on expanded RAS testing including KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146)
Left ventricular ejection fraction >= 50 assessed by echocardiography
Negative pregnancy test done within 14 days 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 is required 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
Absolute neutrophil count (ANC) >= 1,500 /mm^3 (performed within 14 days of treatment initiation)
Platelets >= 100,000 / mcL (performed within 14 days of treatment initiation)
Hemoglobin > 9 g/dL or >= 5.6 mmol/L (performed within 14 days of treatment initiation)
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 (performed within 14 days of treatment initiation)
* Creatinine clearance should be calculated per institutional standard
Total bilirubin =< 1.5 x upper limit of normal (ULN), except for subjects with known Gilbert's disease who may enroll if the conjugated bilirubin is >= 1.5 x ULN (performed within 14 days of treatment initiation)
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (performed within 14 days of treatment initiation)
International Normalized Ratio (INR) or Prothrombin Time (PT) (performed within 14 days of treatment initiation)
* For patients not taking warfarin: INR =< 1.5 or 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
Activated Partial Thromboplastin Time (aPTT) (performed within 14 days of treatment initiation)
* For patients not taking warfarin: INR =< 1.5 or PT =< 1.5 x ULN; and either PTT or aPTT =< 1.5 x ULN
Exclusion Criteria
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
Active infection requiring systemic therapy
Other anticancer or experimental therapy. No other experimental therapies (including chemotherapy, radiation, hormonal treatment, gene therapy, vaccine therapy, angiogenesis inhibitors, matrix metalloprotease inhibitors, thalidomide, 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)
Any known chronic (non-transient) liver disease in the patient’s past medical history such as (but not limited to) cirrhosis, NASH (non-alcoholic steatohepatitis) or non-alcoholic fatty liver disease (NAFLD)
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
Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications
Use of a strong cytochrome P450 (CYP)2C8 inhibitor that is not adequately cleared (five half-lives of elapsed time) before study initiation. In addition, use of a strong CYP3A4 or CYP2C8 inducer that is taken within 5 days prior to the first dose of study will also be an exclusion criteria
Additional locations may be listed on ClinicalTrials.gov for NCT05672524.
Locations matching your search criteria
United States
New Jersey
Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Andrea Cercek
Phone: 646-888-4189
Middletown
Memorial Sloan Kettering Monmouth
Status: Active
Contact: Andrea Cercek
Phone: 646-888-4189
Montvale
Memorial Sloan Kettering Bergen
Status: Active
Contact: Andrea Cercek
Phone: 646-888-4189
New York
Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Andrea Cercek
Phone: 646-888-4189
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Andrea Cercek
Phone: 646-888-4189
Uniondale
Memorial Sloan Kettering Nassau
Status: Active
Contact: Andrea Cercek
Phone: 646-888-4189
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Andrea Cercek
Phone: 646-888-4189
PRIMARY OBJECTIVE:
I. To determine the clinical complete response rate after the completion of neoadjuvant tucatinib, trastuzumab and capecitabine and oxaliplatin (CAPOX)/flurourcil, oxaliplatin, leucovorin (FOLFOX) (assessed around week 21 +/- 4 weeks) in subjects with HER2-positive, RAS wild-type locally advanced rectal adenocarcinoma.
SECONDARY OBJECTIVES:
I. Determine the clinical complete response rate after the completion of neoadjuvant tucatinib, trastuzumab, and CAPOX/FOLFOX sustained for 12 months in subjects with HER2-positive, RAS wild-type locally advanced rectal adenocarcinoma.
II. Determine the overall response rate (ORR) and clinical complete response (cCR) rate of patients after six weeks of tucatinib/trastuzumab treatment, and separately in patients who receive induction tucatinib/trastuzumab, CAPOX/FOLFOX and chemoradiation.
III. Determine the pathologic complete response rate (pCR) of patients who receive tucatinib and trastuzumab, and CAPOX/FOLFOX and eventually undergo surgical resection of the rectum.
IV. Determine the safety and tolerability of combination tucatinib/trastuzumab/CAPOX/FOLFOX neoadjuvant treatment in subjects with HER2-positive, locally advanced rectal cancer.
EXPLORATORY OBJECTIVES:
I. To describe the molecular characteristics of response and resistance to trastuzumab/tucatinib plus CAPOX or FOLFOX therapy in HER2-positive tumors and circulating tumor deoxyribonucleic acid (DNA) (ctDNA) through assessment of HER2 expression, mutational quantity and mutational landscape in tumor tissue and plasma throughout treatment.
II. To describe change of HER2 tissue and HER2 circulating tumor DNA (ctDNA) pattern throughout treatment and between patients with and without cCR.
III. To describe the utility of 89Zr-Trastuzumab positron emission tomography (PET)/magnetic resonance imaging (MRI) imaging to detect HER2+ tumor tissue, HER2 expression level, and therapeutic response to HER2 targeted therapy.
OUTLINE: Patients are assigned to 1 of 2 cohorts at the discression of the treating physician.
COHORT I: Patients receive tucatinib orally (PO) twice per day (BID) and trastuzumab intravenously (IV) on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of progressive disease or unacceptable toxicity for 7 cycles. Starting with cycle 3 patients receive capecitabine PO BID for the first week of each cycle and oxaliplatin IV on day 1 of each cycle. Patients whose cancer has not completely responded undergo standard of care radiation therapy with capecitabine PO BID or fluorouracil IV continuously during radiation for 5.5 weeks. Patients also undergo computed tomography (CT), rectal MRI, endoscopic biopsy, and collection of blood samples throughout the trial. Patients may also undergo fludeoxyglucose F-18 (FDG) PET-CT and zirconium Zr 89 trastuzumab (89Zr-trastuzumab) PET-MRI imaging at baseline and at end of induction chemotherapy.
COHORT II: Patients receive tucatinib PO BID and trastuzumab IV on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of progressive disease or unacceptable toxicity for 7 cycles. Starting with cycle 3 patients receive oxaliplatin IV and fluorouracil continuously over 46 hours every 2 weeks. Patients whose cancer has not completely responded undergo standard of care radiation therapy with capecitabine PO BID or fluorouracil IV continuously during radiation for 5.5 weeks. Patients also undergo CT, rectal MRI, endoscopic biopsy, and collection of blood samples throughout the trial. Patients may also undergo FDG PET-CT and 89Zr-trastuzumab PET-MRI imaging at baseline and at end of induction chemotherapy.
After completion of study treatment, patients are followed up every 4 months for 2 years and then every 6 moths for 3 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center