A Trial of mFOLFIRI With MEK162 in Patients With Advanced RAS (HRAS, NRAS, or KRAS) Positive Metastatic Colorectal Cancers

  • STATUS
    Recruiting
  • End date
    Apr 30, 2023
  • participants needed
    30
  • sponsor
    University of Utah
Updated on 6 May 2022

Summary

This is a Phase 1b, open label, dose-finding study to determine the Maximum Tolerated Dose (MTD) of MEK162 in combination with mFOLFIRI, and to evaluate the response rate, clinical benefit rate and additional safety parameters of the treatment combination

Details
Condition Advanced KRAS Positive Metastatic Colorectal Cancer
Treatment MEK162 and mFOLFIRI
Clinical Study IdentifierNCT02613650
SponsorUniversity of Utah
Last Modified on6 May 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Age > 18 years old
Patients with histologically confirmed RAS (HRAS, NRAS, or KRAS) positive metastatic colorectal cancer
Patients must have progressed during or after first-line treatment for metastatic disease with oxaliplatin and fluoropyrimidines based chemotherapy (with failure within six months) or not be a candidate for oxaliplatin (i.e. neuropathy)
ECOG Performance Status 0-1
Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines
Adequate bone marrow, organ function and laboratory parameters as defined by the protocol
Adequate cardiac function as defined by the protocol
Must have recovered from adverse effects of any prior surgery, radiotherapy or other antineoplastic therapy. Alopecia and CTCAE grade 1 peripheral neuropathy is acceptable
Willingness and ability to comply with all study procedures and able to take oral medications
Patients must be willing to undergo biopsy according to the institute's own guidelines and requirements for such procedures unless deemed unsafe by the investigator
Dose Expansion Phase Additional Inclusion Criteria
Patients must have measurable disease as defined by RECIST v1.1 (at least one lesion ≥ 10mm in at least one dimension when assessed by CT or MRI, or a cutaneous lesion with clearly defined margins that measures ≥ 10 mm in at least one dimension)
Patients must be irinotecan refractory. Patients must have progressed on prior irinotecan therapy but must be able to tolerate standard irinotecan doses

Exclusion Criteria

UGT1A1 28 homozygous patients
Previous treatment with any MEK inhibitor
Treatment with systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any investigational therapy ≤ 4 weeks (<6 weeks for nitrosurea or mitomycin-C, antibodies except for trastuzumab) or ≤ 5-half lives of the investigational therapy prior to starting study treatment, whichever is longer
Patient received radiotherapy ≤ 2 weeks prior to the first dose of study treatment except localized radiation therapy for symptomatic bone metastasis
Have had a diagnosis of another malignancy, unless the patient has been disease-free for at least 3 years following the completion of curative intent therapy, with the following exceptions
Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed
Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed
History or current evidence of retinal vein occlusion (RVO) or current risk factors
for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of
Personal history of Gilbert's syndrome
hyperviscosity or hypercoagulability syndromes
Uncontrolled arterial hypertension defined by blood pressure >150 mmHg systolic and/or 100 mmHg diastolic at rest (average 3 consecutive readings at least 5 minutes apart) despite appropriate medical therapy
Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following
History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) <6 months prior to screening
Symptomatic chronic heart failure; evidence of clinically significant cardiac arrhythmias and/or conduction abnormalities < 6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia
Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C
Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on MEK162 treatment
infection (Note: if not suspected, testing is not required at baseline)
Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection that under the judgment of the PI may impair absorption of study drugs)
Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication.(patients may not receive drug through a feeding tube), social/ psychological issues, etc
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
Patients who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure
Sexually active males, unless they use a condom during intercourse while taking the drug through 90 days after the end of systemic exposure to study drug/treatment. In addition, male participants should not father a child in this period and must refrain from donating sperm during the study through 90 days after the end of systemic exposure of study drug/treatment. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid
Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study
A positive β-hCG result will not be exclusionary if it is suspected to originate from a malignancy and the patient has undergone a confirmatory ultrasound within 72 hours prior to starting MEK162 therapy
Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of
contraception from screening through 30 days after the last dose of study
drug/treatment discontinuation
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