| Eligibility |
Inclusion Criteria:
- Histologically or cytologically confirmed colorectal adenocarcinoma, with metastatic
disease documented on diagnostic imaging studies
- Progression during or within 6 months after fluoropyrimidine, irinotecan, and
oxaliplatin; for oxaliplatin-based therapy, failure of therapy will also include
patients who progressed within 12 months of adjuvant therapy and patients who had
oxaliplatin discontinued secondary to toxicity or allergic reaction; patients with a
known history of Gilbert's disease who cannot receive irinotecan or patients who are
intolerant of irinotecan or fluoropyrimidine are eligible
- Confirmed wild-type status in KRAS exons 2, 3, and 4; NRAS exons 2, 3, and 4; and
BRAF, by standard of care testing of tumor specimen; tissue used for testing may have
been collected prior to treatment with anti-EGFR therapy
- Patient must have been already tested and have available results of the mutations
status of KRAS/NRAS/BRAF/MEK (MAP2K1) and EGFR from the circulating tumor DNA within
10 weeks prior to starting study therapy
- Previous treatment with anti-EGFR therapy with evidence of clinical benefit, as
defined by complete response, partial response, or prolonged stable disease with 16 or
more weeks of treatment without radiographic progression, as assessed by the treating
physician and documented in the medical record; this treatment may have occurred at
any point in the patient's clinical course for treatment of metastatic colorectal
cancer
- Ultimate progression through previous treatment with anti-EGFR therapy, with
documented clinical progression; patients who discontinued anti-EGFR therapy for any
other reason, such as decline in performance status, hypersensitivity, or other
adverse effects of therapy, are not eligible
- All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
Events (CTCAE) (version 4.0) =< grade 1 (except =< grade 2 for alopecia peripheral
neuropathy)
- Radiographically measurable disease present per Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Blood counts performed within 3 weeks prior to starting study therapy must have
absolute neutrophil count >= 1,500/mm^3
- Blood counts performed within 3 weeks prior to starting study therapy must have
platelets >= 100,000/mm^3
- Blood counts performed within 3 weeks prior to starting study therapy must have
hemoglobin >= 9 g/dL
- Liver function tests performed within 3 weeks prior to starting study therapy must
have total bilirubin =< 1.5 x upper limit of normal (ULN)
- Liver function tests performed within 3 weeks prior to starting study therapy must
have alanine aminotransferase and aspartate aminotransferase =< 2.5 x ULN (or =< 5 x
ULN if liver metastases are present)
- Liver function tests performed within 3 weeks prior to starting study therapy must
have albumin >= 2.5 g/dL
- Serum creatinine performed within 3 weeks prior to starting study therapy must be =<
1.5 x ULN, or have calculated creatinine clearance (using Cockcroft-Gault formula) of
>= 50 mL/minute
- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
time (PTT) performed within 3 weeks prior to starting study therapy must be =< 1.5 x
ULN
- Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) by
echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 3 weeks prior
to starting study therapy
- Women of childbearing potential must have a negative serum pregnancy test within 14
days prior to randomization and must agree to use effective contraception throughout
the treatment period and for 4 months after the last dose of study treatment
- Ability to sign informed consent form; informed consent form for this study must be
signed prior to the performance of any study-specific procedures and initiation of any
study therapy
- Ability to swallow and retain oral medication, with no clinically significant
gastrointestinal abnormalities that may alter absorption such as malabsorption
syndrome or major resection of the stomach or bowels
- In cohort 1, must have EGFR S492R or other ectodomain mutation detected from
circulating tumor DNA from plasma collected after progression on prior anti-EGFR
therapy; may have a concomitant mutation in KRAS, NRAS, or BRAF, if there is at least
a 5-fold higher allele frequency of the most prevalent EGFR mutation than the most
prevalent KRAS/NRAS/BRAF mutation
- In cohort 2, must have one or more mutations found in KRAS exon 2, 3, or 4; NRAS exon
2, 3, or 4; BRAF codon 600; or in MEK (MAP2K1); may have a concomitant EGFR ectodomain
mutation, if the most prevalent EGFR ectodomain mutation does not have over a 5-fold
higher allele frequency than the most prevalent KRAS/NRAS/BRAF mutation
- In cohort 3, must not have EGFR ectodomain mutation or any mutations in KRAS, NRAS, or
BRAF
Exclusion Criteria:
- Past treatment with any MEK or ERK inhibitor
- Previous retreatment with anti-EGFR therapy following progression on initial course of
anti-EGFR therapy
- Known untreated brain metastasis or brain metastasis treated within 3 months prior to
enrollment in this trial
- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression
- History of interstitial lung disease or pneumonitis
- History of any other malignancy within 3 years, except for adequately treated
carcinoma in situ of the cervix or non-melanoma skin cancer and/or subjects with
indolent second malignancies are eligible
- Prior treatment within 21 days of the first dose of study drug with any other
chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational
treatment, or failure to recover from adverse effects of prior therapies administered
over 4 weeks prior to study day 1; all toxicities from prior therapies must be =<
grade 1 (or =< grade 2 for alopecia or peripheral neuropathy); prior systemic
treatment in the adjuvant setting is allowed
- Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily
or weekly chemotherapy without the potential for delayed toxicity within 14 days prior
to randomization
- Impaired cardiac function or clinically significant cardiac disease, as defined: a)
left ventricular ejection fraction < lower limit of normal (LLN) on multiple gated
acquisition scan (MUGA) or echocardiogram; b) congenital long QT syndrome or family
history of unexpected sudden cardiac death; c) corrected QT (QTc) corrected with
Bazett's formula (QTcB) >= 480 ms.; d) history or evidence of current clinically
significant uncontrolled arrhythmias; note subjects with atrial fibrillation
controlled for > 30 days prior to dosing are eligible; e) history of acute coronary
syndromes (including myocardial infarction and unstable angina), coronary angioplasty,
or stenting within 6 months prior to randomization; f) history or evidence of current
>= class II congestive heart failure as defined by New York Heart Association (NYHA);
g) treatment refractory hypertension defined as a blood pressure of systolic > 140
mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive
therapy; h) patients with intra-cardiac defibrillators
- Any serious and/or unstable pre-existing medical disorder (aside from malignancy
exception above), psychiatric disorder, or other conditions that could interfere with
subject's safety, obtaining informed consent, or compliance to the study procedures
- History of retinal vein occlusion (RVO)
- Pregnant or breastfeeding, or planning to become pregnant within 6 months after the
end of treatment
- History of organ allograft or other history of immunodeficiency
- Inability or unwillingness to comply with study and/or follow-up requirements
- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO)
- Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C
virus (HCV) infection; subjects with laboratory evidence of cleared HBV and HCV
infection will be permitted
- Current use of a prohibited medication
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