| Eligibility |
Inclusion Criteria:
- Provision of signed Informed Consent prior to any screening procedures being
performed. The informed consent process will be conducted in accordance with MD
Anderson Office of Clinical Research SOP 04 and as indicated in Appendix 2.
- Age =18 years at the time of informed consent.
- Histologically (or cytologically) confirmed diagnosis of adenocarcinoma of the colon
or rectum, with clinical confirmation of unresectable and/or metastatic disease that
is measureable according to RECIST1.1 criteria.
- Baseline tissue-based KRAS, NRAS, EGFR, BRAF wild-type tumor. If MEK1 was tested, must
be wild-type tumor
- Prior treatment with at least one systemic chemotherapy regimen for mCRC, or
recurrence/progression with development of unresectable or metastatic disease within 6
months of adjuvant chemotherapy for resected colorectal cancer.
- Participants who received chemotherapy must have recovered (Common Terminology
Criteria for Adverse Events [CTCAE] Grade .1) from the acute effects of chemotherapy
except for residual alopecia or Grade 2 peripheral neuropathy prior to randomization.
A washout period of at least 21 days is required between last chemotherapy dose and
randomization (provided the participant did not receive radiotherapy).
- Participants who received radiotherapy must have completed and fully recovered from
the acute effects of radiotherapy. A washout period of at least 14 days is required
between end of radiotherapy and randomization
- Left-sided primary tumor
- Prior treatment with, and progression on, anti-EGFR therapy (cetuximab or
panitumumab).
- ECOG performance status = 1.
- Adequate bone marrow, organ function and laboratory parameters:
- Absolute neutrophil count (ANC) = 1.5 x 109/L,
- Hemoglobin (Hgb) = 9 g/dL with or without transfusions,
- Platelets (PLT) = 100 x 109/L without transfusions,
- AST and/or ALT = 2.5 x upper limit of normal (ULN)
- Total bilirubin = 1.5 x ULN and < 2 mg/dL Note: Participants who have a total
bilirubin level > 1.5 x ULN will be allowed if their indirect bilirubin level is = 1.5
x ULN
- Serum Creatinine = 1.5 x ULN, or calculated creatinine clearance (determined as per
Cockcroft-Gault) = 50mL/min at screening.
- QTc interval = 480 ms (preferably the mean from triplicate ECGs);
- Able to take oral medications.
- Female participants are either postmenopausal for at least 1 year, are surgically
sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid
pregnancy from screening through follow-up if of childbearing potential.
Note: Permitted contraception methods include: male condom with spermicide, female condom
with spermicide, diaphragm with spermicide, cervical sponge, or cervical cap with
spermicide. Also see the definition of highly effective method of contraception in Appendix
1. These should be communicated to the participants and their understanding confirmed. For
all females, the pregnancy test result must be negative within 24 hours of starting
treatment on study and within 24 hours prior to each cycle. Males must agree to take
appropriate precautions to avoid fathering a child from screening through 100 days
following the end of therapy.
Exclusion Criteria:
- History of a Grade 3 or 4 allergic reaction or intolerability attributed to cetuximab.
- Right-sided or transverse colonic primary tumor.
- Baseline tissue-based KRAS, NRAS, EGFR, BRAF and MEK1 mutated tumor
- Active infection requiring concurrent antibiotic use.
- Currently using concomitant medications that are strong inhibitors or inducers of
CYP3A4.
- Previously completed or withdrawn from this study or any other study investigating an
ERK1/2 inhibitor.
- Any known symptomatic brain metastasis. Note: Participants previously treated or
untreated for this condition who are asymptomatic in the absence of corticosteroid and
anti-epileptic therapy are allowed. Known brain metastases must be stable for = 4
weeks, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography
[CT]) demonstrating no current evidence of progressive brain metastases at screening.
- Known leptomeningeal disease
- Previous or concurrent malignancy within 3 years of study entry, with the following
exceptions: adequately treated basal or squamous cell skin cancer, superficial bladder
cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other
noninvasive or indolent malignancy; other solid tumors treated curatively without
evidence of recurrence for at least 3 years prior to study entry.
- 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 (i.e. Grade 2 or higher), history or current
evidence of clinically significant cardiac arrhythmia and/or conduction
abnormality <6 months prior to screening except atrial fibrillation and
paroxysmal supraventricular tachycardia;
- The participant has a personal history of any of the following conditions:
syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin
(including, but not limited to, ventricular tachycardia and ventricular
fibrillation), or sudden cardiac arrest.
- Uncontrolled hypertension defined as persistent elevation of systolic blood pressure =
150 mmHg or diastolic blood pressure = 90 mm Hg, despite current therapy;
- The participant has active systemic bacterial infection (requiring intravenous (IV)
antibiotics at time of initiating study treatment,) fungal infection, or detectable
viral infection (such as known human immunodeficiency virus positivity or with known
active hepatitis B or C (for example, hepatitis B surface antigen positive.) Screening
is not required for enrollment.; Known history of acute or chronic pancreatitis
(history of acute pancreatitis with no recurrent events in the prior 24 months are
permitted)
- Impaired gastrointestinal function or disease that may significantly alter the
absorption of study drug (e.g., ulcerative diseases, uncontrolled vomiting,
malabsorption syndrome, small bowel resection with decreased intestinal absorption).
- Any other condition that would, in the Investigator's judgment, contraindicate the
participants participation in the clinical study due to safety concerns or compliance
with clinical study procedures.
- For participants receiving abemaciclib: The participant has serious and/or
uncontrolled preexisting medical condition(s) that, in the judgment of the
investigator, would preclude participation in this study (for example, interstitial
lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal
impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical
resection involving the stomach or small bowel, or preexisting Crohn's disease or
ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or
higher diarrhea).
- Major surgery = 6 weeks prior to starting study drug or failure to recover from side
effects of such procedure at the discretion of the treating investigator.
- 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.
- 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.
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