| Eligibility |
Inclusion Criteria:
- Histologically proven, unresectable distant metastatic or locally advanced colorectal
adenocarcinoma
- KRAS, NRAS wild type
- BRAF v600E wildtype
- Measurable disease
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
- Life expectancy of >= 3 months per estimation of treating physician
- Absolute neutrophil count (ANC) >= 1200/mm^3 (obtained =< 7 days prior to
randomization)
- Platelet count >= 75,000/mm^3 (obtained =< 7 days prior to randomization)
- Hemoglobin >= 9.0 g/dL (obtained =< 7 days prior to randomization)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 7 days prior to
randomization)
- Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) =< 2.5 x ULN (=<
5 x ULN for subjects with liver involvement of their cancer) (obtained =< 7 days prior
to randomization)
- Serum creatinine =< 1.5 x ULN (obtained =< 7 days prior to randomization)
- International normalized ratio (INR)/partial thromboplastin time (PTT) =< 1.5 x ULN
(obtained =< 7 days prior to randomization)
- NOTE: Patients who are therapeutically treated with an agent such as warfarin or
heparin will be allowed to participate provided that no prior evidence of
underlying abnormality in coagulation parameters exists. Close monitoring of at
least weekly evaluations will be performed until INR/PTT is stable based on a
measurement that is pre-dose as defined by the local standard of care
- Alkaline phosphatase limit =< 2.5 x ULN (=< 5 x ULN for patients with liver
involvement of their cancer) (obtained =< 7 days prior to randomization)
- Negative serum pregnancy test done =< 7 days prior to randomization for women of
childbearing potential only.
- NOTE: Post-menopausal women (defined as no menses for at least 1 year) and
surgically sterilized women are not required to undergo a pregnancy test. The
definition of adequate contraception will be based on the judgment of the
treating physician
- Provide informed written consent
- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study)
- Disease progression on or intolerable to any of the following: fluoropyrimidine,
oxaliplatin and irinotecan
- Able to swallow and retain oral medication
- Willing to provide tissue and blood samples for correlative research purposes
- Willing to allow transfer of tissue and blood samples, clinical information, and
outcome data collected from this trial for future research
Exclusion Criteria:
- Prior treatment with regorafenib, cetuximab or panitumumab
- Major surgical procedure, open biopsy, or significant traumatic injury =< 28 days
prior to randomization
- Congestive heart failure > New York Heart Association (NYHA) class 2.
- NOTE: Class 3 is defined as marked limitation in activity due to symptoms, even
during less-than-ordinary activity, e.g., walking short distances (20-100m). They
are comfortable at rest. Class 4 is defined as patients with severe limitations.
Experiences symptoms even while at rest. Mostly bed bound
- Unstable angina (angina symptoms at rest), new-onset angina (begun =< 3 months prior
to randomization) or myocardial infarction =< 6 months prior to randomization
- Cardiac arrhythmias requiring anti-arrhythmic therapy. Note: Pace makers, beta
blockers or digoxin are permitted
- Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic pressure >
90 mmHg despite optimal medical management)
- History of or current pheochromocytoma
- Arterial or venous thrombotic or embolic events such as cerebrovascular accident
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism =<
6 months prior to randomization
- Ongoing infection > grade 2 National Cancer Institute (NCI)-Common Terminology
Criteria for Adverse Events (CTCAE) version (v)5.0
- Known history of chronic hepatitis B or C
- Patients with seizure disorder requiring medication
- Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from
definitive therapy, has a negative imaging study within 4 weeks of randomization and
is clinically stable with respect to the tumor at the time of randomization. Note:
Patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy
is acceptable provided that the dose is stable for one month prior to and following
screening radiographic studies)
- History of organ allograft (including corneal transplant)
- Evidence or history of bleeding diathesis or any hemorrhage or bleeding event > CTCAE
v5.0 grade 3 =< 4 weeks prior to randomization
- Non-healing wound, ulcer, or bone fracture
- Substance abuse, medical, psychological or social conditions that may interfere with
the patient?s participation in the study or evaluation of the study results
- High-frequency microsatellite instability (MSI-H) patients who have not received prior
PD-1 monoclonal antibody (mAb) therapy
- Concurrent anti-cancer therapy =< 3 weeks from randomization (chemotherapy, radiation
therapy, surgery, immunotherapy, biologic therapy, or tumor embolization)
- Known hypersensitivity to any of the study drugs, study drug classes, or excipients in
the formulation
- Interstitial lung disease with ongoing signs and symptoms at the time of informed
consent
- History of known persistent proteinuria of CTCAE v5.0 grade 3 or higher (>= 3.5 g/24
hrs)
- Any malabsorption condition
- Unresolved toxicity greater than CTCAE v5.0 grade 1 attributed to any prior
therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity =< grade 2
- Albumin levels < 2.5 g/dl
- Any of the following because this study involves an agent that has known genotoxic,
mutagenic and teratogenic effects:
- Pregnant women
- Nursing women
- Men or women of childbearing potential who are unwilling to employ adequate
contraception
- NOTE: Men and women of childbearing potential must agree to use adequate
contraception beginning at the signing of the informed consent form (ICF) until
at least 3 months after the last dose of study drug. The definition of adequate
contraception will be based on the judgment of the principal investigator or a
designated associate
- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the treating physician, would make the patient inappropriate for entry into this
study or interfere significantly with the proper assessment of safety and toxicity of
the prescribed regimens
- Known history of human immunodeficiency virus (HIV) infection or active hepatitis B or
C infection requiring treatment with antiviral therapy
- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm
- Previous or concurrent cancer that is distinct in primary site or histology from
colorectal cancer =< 3 years prior to randomization EXCEPT for cervical cancer
in-situ, treated ductal carcinoma in situ of the breast, curatively treated
nonmelanoma skin carcinoma, noninvasive aerodigestive neoplasms, or superficial
bladder tumor (Ta [Non-invasive tumor], Tis [carcinoma in situ] and T1 [Tumor invades
lamina propria]). Note: All cancer treatments for cancers that were distinct in a
primary site other than colorectal must be completed at least 3 years prior to
randomization (i.e., signature date of the informed consent form)
- Pleural effusion or ascites that causes respiratory compromise (>= CTCAE v5.0 grade 2
dyspnea)
- Any condition which, in the treating physician?s opinion, makes the subject unsuitable
for trial participation
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