This phase II clinical trial studies how well panitumumab with or without trametinib works in
treating patients with stage IV colorectal cancer. Immunotherapy with monoclonal antibodies,
such as panitumumab, may help the body's immune system attack the cancer, and may interfere
with the ability of tumor cells to grow and spread. Trametinib may stop the growth of tumor
cells by blocking some of the enzymes needed for cell growth. Giving panitumumab with or
without trametinib may work better in treating patients with stage IV colorectal cancer.
PRIMARY OBJECTIVES:
I. To evaluate the anti-tumor efficacy of panitumumab monotherapy in patients who were
initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy
and subsequently have detectable EGFR ectodomain mutation post-progression in circulating
free tumor deoxyribonucleic acid (DNA).
II. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in
patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior
anti-EGFR therapy and subsequently have detectable levels of KRAS, NRAS, and/or BRAF mutation
post-progression in circulating free tumor DNA.
III. To evaluate the anti-tumor efficacy of panitumumab monotherapy in patients who were
initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy
and subsequently do not have detectable KRAS, NRAS, BRAF, or EGFR ectodomain mutation
post-progression in circulating free tumor DNA.
SECONDARY OBJECTIVES:
I. To evaluate the toxicities of panitumumab and trametinib combination therapy.
II. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in
patients who were initially KRAS/NRAS/BRAF wild-type at baseline who progressed on prior
anti-EGFR therapy, developed detectable EGFR ectodomain mutations, and progress through
retreatment with panitumumab.
III. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in
patients who were initially KRAS/NRAS/BRAF wild-type at baseline who progressed on prior
anti-EGFR therapy, did not develop detectable mutations in KRAS, NRAS, BRAF, or EGFR
ectodomain, and progress through retreatment with panitumumab.
IV. To evaluate clinical outcomes with panitumumab monotherapy in patients who were initially
KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and
subsequently have detectable EGFR ectodomain mutation post-progression in circulating free
tumor DNA.
V. To evaluate clinical outcomes with panitumumab and trametinib combination therapy in
patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior
anti-EGFR therapy and subsequently have detectable levels of KRAS, NRAS, and/or BRAF mutation
post-progression in circulating free tumor DNA.
VI. To evaluate clinical outcomes with panitumumab monotherapy in patients who were initially
KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and
subsequently do not have detectable KRAS, NRAS, BRAF, or EGFR ectodomain mutation
post-progression in circulating free tumor DNA.
VII. To study the biological basis of development of primary and secondary resistance to
anti-EGFR antibodies and MEK inhibitors.
OUTLINE: Patients are assigned to 1 of 3 cohorts.
COHORT 1: Patients with EGFR ectodomain mutation receive panitumumab intravenously (IV) over
30-90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or
unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.
COHORT 2: Patients with KRAS, NRAS, or BRAF mutation receive trametinib orally (PO) once
daily (QD) on days 1-14 and panitumumab as in Cohort 1. Cycles repeat every 14 days in the
absence of disease progression or unacceptable toxicity.
COHORT 3: Patients without EGFR ectodomain, KRAS, NRAS, or BRAF mutation receive panitumumab
as in Cohort 1. Cycles repeat every 14 days in the absence of disease progression or
unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.
After completion of study treatment, patients are followed up for 4 weeks and then every 3
months for 24 months.
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
