A Phase 2 Study of MK-2206 in Previously Treated Metastatic Colorectal Cancer Patients Enriched for PTEN Loss and PIK3CA Mutation
Inclusion Criteria:
- Patients must have histologically confirmed, radiologically measurable metastatic or
unresectable colorectal adenocarcinoma that is amenable to image-guided biopsy and
for which standard curative or palliative measures do not exist or are no longer
effective; disease in previously radiated regions may not be considered measurable
unless there has been demonstrated progression in the lesion
- Patients must have failed available therapy for the treatment of advanced colorectal
cancer; this is defined as progressive disease during or within 6 months after
fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab, and for v-Ki-ras2 Kirsten rat
sarcoma viral oncogene homolog (KRAS) wild-type patients, anti-epidermal growth
factor receptor (EGFR) antibody (cetuximab or panitumumab) containing therapies, with
most recent progression by Response Evaluation Criteria in Solid Tumors (RECIST)
criteria; patients who had at least stable disease as best response on their prior
therapies (listed above) should have received at least 2 months (approximately 60
days) of treatment; for oxaliplatin-based therapy, failure of therapy will also
include patients who progressed within 12 months of adjuvant therapy and patients who
had oxaliplatin stopped due to toxicity
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- Life expectancy of greater than 12 weeks
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
2.5 X institutional upper limit of normal or =< 5 X institutional upper limit of
normal for patients with known liver metastasis
- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- Women of child-bearing potential and men must agree to use adequate contraception
(double barrier method of birth control; abstinence) prior to study entry, for the
duration of study participation, and 4 months after completion of MK-2206
administration; should a woman become pregnant or suspect she is pregnant while she
or her partner is participating in this study, she should inform her treating
physician immediately; men treated or enrolled on this protocol must also agree to
use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of MK-2206 administration
- Patients must be able to swallow whole tablets; nasogastric or gastrostomy (G) tube
administration is not allowed; tablets must not be crushed or chewed
- Ability to understand and the willingness to sign a written informed consent document
- Tumor must be wild type for the KRAS and BRAF oncogenes, and must have known PIK3CA,
AKT mutation status and PTEN expression status
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study; if the patient has residual
toxicity from prior treatment, toxicity must be =< grade 1 (or =< grade 2 for
peripheral neuropathy and/or alopecia)
- Patients who are receiving or have received any other investigational agents within
30 days of study day 1
- Patient has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; however, patients with CNS metastases who have completed a course of
therapy would be eligible for the study provided they are clinically stable for at
least 1 month prior to entry as defined as:
- No evidence of new or enlarging CNS metastasis
- Off steroids that are used to minimize surrounding brain edema
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK-2206
- Patients receiving any medications or substances that are inhibitors or inducers of
cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP450 3A4) are ineligible
- Patients with diabetes or in risk for hyperglycemia should not be excluded from
trials with MK-2206, but the hyperglycemia should be well controlled on oral agents
before the patient enters the trial
- Cardiovascular baseline corrected QT by Fridericia's (QTcF) > 450 msec (male) or QTcF
> 470 msec (female) will exclude patients from entry on study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with MK-2206
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible
- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or
any other cancer from which the patient has been disease free for five years