PRIMARY OBJECTIVES:
I. To determine the response rate to MK-2206 (Akt inhibitor MK2206), defined as complete
response (CR) + partial response (PR).
SECONDARY OBJECTIVES:
I. To determine response rate to MK-2206 in patients with phosphatase and tensin homolog
(PTEN) loss or phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
(PIK3CA) mutation in a pretreatment biopsy from a metastatic site.
II. To determine progression-free survival (PFS) and overall survival (OS). III. To determine
the time to treatment failure (TTF), and duration of tumor response (DR).
IV. To determine the safety profile and tolerability of this regimen in this patient
population.
V. To determine effect of PTEN, v-raf murine sarcoma viral oncogene homolog B1 (BRAF),
PIK3CA, and AKT mutations and semi-quantitative grading of PTEN expression on clinical
response.
OUTLINE:
Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, 15, and 22. Treatment repeats
every 28 days for up to 24 months in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up every 6 months.
Inclusion Criteria:
- Patients must have histologically confirmed, radiologically measurable metastatic or
locally advanced unresectable colorectal adenocarcinoma that is amenable to
image-guided biopsy; disease in previously radiated regions may not be considered
measurable unless there has been demonstrated progression in the lesion
- Patients must have progressed on or been intolerant to a fluoropyrimidine-based
chemotherapy regimen; there is no limit on the number of prior treatment regimens
permitted
- 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 =< institution upper limit of normal
- 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 =< institution upper limit of normal 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 v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
(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, or who have previously received MK-2206 at any time
- 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
