A Phase Ib Dose-escalation Trial of the AKT Inhibitor MK2206 in Combination With Weekly Paclitaxel With or Without Trastuzumab
1. Histologically or cytologically-confirmed metastatic or locally advanced,
unresectable HER2+ cancer. HER2+ will be defined as 3+ expression by
immunohistochemistry (IHC) OR >2-fold gene amplification by Fluorescence In Situ
2. Male or female and ≥18 years of age on the day of signing informed consent.
3. Performance status of 0-2 on the ECOG Performance Scale and life expectancy > 3
4. Have evaluable disease. Measureable disease is not required
5. Adequate organ function as indicated by the following laboratory values:
- Absolute neutrophil count (ANC) = ≥1,500 /μL
- Platelets = ≥100,000 /μL
- Hemoglobin = ≥9 g/dL
- Serum creatinine = ≤1.5 x upper limit of normal (ULN) OR calculated creatinine
clearance = ≥60 mL/min for patients with creatinine levels >1.5 x institutional
- Serum total bilirubin = ≤1.5 x ULN OR direct bilirubin ≤ ULN for patients with
total bilirubin levels >1.5 x ULN
- AST (SGOT) and ALT (SGPT) = ≤2.5 x ULN
- Prothrombin time (PT)/INR = ≤1.2 x ULN
- Partial thromboplastin time (PTT) = ≤1.2 x ULN
- Fasting serum glucose = ≤126 mg/dl
- Hemoglobin A1c (HgbA1c) = ≤7%
- Potassium = in normal range
6. Female patient of childbearing potential must test negative for pregnancy and agree
to the use of effective methods of contraception while on study.
7. Voluntarily agree to participate by giving written informed consent.
8. Able to swallow capsules and has no surgical or anatomical condition that will
prevent the patient from swallowing and absorbing oral medications on an ongoing
9. Prior taxane, trastuzumab, lapatinib, and other HER2 directed therapy in the adjuvant
or metastatic setting is allowed.
10. Any number of prior lines of chemotherapy in the metastatic setting is allowed.
11. Concomitant use of bisphosphonates is allowed.
12. Patients with stable and clinically insignificant central nervous system (CNS)
disease are allowed. Patients must be off steroids with no new CNS symptoms or
findings on radiographic imaging for 1 month.
1. Patient who has had chemotherapy, radiotherapy, or hormonal therapy within 3 weeks (6
weeks for nitrosoureas, mitomycin C or bevacizumab), or who has not recovered from
the adverse events due to previous agents administered more than 4 weeks prior to
Study Day 1. Patient must not have received trastuzumab or lapatinib within 2 weeks
of study Day 1. If the patient has residual toxicity from prior treatment, toxicity
must be ≤ Grade 1.
2. Less than 4 weeks post major surgical procedure (defined as one that required general
anesthesia)(all surgical wounds must be fully healed).
3. Currently participating or has participated in a study with an investigational
compound or device within 30 days of Study Day 1.
4. Known active 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: (1) no evidence of new or enlarging CNS metastasis (2) off steroids that are used
to minimize surrounding brain edema. Patients with clinically insignificant brain
metastases that do not require treatment are eligible.
5. Has a primary central nervous system tumor.
6. Known hypersensitivity to the components of study drug or its analogs.
7. History or current evidence of clinically significant heart disease including:
- Left ventricular ejection fraction (LVEF) <50% on screening echocardiogram or
multigated acquisition (MUGA) scan.
- Clinically significant congestive heart failure, unstable angina pectoris,
- Clinically significant cardiac arrhythmia,
- Myocardial infarction during the last 6 months, and/or a current
electrocardiogram (ECG) tracing that is abnormal in the opinion of the treating
- QTc (QT corrected) prolongation >450 msec (Bazett's Formula), congenitally long
QT syndrome, and/or current anti-arrhythmic therapy, has received any marketed
or experimental compound in the last 4 weeks prior to entering the study with
possible or known effects of QT prolongation, or cumulative high-dose
8. Evidence of clinically significant bradycardia (heart rate <50), or a history of
clinically significant bradyarrhythmias such as sick sinus syndrome, 2nd degree AV
block (Mobitz Type 2), or patients taking beta blockers, non-dihydropyridine calcium
channel blockers, or digoxin.
9. Uncontrolled hypertension (≥140/90 mmHg). Patients who are controlled on
antihypertensive medication will be allowed to enter the study.
10. Significant risk for hypokalemia (e.g., patients on high dose diuretics, or with
recurrent uncontrolled diarrhea)
11. History or current evidence of any condition, therapy, or lab abnormality that might
confound the results of the study, interfere with the patient's participation for the
full duration of the study, or is not in the best interest of the patient to
participate, in the opinion of the treating Investigator.
12. Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial.
13. Current regular user (including "recreational use") of any illicit drugs or had a
recent history (within the last year) of drug or alcohol abuse.
14. Pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study.
15. Known to be Human Immunodeficiency Virus (HIV)-positive.
16. Known history of Hepatitis B or C or active Hepatitis A.
17. Symptomatic ascites or pleural effusion. A patient who is clinically stable following
treatment for these conditions is eligible.
18. Treatment with oral corticosteroids (note: inhaled corticosteroids are permitted). IV
decadron pre-medication is allowed.
19. Baseline neuropathy of ≥ grade 2.
20. Known allergic reactions to paclitaxel or IV contrast dye despite standard
21. Patients who require medications that are potent CYP3A4 inhibitors or inducers.
Patients who have discontinued any of these medications must have a wash-out period
of at least 5 days or at least 5 half-lives of the drug (whichever is longer) prior
to the first dose of MK-2206.
22. Patients requiring warfarin therapy. Low molecular weight heparin is permitted.