MK-2206, Paclitaxel and Trastuzumab in Treating Patients With HER2-overexpressing Solid Tumor Malignancies

A Phase Ib Dose-escalation Trial of the AKT Inhibitor MK2206 in Combination With Weekly Paclitaxel With or Without Trastuzumab

The purpose of this study is to test the safety and safest highest dose of an investigational drug called MK-2206 when given in combination with paclitaxel and trastuzumab in patients with Human Epidermal growth factor Receptor 2 (HER2)-overexpressing solid tumor malignancies.

The purpose of this study is to determine the safety and maximum tolerated dose (MTD) of MK-2206 in combination with paclitaxel and trastuzumab when given to patients with HER2-overexpressing solid tumor malignancies. MK-2206 is an oral drug (taken by mouth) that turns off a protein called AKT inside cancer cells. This could be helpful in treating treatment-resistant cancers, because AKT allows cells to survive despite active anticancer treatment. In the case of HER2-positive cancers, laboratory studies suggest that the drug combination of MK-2206 and paclitaxel and trastuzumab may be effective.

Inclusion Criteria:

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 Hybridization (FISH).

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 months.

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 ULN
   • 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 basis.

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.

Exclusion Criteria:

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 Investigator,
   • 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 anthracycline therapy.

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 prophylaxis.

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.