MK-2206, Paclitaxel and Trastuzumab in Treating Patients With HER2-overexpressing Solid Tumor Malignancies
Condition: Advanced Solid Tumors; Tumors; Cancer
MeSH terms: Neoplasms
Intervention: MK-2206; Paclitaxel; Trastuzumab
Intervention description: Different dose levels of MK-2206 will studied, and co-administered with paclitaxel and trastuzumab. MK-2206 will be given orally with a starting dose of 135 mg weekly; 80 mg/m2 weekly - paclitaxel; 2 mg/kg weekly after a 1-time loading dose of 4 mg/kg - trastuzumab
Intervention MeSH terms: Paclitaxel; Trastuzumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Neoplasms; Paclitaxel; Trastuzumab

Summary:

      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.
    

Eligibility criteria:

        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.