Dose Finding Study Of PF-05212384 With Paclitaxel And Carboplatin In Patients With Advanced Solid Tumor

Inclusion Criteria:

• Age >18 years.

• Histological or cytological diagnosis of advanced/metastatic breast, NSCLC, ovarianand endometrial, small cell lung cancer (SCLC) and Head and Neck (HNSCC) cancer forwhich there is an indication to the use of paclitaxel and carboplatin.

• For patients enrolled to Part 1, lesions may be measurable or non measurable; forpatients enrolled to Part 2, at least one measurable lesion is requested.

• All patients must provide an archived or fresh tumor sample; paired fresh tumorbiopsies are mandatory for patients enrolled to Part 2 (at baseline and on Day 22 ofCycle 1).

• ECOG Performance Status must be 0 or 1.

• Adequate Bone Marrow Function, including:

1. Absolute Neutrophil Count (ANC) ≥1,500/mm3 (or ≥1.5 x 109/L);

2. Platelets ≥100,000/mm3 (or ≥100 x 109/L);

3. Hemoglobin ≥9 g/dL.

• Adequate renal function, including: serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated creatinine clearance ≥ 60 ml/min as calculated using the methodstandard for the institution.

• Adequate Liver Function, including:

1. Total serum bilirubin ≤1.0 mg/dL Aspartate and Alanine Aminotransferase AST &ALT) ≤2.5 x ULN; ≤5.0 x ULN if there is liver involvement secondary to tumor.

2. Alkaline phosphatase ≤2.5 x ULN; (≤5 x ULN in case of bone metastasis).

• Adequate glucose control, including no previous diagnosis of diabetes mellitus andHbA1c <7%.

• Adequate cardiac function, including: 12 Lead ECG with normal tracing or nonclinically significant changes that do not require medical intervention.

• Resolved acute effects of any prior therapy to baseline severity or Grade

• 1 CTCAE except for AEs not constituting a safety risk by Investigator judgment.

• Serum/urine pregnancy test (for females of childbearing potential) negative atscreening and at baseline.

• Female patients must be surgically sterile or be postmenopausal, or must agree to useeffective contraception during the period of the trial and for at least 90 days aftercompletion of treatment. Male patients must be surgically sterile or must agree to useeffective contraception during the period of the trial and for at least 90 days aftercompletion of treatment. The decision of effective contraception will be based on thejudgment of the principal Investigator or a designated associate.

• Willingness and ability to comply with the study scheduled visits, treatment plans,laboratory tests and other procedures.

• Written informed consent.

Exclusion Criteria:

• More than 2 prior lines of chemotherapy for advanced disease for Part 1, more than 1prior line of chemotherapy for advanced disease for Part 2.

• Resistance to platinum agents (progression during the treatment or within 3 month fromthe stop of the treatment).

• Prior treatment with weekly paclitaxel with tumor progression.

• Pre-existing neuropathy ≥ G2.

• Patients with known active brain metastases. Patients with previously diagnosed brainmetastases are eligible if they have completed their CNS treatment and have recoveredfrom the acute effects of radiation therapy or surgery prior to the start of studymedication, have discontinued corticosteroid treatment for these metastases for atleast 4 weeks and are neurologically stable.

• Chemotherapy, radiotherapy (other than palliative radiotherapy to lesions that willnot be followed for tumor assessment on this study, ie, non target lesions),biological or investigational agents within 4 weeks of the start of the studytreatment (6 weeks for mitomycin C or nitrosoureas).

• Any surgery (not including minor procedures such as lymph node biopsy, needle biopsy,and/or placement of port-a-cath) within 4 weeks of the start of the study treatment ornot fully recovered from any side effects of previous procedures.

• For patients enrolling to Part 2, prior therapy with an agent that is known orproposed to be active by action on PI3K and/or mTOR completed within the last 6months.

• Uncontrolled or significant cardiovascular disease:

• A myocardial infarction within 12 months.

• Uncontrolled angina within 6 months.

• Congestive heart failure within 6 months.

• Diagnosed or suspected congenital long QT syndrome.

• Any history of ventricular arrhythmias (such as ventricular tachycardia, ventricularFibrillation, or Torsades de pointes).

• Any history of second or third degree heart block (may be eligible if currently have apacemaker).

• Heart rate <50/minute on pre entry electrocardiogram.

• Uncontrolled hypertension.

• Current use or anticipated need for food or drugs that are known potent CYP3A4inhibitors. Because inhibition of CYP3A4 isoenzymes may increase PF- 05212384 exposureleading to a potential increases in toxicities, the use of known strong inhibitors (strong CYP3A4 Inhibitors: grapefruit juice or grapefruit/grapefruit related citrusfruits (eg, Seville oranges, pomelos), ketoconazole, miconazole, itraconazole,voriconazole, posaconazole, erythromycin, clarithromycin, telithromycin, verapamil,indinavir, saquinavir, ritonavir, nelfinavir, nefazodone, lopinavir, atazanavir,amprenavir, fosamprenavir and delavirdine, troleandomycin, mibefradil, conivaptan) arenot permitted from 10 days prior to the first dose of study drug untildiscontinuation. Concurrent administration of herbal preparations and current oranticipated need for food or drugs that are known substrates of UGT1A9 (eg, propofol,acetaminophen, and propranolol), of which PF-05212384 is a strong inhibitor, is notpermitted from 10 days prior to the first dose of study drug until discontinuation.

• Current or anticipated need for food or drugs that are known potent CYP3A4 inducers.PF-05212384 metabolism may be induced when taking strong CYP3A4 inducers (eg,phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine,St. John's Wort) resulting in reduced plasma concentrations. Therefore coadministration of study drug in combination with these and other strong CYP3A4inducers is not permitted from 10 days prior to the first dose of study drug untilstudy treatment discontinuation.

• Breast feeding or intercurrent pregnancy; no use of highly effective contraception ornot agreeing to continue highly effective contraception for 90 days after last dose ofinvestigational product.

• Any mental disorder that would limit the understanding or rendering of informedconsent and/or compromise compliance with the requirements of the protocol.