TAK-659 and Paclitaxel in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES I. To define the maximum tolerated doses (MTD) of spleen tyrosine kinase
inhibitor TAK-659 (TAK-659) and paclitaxel.

II. To define the safety profiles of the combination.

SECONDARY OBJECTIVES I. To evaluate clinical response signals to the combination. II. To
analyze pharmacokinetic interactions between TAK-659 and paclitaxel. III. To assess
predictive biomarkers (baseline molecular mutation status) and/or resistant pathways by
comparing molecular signatures at baseline versus at time of relapse in patients who have
achieved objective responses.

OUTLINE: This is a dose-escalation study of spleen tyrosine kinase inhibitor TAK-659 and
paclitaxel.

Patients receive spleen tyrosine kinase inhibitor TAK-659 orally (PO) once daily (QD) and
paclitaxel intravenously (IV) over approximately 1 hour on days 1, 8, and 15. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days.

Inclusion Criteria:

- All patients have advanced malignancy (high-grade epithelial ovarian cancer or cancer
harboring K-RAS mutation), either refractory to standard therapy or for which no
effective standard therapy is available

- Patients must have measurable or evaluable disease, as defined by Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1

- Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 and life
expectancy of greater than 3 months and/or other performance status of 0 to 1

- Female patients who:

- Are postmenopausal for at least 1 year before the screening visit, OR

- Are surgically sterile, OR

- If they are of childbearing potential, agree to practice 1 highly effective
method of contraception and one additional effective (barrier) method at the same
time, from the time of signing the informed consent through 180 days after the
last dose of study drug, OR

- Agree to practice true abstinence, when is in line with the preferred and usual
lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation,
symptothermal, postovulation methods), withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception. Female and
male condoms should not be used together)

- Agree not to donate eggs (ova) during the course of this study or 180 days after
receiving their last dose of study drug

- Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:

- Agree to practice effective barrier contraception during the entire study
treatment period and through 180 days after the last dose of study drug, or

- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,
symptothermal, postovulation methods for the female partner] and withdrawal are
not acceptable methods of contraception. Female and male condoms should not be
used together.)

- Agree not to donate sperm during the course of this study or within 180 days
after receiving their last dose of study drug

- Absolute neutrophil count (ANC) >= 1,500/uL

- Platelet count >= 100,000/uL (red blood cell count [RBC] and platelet transfusion
allowed >= 14 days before assessment)

- Hemoglobin >= 8 g/dL (RBC and platelet transfusion allowed >= 14 days before
assessment)

- Total bilirubin =< 1.5 x the upper limit of the normal range (ULN) (except patients
with Gilbert's syndrome, who must have a total bilirubin =< 3.0 mg/dL)

- Aminotransferases alanine (ALT) and aspartate (AST) =< 2.5 x ULN or =< 5 x ULN if
hepatic metastasis

- Serum creatinine =< 1 x ULN and creatine clearance >= 60 mL/min either as estimated by
the Cockcroft-Gault equation or based on urine collection (12 or 24 hours) if serum
creatinine is abnormal

- Lipase =< 1.5 x ULN with no clinical symptoms suggestive of pancreatitis or
cholecystitis

- Amylase =< 1.5 x ULN with no clinical symptoms suggestive of pancreatitis or
cholecystitis

- Blood pressure =< grade 1 (hypertensive patients are permitted if their blood pressure
is controlled to =< grade 1 by hypertensive medications and glycosylated hemoglobin is
=< 6.5%)

- Recovered (=< grade 1 toxicity) from the reversible effects of prior anticancer
therapy

- Voluntary written consent must be given before performance of any study related
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the patient at any time without prejudice to future medical care

- Patients may receive palliative radiation therapy immediately before or during the
treatment if the radiation therapy is not delivered to the sole target lesions

- Patients must be able to take oral medications without medical history of
malabsorption or other chronic gastrointestinal disease, or conditions that may hamper
compliance and/or absorption of the study agents

- Patients have prior therapy with a taxane

- Patients agree to provide archival tissue block or 10 formalin-fixed paraffin-embedded
(FFPE) slides paraffin for use in pharmacodynamics correlative studies

Exclusion Criteria:

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring intravenous antibiotics, symptomatic congestive heart failure (New
York Heart Association [NYHA] Class III or IV), or history of myocardial infarction,
unstable angina, stroke or transient ischemic attack within 6 months prior to study
enrollment

- Active brain metastases or leptomeningeal metastases

- Known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to any
particular combination drug will result in a patient being ineligible for inclusion in
that particular cohort

- History of drug-induced pneumonitis requiring treatment with steroids; history of
idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis
on screening chest computed tomography (CT) scan; history of radiation pneumonitis in
the radiation field (fibrosis) is permitted

- Female patients who are both lactating and breastfeeding or have a positive serum
pregnancy test during the screening period or a positive urine pregnancy test on day 1
before first dose of study drug

- Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol

- Life-threatening illness unrelated to cancer that could, in the investigator's
opinion, make the patient not appropriate for this study

- Known human immunodeficiency virus (HIV) positive

- Known hepatitis B surface antigen positive, or known or suspected active hepatitis C
infection

- Any treatment specific for systemic tumor control within 3 weeks prior to the
initiation of the study drugs; or within 2 weeks if cytotoxic agents were given weekly
(within 6 weeks for nitrosoureas or mitomycin C), or within 5 half-lives for targeted
agents with half-lives and pharmacodynamic effects lasting less than 4 days (that
includes but is not limited to erlotinib, sorafenib, sunitinib, bortezomib, and other
similar agents), or failure to recover from toxic effects of any therapy prior to the
study drug treatment

- Any clinically significant comorbidities, such as uncontrolled pulmonary disease,
known impaired cardiac function or clinically significant cardiac disease (specified
below), active central nervous system (CNS) disease, active infection, or any other
condition that could compromise the patient's participation in the study. Patients
with any of the following cardiovascular conditions are excluded:

- Acute myocardial infarction within 6 months before starting study drug

- Current or history of New York Heart Association Class III or IV heart failure

- Evidence of current, uncontrolled cardiovascular conditions including cardiac
arrhythmias, angina, pulmonary hypertension, or electrocardiographic evidence of
acute ischemia or active conduction system abnormalities

- Fridericia corrected QT interval (QTcF) > 450 milliseconds (msec) (men) or > 475
msec (women) on a 12-lead electrocardiogram (ECG) during the screening period

- Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and
intervals that, in the opinion of the investigator, are considered to be
clinically significant

- Use or consumption of any of the following substances:

- Medications or supplements that are known to be inhibitors of P-glycoprotein (gp)
and/or strong reversible inhibitors of CYP3A within 5 times the inhibitor
half-life (if a reasonable half-life estimate is known), or within 7 days (if a
reasonable half-life estimate is unknown), before the first dose of study drug.
In general, the use of these agents is not permitted during the study except in
cases where an adverse event (AE) must be managed

- Medications or supplements that are known to be strong CYP3A mechanism-based
inhibitors or strong CYP3A inducers and/or P-gp inducers within 7 days, or within
5 times the inhibitor or inducer half-life (whichever is longer), before the
first dose of study drug. In general, the use of these agents is not permitted
during the study except in cases where an AE must be managed

- Grapefruit-containing food or beverages within 5 days before the first dose of
study drug. Note that grapefruit-containing food and beverages are not permitted
during the study

- Major surgery within 14 days before the first dose of study drug and not recovered
fully from any complications from surgery

- Systemic infection requiring parenteral antibiotic therapy or other serious infection
(bacterial, fungal or viral) within 21 days before the first dose of study drug.
Patients who are at substantial risk of developing an infection may receive
prophylaxis at the study of study treatment per investigator's discretion

- Active secondary malignancy that requires treatment. Patients with non-melanoma skin
cancer or carcinoma in situ of any type are not excluded if they have undergone
complete resection and are considered disease-free at the time of study entry

- Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
absorption or tolerance of TAK-659 including difficulty swallowing tablets or diarrhea
> grade 1 despite supportive therapy. History of abdominal fistula, gastrointestinal
perforation, or intra-abdominal abscess within 6 months prior to study enrollment

- Patients with clinical bleeding, active gastric or duodenal ulcer

- Grade 2 or higher peripheral neuropathy

- Left ventricular ejection fraction (LVEF) is less than 50% on echocardiography (ECHO)
or multiple-gated acquisition (MUGA) scanning or QTc is greater than 450 milliseconds
(msec) for men and greater than 475 msec for women at screening

- Treatment with high-dose corticosteroids for anticancer purposes within 14 days before
the first dose of TAK-659; daily dose equivalent to 10 mg oral prednisone or less is
permitted. Corticosteroids for topical use or in nasal spray or inhalers, or for
premedication for paclitaxel are allowed

- Lack of suitable venous access for the study-required blood sampling

- Grade 1 or higher ophthalmologic disease