Phase I Study of PI3(Phosphoinositol 3)-Kinase Inhibitor BAY80-6946 With Paclitaxel in Patients With Advanced Cancer

Inclusion Criteria:

• No prior paclitaxel treatment for subjects in the dose escalation phase. MTD (maximum tolerated dose) cohort expansion subjects may have had prior paclitaxel, but must not have experienced moderate or severe hypersensitivity reactions to the drug. Peripheral neuropathy must be Grade ≤ 1.
• No history of hypersensitivity (allergy) to drugs formulated in Cremophor EL (polyoxyethylated castor oil), such as vitamin K, cyclosporin for injection concentrate and teniposide for injection concentrate

• Histological or cytological documentation of non-hematologic malignant solid tumor, excluding primary brain or spinal tumors. Patients with prior central nervous system metastases are eligible if all of the following apply:

  • Definitive treatment for all lesions (e.g. surgery, radiation) was completed at least three months prior to enrollment
  • All lesions must be stable or improving on MRI scan performed within one month of enrollment
  • All symptoms of the prior CNS metastases are stable
• At least one measurable lesion or evaluable disease, as per RECIST 1.1
• ECOG (eastern cooperative oncology group) Performance Status Assessment of 0 or 1
• Life expectancy of at least 12 weeks
• Serum creatinine ≤ 1.5 x ULN (upper limit of normal)
• Total bilirubin ≤ 1.5 x ULN
• Alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement with cancer)
• Aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement with cancer)
• PT-INR/PTT (Prothrombin time-international normalized ratio / partial thromboplastin time) < 1.5 x ULN (Subjects who are therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided no other abnormalities in the coagulation parameters exist). Low-dose aspirin is permitted (≤ 100 mg daily)

Exclusion Criteria:

• Medical and surgical history

  • Prior paclitaxel treatment
  • History of moderate to severe hypersensitivity (allergy) to drugs formulated in Cremophor EL (polyoxyethylated castor oil), such as vitamin K, cyclosporin for injection concentrate and teniposide for injection concentrate
  • History of cardiac disease; congestive heart failure (CHF) > NYHA Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; new onset angina within 3 months prior to study entry or unstable angina, or ventricular cardiac arrhythmias requiring anti-arrhythmic therapy
  • Prior diagnosis of Type 1 or 2 diabetes mellitus, hyperglycemia (defined as consistent fasting blood or plasma glucose > 125 mg/dL) or HgBA1c ≥ 7%
  • Use of systemic corticosteroids within 2 days of the start of study treatment (topical or inhaled steroids are permitted)
  • Poorly controlled hypertension, defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management
  • Use of strong inhibitors of CYP3A4 (eg, ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir, nefazodone and saquinavir) and strong inducers of CYP3A4 (eg, rifampin) are not permitted from Day -14 of Cycle 1 and for the duration of the study

• Excluded therapies and medications for cancer

  • Prior paclitaxel treatment (dose escalation patients only)
  • Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of first study treatment. Hormonal therapy during the study or within 2 weeks of first study treatment.

High dose chemotherapy with autologous stem cell rescue within 6 months prior to first study treatment; or any high dose chemotherapy with allogeneic stem cell rescue.. Subjects are also excluded if the autologous stem cell rescue has been done prior to 6 months, but the investigator or sponsor feels that residual toxicities from these procedures will increase the risk associated with study treatments Subjects must have recovered from the acute toxic effects of the previous anti-cancer chemotherapy or immunotherapy (with the exception of alopecia)

• Bisphosphonate therapy during the first 2 cycles of treatment