Phase 1 Study of PI3 (Phosphatidylinositol-3)-Kinase Inhibitor Copanlisib With Gemcitabine or Cisplatin Plus Gemcitabine in Patients With Advanced Cancer

A Phase 1 Study of Copanlisib(Phosphatidylinositol-3 Kinase Inhibitor) in Combination With Gemcitabine (Treatment A) or Cisplatin Plus Gemcitabine (Treatment B) in Subjects With Advanced Solid Malignancy

This open label Phase I study involves treating subjects with advanced cancer with Copanlisib in combination with either gemcitabine or cisplatin plus gemcitabine. It will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of Copanlisib in combination with gemcitabine and Copanlisib in combination with cisplatin and gemcitabine. The trial will involve multiple participating sites from the US. Up to a maximum of 70 subjects will be enrolled in the study.

Inclusion Criteria:

• Subjects, at least 18 years of age, with advanced or refractory solid tumors in whom gemcitabine (Treatment A) or cisplatin plus gemcitabine (Treatment B) is appropriate medical therapy as determined by the treating physician
• Histological or cytological documentation of non-hematologic, malignant solid tumor, excluding primary brain or spinal tumors, with no current involvement in the CNS
• At least one measurable lesion or evaluable disease, as per RECIST 1.1
• Eastern Cooperative Oncology Group (ECOG) Performance Status Assessment of 0 or 1
• Life expectancy of at least 12 weeks
• Alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN; ≤5 x ULN for subjects with liver involvement with cancer)
• Aspartate aminotransferase (AST) ≤ 3.0 x ULN (≤ 5 x ULN for subjects with liver involvement with cancer)
• Total bilirubin ≤ 2.0 x ULN
• Serum creatinine ≤ 1.5 x ULN
• Prothrombin time-international normalized ratio/partial thromboplastin time (PT-INR/PTT) < 1.5 x ULN (Subjects who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists). Low-dose aspirin is permitted (≤ 100 mg daily).

Exclusion Criteria:

• History of cardiac disease congestive; congestive heart failure > New York Heart Association functional classification system (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
• Current diagnosis of Type 1 or 2 diabetes mellitus, hyperglycemia (defined as consistent fasting blood glucose > 125 mg/dL) or HgBA1c ≥ 7%
• Use of systemic corticosteroids within 2 weeks of the start of study treatment (topical or inhaled steroids are permitted). Single doses of systemic corticosteroids given as premedication for procedures or non-study drugs may be administered up to 24 hours of first dosing of Copanlisib.
• Poorly controlled hypertension, defined as systolic blood pressure (BP) > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management
• Poorly controlled seizure disorder
• Subjects undergoing renal dialysis
• 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.
• 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.
• Bisphosphonate therapy during the first 2 cycles of treatment
• Biological response modifiers, such as granulocyte colony stimulating factor (G-CSF) within 4 weeks of first study treatment
• Radiotherapy to target lesions during study or within 4 weeks of first study treatment
• Known hypersensitivity to the study drugs or active substances or excipients of the preparations
• Use of St John's Wort is prohibited from Day -14 and for the duration of the study