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

Study Overview
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Brief Summary
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This open label Phase 1 study involves treating subjects with advanced cancer with BAY80-6946 in combination with paclitaxel. It will determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of BAY80-6946 in combination with paclitaxel. The trial will involve multiple participating sites from the US. Following determination of the MTD, an expansion cohort of 20 evaluable subjects with breast cancer was planned. Finally, 16 patients have been enrolled to treatment (Cohort 3). A new expansion cohort with modified dosing cohort is now introduced (Cohort 4: breast cancer expansion cohort with modified dosing) in which another 20 subjects are planned to be enrolled to treatment.

Official Title
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A Phase 1 Study of BAY80-6946 (Phosphatidylinositol 3΄-Kinase Inhibitor) in Combination With Paclitaxel in Subjects With Advanced Solid Malignancy

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Copanlisib (BAY80-6946)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have defined tumor classification (ie, TNBC, HER2+ or Luminal) for enrollment. If tumor classification is not available the subject cannot be enrolled. Tumor classification can be based on analysis of archived tumor tissue, or analysis of tumor tissue collected at any time proximal to screening. Subject profile can also be derived from analysis of fresh tumor tissue obtained during screening. Shipment of specimens (archival or fresh tumor tissue, blood, and plasma) to a central lab can take place after subject enrollment. No prior paclitaxel treatment for subjects in the dose escalation phase. MTD 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. 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 (eg, 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 Performance Status Assessment of 0 or 1 Life expectancy of at least 12 weeks Exclusion Criteria:- 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 Pre-existing interstitial lung disease and/or severe impaired pulmonary function 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% Active clinically serious infections Grade ≥ 2 (NCI-CTCAE version 4.0), including viral hepatitis Poorly controlled seizure disorder Poorly controlled hypertension, defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management Known human immunodeficiency virus (HIV) infection or chronic hepatitis C or B Subjects undergoing renal dialysis Known bleeding diathesis Pregnant or breast feeding women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Copanlisib (BAY80-6946)<br>The treatment of consists of repetitive cycles, each over 4 weeks. It continues until disease progression or limiting toxicity. If paclitaxel is discontinued for toxicity, BAY80-6946 may continue at the discretion of the investigator if a clinical benefit (response or stable disease for 6 months) is noted. | Drug: Paclitaxel<br>* Paclitaxel (80 mg/m2 in Cohort 1, 2 and 3, 90 mg/m2 in Cohort 4) as 60-minute iv infusion once weekly on Days 1, 8, 15 and 22 (Day 22 in Cohort 1, 2 and 3 only) in 28-day cycles The following intravenous premedications are required 30 to 60 minutes before paclitaxel infusion: Dexamethasone (10 mg), diphenhydramine (50 mg) and either cimetidine (300 mg) or ranitidine (50 mg) Alternatively, for premedications other than dexamethasone, the standard institutional regimen is permitted.<br>Drug: Copanlisib (BAY80-6946)<br>* BAY80-6946 (0.6 mg/kg in Cohort 1, 0.8 mg/kg in Cohort 2, 3 and 4) as 60-minute iv infusion once weekly on Days 2, 9, 16 and 23 (Day 23 in Cohort 1, 2 and 3 only) in 28-day cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse event collection |  | Up to 3 years or longer if indicated | 
| Maximum tolerated dose, measured by adverse event profile |  | Up to 3 years or longer if indicated | 
| Pharmacokinetics characterized by Cmax of BAY80-6946 (and its metabolite(s), if needed) | Cmax: maximum drug concentration in plasma after single dose administration | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by Cmax/D of BAY80-6946 (and its metabolite(s), if needed) | Cmax/D: Cmax divided by total dose in [mg] | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by tmax of BAY80-6946 (and its metabolite(s), if needed) | tmax: time to reach maximum drug concentration in plasma after single (first) dose | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by AUC(0-tlast) of BAY80-6946 (and its metabolite(s), if needed) | AUC(0-tlast): AUC from time 0 to the last data point above lower limit of quantification | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by AUC (if possible) of BAY80-6946 (and its metabolite(s), if needed) | AUC: area under the plasma concentration vs time curve from zero to infinity | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by AUC/D of BAY80-6946 (and its metabolite(s), if needed) | AUC/D: AUC divided by total dose in [mg] | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by half-life of BAY80-6946 (and its metabolite(s), if needed) |  | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by partial AUC values [eg, AUC(0-25)] of BAY80-6946 (and its metabolite(s), if needed) | AUC(0-25): area under the plasma concentration vs time curve from zero to 25 h p.a. | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by clearance of BAY80-6946 (and its metabolite(s), if needed) |  | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by volume of distribution of BAY80-6946 (and its metabolite(s), if needed) |  | Multiple time points up to 6 weeks | 
| Estimation of percent of dose excreted [unchanged or as metabolites, if relevant) renally during 0 - 25 h after start of BAY80-6946 infusion (AE,ur(0-25)] (for Cohort 4 only) | AE,ur(0-25): amount of drug excreted via urine during the collection interval 0 - 25 h | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by Cmax of Paclitaxel and 6-OH paclitaxel |  | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by tmax of Paclitaxel and 6-OH paclitaxel |  | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by AUC(0-t) of Paclitaxel and 6-OH paclitaxel |  | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by AUC of Paclitaxel and 6-OH paclitaxel |  | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by half-life of Paclitaxel and 6-OH paclitaxel |  | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by clearance of Paclitaxel and 6-OH paclitaxel |  | Multiple time points up to 6 weeks | 
| Pharmacokinetics characterized by volume of distribution (If possible and needed) of Paclitaxel and 6-OH paclitaxel |  | Multiple time points up to 6 weeks | 
| Effect of BAY80-6946 on paclitaxel PK will be assessed by comparing Cmax of Cycle 1 Day 1 and Cycle 1 Day 15 |  | Multiple time points up to 6 weeks | 
| Effect of BAY80-6946 on paclitaxel PK will be assessed by comparing AUC(0-tlast) of Cycle 1 Day 1 and Cycle 1 Day 15 |  | Multiple time points up to 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with mutational status |  | Up to 3 years or longer if indicated | 
| Tumor Response as measured by RECIST 1.1 criteria |  | Up to 3 years or longer if indicated | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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phase I, phosphatidylinositol 3΄-kinase (PI3K), paclitaxel, Maximum tolerated Dose