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.

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: Gemcitabine; Drug: BAY80-6946; Drug: Cisplatin; Drug: NaCl; Drug: BAY80-6964 fixed dose

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
  • Minnesota
    • Rochester, Minnesota, United States, 55905
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7305

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment A: Gemcitabine-Copanlisib; The treatment consists of repetitive cycles, each over 28 days. Treatment continues until disease progression or dose limiting toxicity. If gemcitabine is discontinued for toxicity, Copanlisib may be continued at the discretion of the Investigator if a clinical benefit (response or stable disease for 3 months) is noted. - Hour 0 to 0.5: Gemcitabine (1000 mg/m2 as 30-minute IV infusion) on Days 1, 8 and 15 every 28 days - Hour 1.5 to 2.5: BAY80-6946 (starting dose = 0.6 mg/kg as 60-minute IV infusion, starting 1 hour post completion of gemcitabine infusion) on Days 1, 8 and 15 every 28 days	Drug: Gemcitabine; Gemcitabine 1000mg/m2 as 30-minutes IV infusion; Drug: BAY80-6946; Escalated dose starting from 0.6 mg/kg in 100 mL of 0.9% NaCl as 60-minutes IV infusion
EXPERIMENTAL: Treatment B: Cisplatin-Gemcitabine-Copanlisib; Treatment consists of repetitive 21 day cycles for a maximum of 8 cycles. Treatment continues until disease progression, DLT or completion of 8 cycles. After 8 cycles, gemcitabine and Copanlisib, without cisplatin, may continue at the discretion of the Investigator until disease progression or DLT if a clinical benefit is noted (response or stable disease for 3 months). Treatment is administered on Days 1 and 8 every 21 days as follows: - Hour 0 to 1: Cisplatin IV infusion over 60 min (One liter of 0.9% NaCl including 25 mg/m2 cisplatin, 20 mmol of potassium chloride, and 8 mmol of magnesium sulfate) - Hour 1 to 1.5: IV infusion of 500 ml of 0.9% NaCl over 30 min - Hour 1.5 to 2: Gemcitabine (1000 mg/m2 as 30 min IV infusion) - Hour 3 to 4: Copanlisib IV infusion at the MTD determined in Treatment A over 60 min. [If Treatment A MTD is not tolerable, further subject enrollment will begin at one Copanlisib Dose Level lower with the cisplatin-gemcitabine doses remaining constant.]	Drug: Gemcitabine; Gemcitabine 1000mg/m2 as 30-minutes IV infusion; Drug: Cisplatin; 1 liter of 0.9% NaCl including 25 mg/m2 cisplatin, 20 mmol of potassium chloride, and 8 nmol of magnesium sulfate over 60 minutes; Drug: NaCl; Infusion of 500 ml of 0.9% NaCl over 30-minutes; Drug: BAY80-6964 fixed dose; BAY80-6946 IV infusion at the maximum tolerated dose determined in Treatment A over 60 min. [If Treatment A MTD is not tolerable, further subject enrollment will begin at one BAY80-6946 Dose Level lower with the cisplatin-gemcitabine doses remaining constant.]

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose, measured by adverse event profile	Up to 3 years or longer if indicated
Adverse event collection	Up to 3 years or longer if indicated

Secondary Outcome Measures

Outcome Measure	Time Frame
Maximum drug concentration in plasma (Cmax) of Copanlisib with gemcitabine or cisplatin plus gemcitabine	Approximately 18 months
The time of the maximum concentration (Tmax) of Copanlisib with gemcitabine or cisplatin plus gemcitabine	Approximately 18 months
Area under the curve (AUC) of Copanlisib with gemcitabine or cisplatin plus gemcitabine	Approximately 18 months
Area under the concentration time curve (AUC (0-tn)) of Copanlisib with gemcitabine or cisplatin plus gemcitabine	Approximately 18 months
Half life (t1/2) of Copanlisib with gemcitabine or cisplatin plus gemcitabine	Approximately 18 months
Biomarker evaluation including analysis of pathway activation in tumor tissue and blood/plasma	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

Collaborators and Investigators

• Sponsor: Bayer

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 18, 2011
• Primary Completion (ACTUAL): July 20, 2015
• Study Completion (ACTUAL): December 18, 2015

Study Registration Dates

• First Submitted: September 15, 2011
• First Submitted That Met QC Criteria: October 26, 2011
• First Posted (ESTIMATE): October 27, 2011

Study Record Updates

• Last Update Posted (ACTUAL): October 4, 2017
• Last Update Submitted That Met QC Criteria: October 2, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: cisplatin; phase I; gemcitabine; maximum tolerated dose; phosphatidylinositol-3 kinase inhibitor
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine; Cisplatin
• Other Study ID Numbers: 12875