Phase Ib Study of PI3(Phosphoinositol 3)-Kinase Inhibitor Copanlisib With MEK (Mitogen-activated Protein Kinase) Inhibitor Refametinib (BAY86-9766) in Patients With Advanced Cancer

Phase Ib Trial of the Combination of PI3K Inhibitor BAY 80-6946 and Allosteric-MEK Inhibitor BAY 86-9766 in Subjects With Advanced Cancer

The PI3K (phosphoinositol 3-Kinase) inhibitor Copanlisib and the MEK (mitogen-activated protein kinase) inhibitor Refametinib (BAY86-9766)have both been tested as single agent treatments in other phase I studies. This study will test the combination of these two drugs to try and answer the following questions:

1. What are the side effects of the combination of Copanlisib and Refametinib (BAY86-9766)when given together at different/increasing dose levels?
2. What dose level of Copanlisib and Refametinib (BAY86-9766) should be tested in future clinical research studies?
3. How much Copanlisib is in the blood at specific times after administration and does adding Refametinib (BAY86-9766) have an affect?
4. How much Refametinib (BAY86-9766) is in the blood at specific times after administration and does adding Copanlisib have an affect?
5. Does the combination of Refametinib (BAY86-9766) and Copanlisib have an effect on tumors?

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: Copanlisib + Refametinib (BAY86-9766); Drug: Copanlisib + Refametinib (BAY86-9766)

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Baden-Württemberg
    • Freiburg, Baden-Württemberg, Germany, 79106
• Netherlands
  • Rotterdam, Netherlands, 3015 CE
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85260
  • Nevada
    • Las Vegas, Nevada, United States, 89169
  • South Carolina
    • Greenville, South Carolina, United States, 29605
  • Texas
    • Houston, Texas, United States, 77030
    • Tyler, Texas, United States, 75702
  • Washington
    • Vancouver, Washington, United States, 98684

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:

• Age greater than/equal to 18 years old
• ECOG Performance Status of 0 - 1
• Life expectancy of at least 12 weeks
• Patients with advanced, histologically or cytologically confirmed solid tumors, refractory to any standard therapy or have no standard therapy available
• LVEF (left ventricular ejection fraction) > or = to the lower limit of normal for the institution
• Radiographically or clinically evaluable tumor

• Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 14 days prior to start of first dose:

  • Hemoglobin > 9.0 g/dL
  • Absolute neutrophil count (ANC) > or = 1500/mm3
  • Platelet count > or = 100,000 /mm3
  • Total bilirubin < or = 1.5 times the upper limit of normal
  • ALT (alanine aminotransferase) and AST (aspartate aminotransferase) < or = 2.5 x upper limit of normal (< or = 5 x upper limit of normal for patients with liver involvement)
  • PT-INR (prothrombin-international normalized ratio) and PTT (partial thromboplastin time) < or = 1.5 times the upper limit of normal
  • Serum creatinine < or = 1.5 times the upper limit of normal

Exclusion Criteria:

• History of impaired cardiac function or clinically significant cardiac disease (i.e. congestive heart failure (CHF) NYHA (New York Heart Association) Class III or IV); active coronary artery disease, myocardial infarction within 6 months of study entry; new onset or unstable angina within 3 months of study entry, or cardiac arrhythmias requiring anti-arrhythmic therapy
• Type 1 or type 2 diabetes mellitus or fasting glucose > 125 mg/dL or HgBA1c > or = 7.0
• Use of systemic corticosteroids within 2 weeks of study entry
• History of retinal vein occlusion
• Known glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Active clinically serious infection
• Uncontrolled hypertension
• Positive for HIV, or chronic Hepatitis B or C
• Subjects undergoing renal dialysis
• Known bleeding diathesis
• Ongoing substance abuse
• Pregnant or breast-feeding women

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm 1

Drug: Copanlisib + Refametinib (BAY86-9766); Copanlisib will be administered as an IV infusion weekly for 3 weeks in combination with Refametinib (BAY86-9766) at varying dose levels. Refametinib (BAY86-9766) is administered orally twice a day starting at Day 4 of Cycle 1.; Drug: Copanlisib + Refametinib (BAY86-9766); Copanlisib will be administered as an IV infusion weekly in combination with Refametinib (BAY86-9766) at varying dose levels. Refametinib (BAY86-9766) is administered orally twice a day starting at Day 6 of Cycle 1 on a 4 day on, 3 day off schedule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum Tolerated Dose	2 years
Comparison of the Copanlisib AUC when given alone with the AUC when given with Refametinib (BAY86-9766)	At day 15
Comparison of the Refametinib (BAY86-9766) AUC when given alone with the AUC when given with Copanlisib	At day 15

Secondary Outcome Measures

Outcome Measure	Time Frame
Tumor Response as measured by RECIST 1.1 criteria	3 years
Biomarker evaluation including analysis of pathway activation in blood and plasma	3 years
Tumor Response as measured by FDG-PET at MTD and expansion cohort(s)	3 years
Pharmacodynamic biomarker evaluation analysis using paired tumor biopsies	3 years

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Ramanathan RK, Von Hoff DD, Eskens F, Blumenschein G Jr, Richards D, Genvresse I, Reschke S, Granvil C, Skubala A, Pena C, Mross K. Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer. Target Oncol. 2020 Apr;15(2):163-174. doi: 10.1007/s11523-020-00714-0. Erratum In: Target Oncol. 2020 Dec;15(6):803.

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: June 30, 2011
• First Submitted That Met QC Criteria: July 11, 2011
• First Posted (Estimate): July 12, 2011

Study Record Updates

• Last Update Posted (Estimate): April 17, 2015
• Last Update Submitted That Met QC Criteria: April 16, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Tolerability
• Other Study ID Numbers: 12876; 2010-024082-45 (EudraCT Number)