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Safety, Tolerability, Efficacy and Pharmacokinetics of Copanlisib in Pediatric Patients

Primary Purpose

Mixed Tumor, Malignant

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
BAY806946
Sponsored by
Bayer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mixed Tumor, Malignant focused on measuring Phase I: relapsed or refractory solid tumors or lymphoma, Phase II: relapsed or refractory solid tumors (neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing sarcoma)

Eligibility Criteria

6 Months - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Signed informed consent form by patients and/or patients' parents/legal guardians and age appropriate assent form by the patients obtained before any study specific procedure
  • Male or female patients from 6 months to ≤ 21 years old at the time of study enrollment

  • Confirmation of diagnosis:

    • Phase I: Patients must have histologic verification of a solid tumor or lymphoma malignancy at diagnosis, with measurable or evaluable disease, for which there is no standard curative anti-cancer treatment or treatment is no longer effective and must have received ≥ 1 prior line of therapy.
    • Phase II: patients must have histologically verified tumor at initial diagnosis and radiologically or histologically confirmed status at inclusion as indicated in the following: neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing sarcoma.
    • In Phase II, patients with solid tumors must have measurable disease (evaluable disease is acceptable for neuroblastoma and Ewing sarcoma). Tumor assessment will be done via computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography-computed tomography (PET-CT). Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, may be considered measurable if there has been demonstrated progression in the lesion. Bone scans (if clinically indicated) should be obtained within ≤ 4 weeks prior to the start of treatment.
  • Performance level: Lansky ≥ 50% for patients ≤ 16 years of age and Karnofsky ≥ 50% for patients > 16 years of age.
  • Adequate bone marrow, renal and liver function.

Exclusion Criteria:

  • Active or uncontrolled infection (National Cancer Institute (NCI)-CTCAE Grade ≥ 2).
  • History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator).
  • Diabetes mellitus.
  • Uncontrolled arterial hypertension despite optimal medical management (per institutional guidelines).
  • Patients with central nervous system (CNS) malignancies.

Sites / Locations

  • Children's Hospital of Alabama
  • Children's Hospital of Los Angeles
  • Children's Hospital of Orange County
  • The Children's Hospital
  • Children's National Medical Center
  • Children's Healthcare of Atlanta
  • Riley Hospital For Children
  • Dana-Farber Cancer Institute
  • C.S. Mott Children's Hospital
  • Columbia University Medical Center
  • Memorial Sloan-Kettering Cancer Center
  • Cincinnati Children's Hospital and Medical Center
  • Children's Hospital of Philadelphia
  • Children's Hospital of Pittsburgh of UPMC
  • St. Jude Children's Research Hospital
  • University of Texas Southwestern Medical Center
  • Cook Children's Medical Center
  • Texas Children's Hospital
  • Seattle Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Dose escalation of BAY806946 in Phase 1

Patients with Neuroblastoma in Phase 2

Patients with Osteosarcoma in Phase 2

Patients with Rhabdomyosarcoma in Phase 2

Patients with Ewing sarcoma in Phase 2

Arm Description

It is estimated that 2 or 3 dose cohorts may be evaluated in phase 1 of the study. Safety and MTD/RP2D dose will be evaluated in 2 age groups (< 1 year old and ≥ 1 year old).

Recommended Phase 2 dose (RP2D) for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.

RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.

RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.

RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.

Outcomes

Primary Outcome Measures

The maximum tolerated dose (MTD)
Phase 1: The highest dose level of copanlisib that can be given so that not more than 1 out of 6 patients experience a DLT during the DLT evaluation period.
Dose-limiting Toxicities(DLTs)
Phase 1
Number of participants with Treatment-emergent Adverse Events(TEAEs)
Phase 1
Number of participants with Serious Adverse Events (SAEs)
Phase 1
Number of participants with Treatment-related Adverse Events (AEs).
Phase 1
Objective response rate (ORR)
Phase 2:ORR is the primary efficacy variable in neuroblastoma, Ewing sarcoma and rhabdomyosarcoma.
Disease control rate (DCR)
Phase 2:DCR is the primary efficacy variable in osteosarcoma.
Progression-free survival (PFS)
Phase 2: PFS is considered as co-primary (descriptively evaluated) variable in patients with osteosarcoma.

Secondary Outcome Measures

Copanlisib maximum drug concentration (Cmax)
Phase 1.
Area under the curve (AUC(0-168))
Phase 1
Objective response rate (ORR)
Phase 1: ORR by dose cohort is defined as the number of responders divided by the number of patients in full analysis set (FAS) in the indication
Duration of response (DOR)
Phase 2: DOR is defined as the time from the date of first observed tumor response (Complete response (CR) or Partial response (PR)) until first subsequent disease progression or until death (if death occurs before progression is documented) due to any cause
PFS in each indication except for osteosarcoma
Phase 2: PFS is defined as the time from first dose of study drug to disease progression according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST1.1) for solid tumor patients (except osteosarcoma) and SIOPEN or Curie score for neuroblastoma patients with Iodine-123 metaiodobenzylguanidine (MIBG)-avid disease, or death (if death occurs before progression is documented).
Overall survival (OS)
Phase 2: OS is defined as the time from first dose of study drug until death from any cause or until the last date the patient is known to be alive.
Number of participants with Treatment-emergent AEs
Phase 2: A treatment emergent AE is defined as any event arising or worsening after start of test drug administration until 30 days after the last dose of the study drug intake (end of safety followup).
Number of participants with treatment emergent SAEs
Phase 2: The severity of AEs will be graded using the NCI CTCAE v 4.03 dictionary
Number of participants with treatment-emergent clinically significant change in laboratory parameters, ECGs or vital signs
Phase 2:The severity of AEs will be graded using the NCI CTCAE v 4.03 dictionary

Full Information

First Posted
February 19, 2018
Last Updated
February 28, 2023
Sponsor
Bayer
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1. Study Identification

Unique Protocol Identification Number
NCT03458728
Brief Title
Safety, Tolerability, Efficacy and Pharmacokinetics of Copanlisib in Pediatric Patients
Official Title
A Non-randomized, Open-label, Multi-center, Phase I/II Study of Phosphatidylinositol-3-kinase (PI3K) Inhibitor Copanlisib in Pediatric Patients With Relapsed/Refractory Solid Tumors or Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Terminated
Why Stopped
no anticipated benefit over available standard therapies
Study Start Date
April 30, 2018 (Actual)
Primary Completion Date
February 1, 2023 (Actual)
Study Completion Date
February 1, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bayer

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study is designed to investigate whether the use of copanlisib is safe, feasible and beneficial to pediatric patients with solid solid tumors or lymphoma that are recurrent or refractory to standard therapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mixed Tumor, Malignant
Keywords
Phase I: relapsed or refractory solid tumors or lymphoma, Phase II: relapsed or refractory solid tumors (neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing sarcoma)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dose escalation of BAY806946 in Phase 1
Arm Type
Experimental
Arm Description
It is estimated that 2 or 3 dose cohorts may be evaluated in phase 1 of the study. Safety and MTD/RP2D dose will be evaluated in 2 age groups (< 1 year old and ≥ 1 year old).
Arm Title
Patients with Neuroblastoma in Phase 2
Arm Type
Experimental
Arm Description
Recommended Phase 2 dose (RP2D) for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Arm Title
Patients with Osteosarcoma in Phase 2
Arm Type
Experimental
Arm Description
RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Arm Title
Patients with Rhabdomyosarcoma in Phase 2
Arm Type
Experimental
Arm Description
RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Arm Title
Patients with Ewing sarcoma in Phase 2
Arm Type
Experimental
Arm Description
RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Intervention Type
Drug
Intervention Name(s)
BAY806946
Intervention Description
Copanlisib will be dosed on Day 1, Day 8, and Day 15 of every 28-day cycle. Phase 1: 2 or 3 dose cohorts may be evaluated in phase 1 of the study. Phase 2: RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Primary Outcome Measure Information:
Title
The maximum tolerated dose (MTD)
Description
Phase 1: The highest dose level of copanlisib that can be given so that not more than 1 out of 6 patients experience a DLT during the DLT evaluation period.
Time Frame
Cycle 1 (28 days)
Title
Dose-limiting Toxicities(DLTs)
Description
Phase 1
Time Frame
Cycle 1 (28 days)
Title
Number of participants with Treatment-emergent Adverse Events(TEAEs)
Description
Phase 1
Time Frame
Approximately 13 months
Title
Number of participants with Serious Adverse Events (SAEs)
Description
Phase 1
Time Frame
Approximately 13 months
Title
Number of participants with Treatment-related Adverse Events (AEs).
Description
Phase 1
Time Frame
Approximately 13 months
Title
Objective response rate (ORR)
Description
Phase 2:ORR is the primary efficacy variable in neuroblastoma, Ewing sarcoma and rhabdomyosarcoma.
Time Frame
Up to 31 months
Title
Disease control rate (DCR)
Description
Phase 2:DCR is the primary efficacy variable in osteosarcoma.
Time Frame
Up to 31 months
Title
Progression-free survival (PFS)
Description
Phase 2: PFS is considered as co-primary (descriptively evaluated) variable in patients with osteosarcoma.
Time Frame
Up to 31 months
Secondary Outcome Measure Information:
Title
Copanlisib maximum drug concentration (Cmax)
Description
Phase 1.
Time Frame
Cycle 1 Day 1 and Day 15
Title
Area under the curve (AUC(0-168))
Description
Phase 1
Time Frame
Cycle 1 Day 1 and Day 15
Title
Objective response rate (ORR)
Description
Phase 1: ORR by dose cohort is defined as the number of responders divided by the number of patients in full analysis set (FAS) in the indication
Time Frame
Approximately 12 months
Title
Duration of response (DOR)
Description
Phase 2: DOR is defined as the time from the date of first observed tumor response (Complete response (CR) or Partial response (PR)) until first subsequent disease progression or until death (if death occurs before progression is documented) due to any cause
Time Frame
Up to 31 months
Title
PFS in each indication except for osteosarcoma
Description
Phase 2: PFS is defined as the time from first dose of study drug to disease progression according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST1.1) for solid tumor patients (except osteosarcoma) and SIOPEN or Curie score for neuroblastoma patients with Iodine-123 metaiodobenzylguanidine (MIBG)-avid disease, or death (if death occurs before progression is documented).
Time Frame
Up to 31 months
Title
Overall survival (OS)
Description
Phase 2: OS is defined as the time from first dose of study drug until death from any cause or until the last date the patient is known to be alive.
Time Frame
Up to 31 months
Title
Number of participants with Treatment-emergent AEs
Description
Phase 2: A treatment emergent AE is defined as any event arising or worsening after start of test drug administration until 30 days after the last dose of the study drug intake (end of safety followup).
Time Frame
Up to 32 months
Title
Number of participants with treatment emergent SAEs
Description
Phase 2: The severity of AEs will be graded using the NCI CTCAE v 4.03 dictionary
Time Frame
Up to 32 months
Title
Number of participants with treatment-emergent clinically significant change in laboratory parameters, ECGs or vital signs
Description
Phase 2:The severity of AEs will be graded using the NCI CTCAE v 4.03 dictionary
Time Frame
Up to 32 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed informed consent form by patients and/or patients' parents/legal guardians and age appropriate assent form by the patients obtained before any study specific procedure Male or female patients from 6 months to ≤ 21 years old at the time of study enrollment Confirmation of diagnosis: Phase I: Patients must have histologic verification of a solid tumor or lymphoma malignancy at diagnosis, with measurable or evaluable disease, for which there is no standard curative anti-cancer treatment or treatment is no longer effective and must have received ≥ 1 prior line of therapy. Phase II: patients must have histologically verified tumor at initial diagnosis and radiologically or histologically confirmed status at inclusion as indicated in the following: neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing sarcoma. In Phase II, patients with solid tumors must have measurable disease (evaluable disease is acceptable for neuroblastoma and Ewing sarcoma). Tumor assessment will be done via computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography-computed tomography (PET-CT). Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, may be considered measurable if there has been demonstrated progression in the lesion. Bone scans (if clinically indicated) should be obtained within ≤ 4 weeks prior to the start of treatment. Performance level: Lansky ≥ 50% for patients ≤ 16 years of age and Karnofsky ≥ 50% for patients > 16 years of age. Adequate bone marrow, renal and liver function. Exclusion Criteria: Active or uncontrolled infection (National Cancer Institute (NCI)-CTCAE Grade ≥ 2). History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator). Diabetes mellitus. Uncontrolled arterial hypertension despite optimal medical management (per institutional guidelines). Patients with central nervous system (CNS) malignancies.
Facility Information:
Facility Name
Children's Hospital of Alabama
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
Children's Hospital of Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027-6089
Country
United States
Facility Name
Children's Hospital of Orange County
City
Orange
State/Province
California
ZIP/Postal Code
92868-3974
Country
United States
Facility Name
The Children's Hospital
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010-2970
Country
United States
Facility Name
Children's Healthcare of Atlanta
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Riley Hospital For Children
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
C.S. Mott Children's Hospital
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Cincinnati Children's Hospital and Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Children's Hospital of Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
University of Texas Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Cook Children's Medical Center
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104-2796
Country
United States
Facility Name
Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

Learn more about this trial

Safety, Tolerability, Efficacy and Pharmacokinetics of Copanlisib in Pediatric Patients

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