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

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ClinicalTrials.gov Identifier: NCT03458728
Recruitment Status : Recruiting
First Posted : March 8, 2018
Last Update Posted : June 25, 2021
Sponsor:
Information provided by (Responsible Party):
Bayer

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.

Condition or disease Intervention/treatment Phase
Mixed Tumor, Malignant Drug: BAY806946 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 142 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 30, 2018
Estimated Primary Completion Date : February 26, 2025
Estimated Study Completion Date : April 21, 2027


Arm Intervention/treatment
Experimental: Dose escalation of BAY806946 in Phase 1
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).
Drug: BAY806946
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.

Experimental: Patients with Neuroblastoma in Phase 2
Recommended Phase 2 dose (RP2D) for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Drug: BAY806946
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.

Experimental: Patients with Osteosarcoma in Phase 2
RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Drug: BAY806946
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.

Experimental: Patients with Rhabdomyosarcoma in Phase 2
RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Drug: BAY806946
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.

Experimental: Patients with Ewing sarcoma in Phase 2
RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Drug: BAY806946
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 Measures :
  1. The maximum tolerated dose (MTD) [ Time Frame: Cycle 1 (28 days) ]
    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.

  2. Dose-limiting Toxicities(DLTs) [ Time Frame: Cycle 1 (28 days) ]
    Phase 1

  3. Number of participants with Treatment-emergent Adverse Events(TEAEs) [ Time Frame: Approximately 13 months ]
    Phase 1

  4. Number of participants with Serious Adverse Events (SAEs) [ Time Frame: Approximately 13 months ]
    Phase 1

  5. Number of participants with Treatment-related Adverse Events (AEs). [ Time Frame: Approximately 13 months ]
    Phase 1

  6. Objective response rate (ORR) [ Time Frame: Up to 31 months ]
    Phase 2:ORR is the primary efficacy variable in neuroblastoma, Ewing sarcoma and rhabdomyosarcoma.

  7. Disease control rate (DCR) [ Time Frame: Up to 31 months ]
    Phase 2:DCR is the primary efficacy variable in osteosarcoma.

  8. Progression-free survival (PFS) [ Time Frame: Up to 31 months ]
    Phase 2: PFS is considered as co-primary (descriptively evaluated) variable in patients with osteosarcoma.


Secondary Outcome Measures :
  1. Copanlisib maximum drug concentration (Cmax) [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Phase 1.

  2. Area under the curve (AUC(0-168)) [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Phase 1

  3. Objective response rate (ORR) [ Time Frame: Approximately 12 months ]
    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

  4. Duration of response (DOR) [ Time Frame: Up to 31 months ]
    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

  5. PFS in each indication except for osteosarcoma [ Time Frame: Up to 31 months ]
    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).

  6. Overall survival (OS) [ Time Frame: Up to 31 months ]
    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.

  7. Number of participants with Treatment-emergent AEs [ Time Frame: Up to 32 months ]
    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).

  8. Number of participants with treatment emergent SAEs [ Time Frame: Up to 32 months ]
    Phase 2: The severity of AEs will be graded using the NCI CTCAE v 4.03 dictionary

  9. Number of participants with treatment-emergent clinically significant change in laboratory parameters, ECGs or vital signs [ Time Frame: Up to 32 months ]
    Phase 2:The severity of AEs will be graded using the NCI CTCAE v 4.03 dictionary



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03458728


Contacts
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Contact: Bayer Clinical Trials Contact (+) 1-888-8422937 clinical-trials-contact@bayer.com

Locations
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Sponsors and Collaborators
Bayer
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT03458728    
Other Study ID Numbers: 19176
2017-000383-15 ( EudraCT Number )
First Posted: March 8, 2018    Key Record Dates
Last Update Posted: June 25, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Availability of this study's data will 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.clinicalstudydatarequest.com 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 Study sponsors section of the portal.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Phase I: relapsed or refractory solid tumors or lymphoma
Phase II: relapsed or refractory solid tumors (neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing sarcoma)
Additional relevant MeSH terms:
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Mixed Tumor, Malignant
Neoplasms, Complex and Mixed
Neoplasms by Histologic Type
Neoplasms