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

Phase 1

Terminated

• Conditions: Rhabdomyosarcoma; Osteosarcoma; Ewing Sarcoma; Neuroblastoma; Relapsed or Refractory Solid Tumors or Lymphoma in Children
• Interventions: Drug: Copanlisib (BAY806946)

• Registration Number: NCT03458728
• Lead Sponsor: 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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2018-02-19
• Study First Submitted QC: 2018-03-07
• Study First Posted: 2018-03-08
• Study Start: 2018-04-30
• Primary Completion: 2023-02-01
• Study Completion: 2023-02-01
• Results First Submitted: 2023-09-26
• Status Verified: 2023-11
• Results First Submitted QC: 2023-11-29
• Last Update Submitted: 2023-11-29
• Results First Posted: 2023-12-04
• Last Update Posted: 2023-12-04

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 31

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.
  • 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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dose escalation of BAY806946 in Phase 1	Copanlisib (BAY806946)	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).
Patients with Neuroblastoma in Phase 2	Copanlisib (BAY806946)	Recommended Phase 2 dose (RP2D) for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Patients with Ewing sarcoma in Phase 2	Copanlisib (BAY806946)	RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Patients with Osteosarcoma in Phase 2	Copanlisib (BAY806946)	RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Patients with Rhabdomyosarcoma in Phase 2	Copanlisib (BAY806946)	RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.

Primary Outcome Measures

Name	Time	Method
Phase 1: Number of Subjects With Dose Limiting Toxicity (DLT)	Cycle 1 (28 days)	DLT was observed during first cycle of treatment, and assessed as possibly, probably or definitely related to treatment with copanlisib. The DLT observation period for the purposes of dose-escalation was the first cycle of therapy.
Phase 2: Objective Response Rate (ORR)	Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.	ORR was defined separately in each indication, as the number of responders divided by the number of subjects in FAS in the indication.
Phase 2: Disease Control Rate (DCR)	Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.	The DCR was defined as the number of subjects with disease control divided by the number of subjects in FAS or per protocol set (PPS) in the indication.
Phase 2: Progression-free Survival (PFS)	Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Phase 1: Number of Subjects With Serious Adverse Events (SAEs)	Up to 150 days.	This endpoint was performed on SAF.
Phase 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)	After the first study intervention up to 30 days after the last dose of the study drug intake (end of safety follow up), with a maximum of 145 days.	TEAE was defined as any event arising or worsening after start of study drug administration until 30 days after the last dose of the study drug intake (end of safety follow-up).; This endpoint was performed on SAF.
Phase 1: Number of Participants With Treatment-related Adverse Events (AEs).	Up to 145 days.	This endpoint was performed on SAF.
Phase 1: The Maximum Tolerated Dose (MTD): 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.	Cycle 1 (28 days)	Maximum tolerated dose (MTD) for copanlisib was defined as the highest dose level where 6 patients have been treated and ≤ 1 participant experienced a DLT. This endpoint was performed on SAF.

Secondary Outcome Measures

Name	Time	Method
Phase 2: Overall Survival (OS)	Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Phase 2: Number of Subjects With Treatment Emergent SAEs	Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Phase 2: PFS in Each Indication Except for Osteosarcoma	Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Phase 2: Number of Subjects With Treatment-emergent Clinically Significant Change in Laboratory Parameters, ECGs and Vital Signs	Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Phase 1: Area Under the Curve (AUC(0-168))	Age ≥ 6 years: Pre-dose, Post-dose on Cycle 1 Day 1 and Day 15 (1-1.25 hour (h), 1.5- 3h, 22-24h). Age < 6 years: Pre-dose, Post-dose on Cycle 1 Day 1 and Day 15 (1-1.25h, 22-24h). Cycle length is 28 days.	AUC(0-168): Area under the concentration-time curve \[AUC\] from 0 to 168 hours after the 3rd dose in a sequence of 3 nominal doses of copanlisib.; PK analysis set: All participants with at least one intake of study drug and with at least one valid measurement for copanlisib were included in the copanlisib PK analysis.
Phase 2: Number of Participants With Treatment-emergent AEs	Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Phase 1: Copanlisib Maximum Drug Concentration (Cmax)	Age ≥ 6 years: Pre-dose, Post-dose on Cycle 1 Day 1 and Day 15 (1-1.25 hour (h), 1.5- 3h, 22-24h). Age < 6 years: Pre-dose, Post-dose on Cycle 1 Day 1 and Day 15 (1-1.25h, 22-24h). Cycle length is 28 days.	Cmax: maximum concentration after the 3rd dose in a sequence of 3 nominal doses of copanlisib.; PK analysis set: All participants with at least one intake of study drug and with at least one valid measurement for copanlisib were included in the copanlisib PK analysis.
Phase 1: Objective Response Rate (ORR)	Up to 150 days	ORR by dose cohort is defined as the number of responders divided by the number of subjects in FAS in the indication.; The analysis of ORR was performed on FAS.
Phase 2: Duration of Response (DOR)	Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.

Trial Locations

Locations (14)

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

The Children's Hospital; 🇺🇸 Aurora, Colorado, United States

Children's Hospital of Alabama; 🇺🇸 Birmingham, Alabama, United States

Children's Hospital of Orange County; 🇺🇸 Orange, California, United States

Children's Healthcare of Atlanta; 🇺🇸 Atlanta, Georgia, United States

Riley Hospital For Children; 🇺🇸 Indianapolis, Indiana, United States

Columbia University Medical Center; 🇺🇸 New York, New York, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Children's Hospital of Pittsburgh of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States

Cincinnati Children's Hospital and Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

St. Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States

Texas Children's Hospital; 🇺🇸 Houston, Texas, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States