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

Neuroblastoma Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03458728
• Other study ID #: 19176
• Secondary ID: 2017-000383-15
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: April 30, 2018
• Est. completion date: February 1, 2023

Study information

• Verified date: November 2023
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 31
• Est. completion date: February 1, 2023
• Est. primary completion date: February 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 21 Years

Eligibility

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.

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.

Related Conditions & MeSH terms

• Ewing Sarcoma
• Lymphoma
• Neuroblastoma
• Osteosarcoma
• Rhabdomyosarcoma
• Sarcoma
• Sarcoma, Ewing

Intervention

Drug:
• Copanlisib (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.

Locations

Country	Name	City	State
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	The Children's Hospital	Aurora	Colorado
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Cincinnati Children's Hospital and Medical Center	Cincinnati	Ohio
United States	Texas Children's Hospital	Houston	Texas
United States	Riley Hospital For Children	Indianapolis	Indiana
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Columbia University Medical Center	New York	New York
United States	Children's Hospital of Orange County	Orange	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	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.	Cycle 1 (28 days)
Primary	Phase 1: Number of Subjects With Dose Limiting Toxicity (DLT)	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.	Cycle 1 (28 days)
Primary	Phase 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)	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.	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.
Primary	Phase 1: Number of Subjects With Serious Adverse Events (SAEs)	This endpoint was performed on SAF.	Up to 150 days.
Primary	Phase 1: Number of Participants With Treatment-related Adverse Events (AEs).	This endpoint was performed on SAF.	Up to 145 days.
Primary	Phase 2: Objective Response Rate (ORR)	ORR was defined separately in each indication, as the number of responders divided by the number of subjects in FAS in the indication.	Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Primary	Phase 2: Disease Control Rate (DCR)	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.	Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Primary	Phase 2: Progression-free Survival (PFS)		Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Secondary	Phase 1: Copanlisib Maximum Drug Concentration (Cmax)	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.	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.
Secondary	Phase 1: Area Under the Curve (AUC(0-168))	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.	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.
Secondary	Phase 1: Objective Response Rate (ORR)	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.	Up to 150 days
Secondary	Phase 2: Duration of Response (DOR)		Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Secondary	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.
Secondary	Phase 2: Overall Survival (OS)		Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Secondary	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.
Secondary	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.
Secondary	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.

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