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

• Sponsor: Bayer (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT03458728
• Collaborator: (none)
• Enrollment: 142
• Locations: 21
• Arms: 5
• Anticipated Duration (Months): 107.7
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Mixed Tumor, Malignant	Drug: BAY806946	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Anticipated 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: Apr 30, 2018
• Anticipated Primary Completion Date: Feb 26, 2025
• Anticipated Study Completion Date: Apr 21, 2027

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. The maximum tolerated dose (MTD) [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) [Cycle 1 (28 days)]

   Phase 1

3. Number of participants with Treatment-emergent Adverse Events(TEAEs) [Approximately 13 months]

   Phase 1

4. Number of participants with Serious Adverse Events (SAEs) [Approximately 13 months]

   Phase 1

5. Number of participants with Treatment-related Adverse Events (AEs). [Approximately 13 months]

   Phase 1

6. Objective response rate (ORR) [Up to 31 months]

   Phase 2:ORR is the primary efficacy variable in neuroblastoma, Ewing sarcoma and rhabdomyosarcoma.

7. Disease control rate (DCR) [Up to 31 months]

   Phase 2:DCR is the primary efficacy variable in osteosarcoma.

8. Progression-free survival (PFS) [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) [Cycle 1 Day 1 and Day 15]

   Phase 1.

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

   Phase 1

3. Objective response rate (ORR) [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) [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 [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) [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 [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 [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 [Up to 32 months]

   Phase 2:The severity of AEs will be graded using the NCI CTCAE v 4.03 dictionary

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027-6089
3	Children's Hospital of Orange County	Orange	California	United States	92868-3974
4	The Children's Hospital	Aurora	Colorado	United States	80045
5	Children's National Medical Center	Washington	District of Columbia	United States	20010-2970
6	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
7	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
8	Riley Hospital For Children	Indianapolis	Indiana	United States	46202
9	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
10	C.S. Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
11	University of Minnesota Medical Center	Minneapolis	Minnesota	United States	55455
12	Columbia University Medical Center	New York	New York	United States	10032
13	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
14	Cincinnati Children's Hospital and Medical Center	Cincinnati	Ohio	United States	45229
15	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
16	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
17	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
18	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
19	Cook Children's Medical Center	Fort Worth	Texas	United States	76104-2796
20	Texas Children's Hospital	Houston	Texas	United States	77030
21	Seattle Children's Hospital	Seattle	Washington	United States	98105

Sponsors and Collaborators

• Bayer

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT03458728
• Other Study ID Numbers: 19176; 2017-000383-15
• First Posted: Mar 8, 2018
• Last Update Posted: Aug 18, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• 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: Mixed Tumor, Malignant

Study Results

No Results Posted as of Aug 18, 2022