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

Study Overview
=================
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.

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

Conditions
-----------------
Relapsed or Refractory Solid Tumors or Lymphoma in Children, Neuroblastoma, Osteosarcoma, Rhabdomyosarcoma, Ewing Sarcoma

Intervention / Treatment
-----------------
* Drug: Copanlisib (BAY806946)


Participation Criteria
=================
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. 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.

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation of BAY806946 in Phase 1<br>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: Copanlisib (BAY806946)<br>* 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.<br>|
| Experimental: Patients with Neuroblastoma in Phase 2<br>Recommended Phase 2 dose (RP2D) for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used. | Drug: Copanlisib (BAY806946)<br>* 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.<br>|
| Experimental: Patients with Osteosarcoma in Phase 2<br>RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used. | Drug: Copanlisib (BAY806946)<br>* 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.<br>|
| Experimental: Patients with Rhabdomyosarcoma in Phase 2<br>RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used. | Drug: Copanlisib (BAY806946)<br>* 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.<br>|
| Experimental: Patients with Ewing sarcoma in Phase 2<br>RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used. | Drug: Copanlisib (BAY806946)<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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. | 
| Phase 1: Number of Subjects With Serious Adverse Events (SAEs) | This endpoint was performed on SAF. | Up to 150 days. | 
| Phase 1: Number of Participants With Treatment-related Adverse Events (AEs). | This endpoint was performed on SAF. | Up to 145 days. | 
| 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. | 
| 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. | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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. | 
| 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 | 
| Phase 2: Duration of Response (DOR) |  | 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: 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 Participants With Treatment-emergent AEs |  | 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: 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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Phase I: relapsed or refractory solid tumors or lymphoma, Phase II: relapsed or refractory solid tumors (neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing sarcoma)