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

• ClinicalTrials.gov Identifier: NCT03458728
• Recruitment Status: Terminated
• First Posted: March 8, 2018
• Results First Posted: December 4, 2023
• Last Update Posted: December 4, 2023
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

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
Relapsed or Refractory Solid Tumors or Lymphoma in Children; Neuroblastoma; Osteosarcoma; Rhabdomyosarcoma; Ewing Sarcoma	Drug: Copanlisib (BAY806946)	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 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
• Actual Primary Completion Date: February 1, 2023
• Actual Study Completion Date: February 1, 2023

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: 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.
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: 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.
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: 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.
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: 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.
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: 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.

Outcome Measures

Primary Outcome Measures :

1. 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. [ Time Frame: 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.
2. Phase 1: Number of Subjects With Dose Limiting Toxicity (DLT) [ Time Frame: 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.
3. Phase 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 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.

4. Phase 1: Number of Subjects With Serious Adverse Events (SAEs) [ Time Frame: Up to 150 days. ]
   This endpoint was performed on SAF.
5. Phase 1: Number of Participants With Treatment-related Adverse Events (AEs). [ Time Frame: Up to 145 days. ]
   This endpoint was performed on SAF.
6. Phase 2: Objective Response Rate (ORR) [ Time Frame: 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.
7. Phase 2: Disease Control Rate (DCR) [ Time Frame: 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.
8. Phase 2: Progression-free Survival (PFS) [ Time Frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2. ]

Secondary Outcome Measures :

1. Phase 1: Copanlisib Maximum Drug Concentration (Cmax) [ Time Frame: 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.

2. Phase 1: Area Under the Curve (AUC(0-168)) [ Time Frame: 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.

3. Phase 1: Objective Response Rate (ORR) [ Time Frame: 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.

4. Phase 2: Duration of Response (DOR) [ Time Frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2. ]
5. Phase 2: PFS in Each Indication Except for Osteosarcoma [ Time Frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2. ]
6. Phase 2: Overall Survival (OS) [ Time Frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2. ]
7. Phase 2: Number of Participants With Treatment-emergent AEs [ Time Frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2. ]
8. Phase 2: Number of Subjects With Treatment Emergent SAEs [ Time Frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2. ]
9. Phase 2: Number of Subjects With Treatment-emergent Clinically Significant Change in Laboratory Parameters, ECGs and Vital Signs [ Time Frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2. ]

Eligibility Criteria

• 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.
  • 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

United States, Alabama

Children's Hospital of Alabama

Birmingham, Alabama, United States, 35233

United States, California

Children's Hospital of Orange County

Orange, California, United States, 92868-3974

United States, Colorado

The Children's Hospital

Aurora, Colorado, United States, 80045

United States, District of Columbia

Children's National Medical Center

Washington, District of Columbia, United States, 20010-2970

United States, Georgia

Children's Healthcare of Atlanta

Atlanta, Georgia, United States, 30322

United States, Indiana

Riley Hospital For Children

Indianapolis, Indiana, United States, 46202

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

United States, Ohio

Cincinnati Children's Hospital and Medical Center

Cincinnati, Ohio, United States, 45229

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States, 15224

United States, Tennessee

St. Jude Children's Research Hospital

Memphis, Tennessee, United States, 38105

United States, Texas

Texas Children's Hospital

Houston, Texas, United States, 77030

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98105

Sponsors and Collaborators

Bayer

  Study Documents (Full-Text)

Documents provided by Bayer:

Study Protocol  [PDF] May 5, 2020

Statistical Analysis Plan  [PDF] August 6, 2019

More Information

Additional Information:

Click here to find further information and, after study completion, the study results according to Bayer's transparency standards. 

Click here to find information about studies related to Bayer Healthcare products conducted in Europe 

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT03458728
• Other Study ID Numbers: 19176; 2017-000383-15 ( EudraCT Number )
• First Posted: March 8, 2018
• Results First Posted: December 4, 2023
• Last Update Posted: December 4, 2023
• Last Verified: November 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Plan Description

Availability of this study's data will later 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.vivli.org 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 member section of the portal.

• 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:

Lymphoma; Sarcoma; Neuroblastoma; Osteosarcoma; Rhabdomyosarcoma; Sarcoma, Ewing; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Myosarcoma; Neoplasms, Muscle Tissue