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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03458728
Recruitment Status : Terminated (no anticipated benefit over available standard therapies)
First Posted : March 8, 2018
Results First Posted : December 4, 2023
Last Update Posted : December 4, 2023
Sponsor:
Information provided by (Responsible Party):
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.

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

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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


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.




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. ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03458728


Locations
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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

Additional Information:
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT03458728    
Other Study ID Numbers: 19176
2017-000383-15 ( EudraCT Number )
First Posted: March 8, 2018    Key Record Dates
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.


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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:
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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