Ewing Sarcoma, Neuroblastoma, Osteosarcoma, Relapsed or Refractory Solid Tumors or Lymphoma in Children, Rhabdomyosarcoma
Conditions
Keywords
Phase I: relapsed or refractory solid tumors or lymphoma, Phase II: relapsed or refractory solid tumors (neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing sarcoma)
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.
Interventions
DRUGCopanlisib (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.
Sponsors
Bayer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 21 Years
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. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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. |
| Phase 1: Number of Subjects With Dose Limiting Toxicity (DLT) | 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. |
| Phase 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | 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. |
| Phase 1: Number of Subjects With Serious Adverse Events (SAEs) | Up to 150 days. | This endpoint was performed on SAF. |
| Phase 1: Number of Participants With Treatment-related Adverse Events (AEs). | Up to 145 days. | This endpoint was performed on SAF. |
| Phase 2: Objective Response Rate (ORR) | 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. |
| Phase 2: Disease Control Rate (DCR) | 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Copanlisib Maximum Drug Concentration (Cmax) | 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. |
| 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. | — |
| Phase 1: Area Under the Curve (AUC(0-168)) | 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. |
| Phase 1: Objective Response Rate (ORR) | 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. |
| 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. | — |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 14 centers in United States between 30 APR 2018 (First participant first visit) and 1-Feb-2023 (Last participant last visit).
Pre-assignment details
41 participants were screened into the study (signed informed consent form (ICF)). 10 participants were screening failed. 31 participants were enrolled in the study, all 31 participants received treatment in phase 1 as the study was terminated prior to the initiation of the phase 2.
Participants by arm
| Arm | Count |
|---|---|
| Copanlisib 28mg/m*2, Total Copanlisib was administered Intravenous (IV) on Days 1, 8 and 15 of each 28-day treatment cycle. Treatment was continued until radiological progressive disease, unacceptable toxicity, withdrawal of consent, death or other event specified by the protocol. Copanlisib 28mg/m\*2 (Total) included AMD0 (5 participants who were under the original DLT criteria) and AMD1+ (19 participants who were under the amended DLT criteria). | 24 |
| Copanlisib 35mg/m*2 Copanlisib was administered Intravenous (IV) on Days 1, 8 and 15 of each 28-day treatment cycle. Treatment was continued until radiological progressive disease, unacceptable toxicity, withdrawal of consent, death or other event specified by the protocol. | 7 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Progressive disease - clinical assessment | 1 | 0 |
| Overall Study | Progressive disease - radiological progression | 21 | 6 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Copanlisib 28mg/m*2, Total | Copanlisib 35mg/m*2 | Total |
|---|---|---|---|
| Age, Continuous | 12.5 years STANDARD_DEVIATION 4.6 | 12.3 years STANDARD_DEVIATION 3.8 | 12.5 years STANDARD_DEVIATION 4.3 |
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 10 Participants | 4 Participants | 14 Participants |
| Age, Customized Adults (18-64 years) | 3 Participants | 0 Participants | 3 Participants |
| Age, Customized Children (2-11 years) | 11 Participants | 3 Participants | 14 Participants |
| Age, Customized From 65-84 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 6 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 17 Participants | 3 Participants | 20 Participants |
| Sex: Female, Male Female | 10 Participants | 3 Participants | 13 Participants |
| Sex: Female, Male Male | 14 Participants | 4 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 20 / 24 | 5 / 7 |
| other Total, other adverse events | 23 / 24 | 7 / 7 |
| serious Total, serious adverse events | 10 / 24 | 0 / 7 |
Outcome results
Primary
Phase 1: Number of Participants With Treatment-related Adverse Events (AEs).
This endpoint was performed on SAF.
Time frame: Up to 145 days.
Population: Safety analysis set (SAF): The SAF population was defined as all participants with at least one intake of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Copanlisib_Phase 1 | Phase 1: Number of Participants With Treatment-related Adverse Events (AEs). | 5 Participants |
| Copanlisib 35mg/m*2 | Phase 1: Number of Participants With Treatment-related Adverse Events (AEs). | 0 Participants |
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.
Time frame: Cycle 1 (28 days)
Population: Safety analysis set (SAF): The SAF population was defined as all participants with at least one intake of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Copanlisib_Phase 1 | Phase 1: Number of Subjects With Dose Limiting Toxicity (DLT) | 3 Participants |
| Copanlisib 35mg/m*2 | Phase 1: Number of Subjects With Dose Limiting Toxicity (DLT) | 2 Participants |
Primary
Phase 1: Number of Subjects With Serious Adverse Events (SAEs)
This endpoint was performed on SAF.
Time frame: Up to 150 days.
Population: Safety analysis set (SAF): The SAF population was defined as all participants with at least one intake of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Copanlisib_Phase 1 | Phase 1: Number of Subjects With Serious Adverse Events (SAEs) | 10 Participants |
| Copanlisib 35mg/m*2 | Phase 1: Number of Subjects With Serious Adverse Events (SAEs) | 0 Participants |
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.
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.
Population: Safety analysis set (SAF): The SAF population was defined as all participants with at least one intake of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Copanlisib_Phase 1 | Phase 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | 24 Participants |
| Copanlisib 35mg/m*2 | Phase 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | 7 Participants |
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.
Time frame: Cycle 1 (28 days)
Population: Safety analysis set (SAF): The SAF population was defined as all participants with at least one intake of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Copanlisib_Phase 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. | 28 mg/m*2/dose |
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.
Time frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Population: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
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.
Time frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Population: 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)
Time frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Population: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
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.
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.
Population: For all participants included in the PK analysis set, copanlisib PK was analyzed using an established comprehensive population PK model with incorporation of allometric scaling by Body surface area (BSA) on copanlisib disposition parameters (clearance and volume parameters). The model with allometric scaling enables combining of treatment groups and was used to estimate copanlisib PK parameters (AUC0-168h and Cmax).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Copanlisib_Phase 1 | Phase 1: Area Under the Curve (AUC(0-168)) | 2900 μg∙h/L | Geometric Coefficient of Variation 35.4 |
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.
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.
Population: For all participants included in the PK analysis set, copanlisib PK was analyzed using an established comprehensive population PK model with incorporation of allometric scaling by Body surface area (BSA) on copanlisib disposition parameters (clearance and volume parameters). The model with allometric scaling enables combining of treatment groups and was used to estimate copanlisib PK parameters (AUC0-168h and Cmax).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Copanlisib_Phase 1 | Phase 1: Copanlisib Maximum Drug Concentration (Cmax) | 359 μg/L | Geometric Coefficient of Variation 22.6 |
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.
Time frame: Up to 150 days
Population: Full analysis set (FAS): All subjects with at least one intake of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Copanlisib_Phase 1 | Phase 1: Objective Response Rate (ORR) | 0 Participants |
| Copanlisib 35mg/m*2 | Phase 1: Objective Response Rate (ORR) | 0 Participants |
Secondary
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.
Population: 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
Time frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Population: 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
Time frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Population: 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
Time frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Population: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Secondary
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.
Population: 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
Time frame: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.
Population: Data was not collected for this endpoint due to study was terminated before the initiation of phase 2.