Safety and Efficacy of Cabazitaxel in Pediatric Patients With Refractory Solid Tumors Including Central Nervous System Tumors

Study Overview
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Brief Summary
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Primary Objectives: Phase 1 Part: To determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) of cabazitaxel as a single agent in pediatric participants with recurrent or refractory solid tumors including tumors of the central nervous system. Phase 2 Part: To determine the objective response rate (complete and partial response) and the duration of response to cabazitaxel as a single agent in participants with recurrent or refractory high grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). Secondary Objectives: Phase 1 Part: To characterize the safety and tolerability of cabazitaxel in participants with recurrent or refractory solid tumors including tumors of the central nervous system. To characterize the pharmacokinetic (PK) profile of cabazitaxel in participants with recurrent or refractory solid tumors including tumors of the central nervous system. To evaluate preliminary anti-tumor activity that may be associated with cabazitaxel in participants with recurrent or refractory solid tumors including tumors of the central nervous system. Phase 2 Part: To characterize the safety and tolerability of cabazitaxel in participants with recurrent or refractory HGG or DIPG. To estimate progression free survival in participants with recurrent or refractory HGG or DIPG. To estimate overall survival in participants with recurrent or refractory HGG or DIPG. To characterize the plasma PK profile of cabazitaxel in participants with recurrent or refractory HGG or DIPG.

Detailed Description
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The study duration will include a period for inclusion of up to 3 weeks and a 3-week treatment cycle(s). The participants may continue treatment until disease progression, unacceptable toxicity or willingness to stop followed by a minimum of 30-day follow-up.

Official Title
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A Phase 1-2 Dose Finding, Safety and Efficacy Study of Cabazitaxel in Pediatric Patients With Refractory Solid Tumors Including Tumors of the Central Nervous System

Conditions
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Malignant Solid Tumor - Malignant Nervous System Neoplasm

Intervention / Treatment
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* Drug: Cabazitaxel (XRP6258)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Phase 1 Part (dose escalation): Participants with a histologically confirmed solid tumor including tumors of the central nervous system that was recurrent or refractory and for which no further effective standard treatment was available. All participants must had measurable disease. Participants with diffuse pontine glioma were eligible without a biopsy after evidence of progressive disease post radiation therapy. Phase 2 Part (safety and activity): Participants with recurrent or refractory high grade glioma or diffuse intrinsic pontine glioma for whom no further effective therapy was available. All participants must had measurable disease. Participants with diffuse pontine glioma were eligible without a biopsy after evidence of progressive disease post radiation therapy. Participants with a grade III or grade IV glioma must had pathologic confirmation either at the time of initial diagnosis or at the time of recurrence. Participants aged ≥2 years and ≤18 years Participants met the body surface area (BSA) requirements to be eligible: Minimal BSA requirements for a particular dose level; During the Phase 1 part participants must had a BSA <2.1 m² at the time of enrollment During the Phase 2 part participants with a BSA ≥2.1 m² were eligible, however the actual dose of cabazitaxel for these participants were adjusted to a maximum dose calculated with (capped at) the BSA of 2.1 m² Performance status by: Lansky score ≥60 (participants ≤10 years of age) Karnofsky score ≥60% (participants >10 years of age) Participants who were unable to walk because of paralysis, but who were mobile in a wheelchair, were considered ambulatory for the purpose of assessing the performance score. Participants must had adequate liver, renal and marrow function as defined below: Total bilirubin ≤1.0 x the upper limit of normal (ULN) for age AST (SGOT) and ALT (SGPT) ≤2.5 x ULN Serum creatinine ≤1.5 x ULN for age or creatinine clearance ≥60 mL/min/1.73 m² Absolute neutrophil count ≥1.0x10^9 /L Platelets ≥75x10^9/L (transfusion independent) Hemoglobin ≥8.0 g/dL (could be transfused) Female participants of child-bearing potential must had a negative pregnancy test ≤7 days before starting cabazitaxel treatment. Male and female participants of reproductive potential must agreed to use adequate contraception prior to study entry, for the duration of study participation and for 6 months following the last dose of cabazitaxel. Written informed consent/assent prior to any study-specific procedures. Consent must be obtained from the participant and/or parent(s) or legal guardian(s) and the signature of at least one parent or guardian was required. Investigators also obtained assent of participants according to local, regional or national guidelines. Participants must have recovered from the acute toxic effects of all prior therapy to ≤ grade 1 before entering the study. Exclusion criteria: Prior treatment within the following timeframes: Systemic anti-cancer treatment within 3 weeks (6 weeks for nitrosourea, mitomycin and monoclonal antibodies including bevacizumab) Surgery or smaller field radiation therapy within 4 weeks Treatment with an investigational agent within 4 weeks or within 5 half-lives of the agent, whichever was longer Craniospinal or other large field radiation therapy (defined as >25% of bone marrow irradiated) within 6 months prior to the first dose. Prior systemic radioisotope therapy (this did not include diagnostic imaging or radioimmunoconjugates lacking myelosuppressive properties) or total body irradiation. Prior bone marrow or stem cell transplant Participants with any clinically significant illness that, in the investigator's opinion, could not be adequately controlled with appropriate therapy, would compromise a participant's ability to tolerate cabazitaxel or result in inability to assess toxicity. This included, but was not limited to uncontrolled intercurrent illness including ongoing or active infection, cardiac disease, renal impairment, planned surgery or psychiatric illness/social situations that would limit compliance with study requirements. Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency-syndrome (AIDS)-related disease Known history of hepatitis C or known active hepatitis B infection. Pregnant or breast feeding women Treatment with strong inhibitors or strong inducers of CYP3A4 or enzyme inducing anti-epileptic drugs (EIAED) within 14 days prior to first dose of cabazitaxel and for the duration of study. Non-EIAEDs were permitted. Known history of hypersensitivity to taxanes or polysorbate 80 or G-CSF. Participation in another interventional clinical trial and/or concurrent treatment with any investigational drug. Participants not able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Cabazitaxel 20 mg/m^2<br>Cabazitaxel 20 mg/m^2 intravenous (IV) infusion on Day 1 of each 21-day cycle until disease progression (DP) or discontinuation due to adverse event (AE) or death (from any cause). | Drug: Cabazitaxel (XRP6258)<br>* Pharmaceutical form: Injection Route of administration: Intravenous<br>* Other names: Jevtana;|
| Experimental: Phase 1: Cabazitaxel 25 mg/m^2<br>Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause). | Drug: Cabazitaxel (XRP6258)<br>* Pharmaceutical form: Injection Route of administration: Intravenous<br>* Other names: Jevtana;|
| Experimental: Phase 1: Cabazitaxel 30 mg/m^2<br>Cabazitaxel 30 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause). | Drug: Cabazitaxel (XRP6258)<br>* Pharmaceutical form: Injection Route of administration: Intravenous<br>* Other names: Jevtana;|
| Experimental: Phase 1: Cabazitaxel 35 mg/m^2<br>Cabazitaxel 35 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause). | Drug: Cabazitaxel (XRP6258)<br>* Pharmaceutical form: Injection Route of administration: Intravenous<br>* Other names: Jevtana;|
| Experimental: Phase 2: Cabazitaxel 30 mg/m^2<br>Cabazitaxel at the maximum tolerated dose (MTD) as determined in phase 1 (30 mg/m^2) IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause). | Drug: Cabazitaxel (XRP6258)<br>* Pharmaceutical form: Injection Route of administration: Intravenous<br>* Other names: Jevtana;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Maximum Tolerated Dose of Cabazitaxel | MTD was highest dose level of cabazitaxel at which no more than 1 of 6 evaluable participants experienced dose limiting toxicities (DLT). DLT defined as an AE or abnormal laboratory values related to study treatment: hematologic DLTs: any Grade(G)4 hematologic toxicity except neutropenia G4 lasting≤7 days,G3 or 4 febrile neutropenia except G3 or 4 febrile neutropenia in absence of granulocyte-colony stimulating factor prophylaxis, G4 thrombocytopenia; non-hematologic DLTs:any G≥3 non-hematologic toxicity except G3 nausea or G3 or4 vomiting, G3 or4 diarrhea,G3 or4 dehydration,G3 fatigue lasting≤7 days, inadequately treated hypersensitivity reactions, elevated transaminases<10* upper limit of normal of ≤7 days, re-treatment delay of>2 weeks due to delayed recovery from toxicity related to study treatment to baseline G or≤ G1(except for alopecia) and platelet transfusion during Cycle1. Grades based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. | Cycle 1 (21 days) | 
| Phase 2: Percentage of Participants With Objective Response (OR) | OR in participants was defined as the participants with a Complete Response (CR) or Partial Response (PR) after 3 cycles of cabazitaxel treatment and maintained for at least 4 weeks. CR and PR were based on modified response assessment in neuro-oncology (RANO) criteria for participants with CNS tumors. CR was defined as disappearance of all target lesions. PR was defined as ≥50% decrease in the sum of the products of the two perpendicular diameters of target lesions, compared to the baseline measurement. | Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks) | 
| Phase 2: Duration of Response (DOR) | DOR defined as time (in days) from date of first response until date of first documented progressive disease (PD) or death (from any cause), whichever came first. If progression or death was not observed, participant was censored at the date of participant's last progression-free tumor assessment prior to study cut-off date. PD as per RANO criteria was defined as ≥ 25% increase in the product of perpendicular diameters of any target lesion, taking as reference the smallest product observed since the start of treatment or the appearance of one or more new lesions, or worsening neurologic status not explained by causes unrelated to tumor progression (example, anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy swelling etc.) plus any increase in tumor cross-sectional area (or tumor volume). | Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. Treatment emergent adverse events (TEAEs) were defined as AEs that developed or worsened in grade or became serious during the on-treatment period which was defined as the period from the time of first dose of cabazitaxel until 30 days following the last administration of cabazitaxel. | Baseline up to DP or death due to any cause (maximum duration: 112.1 weeks for Phase 1 and 12.1 weeks for Phase 2) | 
| Phase 1: Number of Participants With Objective Response | OR in participants was defined as the participants with a CR or PR after 3 cycles of cabazitaxel treatment and maintained for at least 4 weeks as assessed by response evaluation criteria in solid tumors (RECIST) version 1.1 and RANO criteria for CNS tumors. For solid tumors, as per RECIST 1.1, CR defined as disappearance of all target and non-target lesions (any pathological lymph nodes, must had reduction in short axis to <10 mm); PR defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. For CNS tumors, as per RANO criteria, CR defined as disappearance of all target and non-target lesions; PR defined as a ≥50% decrease in the sum of the products of the two perpendicular diameters of target lesions, compared to baseline measurement. | Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 112.1 weeks) | 
| Phase 1 and 2: Pharmacokinetics (PK) Parameter of Cabazitaxel: Area Under the Plasma Concentration (AUC) Versus Time Curve | Blood samples for PK parameters were collected at 5 minutes before end of infusion (EOI), 10 minutes, 30 minutes, 3 hours, 7 hours and 71 hours after the EOI on Day 1 of Cycle 1. | Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI | 
| Phase 1 and 2: PK Parameter of Cabazitaxel: Total Plasma Clearance (CL) | Blood samples for PK parameters were collected at 5 minutes before EOI, 10 minutes, 30 minutes, 3 hours, 7 hours and 71 hours after the EOI on Day 1 of Cycle 1. | Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI | 
| Phase 1 and 2: PK Parameter of Cabazitaxel: Volume of Distribution at Steady State (Vss) | Blood samples for PK parameters were collected at 5 minutes before EOI, 10 minutes, 30 minutes, 3 hours, 7 hours and 71 hours after the EOI on Day 1 of Cycle 1. | Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI | 
| Phase 1 and 2: PK Parameter of Cabazitaxel: Maximum Plasma Concentration Observed (Cmax) | Blood samples for PK parameters were collected at 5 minutes before EOI, 10 minutes, 30 minutes, 3 hours, 7 hours and 71 hours after the EOI on Day 1 of Cycle 1. | Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI | 
| Phase 2: Progression Free Survival (PFS) | The PFS was defined as the time (in months) from the date of first dose administration until the date of first documented PD or death (from any cause), whichever came first. If progression or death was not observed, the participant was censored at the date of the participant's last progression-free tumor assessment prior to the study cut-off date. PD as per RANO criteria was defined as ≥25% increase in the product of perpendicular diameters of any target lesion, taking as reference the smallest product observed since the start of treatment or the appearance of one or more new lesions, or worsening neurologic status not explained by causes unrelated to tumor progression (example, anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy swelling etc) plus any increase in tumor cross-sectional area (or tumor volume). The analysis was performed by Kaplan-Meier method. | Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks) | 
| Phase 2: Overall Survival (OS) | OS was defined as the time (in months) from the date of first dose administration until the date of death (from any cause). If death was not observed, the participant was censored at the earliest of the last date the participant was known to be alive and the study cut-off date. The analysis was performed by Kaplan-Meier method. | Baseline up to death or study cut-off (maximum duration: 12.1 weeks) |