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

June 28, 2016 updated by: Sanofi

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

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.

Study Overview

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

39

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Toronto, Canada, M5G 1X8
        • Investigational Site Number 124001
    • Arizona
      • Phoenix, Arizona, United States, 85006
        • Investigational Site Number 840009
    • California
      • Los Angeles, California, United States, 90027
        • Investigational Site Number 840013
      • Palo Alto, California, United States
        • Investigational Site Number 840014
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Investigational Site Number 840007
    • District of Columbia
      • Washington, District of Columbia, United States, 20010
        • Investigational Site Number 840011
    • Florida
      • Orlando, Florida, United States, 32806
        • Investigational Site Number 840005
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Investigational Site Number 840012
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Investigational Site Number 840010
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Investigational Site Number 840002
    • New York
      • New York, New York, United States, 10021
        • Investigational Site Number 840003
    • Texas
      • Houston, Texas, United States, 77030
        • Investigational Site Number 840006
    • Washington
      • Seattle, Washington, United States, 98105
        • Investigational Site Number 840008

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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:

  1. Minimal BSA requirements for a particular dose level;
  2. During the Phase 1 part participants must had a BSA <2.1 m² at the time of enrollment
  3. 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:

  1. Lansky score ≥60 (participants ≤10 years of age)
  2. 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:

  1. Total bilirubin ≤1.0 x the upper limit of normal (ULN) for age
  2. AST (SGOT) and ALT (SGPT) ≤2.5 x ULN
  3. Serum creatinine ≤1.5 x ULN for age or creatinine clearance ≥60 mL/min/1.73 m²
  4. Absolute neutrophil count ≥1.0x10^9 /L
  5. Platelets ≥75x10^9/L (transfusion independent)
  6. 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:

  1. Systemic anti-cancer treatment within 3 weeks (6 weeks for nitrosourea, mitomycin and monoclonal antibodies including bevacizumab)
  2. Surgery or smaller field radiation therapy within 4 weeks
  3. 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Phase 1: Cabazitaxel 20 mg/m^2
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).
Pharmaceutical form: Injection Route of administration: Intravenous
Other Names:
  • Jevtana
Experimental: Phase 1: Cabazitaxel 25 mg/m^2
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).
Pharmaceutical form: Injection Route of administration: Intravenous
Other Names:
  • Jevtana
Experimental: Phase 1: Cabazitaxel 30 mg/m^2
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).
Pharmaceutical form: Injection Route of administration: Intravenous
Other Names:
  • Jevtana
Experimental: Phase 1: Cabazitaxel 35 mg/m^2
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).
Pharmaceutical form: Injection Route of administration: Intravenous
Other Names:
  • Jevtana
Experimental: Phase 2: Cabazitaxel 30 mg/m^2
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).
Pharmaceutical form: Injection Route of administration: Intravenous
Other Names:
  • Jevtana

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phase 1: Maximum Tolerated Dose of Cabazitaxel
Time Frame: Cycle 1 (21 days)
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)
Time Frame: Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks)
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)
Time Frame: Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks)
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)
Time Frame: 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)
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
Time Frame: Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 112.1 weeks)
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
Time Frame: Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
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)
Time Frame: Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
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)
Time Frame: Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
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)
Time Frame: Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
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)
Time Frame: Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks)
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)
Time Frame: Baseline up to death or study cut-off (maximum duration: 12.1 weeks)
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)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2013

Primary Completion (Actual)

July 1, 2015

Study Completion (Actual)

February 1, 2016

Study Registration Dates

First Submitted

December 13, 2012

First Submitted That Met QC Criteria

December 13, 2012

First Posted (Estimate)

December 17, 2012

Study Record Updates

Last Update Posted (Estimate)

August 12, 2016

Last Update Submitted That Met QC Criteria

June 28, 2016

Last Verified

June 1, 2016

More Information

Terms related to this study

Other Study ID Numbers

  • TED12689
  • U1111-1128-5704 (Other Identifier: UTN)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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