Clinical trial NCT01751308: Safety and Efficacy of Cabazitaxel in Pediatric Patients With Refractory Solid Tumors Including Central Nervous System Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Malignant Solid Tumor - Malignant Nervous System Neoplasm
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2012-12-17
Enrollment: 39
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1: Maximum Tolerated Dose of Cabazitaxel
timeFrame: Cycle 1 (21 days)
measure: Phase 2: Percentage of Participants With Objective Response (OR)
timeFrame: Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks)
measure: Phase 2: Duration of Response (DOR)
timeFrame: Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks)
Secondary outcomes:
measure: Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: 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)
measure: Phase 1: Number of Participants With Objective Response
timeFrame: Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 112.1 weeks)
measure: Phase 1 and 2: Pharmacokinetics (PK) Parameter of Cabazitaxel: Area Under the Plasma Concentration (AUC) Versus Time Curve
timeFrame: Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
measure: Phase 1 and 2: PK Parameter of Cabazitaxel: Total Plasma Clearance (CL)
timeFrame: Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
measure: Phase 1 and 2: PK Parameter of Cabazitaxel: Volume of Distribution at Steady State (Vss)
timeFrame: Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
measure: Phase 1 and 2: PK Parameter of Cabazitaxel: Maximum Plasma Concentration Observed (Cmax)
timeFrame: Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
measure: Phase 2: Progression Free Survival (PFS)
timeFrame: Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks)
measure: Phase 2: Overall Survival (OS)
timeFrame: Baseline up to death or study cut-off (maximum duration: 12.1 weeks)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Investigational Site Number 840009
state: Arizona
city: Los Angeles
country: United States
facility: Investigational Site Number 840013
state: California
city: Palo Alto
country: United States
facility: Investigational Site Number 840014
state: California
city: Aurora
country: United States
facility: Investigational Site Number 840007
state: Colorado
city: Washington
country: United States
facility: Investigational Site Number 840011
state: District of Columbia
city: Orlando
country: United States
facility: Investigational Site Number 840005
state: Florida
city: Chicago
country: United States
facility: Investigational Site Number 840012
state: Illinois
city: Baltimore
country: United States
facility: Investigational Site Number 840010
state: Maryland
city: Boston
country: United States
facility: Investigational Site Number 840002
state: Massachusetts
city: New York
country: United States
facility: Investigational Site Number 840003
state: New York
city: Houston
country: United States
facility: Investigational Site Number 840006
state: Texas
city: Seattle
country: United States
facility: Investigational Site Number 840008
state: Washington
city: Toronto
country: Canada
facility: Investigational Site Number 124001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: