Malignant Solid Tumor - Malignant Nervous System Neoplasm
Conditions
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.
Interventions
Pharmaceutical form: Injection Route of administration: Intravenous
Sponsors
Sanofi
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 18 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Maximum Tolerated Dose of Cabazitaxel | 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. |
| Phase 2: Percentage of Participants With Objective Response (OR) | 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. |
| Phase 2: Duration of Response (DOR) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 and 2: PK Parameter of Cabazitaxel: Total Plasma Clearance (CL) | 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. |
| Phase 1 and 2: PK Parameter of Cabazitaxel: Volume of Distribution at Steady State (Vss) | 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. |
| Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 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. |
| Phase 2: Progression Free Survival (PFS) | 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. |
| Phase 2: Overall Survival (OS) | 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. |
| Phase 1 and 2: PK Parameter of Cabazitaxel: Maximum Plasma Concentration Observed (Cmax) | 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. |
| Phase 1: Number of Participants With Objective Response | 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. |
| Phase 1 and 2: Pharmacokinetics (PK) Parameter of Cabazitaxel: Area Under the Plasma Concentration (AUC) Versus Time Curve | 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. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants were enrolled at 12 centers between February 2013 and March 2015.
Pre-assignment details
Phase I was a dose escalation part of Cabazitaxel to determine maximum tolerated dose (MTD). Phase 2 was efficacy and safety evaluation of Cabazitaxel at the MTD, determined in Phase 1.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Cabazitaxel 20 mg/m^2 Cabazitaxel 20 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). | 6 |
| 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). | 3 |
| 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). | 7 |
| 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). | 7 |
| 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). | 16 |
| Total | 39 |
Baseline characteristics
| Characteristic | Total | Phase 2: Cabazitaxel 30 mg/m^2 | Phase 1: Cabazitaxel 35 mg/m^2 | Phase 1: Cabazitaxel 30 mg/m^2 | Phase 1: Cabazitaxel 25 mg/m^2 | Phase 1: Cabazitaxel 20 mg/m^2 |
|---|---|---|---|---|---|---|
| Age, Customized 12-18 years | 13 participants | 6 participants | 1 participants | 2 participants | 1 participants | 3 participants |
| Age, Customized 2-4 years | 4 participants | 2 participants | 0 participants | 2 participants | 0 participants | 0 participants |
| Age, Customized 5-6 years | 8 participants | 4 participants | 1 participants | 0 participants | 1 participants | 2 participants |
| Age, Customized 7-11 years | 14 participants | 4 participants | 5 participants | 3 participants | 1 participants | 1 participants |
| Sex: Female, Male Female | 16 Participants | 8 Participants | 2 Participants | 1 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 23 Participants | 8 Participants | 5 Participants | 6 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 7 / 7 | 7 / 7 | 15 / 16 |
| serious Total, serious adverse events | 4 / 6 | 1 / 3 | 5 / 7 | 3 / 7 | 12 / 16 |
Outcome results
Primary
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.
Time frame: Cycle 1 (21 days)
Population: DLT evaluable population defined as a subset of participants in the Phase 1 part of the study from the AT population who received the first dose of cabazitaxel and had sufficient safety evaluations or experienced a DLT during Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Overall Population | Phase 1: Maximum Tolerated Dose of Cabazitaxel | 30 mg/m^2 |
Primary
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).
Time frame: Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks)
Population: Due to no objective responses in Stage 1 of Phase 2, the analysis of duration of response was not performed.Hence, the data is not reported.
Primary
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.
Time frame: Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks)
Population: Efficacy evaluable population was subset of AT population with measurable disease with a baseline and at least one post-baseline tumor evaluation.Number of participants analyzed=participants with available data for this endpoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Overall Population | Phase 2: Percentage of Participants With Objective Response (OR) | CR | 0 percentage of participants |
| Phase 1: Overall Population | Phase 2: Percentage of Participants With Objective Response (OR) | PR | 0 percentage of participants |
Secondary
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.
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)
Population: Analysis was performed on safety population (AT population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Overall Population | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 6 participants |
| Phase 1: Cabazitaxel 25 mg/m^2 | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 participants |
| Phase 1: Cabazitaxel 30 mg/m^2 | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 7 participants |
| Phase 1: Cabazitaxel 35 mg/m^2 | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 7 participants |
| Phase 2: Cabazitaxel 30 mg/m^2 | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 16 participants |
Secondary
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.
Time frame: Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
Population: PK population (for both Phase 1 and Phase 2 parts of the study) included all participants who received treatment on Day 1 of Cycle 1 and had at least one post-dose PK sample. Number of participants analyzed=participants with available data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Overall Population | Phase 1 and 2: Pharmacokinetics (PK) Parameter of Cabazitaxel: Area Under the Plasma Concentration (AUC) Versus Time Curve | 669.5 ng.h/mL | Standard Deviation 430.6 |
| Phase 1: Cabazitaxel 25 mg/m^2 | Phase 1 and 2: Pharmacokinetics (PK) Parameter of Cabazitaxel: Area Under the Plasma Concentration (AUC) Versus Time Curve | 879.0 ng.h/mL | Standard Deviation 414.7 |
| Phase 1: Cabazitaxel 30 mg/m^2 | Phase 1 and 2: Pharmacokinetics (PK) Parameter of Cabazitaxel: Area Under the Plasma Concentration (AUC) Versus Time Curve | 876.7 ng.h/mL | Standard Deviation 359.9 |
| Phase 1: Cabazitaxel 35 mg/m^2 | Phase 1 and 2: Pharmacokinetics (PK) Parameter of Cabazitaxel: Area Under the Plasma Concentration (AUC) Versus Time Curve | 1002.5 ng.h/mL | Standard Deviation 277.9 |
Secondary
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.
Time frame: Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
Population: Analysis was performed on PK population (for both Phase 1 and Phase 2 parts of the study). Number of participants analyzed=participants with available data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Overall Population | Phase 1 and 2: PK Parameter of Cabazitaxel: Maximum Plasma Concentration Observed (Cmax) | 204.864 ng/mL | Standard Deviation 189.864 |
| Phase 1: Cabazitaxel 25 mg/m^2 | Phase 1 and 2: PK Parameter of Cabazitaxel: Maximum Plasma Concentration Observed (Cmax) | 283.657 ng/mL | Standard Deviation 242.97 |
| Phase 1: Cabazitaxel 30 mg/m^2 | Phase 1 and 2: PK Parameter of Cabazitaxel: Maximum Plasma Concentration Observed (Cmax) | 256.734 ng/mL | Standard Deviation 127.931 |
| Phase 1: Cabazitaxel 35 mg/m^2 | Phase 1 and 2: PK Parameter of Cabazitaxel: Maximum Plasma Concentration Observed (Cmax) | 233.290 ng/mL | Standard Deviation 0.127 |
Secondary
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.
Time frame: Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
Population: Analysis was performed on PK population (for both Phase 1 and Phase 2 parts of the study). Number of participants analyzed=participants with available data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Overall Population | Phase 1 and 2: PK Parameter of Cabazitaxel: Total Plasma Clearance (CL) | 36.05 L/h/m^2 | Standard Deviation 12.91 |
| Phase 1: Cabazitaxel 25 mg/m^2 | Phase 1 and 2: PK Parameter of Cabazitaxel: Total Plasma Clearance (CL) | 32.76 L/h/m^2 | Standard Deviation 12.72 |
| Phase 1: Cabazitaxel 30 mg/m^2 | Phase 1 and 2: PK Parameter of Cabazitaxel: Total Plasma Clearance (CL) | 38.70 L/h/m^2 | Standard Deviation 12.98 |
| Phase 1: Cabazitaxel 35 mg/m^2 | Phase 1 and 2: PK Parameter of Cabazitaxel: Total Plasma Clearance (CL) | 36.61 L/h/m^2 | Standard Deviation 9.98 |
Secondary
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.
Time frame: Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
Population: Analysis was performed on PK population (for both Phase 1 and Phase 2 parts of the study). Number of participants analyzed=participants with available data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Overall Population | Phase 1 and 2: PK Parameter of Cabazitaxel: Volume of Distribution at Steady State (Vss) | 3391.72 L/m^2 | Standard Deviation 686.79 |
| Phase 1: Cabazitaxel 25 mg/m^2 | Phase 1 and 2: PK Parameter of Cabazitaxel: Volume of Distribution at Steady State (Vss) | 3301.96 L/m^2 | Standard Deviation 351.55 |
| Phase 1: Cabazitaxel 30 mg/m^2 | Phase 1 and 2: PK Parameter of Cabazitaxel: Volume of Distribution at Steady State (Vss) | 3371.30 L/m^2 | Standard Deviation 975.98 |
| Phase 1: Cabazitaxel 35 mg/m^2 | Phase 1 and 2: PK Parameter of Cabazitaxel: Volume of Distribution at Steady State (Vss) | 1488.75 L/m^2 | Standard Deviation 1179.11 |
Secondary
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.
Time frame: Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 112.1 weeks)
Population: Analysis was performed on efficacy evaluable population. Number of participants analyzed=participants with available data for this endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Overall Population | Phase 1: Number of Participants With Objective Response | 1 participants |
| Phase 1: Cabazitaxel 25 mg/m^2 | Phase 1: Number of Participants With Objective Response | 0 participants |
| Phase 1: Cabazitaxel 30 mg/m^2 | Phase 1: Number of Participants With Objective Response | 0 participants |
| Phase 1: Cabazitaxel 35 mg/m^2 | Phase 1: Number of Participants With Objective Response | 0 participants |
Secondary
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.
Time frame: Baseline up to death or study cut-off (maximum duration: 12.1 weeks)
Population: Analysis was performed on efficacy evaluable population. Number of participants analyzed=participants with available data for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Overall Population | Phase 2: Overall Survival (OS) | 2.7 months |
Secondary
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.
Time frame: Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks)
Population: Analysis was performed on efficacy evaluable population. Number of participants analyzed=participants with available data for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Overall Population | Phase 2: Progression Free Survival (PFS) | 1.3 months |