Acute Lymphoblastic Leukemia
Conditions
Keywords
Oncology / Haematology, Phase II, Acute Lymphoblastic Leukemia, Parallel group, Pegaspargase, Pharmacokinetics comparability, Lyophilized pegaspargase, Liquid pegaspargase, Pegaspargase formulation, Randomized, open-label
Brief summary
The purpose of this study is to compare the pharmacokinetics (PK) of both lyophilized and liquid S95014 formulations during the induction phase after a single IV dose in newly diagnosed paediatric patients with ALL
Interventions
Lyophilized S95014 will be intravenously administered over 1 hour at the dose of 2500 U/m2 at Day 3 of the induction phase. Patients will receive other backbone chemotherapy agents as per ALL-MB 2015 protocol.
DRUGLiquid S95014
Liquid S95014 will be intravenously administered over 1 hour at the dose of 2500 U/m2 at Day 3 of the induction phase. Patients will receive other backbone chemotherapy agents as per ALL-MB 2015 protocol.
Sponsors
ADIR, a Servier Group company
Les Laboratoires Servier (L.L.S), Russia
Institut de Recherches Internationales Servier
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Patients aged 1 to \< 18 years * Patients with cytologically confirmed and documented newly diagnosed ALL according to National Comprehensive Cancer Network guidelines 2020 (see Appendix 2), excluding B-cell Burkitt ALL * Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 (see Appendix 3) * Highly effective contraception method * Signed informed consent and assent, when appropriate Non-inclusion Criteria: * Unlikely to cooperate in the study * Pregnant and lactating women * Participation in another interventional study at the same time; participation in non-interventional registries or epidemiological studies is allowed * Participant already enrolled in the study (informed consent signed) * Women of childbearing potential tested positive in a serum pregnancy test within 7 days prior to the treatment period * Inadequate hepatic function (bilirubin \> 1.5 times upper limit of normal (ULN), transaminases \> 5x ULN) * Inadequate renal function defined as serum creatinine \> 1.5 x ULN * Prior treatment with chemotherapy or radiotherapy (except steroids and intrathecal therapy) * Prior surgery or bone marrow transplant related to the studied disease * Down Syndrome * Psychiatric illness/social situation that would limit compliance with study requirements * Known history of pancreatitis * Known history of significant liver disease * Known carriers of HIV antibodies * Significant laboratory abnormality likely to jeopardize the patients' safety or to interfere with the conduct of the study, in the investigator's opinion * Pre-existing known coagulopathy (e.g. haemophilia and known protein S deficiency) * History of previous or concurrent malignancy * History of sensitivity to polyethylene glycol (PEG) or PEG-based drugs * Severe or uncontrolled active acute or chronic infection * Uncontrolled intercurrent illness including life-threatening acute tumor lysis syndrome (e.g. with renal failure), symptomatic congestive heart failure, cardiac arrhythmia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics Measurement | Predose up to 600 hours | Area Under the Plasma Asparaginase activity - Time curve from Time zero to infinity (AUCinf) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics Measurements | 14 days post-dose | Observed Plasma Asparaginase Activity 14 days post-dose (Cday 14) of S95014 |
| Activity Measurement | Day 7, 14, 18 and 25 post-dose of either liquid or lyophilized S95014 | Plasma Asparaginase Activity (PAA) of ≥ 0.1 U/mL after the administration of either liquid or lyophilized S95014. |
| Immunogenicity Measurements | Pre-dose, post-dose (sum of 14 and 25 days post-dose) | Anti-drug antibodies (ADA) formation against S95014 and anti-PEG with the lyophilized or liquid formulations (positive patients). |
Countries
Russia
Participant flow
Pre-assignment details
There was a sceening period (from Day-14 to Day-1) to check the eligibility of the patient in the study
Participants by arm
| Arm | Count |
|---|---|
| S95014 Lyophilizate Lyophilized S95014 reconstituted will provide 5 mL of extractable volume with the concentration of 750 U/mL. The vial of lyophilized powder (3.750 U/vial) is reconstituted with 5.2 mL of Sterile Water for Injection to obtain a 750 U/mL solution for single use.
Lyophilized S95014: Lyophilized S95014 will be intravenously administered over 1 hour at the dose of 2500 U/m2 at Day 3 of the induction phase.
Patients will receive other backbone chemotherapy agents as per ALL-MB 2015 protocol. | 43 |
| S95014 Liquid Liquid S95014 is provided as 3.750 U per 5 mL solution in a single use vial to obtain a 750 U/mL solution for single use.
Liquid S95014: Liquid S95014 will be intravenously administered over 1 hour at the dose of 2500 U/m2 at Day 3 of the induction phase.
Patients will receive other backbone chemotherapy agents as per ALL-MB 2015 protocol. | 45 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 2 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | S95014 Liquid | Total | S95014 Lyophilizate |
|---|---|---|---|
| Age, Categorical <=18 years | 45 Participants | 88 Participants | 43 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 5.4 years STANDARD_DEVIATION 3.52 | 6.1 years STANDARD_DEVIATION 3.96 | 6.9 years STANDARD_DEVIATION 4.28 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 44 Participants | 84 Participants | 40 Participants |
| Region of Enrollment Russia | 45 participants | 88 participants | 43 participants |
| Sex: Female, Male Female | 25 Participants | 42 Participants | 17 Participants |
| Sex: Female, Male Male | 20 Participants | 46 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 43 | 2 / 45 |
| other Total, other adverse events | 43 / 43 | 45 / 45 |
| serious Total, serious adverse events | 19 / 43 | 18 / 45 |
Outcome results
Primary
Pharmacokinetics Measurement
Area Under the Plasma Asparaginase activity - Time curve from Time zero to infinity (AUCinf)
Time frame: Predose up to 600 hours
Population: The Pharmacokinetic (PK) Analysis Set included the patients who have received at least one dose of IMP and are evaluable for PK analysis : the patients who had enough samples collected to provide interpretable PK results with no deviations that might have affected the PK interpretation (e.g. infusion interrupted for any reason, deviation in the theoretical administered dose \> 10%, at least one missing PK sample during the 48 first hours, ≥ 2 missing PK samples after the 48-hour time point).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| S95014 Lyophilizate | Pharmacokinetics Measurement | 362028.656 mU*day/mL | Geometric Coefficient of Variation 33.55 |
| S95014 Liquid | Pharmacokinetics Measurement | 352248.907 mU*day/mL | Geometric Coefficient of Variation 31.08 |
Comparison: AUCinf was natural log-transformed and analyzed using an analysis of variance (ANOVA) with fixed effect for formulation. The two one-sided tests procedures were performed on the geometric mean ratio (GMR) between test (S95014 lyophilizate) and reference (S95014 liquid formulation) treatments. The 90% confidence interval for the ratio was obtained within the framework of the ANOVA.p-value: 0.0590% CI: [91.4, 115.6]ANOVA
Primary
Pharmacokinetics Measurement
Maximum observed plasma asparaginase activity (Cmax)
Time frame: Predose up to 600 hours
Population: The Pharmacokinetic (PK) Analysis Set included the patients who have received at least one dose of IMP and are evaluable for PK analysis : the patients who had enough samples collected to provide interpretable PK results with no deviations that might have affected the PK interpretation (e.g. infusion interrupted for any reason, deviation in the theoretical administered dose \> 10%, at least one missing PK sample during the 48 first hours, ≥ 2 missing PK samples after the 48-hour time point).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| S95014 Lyophilizate | Pharmacokinetics Measurement | 1563.115 mU/mL | Geometric Coefficient of Variation 23.11 |
| S95014 Liquid | Pharmacokinetics Measurement | 1672.136 mU/mL | Geometric Coefficient of Variation 41.91 |
Comparison: Cmax was natural log-transformed and analyzed using an analysis of variance (ANOVA) with fixed effect for formulation. The two one-sided tests procedures were performed on the geometric mean ratio (GMR) between test (S95014 lyophilizate) and reference (S95014 liquid formulation) treatments. The 90% confidence interval for the ratio was obtained within the framework of the ANOVA.p-value: 0.0590% CI: [82.9, 105.5]ANOVA
Secondary
Activity Measurement
Plasma Asparaginase Activity (PAA) of ≥ 0.1 U/mL after the administration of either liquid or lyophilized S95014.
Time frame: Day 7, 14, 18 and 25 post-dose of either liquid or lyophilized S95014
Population: The analysis on the Plasma Asparaginase Actvity was performed on the Safety Set analysis, defined as the set of all patients who had received at least one dose of S95014 in the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| S95014 Lyophilizate | Activity Measurement | Number of patients who achieved Day 10 Plasma Asparaginase Activity (PAA) ≥ 0.1 U/mL | 43 Participants |
| S95014 Lyophilizate | Activity Measurement | Number of patients who achieved Day 17 Plasma Asparaginase Activity (PAA) ≥ 0.1 U/mL | 43 Participants |
| S95014 Lyophilizate | Activity Measurement | Number of patients who achieved Day 21 Plasma Asparaginase Activity (PAA) ≥ 0.1 U/mL | 41 Participants |
| S95014 Lyophilizate | Activity Measurement | Number of patients who achieved Day 28 Plasma Asparaginase Activity (PAA) ≥ 0.1 U/mL | 18 Participants |
| S95014 Liquid | Activity Measurement | Number of patients who achieved Day 28 Plasma Asparaginase Activity (PAA) ≥ 0.1 U/mL | 6 Participants |
| S95014 Liquid | Activity Measurement | Number of patients who achieved Day 10 Plasma Asparaginase Activity (PAA) ≥ 0.1 U/mL | 43 Participants |
| S95014 Liquid | Activity Measurement | Number of patients who achieved Day 21 Plasma Asparaginase Activity (PAA) ≥ 0.1 U/mL | 39 Participants |
| S95014 Liquid | Activity Measurement | Number of patients who achieved Day 17 Plasma Asparaginase Activity (PAA) ≥ 0.1 U/mL | 41 Participants |
Secondary
Immunogenicity Measurements
Anti-drug antibodies (ADA) formation against S95014 and anti-PEG with the lyophilized or liquid formulations (positive patients).
Time frame: Pre-dose, post-dose (sum of 14 and 25 days post-dose)
Population: The immunogenicity analyses were carried out in the Immunogenicity Analysis Set (IAS) which includes all patients who had received at least one dose of IMP and had at least one post-dose sample evaluable for immunogenicity testing.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| S95014 Lyophilizate | Immunogenicity Measurements | Pre-dose | Anti-S95014 Negative/ Anti-PEG Not applicable | 38 Participants |
| S95014 Lyophilizate | Immunogenicity Measurements | Pre-dose | Anti-S95014 Positive / Anti-PEG Positive | 2 Participants |
| S95014 Lyophilizate | Immunogenicity Measurements | Pre-dose | Anti-S95014 Positive / Anti-PEG Negative | 3 Participants |
| S95014 Lyophilizate | Immunogenicity Measurements | Post-dose (sum of 14 and 25 days post-dose) | Anti-S95014 Negative/ Anti-PEG Not applicable | 38 Participants |
| S95014 Lyophilizate | Immunogenicity Measurements | Post-dose (sum of 14 and 25 days post-dose) | Anti-S95014 Positive / Anti-PEG Positive | 2 Participants |
| S95014 Lyophilizate | Immunogenicity Measurements | Post-dose (sum of 14 and 25 days post-dose) | Anti-S95014 Positive / Anti-PEG Negative | 3 Participants |
| S95014 Liquid | Immunogenicity Measurements | Post-dose (sum of 14 and 25 days post-dose) | Anti-S95014 Positive / Anti-PEG Positive | 3 Participants |
| S95014 Liquid | Immunogenicity Measurements | Pre-dose | Anti-S95014 Negative/ Anti-PEG Not applicable | 38 Participants |
| S95014 Liquid | Immunogenicity Measurements | Post-dose (sum of 14 and 25 days post-dose) | Anti-S95014 Negative/ Anti-PEG Not applicable | 39 Participants |
| S95014 Liquid | Immunogenicity Measurements | Pre-dose | Anti-S95014 Positive / Anti-PEG Positive | 4 Participants |
| S95014 Liquid | Immunogenicity Measurements | Post-dose (sum of 14 and 25 days post-dose) | Anti-S95014 Positive / Anti-PEG Negative | 1 Participants |
| S95014 Liquid | Immunogenicity Measurements | Pre-dose | Anti-S95014 Positive / Anti-PEG Negative | 1 Participants |
Secondary
Pharmacokinetics Measurements
Observed Plasma Asparaginase Activity 14 days post-dose (Cday 14) of S95014
Time frame: 14 days post-dose
Population: The PKAS included the patients who have received at least one dose of IMP and are evaluable for PK analysis : the patients who had enough samples collected to provide interpretable PK results with no deviations that might have affected the PK interpretation .~Cday-14 could not be calculated in one patient (in S95014 liquid group) who had only 3 positive values exceeding the Lower Limit of Quantification
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| S95014 Lyophilizate | Pharmacokinetics Measurements | 496.599 mU/mL | Geometric Coefficient of Variation 37.96 |
| S95014 Liquid | Pharmacokinetics Measurements | 408.655 mU/mL | Geometric Coefficient of Variation 80.35 |
Comparison: Cday14 was natural log-transformed and analyzed using an analysis of variance (ANOVA) with fixed effect for formulation. The two one-sided tests procedures were performed on the geometric mean ratio (GMR) between test (S95014 lyophilizate) and reference (S95014 liquid formulation) treatments. The 90% confidence interval for the ratio was obtained within the framework of the ANOVA.p-value: 0.0590% CI: [98.7, 149.6]ANOVA