Acute Lymphoblastic Leukemia, Lymphoblastic Leukemia
Conditions
Keywords
ALL, LBL, Asparaginase, Leukemia, Childhood acute lymphoblastic leukemia
Brief summary
This is an open-label, multicenter, dose confirmation, and PK study of JZP-458 in patients (of any age) with ALL/LBL who are hypersensitive to E. coli-derived asparaginases (allergic reaction or silent inactivation). This study is designed to assess the tolerability and efficacy of JZP-458 (only in patients who develop hypersensitivity to an E. coli-derived asparaginase), as measured by asparaginase activity.
Interventions
DRUGIM JZP-458
IM JZP-458 will be administered in Part A, Cohorts 1 & 2
DRUGIV JZP-458
IV JZP-458 will be administered in Part B
Sponsors
Children's Oncology Group
Jazz Pharmaceuticals
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Pediatric and adult patients with a diagnosis of ALL or LBL. 2. Have had an allergic reaction to a long-acting E. coli-derived asparaginase OR have silent inactivation. 3. Have 1 or more courses of E. coli-derived asparaginase remaining in his/her treatment plan. 4. Patients must have, in the opinion of the Investigator, fully recovered from their prior allergic reaction to E. coli-derived asparaginase.
Exclusion criteria
1. Have previously received asparaginase Erwinia chrysanthemi or JZP-458. 2. Have relapsed ALL or LBL. 3. Are concurrently receiving another investigational agent and/or treated with an investigational device at the same time as JZP-458 (within 48 hours) during Course 1 of JZP-458. 4. Have a history of ≥ Grade 3 pancreatitis. 5. Prior history of asparaginase-associated ≥ Grade 3 hemorrhagic event or asparaginase-associated thrombus requiring anticoagulation therapy, excluding catheter-related thrombotic events.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate During the First Course of JZP-458 Administration | Baseline up to 2 weeks | The response rate was defined as the number (proportion) of patients with the last 72-hour nadir serum asparaginase activity (NSAA) level ≥ 0.1 IU/mL during the first course of IM JZP-458. Blood samples were collected for serum asparaginase activity level determination. |
| Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) | Date of written informed consent up to 30 days after last dose of last course, up to approximately 2 years 7 months | An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered related to study drug. AEs were classified by the Investigator using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Last 48-hour NSAA Level ≥ 0.1 IU/mL During The First Course (6 Doses) of JZP-458 Administration | Baseline up to 2 weeks | Blood samples were collected for serum asparaginase activity level determination. |
| Number of Participants With Last NSAA Levels ≥ 0.4 IU/mL During The First Course (6 Doses) of JZP-458 Administration | Baseline up to 2 weeks | Blood samples were collected for serum asparaginase activity level determination. |
| Mean Serum Asparaginase Activity Levels in First Course of JZP-458 Administration | Up to 2 weeks (6 doses) | Serum asparaginase levels serve as a surrogate marker for asparagine depletion. Mean serum asparaginase activity levels in Course 1 are reported. |
| Number of Participants Who Are Anti-drug Antibody Positive or Negative Against JZP-458 | Baseline up to 30 days (ADA- samples) after last dose of last course and up to 6 months (ADA+ samples) after last dose of last course, up to approximately 2 years 7 months | Blood samples were collected for immunogenicity analysis. Anti-drug antibody positive (ADA+) participants were those with a positive result on the first test and also a positive result on the confirmatory test. Anti-drug antibody negative (ADA-) participants had a negative result on the first test. |
Countries
Canada, United States
Participant flow
Recruitment details
A total of 229 participants who met all inclusion and no exclusion criteria were enrolled in the study. One participant did not receive treatment; 228 participants were included in the Safety Analysis Set and 224 participants were included in the Efficacy Analysis Set. The data presented are based on the final database cut (22 November 2022).
Participants by arm
| Arm | Count |
|---|---|
| Part A: JZP-458 IM 25 mg/m^2 (MWF) Participants who received an intramuscular (IM) dose of JZP-458 25 mg/m\^2 on a Monday/Wednesday/Friday (MWF) schedule over 2 weeks based on available data from the Phase 1 (JZP458-101) healthy volunteer study. | 33 |
| Part A: JZP-458 IM 37.5 mg/m^2 (MWF) Participants who received an intramuscular (IM) dose of JZP-458 37.5 mg/m\^2 on a Monday/Wednesday/Friday (MWF) schedule over 2 weeks. | 83 |
| Part A: JZP-458 IM 25 (MW)/50 mg/m^2 (F) Participants who received an intramuscular (IM) dose of JZP-458 25 mg/m\^2 on Mondays and Wednesdays and 50 mg/m\^2 on Fridays on a Monday/Wednesday/Friday (MWF) schedule over 2 weeks. | 51 |
| Part B: JZP-458 IV 25 (MW)/50 mg/m^2 (F) Participants who received an intravenous (IV) dose of JZP-458 25 mg/m\^2 on Mondays and Wednesdays and 50 mg/m\^2 on Fridays on a Monday/Wednesday/Friday (MWF) schedule over 2 weeks. | 61 |
| Total | 228 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part A | Adverse Event | 2 | 12 | 6 | 0 |
| Part A | Death | 1 | 2 | 0 | 0 |
| Part A | Other | 0 | 0 | 1 | 0 |
| Part A | Physician Decision | 2 | 5 | 2 | 0 |
| Part A | Progressive disease | 0 | 2 | 1 | 0 |
| Part A | Protocol deviation | 0 | 0 | 1 | 0 |
| Part A | Withdrawal by parent or guardian | 1 | 0 | 0 | 0 |
| Part A | Withdrawal by participant | 0 | 0 | 1 | 0 |
| Part B | Adverse Event | 0 | 0 | 0 | 21 |
| Part B | Other | 0 | 0 | 0 | 1 |
| Part B | Physician Decision | 0 | 0 | 0 | 7 |
| Part B | Progressive disease | 0 | 0 | 0 | 1 |
| Part B | Recurrent disease | 0 | 0 | 0 | 1 |
| Part B | Withdrawal by parent or guardian | 0 | 0 | 0 | 3 |
| Part B | Withdrawal by participant | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Part A: JZP-458 IM 25 mg/m^2 (MWF) | Part A: JZP-458 IM 37.5 mg/m^2 (MWF) | Part A: JZP-458 IM 25 (MW)/50 mg/m^2 (F) | Part B: JZP-458 IV 25 (MW)/50 mg/m^2 (F) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 25 Participants | 79 Participants | 46 Participants | 54 Participants | 204 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 4 Participants | 5 Participants | 7 Participants | 24 Participants |
| Age, Continuous | 11.5 years STANDARD_DEVIATION 7.11 | 9.0 years STANDARD_DEVIATION 5.08 | 11.3 years STANDARD_DEVIATION 5.41 | 10.4 years STANDARD_DEVIATION 6.3 | 10.3 years STANDARD_DEVIATION 5.86 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 5 Participants | 1 Participants | 3 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 11 Participants | 8 Participants | 2 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 9 Participants | 6 Participants | 10 Participants | 29 Participants |
| Race (NIH/OMB) White | 24 Participants | 58 Participants | 33 Participants | 43 Participants | 158 Participants |
| Sex: Female, Male Female | 16 Participants | 28 Participants | 20 Participants | 25 Participants | 89 Participants |
| Sex: Female, Male Male | 17 Participants | 55 Participants | 31 Participants | 36 Participants | 139 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 33 | 2 / 83 | 0 / 51 | 0 / 61 |
| other Total, other adverse events | 31 / 33 | 81 / 83 | 48 / 51 | 56 / 61 |
| serious Total, serious adverse events | 20 / 33 | 57 / 83 | 34 / 51 | 40 / 61 |
Outcome results
Primary
Number of Participants With Any Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered related to study drug. AEs were classified by the Investigator using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
Time frame: Date of written informed consent up to 30 days after last dose of last course, up to approximately 2 years 7 months
Population: Safety events were assessed in the Safety Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: JZP-458 IM 25 mg/m^2 (MWF) | Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) | 32 Participants |
| Part A: JZP-458 IM 37.5 mg/m^2 (MWF) | Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) | 83 Participants |
| Part A: JZP-458 IM 25 (MW)/50 mg/m^2 (F) | Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) | 49 Participants |
| Part B: JZP-458 IV 25 (MW)/50 mg/m^2 (F) | Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) | 60 Participants |
Primary
Response Rate During the First Course of JZP-458 Administration
The response rate was defined as the number (proportion) of patients with the last 72-hour nadir serum asparaginase activity (NSAA) level ≥ 0.1 IU/mL during the first course of IM JZP-458. Blood samples were collected for serum asparaginase activity level determination.
Time frame: Baseline up to 2 weeks
Population: Response rates were assessed in the Efficacy Analysis Set in participants with available data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: JZP-458 IM 25 mg/m^2 (MWF) | Response Rate During the First Course of JZP-458 Administration | 18 Participants |
| Part A: JZP-458 IM 37.5 mg/m^2 (MWF) | Response Rate During the First Course of JZP-458 Administration | 70 Participants |
| Part A: JZP-458 IM 25 (MW)/50 mg/m^2 (F) | Response Rate During the First Course of JZP-458 Administration | 44 Participants |
| Part B: JZP-458 IV 25 (MW)/50 mg/m^2 (F) | Response Rate During the First Course of JZP-458 Administration | 20 Participants |
Secondary
Mean Serum Asparaginase Activity Levels in First Course of JZP-458 Administration
Serum asparaginase levels serve as a surrogate marker for asparagine depletion. Mean serum asparaginase activity levels in Course 1 are reported.
Time frame: Up to 2 weeks (6 doses)
Population: Serum asparaginase activity levels were assessed in participants with available data in the Efficacy Analysis Set.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Part A: JZP-458 IM 25 mg/m^2 (MWF) | Mean Serum Asparaginase Activity Levels in First Course of JZP-458 Administration | Last 48 hours | 0.45 IU/mL |
| Part A: JZP-458 IM 25 mg/m^2 (MWF) | Mean Serum Asparaginase Activity Levels in First Course of JZP-458 Administration | Last 72 hours | 0.16 IU/mL |
| Part A: JZP-458 IM 37.5 mg/m^2 (MWF) | Mean Serum Asparaginase Activity Levels in First Course of JZP-458 Administration | Last 72 hours | 0.33 IU/mL |
| Part A: JZP-458 IM 37.5 mg/m^2 (MWF) | Mean Serum Asparaginase Activity Levels in First Course of JZP-458 Administration | Last 48 hours | 0.88 IU/mL |
| Part A: JZP-458 IM 25 (MW)/50 mg/m^2 (F) | Mean Serum Asparaginase Activity Levels in First Course of JZP-458 Administration | Last 48 hours | 0.66 IU/mL |
| Part A: JZP-458 IM 25 (MW)/50 mg/m^2 (F) | Mean Serum Asparaginase Activity Levels in First Course of JZP-458 Administration | Last 72 hours | 0.47 IU/mL |
| Part B: JZP-458 IV 25 (MW)/50 mg/m^2 (F) | Mean Serum Asparaginase Activity Levels in First Course of JZP-458 Administration | Last 48 hours | 0.25 IU/mL |
| Part B: JZP-458 IV 25 (MW)/50 mg/m^2 (F) | Mean Serum Asparaginase Activity Levels in First Course of JZP-458 Administration | Last 72 hours | 0.10 IU/mL |
Secondary
Number of Participants Who Are Anti-drug Antibody Positive or Negative Against JZP-458
Blood samples were collected for immunogenicity analysis. Anti-drug antibody positive (ADA+) participants were those with a positive result on the first test and also a positive result on the confirmatory test. Anti-drug antibody negative (ADA-) participants had a negative result on the first test.
Time frame: Baseline up to 30 days (ADA- samples) after last dose of last course and up to 6 months (ADA+ samples) after last dose of last course, up to approximately 2 years 7 months
Population: Immunogenicity was assessed in the Safety Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: JZP-458 IM 25 mg/m^2 (MWF) | Number of Participants Who Are Anti-drug Antibody Positive or Negative Against JZP-458 | Overall confirmed ADA+ | 16 Participants |
| Part A: JZP-458 IM 25 mg/m^2 (MWF) | Number of Participants Who Are Anti-drug Antibody Positive or Negative Against JZP-458 | Overall ADA- | 17 Participants |
| Part A: JZP-458 IM 37.5 mg/m^2 (MWF) | Number of Participants Who Are Anti-drug Antibody Positive or Negative Against JZP-458 | Overall ADA- | 42 Participants |
| Part A: JZP-458 IM 37.5 mg/m^2 (MWF) | Number of Participants Who Are Anti-drug Antibody Positive or Negative Against JZP-458 | Overall confirmed ADA+ | 41 Participants |
| Part A: JZP-458 IM 25 (MW)/50 mg/m^2 (F) | Number of Participants Who Are Anti-drug Antibody Positive or Negative Against JZP-458 | Overall confirmed ADA+ | 25 Participants |
| Part A: JZP-458 IM 25 (MW)/50 mg/m^2 (F) | Number of Participants Who Are Anti-drug Antibody Positive or Negative Against JZP-458 | Overall ADA- | 26 Participants |
| Part B: JZP-458 IV 25 (MW)/50 mg/m^2 (F) | Number of Participants Who Are Anti-drug Antibody Positive or Negative Against JZP-458 | Overall confirmed ADA+ | 34 Participants |
| Part B: JZP-458 IV 25 (MW)/50 mg/m^2 (F) | Number of Participants Who Are Anti-drug Antibody Positive or Negative Against JZP-458 | Overall ADA- | 27 Participants |
Secondary
Number of Participants With Last 48-hour NSAA Level ≥ 0.1 IU/mL During The First Course (6 Doses) of JZP-458 Administration
Blood samples were collected for serum asparaginase activity level determination.
Time frame: Baseline up to 2 weeks
Population: Nadir serum asparaginase activity levels were assessed in the Efficacy Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: JZP-458 IM 25 mg/m^2 (MWF) | Number of Participants With Last 48-hour NSAA Level ≥ 0.1 IU/mL During The First Course (6 Doses) of JZP-458 Administration | 31 Participants |
| Part A: JZP-458 IM 37.5 mg/m^2 (MWF) | Number of Participants With Last 48-hour NSAA Level ≥ 0.1 IU/mL During The First Course (6 Doses) of JZP-458 Administration | 82 Participants |
| Part A: JZP-458 IM 25 (MW)/50 mg/m^2 (F) | Number of Participants With Last 48-hour NSAA Level ≥ 0.1 IU/mL During The First Course (6 Doses) of JZP-458 Administration | 47 Participants |
| Part B: JZP-458 IV 25 (MW)/50 mg/m^2 (F) | Number of Participants With Last 48-hour NSAA Level ≥ 0.1 IU/mL During The First Course (6 Doses) of JZP-458 Administration | 53 Participants |
Secondary
Number of Participants With Last NSAA Levels ≥ 0.4 IU/mL During The First Course (6 Doses) of JZP-458 Administration
Blood samples were collected for serum asparaginase activity level determination.
Time frame: Baseline up to 2 weeks
Population: Nadir serum asparaginase activity levels were assessed in the Efficacy Analysis Set in participants with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: JZP-458 IM 25 mg/m^2 (MWF) | Number of Participants With Last NSAA Levels ≥ 0.4 IU/mL During The First Course (6 Doses) of JZP-458 Administration | Last 48 hours | 16 Participants |
| Part A: JZP-458 IM 25 mg/m^2 (MWF) | Number of Participants With Last NSAA Levels ≥ 0.4 IU/mL During The First Course (6 Doses) of JZP-458 Administration | Last 72 hours | 1 Participants |
| Part A: JZP-458 IM 37.5 mg/m^2 (MWF) | Number of Participants With Last NSAA Levels ≥ 0.4 IU/mL During The First Course (6 Doses) of JZP-458 Administration | Last 72 hours | 20 Participants |
| Part A: JZP-458 IM 37.5 mg/m^2 (MWF) | Number of Participants With Last NSAA Levels ≥ 0.4 IU/mL During The First Course (6 Doses) of JZP-458 Administration | Last 48 hours | 65 Participants |
| Part A: JZP-458 IM 25 (MW)/50 mg/m^2 (F) | Number of Participants With Last NSAA Levels ≥ 0.4 IU/mL During The First Course (6 Doses) of JZP-458 Administration | Last 48 hours | 32 Participants |
| Part A: JZP-458 IM 25 (MW)/50 mg/m^2 (F) | Number of Participants With Last NSAA Levels ≥ 0.4 IU/mL During The First Course (6 Doses) of JZP-458 Administration | Last 72 hours | 23 Participants |
| Part B: JZP-458 IV 25 (MW)/50 mg/m^2 (F) | Number of Participants With Last NSAA Levels ≥ 0.4 IU/mL During The First Course (6 Doses) of JZP-458 Administration | Last 48 hours | 10 Participants |
| Part B: JZP-458 IV 25 (MW)/50 mg/m^2 (F) | Number of Participants With Last NSAA Levels ≥ 0.4 IU/mL During The First Course (6 Doses) of JZP-458 Administration | Last 72 hours | 0 Participants |