Calaspargase Pegol in Adults With ALL

Study Overview
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Brief Summary
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The purpose of this phase 2/3 study is to confirm the recommended doses and to evaluate the safety and pharmacodynamics of Calaspargase pegol for the treatment of adult patients with Philadelphia-negative Acute Lymphoblastic Leukemia.

Detailed Description
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The study will be conducted in 2 parts. Part 1 is a dose confirmation run-in period. Part 2 will enroll the remaining participants at the dose as confirmed in Part 1.

Official Title
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A Multi-center, Open-label, Single-arm Phase 2/3 Trial Evaluating the Safety and Pharmacokinetics of Calaspargase Pegol for Treatment of Adults Aged 22 To >65 Years With Newly-diagnosed Philadelphia-negative ALL.

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Calaspargase pegol (S95015)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥22 and <55 years with newly-diagnosed and cytologically confirmed and documented Philadelphia-negative B-cell or T-cell ALL by World Health Organization (WHO) classification (2016). Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2. No prior therapy for ALL such as chemotherapy and radiation therapy before signing the informed consent except for limited treatment (≤7 days) with corticosteroids or hydroxyurea and a single dose of intrathecal cytarabine. Exclusion Criteria: Patients with Philadelphia chromosome positive ALL, Burkitt's leukemia, mixed lineage/mixed phenotype acute leukemia, and acute undifferentiated leukemia per WHO classification (2016). Patients with Down syndrome. Patients with Hepatitis B (positive for HBs antigen), and Hepatitis C (HCV antibody) at inclusion Participants known to be HIV-positive. Known history of non-gallstone-related pancreatitis. Known severe hepatic impairment (bilirubin >3 x upper limit of normal [ULN]; transaminases >10 times ULN. Pre-existing history of hepatic veno-occlusive disease (VOD). Age ≥ 55 years. BMI > 35 kg/m2.

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Calaspargase pegol (S95015)<br> | Drug: Calaspargase pegol (S95015)<br>* Part 1: S95015 will be administered at dose of 2000 U/m2, 1500 U/m2 or 1000 U/m2 (dose level based on age and BMI) via a 2-hour intravenous infusion at Day 4 (or 5, or 6) of the induction phase, Days 15 and 43 of the consolidation phase, Day 22 of the interim maintenance phase and Days 4 (or 5, or 6) and 43 of the delayed intensification phase. S95015 starting doses for age and BMI groups will be confirmed. Patients will receive premedication prior to calaspargase pegol administration (acetaminophen, histamine-1 blocker, and corticosteroids to prevent hypersensitivity reaction) and other backbone chemotherapy agents based on the CALGB 10403 protocol treatment regimen. Part 2: Patients aged 22 to 39 years + BMI ≤ 35 kg/m2 will be treated with S95015 1750 U/m2. Patients aged 40 to < 55 years + BMI ≤ 35 kg/m2 will be treated with S95015 1500 U/m2, unchanged from Part 1. Patients 55 years or older or those with a BMI greater than 35 kg/m2 will no longer be enrolled into Part 2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) (Part 1) | Including Treatment-emergent adverse events (TEAEs), adverse events of special interests (AESI); laboratory tests; vital signs; serious adverse events (SAEs) and AE. AEs recoded and evaluated throughout the study in accordance with NCI CTCAE criteria 5.0. | From signing the ICF through 30 days after the Calaspargase pegol administration at Day 4 (or Day 5 or Day 6) in the Remission Induction phase. | 
| Adverse Events (AEs) (Part 2) | Including Treatment-emergent adverse events (TEAEs), adverse events of special interest (AESI); laboratory tests; vital signs; serious adverse events (SAEs) and AEs. AEs recoded and evaluated throughout the study in accordance with NCI CTCAE criteria 5.0. | From signing the ICF through 30 days after the last dose of the study drug in Delayed Intensification phase. | 
| Plasma Asparaginase Activity (PAA) level (Part 1) | Assessment of PAA in Part 1 is based on population modeling analysis. | Days 4, 5, 6 (Remission Induction phase) for PAA samples. Days 11, 18, 25 (Remission Induction phase) for TDM samples. | 
| Nadir Plasma Asparaginase Activity (NPAA) (Part 2) | NPAA level ≥0.1 U/mL 21 days after the Remission Consolidation Phase Day 43 dose. | Day 64 (Remission Consolidation Phase). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Asparaginase Activity (PAA) level ≥0.1 U/mL at any time during Remission Induction phase and post- Remission Induction phase, respectively (Part 2) | Pharmacodynamics criterion. | Days 4-5-6 & 11-18-25 (Remission Induction); Days 15-16-43-44 & 22-29-36-50-57-64 (Consolidation); Days 22-23 & 29-36-43 (Interim Maintenance); Days 4-5,43-44 & 11-18-25-50-57-64 (Delayed Intensification) for PAA & TDM samples respectively. | 
| Plasma Asparaginase Activity (PAA) level ≥0.025, ≥0.1, ≥0.2, or ≥0.4 U/mL at predefined time points during Remission Induction phase and post- Remission Induction phase, respectively (Part 2) | Pharmacodynamics criterion. | Days 4-5-6 & 11-18-25 (Remission Induction); Days 15-16-43-44 & 22-29-36-50-57-64 (Consolidation); Days 22-23 & 29-36-43 (Interim Maintenance); Days 4-5-43-44 & 11-18-25-50-57-64 (Delayed Intensification) for PAA & TDM samples respectively. | 
| PAA-derived maximum concentration (Cmax) after the Remission Induction Phase Day 4 dose (Part 1 and 2). | PAA-derived Cmax are based on population modeling analysis. | Days 4, 5, 6 & 11, 18, 25 (Remission Induction); for PAA & TDM samples respectively. | 
| PAA-derived Area Under the PAA-Time Curve From Time 0 to Day 21 (AUC 0-21) after the Remission Induction Phase Day 4 dose (Part 1 and 2). | PAA-derived AUC 0-21 are based on population modeling analysis. | Days 4, 5, 6 & 11, 18, 25 (Remission Induction); for PAA & TDM samples respectively. | 
| Minimal residual disease (MRD) (Part 1 and 2) | Efficacy criterion. | End of remission induction phase (Day 29). | 
| Complete remission (CR) (Part 1 and 2) | Morphologic complete remission rate (CR), morphologic complete remission rate with incomplete blood count recovery (CRi). | Day 29 remission induction therapy | 
| Survival (Part 1 and 2) | 1-year EFS (event-free survival), DFS (disease-free survival) and OS (overall survival) 2-year EFS, DFS, OS 3-year EFS, DFS, OS. | Through study completion an average of 3 months. | 
| Anti-drug (calaspargase pegol) antibody (ADA) development (Part 1 and 2) | Immunogenicity criterion. | D4, D18, D29 (Remission Induction Phase), D15, D43 (Remission Consolidation Phase), D22 (Interim Maintenance Phase), D4, D43 (Delayed Intensification Phase), Day 365 (±7) after the first dose, Day 30 after the last dose if discontinuation. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALL, Acute Lymphoblastic Leukemia, Ph-negative B-cell and T cell ALL, Philadelphia-negative ALL, Calaspargase Pegol, Asparlas, Adult, Acute Lymphocytic Leukemia, Newly diagnosed ALL, Untreated ALL