2157GCCC:Phase 1 of Calaspargase Pegol-mknl w/ Cytarabine and Idarubicin in Newly Dx AML

Study Overview
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Brief Summary
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Characterizing the regimen limiting toxicity (RLT) of chemotherapeutic drug Calaspargase Pegol-mknl as remission induction and consolidation chemotherapy in patients with newly diagnosed Acute Myeloid Leukemia (AML) and Identifying the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Calaspargase Pegol-mknl.

Detailed Description
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This is a single center, non-randomized, open-label, phase I study evaluating regimen-limiting toxicities of Calaspargase Pegol-mknl administered intravenously in Adult Patients with Newly Diagnosed Acute Myeloid Leukemia (AML). The trial will consist of the induction and consolidation phases of therapy. At the induction phase ( it usually lasts for 29 days): a high-dose of Cytarabine will be administered IV for six doses, plus Idarubicin administered IV for three doses and Calaspargase Pegol-mknl administered IV one dose, using a dose-escalation scheme. At the consolidation phase (single cycle of consolidation lasts 4-8 weeks): a high-dose of Cytarabine will be administered IV for six doses, and Calaspargase Pegol-mknl administered IV for one dose, using a dose-escalation scheme. The FDA (The US Food and Drug Administration) has not approved Calaspargase Pegol-mknl for Adult Patients with Newly Diagnosed Acute Myeloid Leukemia (AML).

Official Title
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2157GCCC: A Phase I Trial of Calaspargase Pegol-mknl in Combination With High Dose Cytarabine and Idarubicin in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Calaspargase pegol-mknl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A histologically or pathologically confirmed diagnosis of AML based on WHO classification. Patients with myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) evolving into AML who are candidates for AML induction therapy are eligible for enrollment. Age 18-65 years old. ECOG performance status < 3. Patients must have normal organ function as defined below: Total bilirubin ≤2X the institutional upper limit of normal (ULN) (except in patients with leukemic infiltration of the liver) AST(SGOT)/ALT(SGPT) ≤3X ULN (except if attributable to leukemic infiltration of the liver) Creatinine Clearance (CrCl) ≥ 40 mL/min (except in patients with evidence of tumor lysis syndrome) Left ventricular ejection fraction (LVEF) ≥50% Female patients of childbearing potential must have a negative pregnancy test <1 week before enrollment. Female patients of childbearing potential who are sexually active and male patients who are sexually active and have female partners of childbearing potential must agree to use a highly effective method of non-hormonal contraception. Contraception should be used during treatment and for at least 3 months after the last dose of Calaspargase pegol-mknl. Ability to understand and willingness to sign a written informed consent document. Agree to comply with the study requirements and agrees to come to the clinic/hospital for required study visits Exclusion Criteria: Patients with the following clinical histories are excluded: severe pancreatitis not related to cholelithiasis. Severe acute pancreatitis as defined by lipase elevation >5X ULN and with signs or symptoms unprovoked DVT PE serious or life-threatening thrombosis in any location of the body hemorrhagic or thromboembolic stroke major hemorrhagic event within three weeks before signing ICF; hemorrhage due to thrombocytopenia from underlying AML is excluded patients with hemorrhagic diathesis neurologic/cerebellar disorders that may confound the toxicity monitoring of HiDAC history of serious hypersensitivity reactions to pegylated L-asparaginase therapy Patients receiving any other investigational agents or concurrent chemotherapy or immunotherapy. Hydroxyurea for blast count control is permitted before starting treatment and up to a maximum of 10 days after starting treatment on the study. Patients with AML with any of the following cytogenetic abnormalities: t(15;17), t(8;21), inv(16), t(16;16). Pregnant women and female patients who are lactating and do not agree to stop breast-feeding. Uncontrolled undercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled active seizure disorder, or psychiatric illness/social situations that per site Principal Investigator's judgment would limit compliance with study requirements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 4 parallel-arm study of the different dose of Calaspargase Pegol-mknl with combination with High Dose Cytarabine and /or Idarubicin in Adult Patients with Newly Diagnosed Acute Myeloid Leukemia
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Calaspargase pegol-mknl dose level 1<br>Induction Phase (It usually lasts 29 days): The subject will take Cytarabine 3000 mg/m2 in an IV every 12 hours on days 1, 3, 5 for 6 doses. The subject will take Idarubicin 12 mg/m2 for three doses in an IV after the first, third, and fifth High-dose Cytarabine. The subject will take a dose of 750 U/m2 of Calaspargase pegol-mknl in an IV after the last (6th) dose of High-dose Cytarabine every 21 days ( per cycle). Consolidation Phase ( One cycle of consolidation lasts 4-8 weeks): The subject will take Cytarabine 3000 mg/m2 in an IV every 12 hours on days 1, 3, 5 for 6 doses. The subject will take a dose of 750 U/m2 of Calaspargase pegol-mknl in an IV after the last (6th) dose of High-dose Cytarabine. A single cycle of consolidation may last between 4-8 weeks in duration. | Drug: Calaspargase pegol-mknl<br>* Calaspargase pegol-mknl<br>|
| Experimental: Calaspargase pegol-mknl dose level 2<br>Induction Phase (It usually lasts 29 days): The subject will take Cytarabine 3000 mg/m2 in an IV every 12 hours on days 1, 3, 5 for 6 doses. The subject will take Idarubicin 12 mg/m2 for three doses in an IV after the first, third, and fifth High-dose Cytarabine. The subject will take a dose of 1,000 U/m2 of Calaspargase pegol-mknl in an IV after the last (6th) dose of High-dose Cytarabine every 21 days ( per cycle). Consolidation Phase ( One cycle of consolidation lasts 4-8 weeks): The subject will take Cytarabine 3000 mg/m2 in an IV every 12 hours on days 1, 3, 5 for 6 doses. The subject will take a dose of 1,000 U/m2 of Calaspargase pegol-mknl in an IV after the last (6th) dose of High-dose Cytarabine(every 21 days ( per cycle). A single cycle of consolidation may last between 4-8 weeks in duration. | Drug: Calaspargase pegol-mknl<br>* Calaspargase pegol-mknl<br>|
| Experimental: Calaspargase pegol-mknl dose level 3<br>Induction Phase (It usually lasts 29 days): The subject will take Cytarabine 3000 mg/m2 in an IV every 12 hours on days 1, 3, 5 for 6 doses. The subject will take Idarubicin 12 mg/m2 for three doses in an IV after the first, third, and fifth High- dose Cytarabine. The subject will take a dose of 1,500 U/m2 of Calaspargase pegol-mknl in an IV after the last (6th) dose of High-dose Cytarabine every 21 days ( per cycle). Consolidation Phase ( One cycle of consolidation lasts 4-8 weeks): The subject will take Cytarabine 3000 mg/m2 in an IV every 12 hours on days 1, 3, 5 for 6 doses. The subject will take a dose of 1,500 U/m2 of Calaspargase pegol-mknl in an IV after the last (6th) dose of High-dose Cytarabine. A single cycle of consolidation may last between 4-8 weeks in duration. | Drug: Calaspargase pegol-mknl<br>* Calaspargase pegol-mknl<br>|
| Experimental: Calaspargase pegol-mknl dose level 4<br>Induction Phase (It usually lasts 29 days): The subject will take Cytarabine 3000 mg/m2 in an IV every 12 hours on days 1, 3, 5 for 6 doses. The subject will take Idarubicin 12 mg/m2 for three doses in an IV after the first, third, and fifth High-dose Cytarabine. The subject will take a dose of 2,000 U/m2 of Calaspargase pegol-mknl in an IV after the last (6th) dose of High-dose Cytarabine every 21 days ( per cycle). Consolidation Phase ( One cycle of consolidation lasts 4-8 weeks): The subject will take Cytarabine 3000 mg/m2 in an IV every 12 hours on days 1, 3, 5 for 6 doses. The subject will take a dose of 2,000 U/m2 of Calaspargase pegol-mknl in an IV after the last (6th) dose of High-dose Cytarabine per cycle. A single cycle of consolidation may last between 4-8 weeks in duration. | Drug: Calaspargase pegol-mknl<br>* Calaspargase pegol-mknl<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Outcome Measure | 1. Incidence of regimen limiting toxicities (RLTs) and Incidence of treatment-emergent adverse events (TEAE). | From the first day of treatment until 30 days after receiving Calaspargase Pegol-mknl | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. CR+CRh+CRi | Complete remission (CR) + complete remission with partial hematologic recovery (CRh) + complete remission with incomplete count recovery (CRi) | Within 4-8 weeks following completion of induction regimen and completion of consolidation therapy | 
| 2. The duration of CR/CRh/CRi. | The duration of Complete remission (CR) / complete remission with partial hematologic recovery (CRh) / complete remission with incomplete count recovery (CRi) | immediately after the intervention | 
| 3. Achievement of MRD <0.02% at the end of Induction therapy with Calaspargase pegol-mknl. | Achievement of MRD <0.02% at the end of Induction therapy with Calaspargase pegol-mknl. | During the intervention | 
| 4. Event-free survival (EFS). | Event-free survival (EFS). | From the first date of intervention until the first documented progression or the date of death from any causes, whichever came first, assessed up to 100 months | 
| 5. Overall survival (OS) | Overall survival (OS) | From the first date of intervention until the first documented progression or the date of death from any causes, whichever came first, assessed up to 100 months | 
| 6. Proceeding to allo-HSCT after Calaspargase pegol-mknl treatment | Proceeding to allo-HSCT after Calaspargase pegol-mknl treatment | Immediately after the intervention | 
| 7. Plasma asparagine and glutamine and other amino acids levels at baseline and weekly after administration of Calaspargase pegol-mknl. for four weeks. | Plasma asparagine and glutamine and other amino acids levels at baseline and weekly after administration of Calaspargase pegol-mknl. for four weeks. | At baseline and weekly after administration of Calaspargase pegol-mknl for four weeks | 
| 8.Plasma asparaginase activity at baseline and weekly after administration of Calaspargase pegol-mknl for four weeks | Plasma asparaginase activity at baseline and weekly after administration of Calaspargase pegol-mknl for four weeks | At baseline and weekly after administration of Calaspargase pegol-mknl for four weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia