Study Summary
This trial is testing a new chemotherapy drug to treat AML. They are trying to find the best dose of the drug to minimize side effects while still being effective.
Eligible Conditions
- Acute Myeloid Leukemia
Treatment Effectiveness
Effectiveness Progress
Study Objectives
1 Primary · 8 Secondary · Reporting Duration: 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
After the enrollment of the study subjects
Exploratory Endpoint 1
Exploratory Endpoint 2
Exploratory Endpoint 3
Exploratory Endpoint 4
At baseline and weekly after administration of Calaspargase pegol-mknl for four weeks
7. Plasma asparagine and glutamine and other amino acids levels 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
During the intervention
3. Achievement of MRD <0.02% at the end of Induction therapy with Calaspargase pegol-mknl.
Month 100
4. Event-free survival (EFS).
5. Overall survival (OS)
Day 30
Measure
Immediately after the intervention
6. Proceeding to allo-HSCT after Calaspargase pegol-mknl treatment
Week 8
1. CR+CRh+CRi
immediately after the intervention
2. The duration of CR/CRh/CRi.
Trial Safety
Safety Progress
Trial Design
4 Treatment Groups
Calaspargase pegol-mknl dose level 4
1 of 4
Calaspargase pegol-mknl dose level 1
1 of 4
Calaspargase pegol-mknl dose level 3
1 of 4
Calaspargase pegol-mknl dose level 2
1 of 4
Experimental Treatment
24 Total Participants · 4 Treatment Groups
Primary Treatment: Calaspargase pegol-mknl · No Placebo Group · Phase 1
Calaspargase pegol-mknl dose level 4
Drug
Experimental Group · 1 Intervention: Calaspargase pegol-mknl · Intervention Types: DrugCalaspargase pegol-mknl dose level 1
Drug
Experimental Group · 1 Intervention: Calaspargase pegol-mknl · Intervention Types: DrugCalaspargase pegol-mknl dose level 3
Drug
Experimental Group · 1 Intervention: Calaspargase pegol-mknl · Intervention Types: DrugCalaspargase pegol-mknl dose level 2
Drug
Experimental Group · 1 Intervention: Calaspargase pegol-mknl · Intervention Types: DrugTrial Logistics
Trial Timeline
Screening: ~3 weeks
Treatment: Varies
Reporting: 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
Who is running the clinical trial?
University of Maryland, BaltimoreLead Sponsor
610 Previous Clinical Trials
333,781 Total Patients Enrolled
Ashkan Emadi, M.D.,Ph.D.Principal InvestigatorUniversity of Maryland, Baltimore
1 Previous Clinical Trials
30 Total Patients Enrolled
Eligibility Criteria
Age 18 - 65 · All Participants · 10 Total Inclusion Criteria
Mark “Yes” if the following statements are true for you:You have a histologically or pathologically confirmed diagnosis of AML based on WHO classification.
You are able to understand and are willing to sign a written informed consent document.
Total bilirubin ≤2x the institutional ULN.
AST/ALT ratio is greater than 3x ULN.
Creatinine Clearance (CrCl) ≥ 40 mL/min.
You agree to come to the clinic/hospital for required study visits.
You have a left ventricular ejection fraction (LVEF) of 50% or more.
References
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- Emadi, Ashkan, Jennie Y. Law, Erin T. Strovel, Rena G. Lapidus, Linda J. B. Jeng, Myounghee Lee, Miriam G. Blitzer, et al.. 2017. “Asparaginase Erwinia Chrysanthemi Effectively Depletes Plasma Glutamine in Adult Patients with Relapsed/refractory Acute Myeloid Leukemia”. Cancer Chemotherapy and Pharmacology. Springer Science and Business Media LLC. doi:10.1007/s00280-017-3459-6.
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- Capizzi, R L, R Davis, B Powell, J Cuttner, R R Ellison, M R Cooper, R Dillman, W B Major, E Dupre, and O R McIntyre. 1988. “Synergy Between High-dose Cytarabine and Asparaginase in the Treatment of Adults with Refractory and Relapsed Acute Myelogenous Leukemia--a Cancer and Leukemia Group B Study.”. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO). doi:10.1200/jco.1988.6.3.499.
- Wetzler, Meir, Chris Andrews, Laurie A. Ford, Sheila Tighe, Maurice Barcos, Sheila N. J. Sait, AnneMarie W. Block, et al.. 2011. “Phase 1 Study of Arsenic Trioxide, High-dose Cytarabine, and Idarubicin to Down-regulate Constitutive Signal Transducer and Activator of Transcription 3 Activity in Patients Aged Cancer. Wiley. doi:10.1002/cncr.26097.
- Fopp, M., M.F. Fey, M. Bacchi, F. Cavalli, J. Gmuer, E. Jacky, L. Schmid, et al.. 1997. “Post-remission Therapy of Adult Acute Myeloid Leukaemia: One Cycle of High-dose Versus Standard-dose Cytarabine”. Annals of Oncology. Elsevier BV. doi:10.1023/a:1008267904952.
- ASLANIAN, Ara M., Bradley S. FLETCHER, and Michael S. KILBERG. 2001. “Asparagine Synthetase Expression Alone Is Sufficient to Induce L-asparaginase Resistance in MOLT-4 Human Leukaemia Cells”. Biochemical Journal. Portland Press Ltd.. doi:10.1042/bj3570321.
- Gallinetti, Jordan, Eylul Harputlugil, and James R. Mitchell. 2012. “Amino Acid Sensing in Dietary-restriction-mediated Longevity: Roles of Signal-transducing Kinases GCN2 and TOR”. Biochemical Journal. Portland Press Ltd.. doi:10.1042/bj20121098.
- Horvath, Thomas D., Wai Kin Chan, Michael A. Pontikos, Leona A. Martin, Di Du, Lin Tan, Marina Konopleva, John N. Weinstein, and Philip L. Lorenzi. 2019. “Assessment of L-asparaginase Pharmacodynamics in Mouse Models of Cancer”. Metabolites. MDPI AG. doi:10.3390/metabo9010010.
- Bade, Najeebah A, Crystal Lu, Ciera L Patzke, Maria R Baer, Vu H Duong, Jennie Y Law, Seung T Lee, et al.. 2019. “Optimizing Pegylated Asparaginase Use: An Institutional Guideline for Dosing, Monitoring, and Management”. Journal of Oncology Pharmacy Practice. SAGE Publications. doi:10.1177/1078155219838316.
- Emadi, Ashkan. 2015. “Exploiting AML Vulnerability: Glutamine Dependency”. Blood. American Society of Hematology. doi:10.1182/blood-2015-07-659508.
- Fernandez, Hugo F., Zhuoxin Sun, Xiaopan Yao, Mark R. Litzow, Selina M. Luger, Elisabeth M. Paietta, Janis Racevskis, et al.. 2009. “Anthracycline Dose Intensification in Acute Myeloid Leukemia”. New England Journal of Medicine. Massachusetts Medical Society. doi:10.1056/nejmoa0904544.
- Vrooman, Lynda M., Traci M. Blonquist, Kristen E. Stevenson, Jeffrey G. Supko, Sarah K. Hunt, Sarah M. Cronholm, Victoria Koch, et al.. 2021. “Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001”. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO). doi:10.1200/jco.20.03692.
- Emadi, Ashkan, Hania Zokaee, and Edward A. Sausville. 2014. “Asparaginase in the Treatment of Non-all Hematologic Malignancies”. Cancer Chemotherapy and Pharmacology. Springer Science and Business Media LLC. doi:10.1007/s00280-014-2402-3.
- Patzke, Ciera L., Alison P. Duffy, Vu H. Duong, Firas El Chaer, James A. Trovato, Maria R. Baer, Søren M. Bentzen, and Ashkan Emadi. 2020. “Comparison of High-dose Cytarabine, Mitoxantrone, and Pegaspargase (ham-pega) to High-dose Cytarabine, Mitoxantrone, Cladribine, and Filgrastim (CLAG-M) as First-line Salvage Cytotoxic Chemotherapy for Relapsed/refractory Acute Myeloid Leukemia”. Journal of Clinical Medicine. MDPI AG. doi:10.3390/jcm9020536.
- Willemze, Roelof, Stefan Suciu, Giovanna Meloni, Boris Labar, Jean-Pierre Marie, Constantijn J.M. Halkes, Petra Muus, et al.. 2014. “High-dose Cytarabine in Induction Treatment Improves the Outcome of Adult Patients Younger Than Age 46 Years with Acute Myeloid Leukemia: Results of the EORTC-GIMEMA AML-12 Trial”. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO). doi:10.1200/jco.2013.51.8571.
- Chien, Wei-Wen, Céline Le Beux, Nicolas Rachinel, Michel Julien, Claire-Emmanuelle Lacroix, Soraya Allas, Pierre Sahakian, et al.. 2015. “Differential Mechanisms of Asparaginase Resistance in B-type Acute Lymphoblastic Leukemia and Malignant Natural Killer Cell Lines”. Scientific Reports. Springer Science and Business Media LLC. doi:10.1038/srep08068.
- Li, Ruo-Jing, Runyan Jin, Chao Liu, Xianhua Cao, Michael L. Manning, Xu Michael Di, Donna Przepiorka, et al.. 2020. “FDA Approval Summary: Calaspargase Pegol-mknl for Treatment of Acute Lymphoblastic Leukemia in Children and Young Adults”. Clinical Cancer Research. American Association for Cancer Research (AACR). doi:10.1158/1078-0432.ccr-19-1255.
- Richards, Nigel G. J., and Michael S. Kilberg. 2006. “Asparagine Synthetase Chemotherapy”. Annual Review of Biochemistry. Annual Reviews. doi:10.1146/annurev.biochem.75.103004.142520.
- Emadi, Ashkan, Bandish Kapadia, Dominique Bollino, Binny Bhandary, Maria R. Baer, Sandrine Niyongere, Erin T. Strovel, et al.. 2020. “Venetoclax and Pegcrisantaspase for Complex Karyotype Acute Myeloid Leukemia”. Leukemia. Springer Science and Business Media LLC. doi:10.1038/s41375-020-01080-6.
- Loken, Michael R., Todd A. Alonzo, Laura Pardo, Robert B. Gerbing, Susana C. Raimondi, Betsy A. Hirsch, Phoenix A. Ho, et al.. 2012. “Residual Disease Detected by Multidimensional Flow Cytometry Signifies High Relapse Risk in Patients with De Novo Acute Myeloid Leukemia: A Report from Children's Oncology Group”. Blood. American Society of Hematology. doi:10.1182/blood-2012-02-408336.
- American Cancer Society. Key Statistics for AML. (2020).
- Willemze, Roelof, Stefan Suciu, Giovanna Meloni, Boris Labar, Jean-Pierre Marie, Constantijn J.M. Halkes, Petra Muus, et al.. 2014. “High-dose Cytarabine in Induction Treatment Improves the Outcome of Adult Patients Younger Than Age 46 Years with Acute Myeloid Leukemia: Results of the EORTC-GIMEMA AML-12 Trial”. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO). doi:10.1200/jco.2013.51.8571.
- FDA. CALASPARGASE PEGOL-MKNL FDA approval label (2018).
- Fernandez, Hugo F., Zhuoxin Sun, Xiaopan Yao, Mark R. Litzow, Selina M. Luger, Elisabeth M. Paietta, Janis Racevskis, et al.. 2009. “Anthracycline Dose Intensification in Acute Myeloid Leukemia”. New England Journal of Medicine. Massachusetts Medical Society. doi:10.1056/nejmoa0904544.
- Vrooman, Lynda M., Traci M. Blonquist, Kristen E. Stevenson, Jeffrey G. Supko, Sarah K. Hunt, Sarah M. Cronholm, Victoria Koch, et al.. 2021. “Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001”. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO). doi:10.1200/jco.20.03692.
- Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, Muus P, Mistrik M, Amadori S, Specchia G, Fabbiano F, Nobile F, Sborgia M, Camera A, Selleslag DL, Lefrere F Sr, Magro D, Sica S, Cantore N, Beksac M, Berneman Z, Thomas X, Melillo L, Guimaraes JE, Leoni P, Luppi M, Mitra ME, Bron D, Fillet G, Marijt EW, Venditti A, Hagemeijer A, Mancini M, Jansen J, Cilloni D, Meert L, Fazi P, Vignetti M, Trisolini SM, Mandelli F, de Witte T. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol. 2014 Jan 20;32(3):219-28. doi: 10.1200/JCO.2013.51.8571. Epub 2013 Dec 2.
- Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, Gulati P, Byfield MP, Backer JM, Natt F, Bos JL, Zwartkruis FJ, Thomas G. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14238-43. doi: 10.1073/pnas.0506925102. Epub 2005 Sep 21.
- Aslanian AM, Fletcher BS, Kilberg MS. Asparagine synthetase expression alone is sufficient to induce l-asparaginase resistance in MOLT-4 human leukaemia cells. Biochem J. 2001 Jul 1;357(Pt 1):321-8. doi: 10.1042/0264-6021:3570321.
- Andrulis IL, Argonza R, Cairney AE. Molecular and genetic characterization of human cell lines resistant to L-asparaginase and albizziin. Somat Cell Mol Genet. 1990 Jan;16(1):59-65. doi: 10.1007/BF01650480.
- Gallinetti J, Harputlugil E, Mitchell JR. Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR. Biochem J. 2013 Jan 1;449(1):1-10. doi: 10.1042/BJ20121098.
- Emadi A. Exploiting AML vulnerability: glutamine dependency. Blood. 2015 Sep 10;126(11):1269-70. doi: 10.1182/blood-2015-07-659508. No abstract available.
- Kern W, Estey EH. High-dose cytosine arabinoside in the treatment of acute myeloid leukemia: Review of three randomized trials. Cancer. 2006 Jul 1;107(1):116-24. doi: 10.1002/cncr.21543.
- Aslanian AM, Kilberg MS. Multiple adaptive mechanisms affect asparagine synthetase substrate availability in asparaginase-resistant MOLT-4 human leukaemia cells. Biochem J. 2001 Aug 15;358(Pt 1):59-67. doi: 10.1042/0264-6021:3580059.
- Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in oncology. Biometrics. 2005 Jun;61(2):540-5. doi: 10.1111/j.1541-0420.2005.00311.x.
- Hutson RG, Kitoh T, Moraga Amador DA, Cosic S, Schuster SM, Kilberg MS. Amino acid control of asparagine synthetase: relation to asparaginase resistance in human leukemia cells. Am J Physiol. 1997 May;272(5 Pt 1):C1691-9. doi: 10.1152/ajpcell.1997.272.5.C1691.
- Freeman SD, Hourigan CS. MRD evaluation of AML in clinical practice: are we there yet? Hematology Am Soc Hematol Educ Program. 2019 Dec 6;2019(1):557-569. doi: 10.1182/hematology.2019000060.
- Richards NG, Kilberg MS. Asparagine synthetase chemotherapy. Annu Rev Biochem. 2006;75:629-54. doi: 10.1146/annurev.biochem.75.103004.142520.
- Horvath TD, Chan WK, Pontikos MA, Martin LA, Du D, Tan L, Konopleva M, Weinstein JN, Lorenzi PL. Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer. Metabolites. 2019 Jan 9;9(1):10. doi: 10.3390/metabo9010010.
- Capizzi RL, Davis R, Powell B, Cuttner J, Ellison RR, Cooper MR, Dillman R, Major WB, Dupre E, McIntyre OR. Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute myelogenous leukemia--a Cancer and Leukemia Group B Study. J Clin Oncol. 1988 Mar;6(3):499-508. doi: 10.1200/JCO.1988.6.3.499.
- Lai C, Doucette K, Norsworthy K. Recent drug approvals for acute myeloid leukemia. J Hematol Oncol. 2019 Sep 18;12(1):100. doi: 10.1186/s13045-019-0774-x.
- Patzke CL, Duffy AP, Duong VH, El Chaer F, Trovato JA, Baer MR, Bentzen SM, Emadi A. Comparison of High-Dose Cytarabine, Mitoxantrone, and Pegaspargase (HAM-pegA) to High-Dose Cytarabine, Mitoxantrone, Cladribine, and Filgrastim (CLAG-M) as First-Line Salvage Cytotoxic Chemotherapy for Relapsed/Refractory Acute Myeloid Leukemia. J Clin Med. 2020 Feb 16;9(2):536. doi: 10.3390/jcm9020536.
- Emadi A, Zokaee H, Sausville EA. Asparaginase in the treatment of non-ALL hematologic malignancies. Cancer Chemother Pharmacol. 2014 May;73(5):875-83. doi: 10.1007/s00280-014-2402-3. Epub 2014 Feb 11.
- 2021. "2157GCCC:Phase 1 of Calaspargase Pegol-mknl w/ Cytarabine and Idarubicin in Newly Dx AML". ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04953780.
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