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

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04953780
• Other study ID #: 2157GCCC ; HP-00096801
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: September 27, 2021
• Est. completion date: December 31, 2025

Study information

• Verified date: March 2024
• Source: University of Maryland, Baltimore
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 6
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Calaspargase pegol-mknl
Calaspargase pegol-mknl

Locations

Country	Name	City	State
United States	Greenebaum Cancer Center, University of Maryland Medical Systems	Baltimore	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
University of Maryland, Baltimore

Country where clinical trial is conducted

United States, 

References & Publications (33)

American Cancer Society. Key Statistics for AML. (2020).

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. — View Citation

Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. doi: 10.1200/JCO.2014.55.5763. Epub 2014 Oct 27. — View Citation

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. — View Citation

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. — View Citation

Bade NA, Lu C, Patzke CL, Baer MR, Duong VH, Law JY, Lee ST, Sausville EA, Zimrin AB, Duffy AP, Lawson J, Emadi A. Optimizing pegylated asparaginase use: An institutional guideline for dosing, monitoring, and management. J Oncol Pharm Pract. 2020 Jan;26(1):74-92. doi: 10.1177/1078155219838316. Epub 2019 Mar 27. — View Citation

Bishop JF, Matthews JP, Young GA, Szer J, Gillett A, Joshua D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Herrmann R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja S. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 1996 Mar 1;87(5):1710-7. — View Citation

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. — View Citation

Chien WW, Le Beux C, Rachinel N, Julien M, Lacroix CE, Allas S, Sahakian P, Cornut-Thibaut A, Lionnard L, Kucharczak J, Aouacheria A, Abribat T, Salles G. Differential mechanisms of asparaginase resistance in B-type acute lymphoblastic leukemia and malignant natural killer cell lines. Sci Rep. 2015 Jan 28;5:8068. doi: 10.1038/srep08068. — View Citation

Emadi A, Kapadia B, Bollino D, Bhandary B, Baer MR, Niyongere S, Strovel ET, Kaizer H, Chang E, Choi EY, Ma X, Tighe KM, Carter-Cooper B, Moses BS, Civin CI, Mahurkar A, Shetty AC, Gartenhaus RB, Kamangar F, Lapidus RG. Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia. Leukemia. 2021 Jul;35(7):1907-1924. doi: 10.1038/s41375-020-01080-6. Epub 2020 Nov 16. — View Citation

Emadi A, Law JY, Strovel ET, Lapidus RG, Jeng LJB, Lee M, Blitzer MG, Carter-Cooper BA, Sewell D, Van Der Merwe I, Philip S, Imran M, Yu SL, Li H, Amrein PC, Duong VH, Sausville EA, Baer MR, Fathi AT, Singh Z, Bentzen SM. Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia. Cancer Chemother Pharmacol. 2018 Jan;81(1):217-222. doi: 10.1007/s00280-017-3459-6. Epub 2017 Nov 8. — View Citation

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. — View Citation

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. — View Citation

FDA. CALASPARGASE PEGOL-MKNL FDA approval label <https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761102s000lbl.pdf> (2018).

Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1249-59. doi: 10.1056/NEJMoa0904544. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Li RJ, Jin R, Liu C, Cao X, Manning ML, Di XM, Przepiorka D, Namuswe F, Deisseroth A, Goldberg KB, Blumenthal GM, Pazdur R. FDA Approval Summary: Calaspargase Pegol-mknl For Treatment of Acute Lymphoblastic Leukemia in Children and Young Adults. Clin Cancer Res. 2020 Jan 15;26(2):328-331. doi: 10.1158/1078-0432.CCR-19-1255. Epub 2019 Aug 23. — View Citation

Li W, Gong X, Sun M, Zhao X, Gong B, Wei H, Mi Y, Wang J. High-dose cytarabine in acute myeloid leukemia treatment: a systematic review and meta-analysis. PLoS One. 2014 Oct 9;9(10):e110153. doi: 10.1371/journal.pone.0110153. eCollection 2014. — View Citation

Loken MR, Alonzo TA, Pardo L, Gerbing RB, Raimondi SC, Hirsch BA, Ho PA, Franklin J, Cooper TM, Gamis AS, Meshinchi S. 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. 2012 Aug 23;120(8):1581-8. doi: 10.1182/blood-2012-02-408336. Epub 2012 May 30. — View Citation

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. — View Citation

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. — View Citation

Richards NG, Kilberg MS. Asparagine synthetase chemotherapy. Annu Rev Biochem. 2006;75:629-54. doi: 10.1146/annurev.biochem.75.103004.142520. — View Citation

Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505. doi: 10.1200/JCO.20.03692. Epub 2021 Jul 6. — View Citation

Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, Balcerzak SP, Bickers JN, Hynes HE, Welborn JL, Simon SR, Grever M. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. 1996 Oct 15;88(8):2841-51. — View Citation

Wetzler M, Andrews C, Ford LA, Tighe S, Barcos M, Sait SN, Block AW, Nowak NJ, Baer MR, Wang ES, Baumann H. 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 <60 years with acute myeloid leukemia. Cancer. 2011 Nov 1;117(21):4861-8. doi: 10.1002/cncr.26097. Epub 2011 Mar 31. — View Citation

Willems L, Jacque N, Jacquel A, Neveux N, Maciel TT, Lambert M, Schmitt A, Poulain L, Green AS, Uzunov M, Kosmider O, Radford-Weiss I, Moura IC, Auberger P, Ifrah N, Bardet V, Chapuis N, Lacombe C, Mayeux P, Tamburini J, Bouscary D. Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3521-32. doi: 10.1182/blood-2013-03-493163. Epub 2013 Sep 6. — View Citation

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. — View Citation

* Note: There are 33 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory Endpoint 1	Measurement of asparagine synthetase mRNA and protein expression in patients who have refractory disease or develop relapse	After the enrollment of the study subjects
Other	Exploratory Endpoint 2	Measurement of p90RSK expression and phosphorylation of p70S6K, 4EBP1, and eIF4E in bone marrow cells of Calaspargase pegol-mknl treated patients with AML	After the enrollment of the study subjects
Other	Exploratory Endpoint 3	Measurement of protein expression of MCL-1, BCL2 and BCL-XL in bone marrow cells of Calaspargase pegol-mknl treated patients with AML.	After the enrollment of the study subjects
Other	Exploratory Endpoint 4	Tissue banking for further molecular and functional testing in the future	After the enrollment of the study subjects
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	6. Proceeding to allo-HSCT after Calaspargase pegol-mknl treatment	Proceeding to allo-HSCT after Calaspargase pegol-mknl treatment	Immediately after the intervention
Secondary	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
Secondary	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