PD-1 Inhibitor Combined With Azacytidine and Homoharringtonine，Cytarabine, G-CSF for Refractory or Relapsed AML

Acute Myeloid Leukemia Clinical Trial

Official title:

an Single Center，Single Arm, Phase 3 Study to Evaluate Efficacy and Safety of PD-1 Inhibitor Combined With Azacytidine and HAG Regimen for Patients With Relapsed or Refractory Acute Myeloid Leukemia.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04722952
• Other study ID #: SOOCHOW-HY-2020
• Status: Recruiting
• Phase: Phase 3
• Start date: May 1, 2021
• Est. completion date: January 1, 2024

Study information

• Verified date: December 2021
• Source: The First Affiliated Hospital of Soochow University
• Contact: Han Yue, Ph.D
• Phone: (0086)51267781856
• Email: hanyue[@]suda.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an single center, single arm, phase 3 study to evaluate efficacy and safety of PD-1 Inhibitor combined with DNA methyltransferase inhibitor Azacytidine and HAG regimen for patients with relapsed and refractory acute myeloid leukemia.

Description:

Treatment for Acute Myeloid Leukemia（AML） that has not responded to treatment (refractory) or has returned after treatment (relapsed) often do not work. Researchers want to see if an immunotherapy drug, combined with a less intense chemotherapy, may be able to help.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: January 1, 2024
• Est. primary completion date: January 1, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• Chinese guidelines for the diagnosis and treatment of relapsed and refractory acute myeloid leukemia (2017 edition),excludes acute promyelocytic leukemia (M3?APL)
• Hematopoietic stem cell transplantation =3 months, Discontinue immunosuppressant =3 weeks, Patients without graft-versus-host disease;
• Be at least 18 years of age on day of signing informed consent.
• Have a performance status of less than or equal to 2 on the Eastern Cooperative Oncology Group(ECOG) Performance Scale
• Demonstrate adequate organ function as defined below, all screening labs should

be performed before treatment initiation:

1. ALT(SGPT) less than or equal to 2.5 × Upper Limit of Norma(ULN);

2. AST (SGOT) less than or equal to 2.5 × ULN;

3. Serum total bilirubin Less than or equal to 2.0 × ULN Note: If total bilirubin >2.0×ULN, subjects with Gilbert syndrome records are allowed to join the group

4. Serum Creatinine = 30 mL/min

5. Total white blood cell (WBC) count =10,000/µL; Note: hydroxyurea therapy is allowed to reduce white blood cells to meet this inclusion criteria.white blood cells should be determined =24 hours after the last hydroxyurea administration. Final hydroxyurea administration should not =3 days prior to the first azacytidine administration.

• Treatment without anthracycline or demethylation. Ability to comprehend the investigational nature of the study and provide informed consent

Exclusion Criteria:

• Patients with chronic myeloid leukemia,AML of other myeloproliferative disorders Malignant neoplasms with other progression Those who can not control severe infections and other underlying diseases can not tolerate chemotherapy Patients with cardiac insufficiency: ejection fraction (EF)<30%,New York Heart Association(NYHA) standards,Cardiac insufficiency II or above Patients with liver and kidney dysfunction:Serum bilirubin (SB)=2mg/dl,AST is 2.5 times higher than normal upper limit, serum creatinine (SCr) is more than 2.5 mg/dl Serious mental illness uncooperative Refusal to join the study

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Immunotherapy
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Refractory Leukemia
• Relapsed Adult AML

Intervention

Drug:
• Visilizumab
Azacytidine 75mg/(m2.d) by IV on days 1-7 of every cycle. Anti-PD-1 mAb 200mg by IV on day 8 of every cycle. Homoharringtonine(HHT) 2mg/(m2.d) by IV on days 1-6 of every cycle Cytarabine 10mg/(m2.d) by SC on days 1-7 of every cycle Granulocyte colony-stimulating factor(G-CSF) 300ug/d by SC on days 1-7 of every cycle,until absolute neutrophil count(ANC) > 5X109/L or white blood cell(WBC)> 20X109/L.

Locations

Country	Name	City	State
China	The First Affiliated Hospital of Soochow University	Suzhou	Jiangsu

Sponsors (1)

Lead Sponsor	Collaborator
The First Affiliated Hospital of Soochow University

Country where clinical trial is conducted

China, 

References & Publications (11)

Christman JK. 5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002 Aug 12;21(35):5483-95. Review. — View Citation

Daver N, Garcia-Manero G, Basu S, Boddu PC, Alfayez M, Cortes JE, Konopleva M, Ravandi-Kashani F, Jabbour E, Kadia T, Nogueras-Gonzalez GM, Ning J, Pemmaraju N, DiNardo CD, Andreeff M, Pierce SA, Gordon T, Kornblau SM, Flores W, Alhamal Z, Bueso-Ramos C, Jorgensen JL, Patel KP, Blando J, Allison JP, Sharma P, Kantarjian H. Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study. Cancer Discov. 2019 Mar;9(3):370-383. doi: 10.1158/2159-8290.CD-18-0774. Epub 2018 Nov 8. — View Citation

Gao S, Li Z, Fu JH, Hu XH, Xu Y, Jin ZM, Tang XW, Han Y, Chen SN, Sun AN, Wu DP, Qiu HY. Decitabine in the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndromes, Which Combined with Complex Karyotype Respectively. Asian Pac J Cancer Prev. 2015;16(15):6627-32. — View Citation

Itzykson R, Thépot S, Berthon C, Delaunay J, Bouscary D, Cluzeau T, Turlure P, Prébet T, Dartigeas C, Marolleau JP, Recher C, Plantier I, Stamatoullas A, Devidas A, Taksin AL, Guièze R, Caillot D, Vey N, Adès L, Ifrah N, Dombret H, Fenaux P, Gardin C. Azacitidine for the treatment of relapsed and refractory AML in older patients. Leuk Res. 2015 Feb;39(2):124-30. doi: 10.1016/j.leukres.2014.11.009. Epub 2014 Nov 24. — View Citation

Ivanoff S, Gruson B, Chantepie SP, Lemasle E, Merlusca L, Harrivel V, Charbonnier A, Votte P, Royer B, Marolleau JP. 5-Azacytidine treatment for relapsed or refractory acute myeloid leukemia after intensive chemotherapy. Am J Hematol. 2013 Jul;88(7):601-5. doi: 10.1002/ajh.23464. Epub 2013 May 30. — View Citation

Keating GM. Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Drugs. 2009;69(17):2501-18. doi: 10.2165/11202840-000000000-00000. Review. — View Citation

Ørskov AD, Treppendahl MB, Skovbo A, Holm MS, Friis LS, Hokland M, Grønbæk K. Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation. Oncotarget. 2015 Apr 20;6(11):9612-26. — View Citation

Price SL, Lancet JE, George TJ, Wetzstein GA, List AF, Ho VQ, Fernandez HF, Pinilla-Ibarz J, Kharfan-Dabaja MA, Komrokji RS. Salvage chemotherapy regimens for acute myeloid leukemia: Is one better? Efficacy comparison between CLAG and MEC regimens. Leuk Res. 2011 Mar;35(3):301-4. doi: 10.1016/j.leukres.2010.09.002. Epub 2010 Nov 24. — View Citation

Santini V, Ossenkoppele GJ. Hypomethylating agents in the treatment of acute myeloid leukemia: A guide to optimal use. Crit Rev Oncol Hematol. 2019 Aug;140:1-7. doi: 10.1016/j.critrevonc.2019.05.013. Epub 2019 May 25. Review. — View Citation

Tallman MS, Wang ES, Altman JK, Appelbaum FR, Bhatt VR, Bixby D, Coutre SE, De Lima M, Fathi AT, Fiorella M, Foran JM, Hall AC, Jacoby M, Lancet J, LeBlanc TW, Mannis G, Marcucci G, Martin MG, Mims A, O'Donnell MR, Olin R, Peker D, Perl A, Pollyea DA, Pratz K, Prebet T, Ravandi F, Shami PJ, Stone RM, Strickland SA, Wieduwilt M, Gregory KM; OCN, Hammond L, Ogba N. Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019 Jun 1;17(6):721-749. doi: 10.6004/jnccn.2019.0028. — View Citation

Thol F, Schlenk RF, Heuser M, Ganser A. How I treat refractory and early relapsed acute myeloid leukemia. Blood. 2015 Jul 16;126(3):319-27. doi: 10.1182/blood-2014-10-551911. Epub 2015 Apr 7. Review. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete remission, Incomplete blood count recovery,Partial remission(CR+CRi+PR)	Number of Participants (Responders) Achieving CR+CRi+PR After the Eighth Cycle Treatments	8 months
Secondary	Overall Response Rate (ORR)	Number of Participants (Responders) Achieving Overall Response Rate(ORR) After the Eighth Cycle Treatments	8 months
Secondary	Overall survival (OS)	time from randomization to death from any cause	3 years
Secondary	Event free survival(EFS)	The time between the beginning of the group and the occurrence of any event, including death, progression of the disease, chemotherapy regimen, conversion to chemotherapy, addition of other treatment, occurrence of fatal or intolerable side effects, etc	3 years
Secondary	Progression free survival(PFS)	Time between the beginning of randomization and the progression (in any way) of tumorigenesis or (for any reason) death	3 years