Lymphodepletion and Anti-PD-1 Blockade to Reduce Relapse in AML Patient Not Eligible for Transplant

Acute Myeloid Leukemia Clinical Trial

Official title:

Phase II Trial of Lymphodepletion and Anti-PD-1 Blockade to Reduce Relapse in High Risk AML Patients Who Are Not Eligible for Allogeneic Stem Cell Transplantation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02771197
• Other study ID #: NSH 1150
• Status: Completed
• Phase: Phase 2
• Start date: September 28, 2016
• Est. completion date: July 31, 2023

Study information

• Verified date: September 2023
• Source: Northside Hospital, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

AML is the most common acute leukemia in adults. Most patients can undergo allogeneic stem cell transplantation as a possible cure; however, many patients are not candidates for allogeneic transplant due to age, overall health, psychosocial factors, and/or lack of available donors. Therefore, these patients are unable to receive the therapeutic benefits of the "graft-versus-leukemia" effect of donor immune cells. The aim of this study is to hopefully break immune tolerance to AML cells to provide better outcomes in patients with non-favorable risk AML.

Description:

Non-favorable risk AML patients will undergo a preparative regimen of lymphodepletion of Flu/Mel followed by autologous transplantation. Anti-PD-1 therapy of pembrolizumab will begin on Day +1 following stem cell transplantation and will be administered every 3 weeks for a total of 8 doses. According to the literature, the risk of 2-year relapse is estimated to be 60-80% in patients with non-favorable risk AML in CR-1. With this protocol, investigators hypothesize that following lymphodepleting chemotherapy and pembrolizumab, the 2-year relapse risk will decrease to less than or equal to 35%. The one-sided Wald test at 5% significance level will be used to test the hypothesis. The size of 20 patients yields the power of 90.5% assuming that the actual 2-year leukemia-free survival is 60%.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: July 31, 2023
• Est. primary completion date: August 3, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 78 Years

Eligibility

Inclusion Criteria:

• Non-favorable risk AML
• In CR-1 or subsequent CR
• Completed at least one cycle of consolidation chemotherapy
• Collection of at least 2x106/kg CD34+ cells
• KPS of 70% or greater

Exclusion Criteria:

• Received investigational agent within 4 weeks of first dose
• Prior chemotherapy, radiation therapy within 2 weeks of first dose
• Hypersensitivity to pembrolizumab or any of its excipients
• Received prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

Related Conditions & MeSH terms

• Acute Myeloid Leukemia

Intervention

Drug:
• Fludarabine

• Melphalan

• Pembrolizumab

Locations

Country	Name	City	State
United States	Blood and Marrow Transplant Group of Georgia	Atlanta	Georgia
United States	Northside Hospital	Atlanta	Georgia

Sponsors (2)

Lead Sponsor	Collaborator
Northside Hospital, Inc.	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

United States, 

References & Publications (23)

Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009 Aug 20;114(8):1537-44. doi: 10.1182/b — View Citation

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Chen X, Liu S, Wang L, Zhang W, Ji Y, Ma X. Clinical significance of B7-H1 (PD-L1) expression in human acute leukemia. Cancer Biol Ther. 2008 May;7(5):622-7. doi: 10.4161/cbt.7.5.5689. — View Citation

Cornelissen JJ, van Putten WL, Verdonck LF, Theobald M, Jacky E, Daenen SM, van Marwijk Kooy M, Wijermans P, Schouten H, Huijgens PC, van der Lelie H, Fey M, Ferrant A, Maertens J, Gratwohl A, Lowenberg B. Results of a HOVON/SAKK donor versus no-donor ana — View Citation

Dong H, Chen L. B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med (Berl). 2003 May;81(5):281-7. doi: 10.1007/s00109-003-0430-2. Epub 2003 Apr 30. — View Citation

Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA. Cancer regression and — View Citation

Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA. A — View Citation

Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a — View Citation

Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, Zhou J, Li BZ, Shi YH, Xiao YS, Xu Y, Fan J. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2 — View Citation

Ghebeh H, Barhoush E, Tulbah A, Elkum N, Al-Tweigeri T, Dermime S. FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy. BMC Cancer. 2008 Feb 23;8:57. doi: 10.1186/1 — View Citation

Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc — View Citation

Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004 Aug 1;10(15):5094-100. — View Citation

Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, Wadleigh M, DeAngelo DJ, Stone RM, Sakamaki H, Appelbaum FR, Dohner H, Antin JH, Soiffer RJ, Cutler C. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete re — View Citation

Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, Saudemont A, Quesnel B. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-gamma and TLR ligands via a MyD88-, TRAF6-, an — View Citation

Mumprecht S, Schurch C, Schwaller J, Solenthaler M, Ochsenbein AF. Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood. 2009 Aug 20;114(8):1528-36. doi: 10.1182/blood-2008-0 — View Citation

Shenghui Z, Yixiang H, Jianbo W, Kang Y, Laixi B, Yan Z, Xi X. Elevated frequencies of CD4(+) CD25(+) CD127lo regulatory T cells is associated to poor prognosis in patients with acute myeloid leukemia. Int J Cancer. 2011 Sep 15;129(6):1373-81. doi: 10.100 — View Citation

Shvets A, Chakrabarti R, Gonzalez-Quintial R, Baccala R, Theofilopoulos AN, Prud'homme GJ. Impaired negative regulation of homeostatically proliferating T cells. Blood. 2009 Jan 15;113(3):622-5. doi: 10.1182/blood-2008-03-139964. Epub 2008 Nov 20. — View Citation

Szczepanski MJ, Szajnik M, Czystowska M, Mandapathil M, Strauss L, Welsh A, Foon KA, Whiteside TL, Boyiadzis M. Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia. Clin Cancer Res. 2009 May 15;15(10):3325 — View Citation

Wang X, Zheng J, Liu J, Yao J, He Y, Li X, Yu J, Yang J, Liu Z, Huang S. Increased population of CD4(+)CD25(high), regulatory T cells with their higher apoptotic and proliferating status in peripheral blood of acute myeloid leukemia patients. Eur J Haemat — View Citation

Wrzesinski C, Paulos CM, Gattinoni L, Palmer DC, Kaiser A, Yu Z, Rosenberg SA, Restifo NP. Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest. 2007 Feb;117(2):492-501. doi: 10.1172/JC — View Citation

Wrzesinski C, Paulos CM, Kaiser A, Muranski P, Palmer DC, Gattinoni L, Yu Z, Rosenberg SA, Restifo NP. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J Immunother. 2010 Jan;33(1):1-7 — View Citation

Zhou Q, Bucher C, Munger ME, Highfill SL, Tolar J, Munn DH, Levine BL, Riddle M, June CH, Vallera DA, Weigel BJ, Blazar BR. Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in mur — View Citation

Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, Sharpe AH, Vallera DA, Azuma M, Levine BL, June CH, Murphy WJ, Munn DH, Blazar BR. Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Patients With 2-year Relapse Risk	Hypothesis is that following lymphodepleting chemotherapy and pembrolizumab, the 2-year relapse risk will decrease to =35%	2 years
Secondary	Assess Safety of Pembrolizumab by Recording the Number of Participants With Treatment-related Adverse Events	Assess safety of pembrolizumab in patients with AML following lymphodepleting chemotherapy	6 months