Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non–Small Cell Lung Cancer

Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non–Small Cell Lung Cancer

1. 
   Rosalyn A. Juergens1,


2. 
   John Wrangle1,


3. 
   Frank P. Vendetti3,


4. 
   Sara C. Murphy1,


5. 
   Ming Zhao1,


6. 
   Barbara Coleman1,


7. 
   Rosa Sebree1,


8. 
   Kristen Rodgers2,


9. 
   Craig M. Hooker1,


10. 
    Noreli Franco1,


11. 
    Beverly Lee1,


12. 
    Salina Tsai4,


13. 
    Igor Espinoza Delgado5,


14. 
    Michelle A. Rudek1,


15. 
    Steven A. Belinsky6,


16. 
    James G. Herman1,


17. 
    Stephen B. Baylin1,


18. 
    Malcolm V. Brock2 and


19. 
    Charles M. Rudin1
    

+ Author Affiliations

1. 
   
   
   
   Authors’ Affiliations:¹Department of Oncology, ²Department of Surgery, ³Anti-Cancer Drug Development Graduate Training Program, and ⁴Department of Radiology, Johns Hopkins University, Baltimore, Maryland; ⁵Investigational Drug Branch, National Cancer Institute, Bethesda, Maryland; and ⁶Lovelace Respiratory Research Institute, Albuquerque, New Mexico
   
   

1. 
   Corresponding Authors:
   Charles M. Rudin, MD, PhD, Johns Hopkins University, Cancer Research Building 2, Room 544, 1550 Orleans Street, Baltimore, MD 21231. E-mail: rudin@jhmi.edu; or Malcolm V. Brock, MD, Johns Hopkins University, Cancer Research Building 1, Room 542, 1650 Orleans Street, Baltimore, MD 21231. E-mail: mbrock1@jhmi.edu
   

Abstract

Epigenetic alterations are strongly associated with the development of cancer. We conducted a phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non–small cell lung cancer. This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy. Median survival in the entire cohort was 6.4 months (95% CI 3.8–9.2), comparing favorably with existing therapeutic options. Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035). Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy.

Significance: This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit. Cancer Discovery; 1(7); OF1–OF10. ©2011 AACR.

• 
  Received August 26, 2011.


• 
  Revision received September 26, 2011.


• 
  Accepted October 3, 2011.

• ©2011 American Association for Cancer Research.

Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non–Small Cell Lung Cancer

Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma — Ann Oncol

Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma
J. T. Sandlund1,2,*, C-H. Pui1,2, H. Mahmoud1,2, Y. Zhou1,3, E. Lowe1, S. Kaste2,4, L. E. Kun1,4, M. J. Krasin1,4, M. Onciu1,5, F. G. Behm1,5, R. C. Ribeiro1,2, B. I. Razzouk1,2, S. C. Howard1,2, M. L. Metzger1,2, G. A. Hale1,2, R. Rencher1, K. Graham1 and M. M. Hudson1,2

Ann Oncol (2011) 22 (2): 468-471.
doi: 10.1093/annonc/mdq348
First published online: July 12, 2010

+ Author Affiliations
1Department of Oncology, St Jude Children’s Research Hospital
2Department of Pediatrics, University of Tennessee, Memphis, College of Medicine
3Department of Biostatistics, St. Jude Children’s Research Hospital
4Department of Radiological Sciences, St Jude Children’s Research Hospital
5Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN, USA

*Correspondence to: Dr John T. Sandlund, Department of Oncology, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. Tel: +1 901 595-2427; Fax +1 901 521-9005; E-mail: John.Sandlund@stjude.org.

Received May 5, 2010.
Accepted May 7, 2010.

Abstract
Background: Children with recurrent or refractory malignant lymphoma generally have a poor prognosis. There is a need for new active drug combinations for this high-risk group of patients.

Patients and methods: This study evaluated the activity and toxicity of the methotrexate, ifosfamide, etoposide and dexamethasone (MIED) regimen for childhood refractory/recurrent non-Hodgkin’s lymphoma (NHL) or Hodgkin’s lymphoma (HL). From 1991 through 2006, 62 children with refractory/recurrent NHL (n = 24) or HL (n = 38) received one to six cycles of MIED. Based on MIED response, intensification with hematopoietic stem cell transplantation (HSCT) was considered.

Results: There were 10 complete (CR) and 5 partial responses (PR) among the 24 children with NHL [combined response rate, 63%; 95% confidence interval (CI) 38% to 73%]. There were 13 CR and 18 PR among the 37 assessable children with HL (combined response rate, 84%; 95% CI, 68% to 94%). Although 59% courses were associated with grade IV neutropenia, treatment was well tolerated and without toxic deaths.
Conclusions: MIED is an effective regimen for refractory/recurrent childhood malignant lymphoma, permitting a bridge to intensification therapy with HSCT.

Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma — Ann Oncol