Poster Presentation Advances in Neuroblastoma Research Congress 2016

Pharmacokinetics (PK) of 13-cis Retinoic Acid in COG Phase III Neuroblastoma Studies (#321)

Hwangeui Cho 1 , Shengping Yang 2 , Poonam Sonawane 1 , Alice L Yu 3 , Julie R Park 4 , Susan Kreisman 5 , Arlene Naranjo 6 , Collin Van Ryn 6 , Julia G Villablanca 7 , Patrick Reynolds 1 , Min H Kang 1
  1. Cancer Center and Cell Biology and Biochemistry, Texas Tech University HSC, Lubbock, Texas, United States
  2. Pathology, Texas Tech University HSC, Lubbock, Texas, United States
  3. Department of Pediatrics, University of California San Diego, San Diego, California, United States
  4. Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington, United States
  5. Pediatrics, Duke University, Durham, North Carolina, United States
  6. Biostatistics, University of Florida, Gainsville, Florida, United States
  7. Pediatrics, Children's Hospital Los Angeles-University of Southern California, Los Angeles, California, United States

Background: Isotretinoin (13-cis-retinoic acid; 13-cRA), a differentiation inducer, improves outcome for high-risk neuroblastoma.  Published PK studies suggested that many patients achieve 13-cRA levels lower than 5 mM (effective against neuroblastoma in vitro).  We showed that 4-oxo-13-cRA, a metabolite of 13-cRA was equally active compared to 13-cRA against neuroblastoma in vitro.  We sought to determine the levels of 13-cRA and 4-oxo-13-cRA achieved in patients and their association with clinical outcome.  

 

Methods: Plasma samples (4 hours post-dose, day 14) from COG phase III clinical trials (A-3973, ANBL0532, ANBL0032, and ANBL0931) were obtained for PK analyses.  The relationship of PK to clinical outcome was analyzed, limited to patients treated with ch14.18 antibody.  

 

Results:  In 629 patients, 370 (60%) achieved median plasma concentrations over 5 mM for 13-cRA+4-oxo-13-cRA combined levels. Plasma levels were higher in patients taking whole capsules relative to open-capsule takers (13-cRA: 1.74 vs 1.03, 4-oxo-13-cRA: 7.22 vs 3.27mM). Both 13-cRA (r=0.29) and 4-oxo-13-cRA (r=0.46) concentrations positively correlated with age (p<0.001).  Relationship of PK to overall survival (OS) was analyzed for 524 patients that received both 13-cRA and immunotherapy. In patients ≥18 months old OS at 5 yrs was higher (73 %) for 13-cis-RA plasma levels > 75th percentile (2.5µM) vs. pts with 13-cRA < 25th percentile (0.6µM, 63%) (p=0.039). OS at 5 yrs was also higher for patients ≥18 months-old with 4-oxo-13cRA >5µM vs. <1µM: 76 vs. 66% (p=0.032) and 13-cis-RA + 4-oxo-13-cis-RA >5µM vs. <1µM: 73 vs. 61% (p=0.019).

 

Conclusion:  Combined levels of 13-cRA and the 4-oxo-13-cRA active metabolite were >5 mM in the majority of patients. Age and route of administration influence plasma levels of 13-cRA and 4-oxo-13-cRA. In patients ≥18 months old low plasma levels of 13-cis-RA + 4-oxo-13-cRA  were associated with a lower overall survival.