Oral Presentation Advances in Neuroblastoma Research Congress 2016

A Phase I Study of Lenalidomide in Combination with ch14.18 and isotretinoin in Patients with Refractory/Recurrent Neuroblastoma (RR-NB): New Approaches to Neuroblastoma Therapy (NANT) Consortium Trial (#126)

Araz Marachelian 1 , Julia G Villablanca 1 , Susan Groshen 2 , Denice Wei 2 , Scarlett Czarnecki 1 , Michael A Sheard 1 , Jianping Sun 1 , Kelly A Goldmith 3 , Yael Mosse 4 , Meaghan A Granger 5 , Nita L Seibel , Jeffrey Moscow 6 , Howard Streicher , Katherine K Matthay 7 , Robert C Seeger 1
  1. Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Hospital Los Angeles- University of Southern California, Los Angeles, CA, USA
  2. Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
  3. Division of Hematology/Oncology, Aflac Children's Cancer Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
  4. Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  5. Department of Pediatrics, Cook Children's Hospital, Fort Worth, Texas, USA
  6. Cancer Therapy Evaluation Program, Clinical Investigations Branch, National Cancer Institute, Bethesda, Maryland, USA
  7. Division of Pediatric Hematology/Oncology, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, California, USA

Background: Ch14.18(dinutuximab) increases event free and overall survival in patients with high-risk neuroblastoma given with GM-CSF/IL-2. However, this therapy has significant toxicities and 40% of patients still relapse. Lenalidomide has shown immunomodulatory effects in pediatric solid-tumor patients and is well tolerated. Combining lenalidomide with ch14.18 was supported by preclinical data demonstrating immunomodulatory/anti-tumor effects in neuroblastoma. We are conducting a phase 1 trial to determine the tolerability of lenalidomide in combination with ch14.18 and istotretinoin in patients with RR-NB.

 

Methods: Lenalidomide dose escalation is following a 3+3 design(25, 50, 75 and 100mg /m2/day. The administration schedule is lenalidomide days 1-21, ch14.18(17.5mg/m2/day) days 8-11 and isotretinoin(160mg/m2/day) days 15-28(DL2-5).

 

Results: Twenty-one patients have been enrolled, median age 8.3 years (range: 3.7-20.8), of whom 17 were evaluable for dose escalation. The median number of courses was 2 (range 1–12). Dose limiting toxicity (DLT) of grade 3 diarrhea occurred in 2 patients at DL1, one of whom also experienced neutrophil count recovery delay. Since diarrhea was transient, the protocol was amended to allow this toxicity. Six additional evaluable patients were enrolled on DL1 with no DLT’s (or diarrhea). No grade 3/4 capillary leak or hypotension were reported and one patient had grade 3 fever. Grade 3/4 hematological toxicities observed did not delay subsequent course start except in one patient.. Immunomodulation was seen with increases in frequency of effector NK cells and increased antibody dependent cytotoxicity (ADCC) in patients pre/post therapy on DL1. Pharmacokinetics, ADCC, flow cytometry of NK cells, T cells and monocytes and cytokine analyses will be discussed for all dose levels.

 

Conclusion: Lenalidomide doses up to 75mg/m2/day for 21 days is tolerable in combination with ch14.18 and isotretinoin with acceptable clinical toxicities, and demonstrated immunomodulatory effects. DL5 evaluation is ongoing to determine the optimal dosage of lenalidomide in this regimen.