1. Cooperative Clinical Trials with 13-Cis-Retinoic Acid in Neuroblastoma Katherine K. Matthay, M.D University of California, San Francisco Children’s Oncology Group

2. 13-cis-RA Clinical Studies in Neuroblastoma CCG Phase II trial in recurrent high-risk neuroblastoma employing adult daily continuous dosing (100 mg/m 2 ) Multi-institution Phase I to dose-escalate intermittent (2 weeks/mo) 13-cis-RA in patients after ABMT CCG-3891 Phase III randomized trial, high-risk neuroblastoma in first response

3. Phase I 13-cis-RA J Villablanca, Chair No Patients51 Number Courses407 Median age (years)4 (2-12) Male: Female26:25 MYCN amplified6/35 Type of BMT (allogeneic:autologous)2:49 Months post BMT at entry3 (1-10)

4. 13-cis-RA Dose Escalation 100 mg/m 2 for 14/28 days divided b.i.d. 125 mg/m 2 for 14/28 days divided b.i.d. 160 mg/m 2 for 14/28 days divided b.i.d. 200 mg/m 2 for 14/28 days divided b.i.d.

5. Dose Limiting Toxicity 160 mg/m2: n=24 patients/144 courses –Skin grade 3: n=3 –Hepatic grade 3: n=1 –Neutropenia grade 3: n=1 –Hypercalcemia grade 4: n=1 200 mgm2: DLT in 6/9 patients/ 48 courses –Skin grade 3: n=2 –Hypercalcemia: n=3 (2 were grade 4) –Anemia/thrombocytopenia grade 3: n=1

6. Common Grade 1 and 2 Toxicities Cheilitis Skin Diarrhea Hypertriglyceridemia Elevated Transaminase Hypercalcemia

7. Pharmacokinetics vs Toxicity Peak Plasma Level ≥ 10 µM –6/8 grade 3-4 toxicity (75%) Peak Plasma Level <10 µM –3/20 grade 3-4 toxicity (15%)

8. 13-cis-RA Phase I Clinical Responses 10 patients with assessable disease 4 achieved CR (3 in bone marrow) 5 developed PD 1 had SD

9. Summary of Pharmacokinetics A linear increase with increasing daily dosage in –Plasma peak and trough –AUC The mean peak plasma level at the MTD of 160 mg/m 2 was greater than 5 µM Peak plasma levels ≥ 10 µM were associated with grade 3-4 clinical toxicities

10. Phase I Study of 13-cis-RA Conclusions The MTD of intermittent 13-CRA is 160 mg/m2, divided twice daily Dose limiting toxicities were hypercalcemia, gastrointestinal, hematopoietic and skin Plasma concentrations of 5 uM, which produce sustained growth arrest of neuroblastoma in vitro, can be achieved with acceptable clinical toxicity

11. 13-cis-Retinoic Acid After Intensive Consolidation Therapy for Neuroblastoma Improves Event-Free Survival A Randomized Children’s Cancer Group Study Results of the 2nd Randomization for CCG-3891 Testing effect of 13-cis-RA Therapy on Event-Free Survival K Matthay, Chair

12. CCG-3891 Specific Aims Compare by prospective randomization, the efficacy and toxicity of consolidation chemotherapy vs intensive chemoradiotherapy with ABMT Determine by prospective randomization the effects of 13-cis-retinoic acid on minimal residual disease and relapse-free survival

13. CCG-3891 Induction Chemotherapy Marrow harvest and purging Surgery Local Radiation Consolidation Chemotherapy Myeloablative Chemo/TBI ABMT 13-cis-RA No 13-cis-RA Randomize 8 Weeks Randomize 34 Weeks Dx

14. CCG-3891 Patient Characteristics 539 Patients Study open from Jan 1991 to Apr 1996 Average age at diagnosis = 2.5 years (range 3 months to 17 years) 85 % Stage IV 40 % with MYCN genomic amplification

15. Toxicities in 173 Patients Treated with 13-cis-RA 15% First 3 Months9% Second 3 Months

16. CCG-3891 Event-Free Survival First Randomization

17. CCG-3891 Overall Survival From Time of First Randomization

18. CCG-3891 Event-Free Survival Second Randomization

19. CCG-3891 Overall Survival From Time of Second Randomization

20. CCG-3891 Event-Free Survival From Time of 2 nd Randomization

21. CCG-3891 Overall Survival From Time of 2 nd Randomization

22. CCG-3891 Conclusions Both myeloablative therapy and post- myeloablative therapy with high-dose, pulse 13-cis-retinoic acid improved event-free survival for high-risk neuroblastoma There was an increase in overall survival for both ABMT and 13-cis-RA, which is highest for patients randomized to receive myeloablative therapy followed by 13-cis-RA