Cooperative Clinical Trials with 13-Cis-Retinoic Acid in

Neuroblastoma

Katherine K. Matthay, M.D

University of California, San Francisco

Children’s Oncology Group

13-cis-RAClinical Studies in Neuroblastoma

• CCG Phase II trial in recurrent high-risk neuroblastoma employing adult daily continuous dosing (100 mg/m2)

• 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

Phase I 13-cis-RAJ Villablanca, Chair

No Patients 51

Number Courses 407

Median age (years) 4 (2-12)

Male: Female 26:25

MYCN amplified 6/35

Type of BMT (allogeneic:autologous) 2:49

Months post BMT at entry 3 (1-10)

13-cis-RA Dose Escalation

• 100 mg/m2 for 14/28 days divided b.i.d.

• 125 mg/m2 for 14/28 days divided b.i.d.

• 160 mg/m2 for 14/28 days divided b.i.d.

• 200 mg/m2 for 14/28 days divided b.i.d.

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

Common Grade 1 and 2 Toxicities

• Cheilitis

• Skin

• Diarrhea

• Hypertriglyceridemia

• Elevated Transaminase

• Hypercalcemia

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%)

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

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/m2 was greater than 5 µM

• Peak plasma levels ≥ 10 µM were associated with grade 3-4 clinical toxicities

Phase I Study of 13-cis-RAConclusions

• 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

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

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

CCG-3891

Induction Chemotherapy

Marrow harvestand purging

Surgery

Local Radiation

ConsolidationChemotherapy

MyeloablativeChemo/TBI

ABMT

13-cis-RA

13-cis-RA

No 13-cis-RA

No 13-cis-RA

Randomize8 Weeks

Randomize34 Weeks

Dx

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

Toxicities in 173 Patients Treated with 13-cis-RA

Type of Toxicity % Grade 3 % Grade 4

Hematologic 9 4 Hepatic 5 0.5 Renal 5 3 GI 3 0 Skin 2 2 Hypercalcemia 1 0 Infection 3 0

15% First 3 Months 9% Second 3 Months

CCG-3891 Event-Free Survival First Randomization

CCG-3891 Overall Survival

From Time of First Randomization

CCG-3891 Event-Free Survival Second Randomization

CCG-3891 Overall Survival From Time of Second Randomization

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

CCG-3891 Overall Survival

From Time of 2nd Randomization

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