Cooperative Clinical Trials with 13-Cis-Retinoic Acid in Neuroblastoma
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Cooperative Clinical Trials with 13-Cis-Retinoic Acid in
Neuroblastoma
Katherine K. Matthay, M.D
University of California, San Francisco
Children’s Oncology Group
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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
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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)
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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.
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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
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Common Grade 1 and 2 Toxicities
• Cheilitis
• Skin
• Diarrhea
• Hypertriglyceridemia
• Elevated Transaminase
• Hypercalcemia
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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%)
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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
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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
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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
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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
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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
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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
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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
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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
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CCG-3891 Event-Free Survival First Randomization
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CCG-3891 Overall Survival
From Time of First Randomization
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CCG-3891 Event-Free Survival Second Randomization
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CCG-3891 Overall Survival From Time of Second Randomization
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CCG-3891 Event-Free Survival From Time of 2nd Randomization
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CCG-3891 Overall Survival
From Time of 2nd Randomization
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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