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
• Childrens 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 2625
MYCN amplified 6/35
Type of BMT (allogeneicautologous) 249
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 n24 patients/144 courses
• Skin grade 3 n3
• Hepatic grade 3 n1
• Neutropenia grade 3 n1
• Hypercalcemia grade 4 n1
• 200 mgm2 DLT in 6/9 patients/ 48 courses
• Skin grade 3 n2
• Hypercalcemia n3 (2 were grade 4)
• Anemia/thrombocytopenia grade 3 n1

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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 lt10 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 Childrens
Cancer Group Study
K Matthay, Chair

• Results of the 2nd Randomization for CCG-3891
  Testing effect of 13-cis-RA Therapy on
  Event-Free Survival

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