RTOG 0324 A Phase II Study of Cetuximab C225 in Combination with Chemoradiation in Patients with Sta

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RTOG 0324A Phase II Study of Cetuximab (C225) in
Combination with Chemoradiation in Patients with
Stage IIIA/B Non-small Cell Lung Cancer (NSCLC)

• George Blumenschein, MD, PI

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STUDY CHAIRS

• George Blumenschein, Jr., MD
• Walter J. Curran, MD
• Ritsuko Komaki, MD
• Francisco Robert, MD
• MD Anderson Cancer Center, Thomas Jefferson
  University Hospital, University of Alabama at
  Birmingham

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EGFR Signal Transduction
K
K
PI3-K
pY
pY
MEK
pY
STAT
PTEN
AKT
MAPK
Gene transcription Cell-cycle progression
Metastasis
Proliferation- Maturation
Survival- Apoptosis
Angiogenesis
Courtesy of José Baselga
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Cetuximab (ErbituxTM) Prolongs Survivalin
Patients with Locoregionally Advanced SCCHN A
Randomized Phase III Trial
ErbituxTM Maintenance Doses
ErbituxTM Loading Dose
Week 1 2 3
4 5 6 7 8
N 424
RTX (qd or bid)
Experiment
Registration, Stratify 1) T1-3 vs. T4 2) N0
vs. N 3) KPS (60-80 vs. 90-100) 4) Radiation
Fractionation
Control
RTX Alone (qd or bid)
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LR Control Survival
Bonnen J, ASCO 2004
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Patient Population

• Histologically or cytologically documented NSCLC.
• Patients must be MO
• Patients with T1-T2 with N2 or T3N1 are eligible
  if inoperable.
• Pts with T4 with any N or any T with N2 or N3
  disease are eligible if unresectable.
• ECOG PS ?1

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Treatment Schema RTOG 0324
Consolidation therapy Weeks 9-11 Single agent
C225, 250 mg/m², weekly for 3 weeks followed
by Weeks 12-17 C225, 250 mg/m² weekly, x 6
weeks, given before chemotherapy Paclitaxel,
200 mg/m², and Carboplatin, AUC6, every 3 weeks
for two cycles
Concurrent Chemoradiation and Cetuximab
therapy   Weeks 2-8 C225, 250 mg/m² weekly for 7
weeks, given before chemotherapy
    Paclitaxel, 45mg/m², and Carboplatin,
AUC2, weekly for 7 weeks     RT 63
Gy/7weeks/35 daily fractions (1.8 Gy x 25
fractions, then 2.0 Gy x 9 fractions for a total
dose of 63.0 Gy in 35 fractions over 7 weeks
Initial Loading Dose C225 400 mg/m2, IV
loading dose, Day 1
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Design

• Phase II multi-center single arm study
• 1 cycle 3 weeks
• Weekly C225 starting day 1. A loading dose of
  400 mg/m2 C225 followed by weekly doses of 250
  mg/m2
• Carboplatin AUC 2 and Paclitaxel 45
  mg/m2 starting day 8 and continue weekly
  during RT

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Design

• RT 63 GY/7 wks/35 daily Fx beginning day 8
• 3-week break
• Paclitaxel, 200 mg/m², and Carboplatin AUC6,
  every 3 weeks for two cycles
• C225 weekly throughout treatment
• Interim analysis for early stopping

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Endpoints

• Primary Endpoint
• Feasibility, comprising compliance (completion
  of the treatment regimen with no more than minor
  variations) and safety (estimated toxicity rates
  within acceptable limits).
• Secondary endpoints
• Response rate
• One-year survival rate
• Overall survival
• Time to progression

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Endpoints

• Sample size is 84 patients assuming 5 of the
  patients are ineligible, or inevaluable
• Response will be determined two months after
  completion of adjuvant chemotherapy
• Response determined using the Response
  Evaluation Criteria in Solid Tumors (RECIST)
  criteria.

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Accrual

• Target Accrual 84
• Total accrual (6/3/05) 93

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Study Accrual by Full Member Institutions (Top 5)

• UT MDACC 9
• Med College of WS 7
• Michigan CRC CCOP 7
• Thomas Jefferson U Hosp 7
• Mayo Clinic 4

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Adverse Events Definitely Related to C225(n44)

• Grade
• 1 2 3 4 5
• GI 6 21 6 0 0
• Dysphagia 6 11 1 0 0
• Pulmonary
• Upper Respiratory 7 7 2 0 2
• Worst Non-hematologic 2 13 18 1 2
• (5) (30) (41) (2) (5)

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Adverse Events Not Related to C225(n44)

• Grade
• 1 2 3 4
• Pulmonary
• Upper Respiratory 6 6 3 1
• Worst Non-hematologic 9 10 8
  1 (20) (23) (18) (2)

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Summary

• RTOG 0324 was opened in March.
• The targeted sample size is 84, and the projected
  accrual rate of 5 cases/mo has been exceeded for
  the last 6 mos it has averaged 7.3 pts/mo.
• Grade 5 adverse events (CNs 14 and 31) were
  reviewed jointly by the study chairs, a Group
  Vice Chair (Dr. Abrams), the chair of the RTOG
  Medical Oncology Comm (Dr. Langer) and Deputy
  Group Chair (Dr. Machtay).
• There was no evidence that the protocol needed
  amendment.
• Through 6-3-05, 93 pts were enrolled on the study

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Proposed RTOG 0523

• Addition of cetuximab to ChT/RT will improve
  survival of pts with inoperable stage NSCLC
  compared to pts treated by the same ChT/RT alone.
• EGFR expression within the tumor will correlate
  response overall survival.
• There will be clinically relevant differences in
  QOL between the two arms.
• There will be clinically relevant diff. in
  Quality-Adjusted Life Years (QALY) between the
  two arms.

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• STRATIFY
• STAGE
• IIIA
• IIIB
• PRIMARY
• Lower
• Non-lower
• ZUBROD
• 0
• 1
• IMAGING
• CT
• PET
• Includes
• CT/PET PET
• only

ARM 1 CONCURRENT CHEMORADIATION Pactilataxel
Carboplatin Weekly for 7 wks Plus RT 63Gy/7
wks/35 daily Fx using 3DCRT
SCHEMA
R A N D O M I Z E
Consolidation Therapy Weeks 9-15 Paclitaxel
Carbo every 3 Wks for 6 wks.
Consolidation Therapy C225 wkly for 3
wks Followed by C225 wkly for 6 wks given 30-60
min before chemo Plus Paclitaxel Carbo every
3 Wks for 6 wks.
Arm 2 CONCURRENT C225 CHEMO RT In 2nd wk, C225
wkly for 7 wks, 30-60 min before
chemo Plus Paclitaxel Carbo wkly for 7 wks Plus
RT 63 Gy/7 wks/35 daily Fx
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