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Abstract

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Abstract

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  1. ECOG 2204: An intergroup randomized phase II study of cetuximab (Ce) or bevacizumab (B) in combination with gemcitabine (G) and in combination with capecitabine (Ca) and radiation (XRT) as adjuvant therapy (AdjTx) for patients (pts) with completely-resected pancreatic adenocarcinoma (PC). J. D. Berlin1, P Catalano2, Y Feng2, A. Lowy3, A.W. Blackstock4, P. A. Philip5, R.R. McWilliams6, J. Abbruzzese7, A.B. Benson, III8 1) Vanderbilt Ingram Cancer Center, Nashville, TN; 2) Dana Farber Cancer Institute, Boston, MA; 3) University of California San Diego, San Diego, CA; 4) Wake Forest University, Winston-Salem, NC; 5) Wayne State University, Detroit, MI; 6) Mayo Clinic, Rochester, MN 7) MD Anderson Cancer Center, Houston, TX; 8) Northwestern University, Chicago, IL

  2. Background: At the time this study was developed, Ce and B were being investigated as part of tx for advanced PC. Concern existed over safety of adding Ce or B to standard adjtx if either drug proved to be active in advanced PC. Methods: Pts with resected PC, ECOG PS 0-1 and adequate bone marrow and liver function were eligible to be randomized to either Ce (arm 1) or B (arm 2) in combination with a standard regimen of G given before and after capecitabine (625 mg/m2 bid on days of XRT only) + XRT (50.4 Gy). CE (400 mg/m2 day 1, then 250 mg/m2 weekly), or B (5 mg/kg q 2 weeks until end of XRT, then 10 mg/kg q 2 weeks), was given throughout therapy.  Primary endpoint was rate of pre-specified toxicities (tox) of concern assessed prior to start of XRT and at end of all therapy. This study had a 2-stage design with interim analysis at 25 pts per arm. A total of 126 pts were required assuming a 5% ineligibility and 85% power to detect a 35% rate of specific toxicites. Disease-free (DFS) and overall survival (OS) were secondary endpoints. Results: 137 pts were enrolled, 129 eligible for analysis, 67 on arm 1 and 62 on arm 2. Median age was 60 and  81% had pancreas head primary on both arms. PS  (0/1/2) was 40/60/0% in arm 1 and 48/48/3% for arm 2. 65.7% of pts on arm 1 and 54.8% on arm 2 completed adjtx per protocol. 9% on arm 1 and 12.9% on arm 2 recurred while on therapy and 14.9% on arm 1 and 22.6% on arm 2 stopped treatment due to tox/complications. 1 treatment-related death on arm 2 was due to colon perforation. DFS at 2 years was 16% on arm 1 and 22% on arm 2. OS at two years was 35% on arm 1 and 37% on arm 2. Prior to start of XRT, 9%  in arm 1 and 2% in arm 2 experienced prespeciified grade 3/4 tox of concern. At end of all therapy 27% on arm 1 and 23% on arm 2 had pre-specified gr 3/4 tox of concern, mostly hematologic. Conclusions: Both arms were safe and fairly well tolerated. Over 10% of pts recurred during adjtx even without planned disease assessments. There is no evidence to develop either arm further in adjtx of PC. Efforts should focus on developing new agents and defining whether or not XRT has a role in adjtx of PC. Abstract

  3. Background • At the time this study was designed, cetuximab and bevacizumab were being tested in metastatic pancreas cancer • There were no data on safety of either drug in patients with pancreas cancer post-resection for either drug • Additionally, there was no data for either drug in combination with fluoropyrimidine chemotherapy and radiation to the pancreas/pancreatic bed

  4. Objectives/Endpoints • Primary Endpoint: Toxicity of either of the two regimens • Specific list of toxicities of concern • Measured at two timepoints • Secondary Endpoints • Assess Safety Profiles • Collect tissue specimens for further analysis • Evaluate Disease-free and Overall Survival for the two regimens • Evaluate 2-year Overall Survival • Correlate changes in serum amphiregulin and/or TGF alpha to survival and DFS

  5. Eligibility • Patients with history of pancreas cancer s/p R0 or R1 resection • Surgery completed > 4 and ≤ 8 weeks prior • R2 resection ineligible • Prospective collection of margin status including retroperitoneal resection • Adequate hematologic, hepatic and renal function • Age ≥ 18 years • Ability to Understand and provide Informed Consent • No prior chemotherapy or radiation • Also no EGFR or VEGF inhibitors in the past • ECOG PS 0-2 • No cardiovascular or cerebrovascular disease • No unhealed wounds • No full dose anticoagulation

  6. Study Schema • R0 or R1 resection allowed; tissue requested • Standardized margin definitions given • Serum for TGF alpha obtained RT x 5040 Gy + Capecitabine 825 mg/m2 bid M→F Gemcitabine 1000 mg/m2 qwx 3 of 4 (1 cycles) Gemcitabine 1000 mg/m2 qwx 3 of 4 (3 cycles) R A N D O M I Z E Cetuximab 400 mg/m2 wk 1, then 250 mg/m2 weekly RT x 5040 Gy + Capecitabine 825 mg/m2 bid M→F Gemcitabine 1000 mg/m2 qw x 3 of 4 (1 cycles) Gemcitabine 1000 mg/m2 qw x 3 of 4 (3 cycles) Bevacizumab 5 mg/kg q2w Beva10 mg/kg q2w Bevacizumab and Cetuximab provided through NCI/CTEP

  7. Statistical Design • Randomized, open-label phase II design • Note that it was written into the protocol that at least half the accrual had to come from community/affiliate sites to limit bias from high volume institutions • Stratified only for R0 vs R1 resection • 2 stage design: evaluation after 25 patients per arm completed first cycle of chemotherapy (timepoint 1) • Primary Endpoint: Toxicity, at two timepoints • Evaluated after 4 weeks of gemcitabine + either bevacizumab or cetuximab • Evaluated after all therapy completed • Institutions were required to evaluate and summarize toxicity at end of each portion of treatment • End of first cycle of chemo prior to chemo/xrt • End of chemo/xrt prior to chemo alone • End of all therapy

  8. Primary Endpoint: ToxicityTimepoint 1 • Grade ¾ toxicity rate based on Table 1 <20% is acceptable • 120 patients (60 per arm) needed to randomize to have an 85% power to detect an unacceptable toxicity rate of 35% with a one-sided 9% level exact binomial test for time point (1) = end of first cycle of chemotherapy prior to start of chemo/xrt

  9. Primary Endpoint: ToxicityTimepoint 2 • Grade ¾ toxicity rate based on Table 1 <25% is acceptable • 120 patients (60 per arm) needed to randomize to have an 85% power to detect an unacceptable toxicity rate of 45% with a one-sided 9% level exact binomial test for time point (2) = end of all therapy

  10. Statistics Continued • Interim Analysis: • With 25 patients per arm, the probabilities of observing at least one toxicity with corresponding true rates of 5% and 1% are, respectively, 72% and 22% • Survival: 87% power with a maximum one-sided type I error of 8% using an exact binomial test in each arm to reject a 2-year overall survival of .37 in favor of .52 or higher. • 126 total patients needed assuming 5% ineligibility

  11. Table 1: Toxicities of Concern

  12. Results • 137 patients enrolled over 23 months, including time for interim analysis • 7 patients never started • 2 ineligible, 2 refused assigned arm, 1 had progressive disease prior to starting, 2 other • 1 patient who received therapy was deemed ineligible in each arm • Elevated bilirubin, ampullary carcinoma

  13. Chemotherapy details • 65.7% of patients on cetuximab received all cycles of therapy • 54.8% of patients on bevacizumab received all cycles of therapy • 9% of patients on cetuximab were diagnosed with progression prior to completing therapy • 12.9% of patients on bevacizumab were diagnosed with progression prior to completing therapy • 14.9% of patients on cetuximab discontinued therapy due to toxicity/complication • 22.6%of patients on bevacizumab discontinued therapy due to toxicity/complication

  14. Results • Primary Endpoint: • At end of first cycle of chemotherapy, prior to start of XRT, • 9% of patients on cetuximab had grade 3/4/5 toxicity of concern • 2% of patients on bevacizumab had grade 3/4/5 toxicity of concern • At end of all therapy • 27% of patients on cetuximab had grade 3/4/5 toxicity of concern • 23% of patients on bevacizumab had grade 3/4/5 toxicity of concern

  15. Efficacy • Disease-Free survival (DFS) • Cetuximab arm: 2 year DFS = 16% • Bevacizumab arm: 2 year DFS = 22% • Overall Survival (OS) • Cetuximab arm: 2 year OS = 35% • Bevacizumab arm: 2 year OS = 37%

  16. Toxicities of Concern Arm A = Cetuximab Arm B = Bevacizumab

  17. Arm A = Cetuximab Arm B = Bevacizumab

  18. Arm A = Cetuximab Arm B = Bevacizumab

  19. Overall Survival: A = cetuximab, B = Bevacizumab

  20. Disease Free Survival: A = cetuximab, B = bevacizumab

  21. Conclusions • Both regimens were safe and well-tolerated • Neither arm demonstrated enough clinical activity to warrant further study • Combined with the metastatic disease data, neither cetuximab nor bevacizumab appear to have a role in the treatment of patients with pancreas cancer • Analysis of correlative data is pending

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