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Gem ox panitumumab
1.
2. Biliary tract cancer epidemiology
GB incidence :1.8/100000 GLOBOCAN
GB Ca Delhi 9.2/100000
Cholangiocarcinoma incidence
Prognosis of GC is poor, with <10% survival at 5 years
3. IRCH Protocol in GB malignancy
ICMR Consensus document for management of gallbladder cancer 2014
4. Treatment of Biliary tract malignancy
Lancet Oncol. 2014 Jul;15(8):819-28J Clin Oncol. 2010 Oct 20;28(30):4581-6.
5. Genomic landscape of Biliary tract cancer
Gene and Reference Gallbladder
Carcinoma (%)
Cholangiocarcinoma (%) Detection Method
EHCC IHCC
CTNNB1/β-catenin
Yanagisawa et al
5-9 SEQ
KRAS
Hanada et al 19-38 10-15 45-54 PCR-SSCP
BRAF
Saetta et al 33 0 22 SEQ
EGFR
Leone et al 9-12 6-18 10-20 SEQ
PIK3CA
Riener et al 4 0 9 SEQ
ERBB2/HER2
Nakazawa et al 16 5 0 IHC and FISH
JCO July 20, 2010 vol. 28 no. 21 3531-3540
15. Inclusion criteria
Metastatic or unresectable KRAS WT biliary tract adenocarcinoma(bile
ducts, hepatic duct, cystic duct, common bile duct, ampulla of Vater or
gallbladder adenocarcinoma)
>18 year
No history of chemotherapy or anti-EGFR therapy
ECOG performance status of 0 or 1
Adequate hepatic, renal and hematologic function
16. Exclusion criteria
Patients with concurrent malignancies
Patients with known brain metastasis
Pre-existing grade 2 or higher peripheral neuropathy
17. Study methodology
• CT scans and CA19-9 levels q8wk
• Toxicity :CTCAE version 4.0.
• Treatment was discontinued
disease progression
ECOG PS 3
participant withdrawal.
• Panitumumab
symptomatic skin
nail-related toxicity
any clinically related grade 3 toxicity.
• Gemcitabine and oxaliplatin
ANC <1000 mcl
platelet count <75 000mcl
other grade 3 non-haematologic
toxicities.
D1
• panitumumab at 6mg/kg D1
• Gemcitabine 1000mg/m2
• oxaliplatin at 85mg/m2
D15
• Gemcitabine 1000mg/m2
• oxaliplatin at 85mg/m2
19. Statistical analysis
• Intention-to-treat (ITT) principles
• The primary endpoint :radiographic response rate by RECIST
• secondary endpoints :PFS, OS and toxicity.
• sample size of 30
• power of 80% with a type 1 error set at 0.10.
• PFS:The time from study enrolment to date of cancer progression or
death, whichever occurred first
• OS : the time of enrolment in the study until the date of death from
any cause. The survival analysis calculated by Kaplan–Meier.
• SAS software (v9.3; SAS Institute, Cary,NC, USA)
23. Treatment related adverse events
No statistical correlation between the presence of rash/hypomagnesemia and response
24.
25. Discussion
• This open-label phase II trial was designed to evaluate the efficacy of
panitumumab to GemOx among selected patients with a KRAS WT
allele.
• Response rate of 50%, in evaluable patients and 45% in patients who
received at least one dose of study drug.
• The median PFS was 10.6 months and median OS 20.3 months.
• The combination of gemcitabine, oxaliplatin and panitumumab was
well tolerated with manageable grade 3 and 4 toxicities
26. Critical appraisal
Sample size Adequate :30 patients was required to achieve with
power of 80% to detect an absolute difference in response rate of
20% (50% vs 30%) using a one-sided binomial test with a type 1
error set at 0.102.
Statistics well defined
27. Combinations regimen chosen: A large effect demonstrated
Preclinical synergy
Pre specified improvement in response rate compared to
historical data :Done
Journal of Clinical Oncology, Vol 27, No 19 (July 1), 2009: pp 3073-3076
28. Critical appraisal
Sample size adequate
Statistics well defined yes
Novel single agent tested yes
Pre specified improvement in response
rate compared to historical data
yes
Ongoing phase 3 trial on basis of this trial yes
End point tailored to drug’s mechanism of
action
ORR
Appropriate criteria for assessment yes
Hinweis der Redaktion
GBC carries a worse prognosis than CC; however, GBC tends to exhibit a greater response rate (RR) to chemotherapy.4 After surgery, GBC is more likely recur distantly than EHCC
Lancet Oncol. 2014 May;15(6):569-79. doi: 10.1016/S1470-2045(14)70118-4. Epub 2014 Apr 14.
Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study
Treatment could be delayed for upto 3 weeks to allow for recovery from toxicity, if the patient did not meet re-treatment criteria after a 3-week delay, then the patient will be removed from the study
Waterfall plot of percentage of tumor change from baseline in 28 evaluable patients
GEMOX : favourable side-effect profile, convenient schedule (once every 2 weeks) and similar efficacy when compared to gemcitabine and cisplatin
Priority for this design will be given to studies of novel single agents, prposed to combinations, since the contribution of the experimentalagent will be easier to determine, combination regimens that demonstrate an effect size large enough to assure the editors and readership that the results are not likely to be due to the other active drugs in the regimen, he novelagent has preclinical evidence of synergy with other drugs in thecombination.
5% phase 2 trial not defined and these they recommend further study