Irinotecan CPT11: Can we Predict Toxicity

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Irinotecan (CPT-11) Can we Predict Toxicity ?

• Kerry Williams, M.D
• Grand Rounds
• 01/12/2007

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Case Presentation

• R.L - 78 y/o AAM male
• Metastatic rectal cancer
• Neoadjuvant 5-FU and radiation
• Resection
• Adjuvant FOLFOX
• Progressive disease
• Cetuximab added to FOLFOX
• Progressive disease
• ? Next step ..

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Introduction1

• Colorectal cancer 3rd most common cancer in US.
• Estimated in 2006 alone 148,000 new cases of
  CRC will be diagnosed.
• 55,000 deaths.

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Treatment options

• Multiple agents approved for treatment of
  metastatic CRC
• Fluorouracil
• Leucovorin
• Bevacizumab
• Irinotecan

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Irinotecan

• FDA indications
• Recurrent CRC after treatment with fluorouracil
• Component of combination 1st line chemotherapy
  for patients with metastatic CRC.

Camptosar prescription insert
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Irinotecan

• Semisynthetic analogue of cytotoxic alkaloid
  camptothecin (CPT)
• Obtained from oriental tree, Camptotheca
  acuminata

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2. Iyer L, et al. J Clin Invest. 1998847-854.
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3. Hahn K, et al. Am J Health-Syst Pharm.
200663(22)2211-2217
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Pharmacokinetics

• Plasma peak concentrations reached by end of IV
  infusion
• SN-38 0.5 to 2 hours after infusion period.
• Peak plasma concentrations increase in
  dose-dependant manner
• No impact on gender on PK
• ?? Cross blood brain barrier

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Excretion

• Complete disposition in human not fully
  elucidated
• SN-38 undergoes conjugation (by UDP glucuronyl
  transferase) ? glucuronide metabolite and
  excreted in bile.
• Urine low (11-20
• t1/2 5.8 hrs

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Toxicities

• Hematological
• Neutropenia Grade 4 12 E
• Febrile neutropenia 2-6 E
• Thrombocytopenia Grade 4 2 E
• Hepatic
• Increased bilirubin Grade ¾ 7
• Elevated LFTs Grade ¾ 13
• Gastrointestinal
• Diarrhea Early 51
• Late 88

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DLTs

• Diarrhea
• Early cholinergic syndrome occurs during and up
  to 24 hrs after infusion, responds to atropine
• Late secretory process. Median onset time 11
  days. Loperamide for treatment.
• Neutropenia
• Dose-related, brief, noncumulative
• Day 15-21
• Recovery Day 28-35.
• Higher frequency
• Prior pelvic or abdominal irradiation
• Elevated serum bilirubin
• Receive drug over lt90 minutes

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Can we predict toxicity ?

• Variation in UGT1A1 linked with elevated and
  prolonged levels of SN-38 in plasma4-6
• Leading to myelosuppressive effects

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So why does it matter ?
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Clinical implications

• Single agent Phase III trial (n291)
• Enrolled between August 1998 and January 2001.
• 95 patients ? Weekly (125mg/m2) vs
• 196 patients ? Q 3weekly (300 350mg/m2)
• median follow-up was 15.8 months

7. Fuchs CS et al. JCO 200321807-14.
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Results
7. Fuchs CS et al. JCO 200321807-14.
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Fuchs CS et al. JCO 200321807-14
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Fuchs CS et al. JCO 200321807-14
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• "Pharmacogenomics holds great promise to shed
  scientific light on the often risky and costly
  process of drug development, and to provide
  greater confidence about the risks and benefits
  of drugs in specific populations," said FDA
  Commissioner Mark McClellan.

November 2003 Commissioner, Food and Drug
Administration
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So what do we know about UGT ?
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UGT Genes

• Phase II enzymes
• Superfamily of microsomal enzymes
• Membrane bound
• Localized in endoplasmic reticulum of liver and
  extrahepatic tissues.
• Glucuronidation of endogeous and exogenous
  compounds facilitate elimination via biliary and
  urinary tracts.
• Covalent addition of glucuronic acid to
  lipophilic substrates ? more polar and easily
  eliminated glucuronide conjugate.

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UGT Genes

• Classified into 2 families
• Amino acid sequence
• 17 sequences in human mRNA for different UGTs.
• Expression occurs in tissue specific manner, with
  many of proteins expressed in liver.
• Some enzymes exclusively expressed in specific
  extrahepatic tissues, such as GI tract, brain and
  kidneys.
• Genetic variations identified, and can be
  anticipated.

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UGT 1A1

• Over 30 genetics variants
• Many affect functioning and prevalence of enzyme
• Primary result of UGT1A1 activity ?
  glucuronidation of various exogenous drugs and
  endogenous substrates (bilirubin, estrogen).
• Polymorphisms hyperbilirubinemic syndromes
  (Gilbert and Crigler-Najjar syndromes)
• Decreased function of UGT1A1

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UGT1A1

• TATA promotor region
• Variable repeats of thymine-adenine (TA)
• WILD TYPE promotor (UGT1A11) 6 TA repeats
• 3 variant alleles with 5, 7 and 8 TA repeats ?
• (TA)5, (TA)7, (TA)8 respectively.
• (TA)7 polymorphism UGT1A128
• Homozygous genotype
• 10 of North Americans
• 2 alleles have 7 TA repeats ? 7/7
• (TA)5 (TA)8 less common, African origin

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UGT1A128 and Toxicity

• Phase 1 trial by Gupta et al (1994)8
• Inverse relationship between SN-38
  glucuronidation and frequency of diarrhea
• Innocenti et al, (JCO 2004)5
• 66 patients with advanced malignancies
• Irinotecan 350mg/m2 q 3weeks
• Primary objective association btwn UGT1A1
  genetic variations and toxicities.

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Innocenti et al.

• Frequency grade 4 neutropenia
• 9.5
• 6 patients 7/7 (homozygous) ? 3 developed grade
  4 neutropenia. 9.3 fold higher risk
• 2 / 24 patients with 6/7 genotype
• 0 / 28 patients with 6/6 genotype
• Grade 3 diarrhea 5
• No grade 4

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Innocenti et al5

• SN-38 AUC directly correlated with number of TA
  repeats
• (p0.03)
• In addition to UGT1A128, found a promotor SNP at
  base -3156 (in linkage dysequilibrium with (TA)n
  polymorphism).
• Better predictor of UGT1A1 status than TA
  promotor repeat.
• One patient in study who was homozygous for -3156
  and (TA)7 died of neutropenic-related sepsis.

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Bilirubin Irinotecan Toxicity

• Bilirubin is endogenous substrate for UGT1A1.
• ?? Bilirubin levels serve as surrogate marker for
  UGT1A1 status.
• S.bili gt 2.0 not be treated with irinotecan

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Bilirubin
5. Innocenti et al. J Clin Oncol 2004221382-8.
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• Individuals who are homozygous for the
  UGT1A128 allele are at increased risk for
  neutropenia following initiation of CAMPTOSAR
  treatment. A reduced initial dose should be
  considered for patients known to be homozygous
  for the UGT1A128 allele. Heterozygous patients
  (carriers of one variant allele and one wild-type
  allele which results in intermediate UGT1A1
  activity) may be at increased risk for
  neutropenia however, clinical results have been
  variable and such patients have been shown to
  tolerate normal starting doses.

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Approved Genotyping

• August 2005
• Invader UGT1A1 Molecular Assay
• 1 (wild type)
• 28 (variant) alleles
• Peripheral blood
• Cost 250 - 500

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Limitations

• Evidence of predictive nature of UGT1A128 most
  consistent for increased risk with neutropenia ?
  high dosage regimen (300 350mg/m2) every 3
  weeks.
• Irinotecan-associated diarrhea ???
  administration schedule (weekly regimen,
  increased amount of SN-38G to gut, then converted
  back to SN-38 by enteric bacterial
  b-glucuronidase.

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What about heterozygosity ?
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Limitations

• Heterozygous
• Case report (Steiner M, et al. J Clin Path 2005)
• Patient developed lethal toxicity
• 5-FU/irinotecan regimen
• Grade 4 diarrhea and neutropenia ? sepsis ? MSOF
• Heterozygous (6/7) for UGT1A1
• Heterozygous for known polymorphism in
  drug-metabolizing enzyme of fluorouracil,
  dihydropyrimidine dehydrogenase.
• Controversial.

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Limitations

• Only focus on (TA)6 and (TA)7,
• Not assessing (TA)5 and (TA)8
• ?? UGT1A7 and UGT1A9 play a role in predicting
  toxicity, esp diarrhea in weekly regimens.
• No prospective data

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So what do we do in practice

• Our patient
• 7/7 homozygous for UGT1A128 polymorphism.
• Irinotecan100mg/m2 weekly
• No complications developed.

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Conclusion

• Anybody being considered for irinotecan should be
  evaluated for UGT1A128 homozygosity
• Per package insert, need to dose reduce by one
  dose level (eg 125mg/m2 ? 100mg/m2 ). But still
  no definite guidelines.
• Does heterozygosity infer increased risk of
  toxicity as well ?
• Any impact on diarrhea ?

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References

• American Cancer Society. Overviewcolon and
  rectal cancer.
• Iyer L, King CD, Whitington PF, et al. Genetic
  Predisposition to the Metabolsim of Irinotecan
  (CPT-11).J Clin Invest. 1998847-854.
• Hahn KK, Wolff JJ, Kolesar JM. Pharmacogenetics
  and Irinotecan Therapy. Am J Health-Syst Pharm.
  200663(22)2211-2217.
• Ando Y, Saka H, Ando M et al. Polymorphisms of
  UDP-glucuronosyltransferase gene and irinotecan
  toxicity a pharmacogenetic analysis. Cancer Res
  2000606921-6.
• Innocenti F, Undevia SD, Iyer L et al. Genetic
  Variants in the UDP-glucuronosyltransferase 1A1
  gene predict the risk of severe neutropenia of
  irinotecan. J Clin Oncol 2004221382-8.
• Iyer L, Das S, Janisch L et al. UGT1A128
  polymorphism as a determinant of irinotecan
  disposition and toxicity. Pharmacogenomics J.
  2002243-7.
• Fuchs CS, Moore MR, Harker G et al. Phase III
  comparison of two irinotecan dosing regimens in
  second-line therapy of metastatic CRC. J CO
  200321807-14.
• Gupta E, Lestingi TM, Mick R et al. Metabolic
  fate of irinotecan in humans correlation of
  glucuronidation with diarrhea. Cancer Res
  1994543723-5.
• Steiner M, Seule M, Steiner B et al.
  5-flourouracil/irinotecan induced lethal toxicity
  as a result of a combined pharmacogenetic
  syndrome report of a case. J Clin Path
  200558553-5.
• www.uptodate.com
• Rouits E, Boisdron-Celle M, Dumont A, Guerin O et
  al. Relevance of UGT1A1 polymorphisms in
  irinotecan induced toxicity A molecular and
  clinical study of 75 patients. Clin Cancer Res
  2004105151-5159.
• ODwyer PJ, Catalano RB. Uridine diphosphate
  glucuronosyltransferase (UGT) 1A1 and Irinotecan
  Practical Pharmacogenomics arrives in cancer
  therapy. J Clin Oncol 2006284534-4538.

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