Pegylated Liposomal Doxorubicin Doxil in metastatic breast cancer

1
Pegylated Liposomal Doxorubicin (Doxil) in
metastatic breast cancer

• Rama Suresh M.D.
• Fellow
• Division of Hematology-Oncology
• Washington University School of Medicine

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Structure of Doxil
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Doxil vs. Doxorubicin

• Limited volume of distribution(2.5 to 3 L/m2 vs
  240-690 L/m2)
• Slower clearance from the circulation(0.04 L/h/m2
  vs 27to 59 L/H/M2)
• Prolonged half life (55 hrs vs 0.4 - 2 hrs)
• Three fold greater AUC

4
Monophagocytic system clearance

• Pegylation protects liposome from MPS
• Doxorubicin affects MPS

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Liposomal Anthracycline Preparations
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PEG-LD(Doxil) vs.TLC-99(Myocet)

• Drug delivery to sites of tumor growth Doxil gt
  Myocet gt doxorubicin
• Myocet more acutely toxic than Doxil
• Doxil specific skin toxicity Palmo-plantar
  erythrodysesthesia

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Doxil vs. Myocet

• PEG-LD releases less than 10 of its encapsulated
  doxorubicin 24hrs after IV administration
• Plasma half life of Doxil is 45 to 90 hrs
• Myocet releases more than half its associated
  doxorubicin within 1hr and gt90 of entrapped
  contents within 24 hrs

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Tumor penetration

• Preferentially localize to tumor tissue in animal
  models
• Higher concentration in KS lesion than normal
  skin (Amantrea et al,Clin Pharmacol Ther,1997)
• 4-16 fold higher in malignant pleural effusion
  when given PEG-LD (Gabison et al, Cancer,1994)
• Higher concentration of drug in plasma,
  metastatic breast cancer tissue and less in
  normal tissue (Symon et al, Cancer,1999)

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Decreased cardiotoxicity

• Retrospectively compared endomyocardial biopsies
  in patients treated with PEG-LD and doxorubicin
  (Barry et al)
• 10 pts with KS treated with 20mg/m2 biweekly
  (cumulative dose of 440 to 840mg/m2)
• PEG-LD
• lower biopsy scores when controlled for both peak
  and cumulative dose (0.3 vs 3) or peak dose alone
  (0.3 vs 1.25)

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Equal efficacy but decreased cardiotoxicity

• First line treatment, 509pts, metastatic breast
  cancer
• Primary end points PFS and cardiac toxicity
• 59 had visceral mets and 15 had bony mets
• PFS /OS similar in both arms (OS52)
• Cardiac toxicity2 PLD vs 9 Doxorubicin
• CHF 2 pts PLD vs 12 pts Doxorubicin
• Alopecia, N, V with doxorubicin
• PPE with PEG-LD
• Wigler et al, ASCO, 2002

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FDA-Approved Indications

• Treatment of metastatic carcinoma of the ovary in
  patients with disease refractory to both
  paclitaxel- and platinum-based chemotherapy
  regimens
• Treatment of AIDS-related Kaposis sarcoma in
  patients with disease that has progressed with
  prior combination chemotherapy or in patients
  intolerant of such therapy

Prescribing Information Doxil brand of
doxorubicin HCL liposome injection. ALZA
Pharmaceuticals Inc. Mountain View, CA December
1999
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PEG-LD in Metastatic Breast Cancer
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Doxil in Breast Cancer -Combination Therapy
Combination Response Investigators Doxilcyclo
phosphamide 57-71 Silverman 1999, Holder
1998(Pilot studies) Doxilpaclitaxel 40-78
Jones 2000, Moore 1998, Woll 2001(Phase
2) Doxildocetaxel 55 Sparano 2001 (Phase
1) Doxilvinorelbine 18-36 Martin 2002,
Rimassa 2000(Phase 2) Doxilgemcitabine
33-51 Rivera 2001, 2002 (Phase
1,2) Doxilhyperthermia 60 Park 2001
Includes patients with locally advanced breast
cancer. Abstract submitted for presentation at
SABC 2002.
Rivera E, et al. Submitted to SABC. 2002
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PEG-LD Docetaxel Herceptin

• Ongoing studies
• EORTC
• ECOG E3198
• Cardiotoxicity

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PEG-LD and Gemcitabine- Phase 1
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PEG-LD and Gemcitabine Phase 1
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Doxil and Gemcitabine Phase 2

• Metastatic breast cancer patients who did not get
  prior chemo
• No limit on prior anthracycline dose
• D 24mg/m2 on d1 and G 800mg/m2 IV on days 1,8 of
  21 day cycle
• 48 pts
• 244 courses administered
• No cardiac toxicity
• Grade 3/4 neutropenia 25, Grade 3
  thrombocytopenia 16, grade 3 anemia 6, grade 3
  fatigue 20, Grade 3 stomatitis 8, grade 3 PPE
  4, 2pts had HUS 1M post chemo, 1pt neutropenic
  fever
• 35 eligible for evaluation (4 not eligible, 9 too
  early to evaluate)
• RR 51 (2CR, 16PR, 8SD, 9PD)
• Rivera et al SABC, 2002 (Abstr 342)

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Phase 2 study of Doxil and Gemcitabine/-trastuzum
ab

• Primary Objective To assess response rate of
  above combination regimen in metastatic breast
  cancer.
• Secondary Objective(s)
• Assess cardiotoxicity of combination therapy
  with Doxil and trastuzumab.
• Pharmacogenomics of gemcitabine toxicity
• Correlate gene expression with clinical response

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Gemcitabine metabolic pathway
Cell membrane
SLC28A1 SLC28A2 SLC29A1 SLC29A2
dFdCDP
UMP-CMPK
DCK
dFdCMP
dFdC
dFdC
PDK
RRM1 RRM2
DCTD
dFdCTP
CDA
POLA2 POLE
dFdU
dFdU
dFdUMP
TYMS
dTMP DNA dCTP dCDP
dUMP
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Polymorphisms of gemcitabine metabolic pathway
genes

• Genomic DNA from 95 European and Africans each
  analyzed for 12 SNPs
• Public database SNPs
• PCR
• Pyrosequencing
• Theoretical alteration in protein structure
• 7 of 12 SNPs had significant difference in allele
  frequencies
• 5 of those 7 encode for an AA change

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Gene Expression

• Gene expression profiling of primary tumor cells
  helps identify subclasses which may be associated
  with outcomes and may be used to predict
  prognosis in breast cancer. (Sorlie et al, Proc
  Natl Acad Sci USA 9810869-10874, 2001 and Van t
  Veer et al, Nature 415(6871) 530-536, 2002,
  Jenessen et al, Hum Genet 111 411-420,2002).
• Gene expression profiles derived from FNA of
  primary breast tumors can help distinguish tumors
  with complete response to chemotherapy from
  tumors that do not respond (Sotiriou et al,
  Breast Cancer Research 4(3) R3, 2002).
• We will evaluate this in metastatic tumor cells
  and correlate this with response of tumor to
  chemotherapy Dr. Mark Watson
• Data will be available to all Wash. Univ.
  investigators

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Study Schema
Doxil 20mg/m2Gem 2000mg/m2 on D1 and D15 of 28
day cycle x 6, or until disease progression
Biopsy CBC, CMP RVG, Trop, BNP CT scan C/A/P Bone
scan Blood for DNA extraction
_
Newly diagnosed no prior chemo, hormone refractory
HER2 status

Above drugs Trastuzumab 4mg/kg loading dosex1
and then 2mg/kg weekly
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Conclusion

• Less cardiotoxic than doxorubicin
• Equally efficacious
• Best response rate with paclitaxel in phase 2
  trials, but significant toxicity
• Doxil Gemcitabine trastuzumab reasonable
  efficacy and low toxicity

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Acknowledgements

• Dr. Paula Fracasso
• Dr. Katherine Weilbaecher
• Dr. Howard McLeod
• Dr. Michael Naughton
• Ms. Ming-Yu Fan (statistician)
• Ms. Laurie Yockey (Orthobiotech)