Clinical Trial to Optimize Photodynamic Therapy with 5Aminolevulinic Acid

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Clinical Trial to Optimize Photodynamic Therapy
with 5-Aminolevulinic Acid

• Norman Nishioka, MD
• David Forcione, MD
• William Puricelli, RN

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Overview

• Background BE and PDT
• Trial design
• Enrollment Data
• Preliminary results
• Adverse events
• Looking forward

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Barretts Esophagus

• Acquired condition in which there is replacement
  of the normal stratified squamous epithelial
  lining of the esophagus with columnar epithelium
• Associated with 0.5 annual risk of developing
  esophageal adenocarcinoma (30-60x above that of
  the general population)
• Since 1974, incidence of esophageal
  adenocarcinoma rising at 21/year exceeding all
  other cancers (however, 13,200 esoph CA, 135,000
  colorectal CA, 170,000 lung CA, 194,000 breast
  CA)

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Barretts Esophagus

• Prevalence varies depending upon cohort and
  definition of BE
• - Autopsy series 0.4-0.9
• - Unselected EGD 0.023
• - Patients with GERD at EGD 6 (gt 3 cm) 12
  (any length)
• - VA population (asymptomatic) 25
• Incidence increasing since 1965parallels the
  utilization rate of upper endoscopy

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Barretts Esophagus

• Higher risk for developing BE
• - GERD at earlier age
• - Increased duration and severity of
• GERD sxs (greater esophageal acid exposure on 24
  hr pH monitoring, lower basal LES, greater DER)
• - Increased severity of nocturnal GERD sxs
• - Increased complications of GERD
• (peptic stricture, bleeding, esophagitis)
• - ?Genetic factors

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Barretts Esophagus
Squamous lined esophagus
GER acid, bile salts, ?other factors/protective
factors
Chronic esophageal mucosal injury
6-12
Physiologic factors ?Genetic factors (?COX-2,
gastrin)
GERD w/o BE
GERD c/b BE
BE with LGD
Stable BE
Esophageal adenocarcinoma
5-40/yr
BE with HGD
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BE-gtHGD-gtEsoph AdenoCA

• Surveillance programs for BE patients designed to
  identify dysplasia and/or early CA
• For confirmed HGD (diffusegtgtfocal) esophagectomy
  remains the gold standard treatmentbut carries
  relatively high morbidity and mortality (5)
• PDT represents an alternative treatment strategy
  for pts with HGD/T1 CA who do not desire surgery,
  or in whom surgery is contraindicated due to
  comorbid conditions

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Photodynamic Therapy

• Two step technique utilizing a combination of a
  drug, light, and oxygen to result in tissue
  destruction
• Phase I Drug is taken up by target tissue and
  takes (or metabolite) on the role of a
  photosensitizing agent
• Phase II Light is delivered to target tissue,
  activating the photosensitizing agent. Oxygen
  radicals are formed which lead to disruption of
  cell membranes and subsequent tissue necrosis
• No mechanisms of resistance and can be used
  repeatedly

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PDT and BE

• Overholt et al. (GIE, 1999) 100 pts with
  BE/Dysp/T1 CA received PDT with porfirmer sodium
  (PfS) followed for mean 19 mos
• - In all 100 pts, gt75 BE mucosa ablated
• - In 44, complete ablation of BE mucosa
• - 77 malignancies ablated
• - 88 HGD ablated
• - 92 LGD ablated
• - 34 stricture rate
• PHOBAR RCT BE/HGD to PDT/PfS PPI vs PPI alone
  and surveillance
• 24 mos - HGD ablation in 77 vs 39,
• - progression in 13 vs 28
• - strictures in 37
• PfS disadvantages need for IV admin, prolonged
  skin photosensitivity (up to 90 days), and high
  stricture rate (up to 50)

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Aminolevulinic acid-based PDT

• ALA synthesis is an early step in the heme
  biosynthetic pathway
• ALA is converted to PPIX in vivo, which serves as
  the photosensitizing agent
• Gossner et al. (Gastroenterology, 1998)
• - 32 patients (mean age 68.5 yrs)
• - 10 pts with HGD, 22 pts with CIS
• - ALA 60 mg/kg light dose 150 J/cm2
• - 100 dysplasia ablation, 77 CA ablation (lt2
  mm)
• - O with complete BE ablation
• Ackroyd et al. (Gut, 2000)
• - 36 patients (mean age 55 yrs) in UK rand to
  ALA-PDT (30 mg/kg) or placebo-PDT
• - Low grade dysplasia
• - 100 dysplasia ablation with ALA-PDT vs 33
  in placebo
• - 88 had gt10 BE ablation (none had 100)

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Aminolevulinic acid-based PDT

• Advantages Oral administration, 36 hr
  photosensitivity, negligible stricture rate
• Disadvantages Superficial mucosa targetting may
  result in inferior ablation rates for BE
• Can we optimize ALA-PDT by manipulating target
  tissue characteristics (PPIX levels) and light
  delivery factors (which influence O2
  availability)?

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SPECIFIC AIMS

• To evaluate the effect of differentiation therapy
  with 13- cis-retinoic acid on the outcome of
  ALA-PDT in patients with Barretts esophagus (BE)
  and high grade dysplasia (HGD) or early
  esophageal CA
• - Retinoids promote cellular differentiation
• - PPIX production is increased in differentiated
  cells
• - Retinoids may promote more uniform
  accumulation of PPIX
• 2) To evaluate the effect of light
  fractionation on the outcome of ALA-PDT
• - Increase availability of oxygen that diffuses
  into the tumor/dysplastic cells during the dark
  cycle.
• 3) To evaluate parameters for predicting BE
  tissue response during ALA-PDT (FCH, PBGD and
  CPO)

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STATISTICAL CONSIDERATIONS

• A sample size of 18 patients in each group
  will have 90 power to detect a minimum
  difference of 28 in the mean percentage of BE
  eradicated between any of the 3 treatment groups
  and the standard treatment group

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ELIGIBILITY CRITERIA

• EXCLUSIONS
• 1) lt18 yo (BE rare in this cohort)
• 2) Hx of porphyria, hypertriglyceridemia (gt500
  mg/dL), IBD, unstable psychiatric disease,
  pseudotumor cerebri
• 3) Concomitant carbamazepine, Vit A,
  tetracycline, doxycycline, minocycline
• 4) Women of childbearing age unable to commit to
  2 forms of contraception and regular HCG testing
• 5) Thoracic XRT or chemotherapy within 4 weeks
  of enrollment
• 6) Prior PDT
• 7) Esophageal strictures unresponsive to
  dilation
• 8) Contraindication to conscious sedation or
  endoscopy
• 9) Contraindication to PPI
• 10) WBC lt2.5, PLT lt50K, Hb lt9, INR gt1.5x ULN
• 11) Cr gt 1.5 x ULN
• 12) Bili gt 1.5x ULN, or AST, ALT gt2.5x ULN
• 13) Class III or IV NYHA cardiovascular status
• 14) Esophageal ulcers gt 1cm
• 15) Portal HTN with esophageal varices

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Screening EGD
PDT
ALAPDT001
3 mos post-PDT
48 hrs post-PDT
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ENROLLMENT
DSMB CONVENED 3/2003
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Adverse Events
ALAPDT002
ALAPDT003
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• ALA has been shown to cause reversible
• hemodynamic alterations (particularly in
• SVR/PVR), but in clinical trials, has only rarely
  
• been associated with sustained
• tachyarrhthymias, and has not been associated
• with documented cardiovascular mortality.

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PROTOCOL MODIFICATIONS FOLLOWING INITIAL SAEs

• Exclusion criteria
• - Hx cardiomyopathy/EFlt30
• - Hx unstable arrythmia
• - Pre-ALA SBPlt100
• Treatment session
• - IVF with LR
• - Zofran (instead of compazine)
• - Continous cardiac monitoring after ALA

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Protocol

• Enrollment
• 2 weeks of premedication (placebo or accutane)
• Endoscopy unit 5 hours before PDT
• Review photosensitivity protection
• Baseline VS, heart rhythm
• IVF and zofran
• Baseline spectroscopy measures (buccal mucosa)
• ALA 30 mg/kg 4 hours prior to PDT
• Monitoring in Endo unit
• EGD (qcm video clips)
• Repeat spectroscopy (buccal, BE x2, Squam)
• Bx for confocal microscopy and enzyme measures
• ALA PDT (fractionated vs unfractionated) with a
  centering balloon
• Repeat spectroscopy following PDT from BE,
  squamous, and buccal mucosa
• Pt returns in 48 hrs for repeat endoscopy

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ALAPDT003 Fluorescence

• Wavelength 405nm
• Tuned to detect PPIX 635nm peak

Left BM pre-PDT
Left BM pre-ALA
Right BM post-PDT
Left BM post-PDT
38 cm BE pre-PDT
38 cm BE post-PDT
37 cm BE post-PDT
Right BM pre-ALA
Right BM pre-PDT
37 cm BE pre-PDT
32 Squ pre-PDT
32 Squ post-PDT
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Confocal fluorescence imaging
Hematoxylin and Eosin
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ENROLLMENT
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Results

• ALAPDT001
• 10/02 12/03 3/03 4/03 7/03
• HGD/IMCA ALA-PDT1 HGD ALA-PDT2 HGD
• _at_40 cm _at_41 cm _at_41 cm
• 8 cm 8 cm 8 cm 8 cm 8 cn
• ALAPDT003
• 2/03 4/03 8/03 9/03
• HGD ALA-PDT1 HGD ALA-PDT2
• _at_37-39 cm _at_38 cm
• 3 cm 3 cm 3 cm 3 cm

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ALAPDT006

• 64 yo WM referred for evaluation/rx of BE c/b
  HGD/IMCA
• PMHx Hyperlipidemia
• HTN
• Past smoker (70 p-y)
• Atypical CP (- cardiac cath MGH 2002)
• Hypothyroidism
• Pituitary adenoma (s/p resection 5/03)
• Gout
• ?Excess EtOH use

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ALAPDT006

• Meds Protonix 40 mg/ Norvasc 10 mg/d
• Lopid 600 mg/bid
• Buspar 30 mg/d
• Nulev 0.125 mg/d
• Zestril 10 mg/d
• Prednisone 5 mg/d
• Androgel 5 mg/d
• Synthroid 0.125 mg/d
• Lipitor 20 mg/d

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Sequence of events

• 9/24/2003-10/8/2003 Accutane 80 mg/d (divided
  bid)
• -no adverse events reported
• 10/8/2003 ALA PDT session
• 0925 BP 127/66, given ALA 2181 mg, zofran 8 mg,
  IVF
• 0925-1300 VSS, asymptomatic
• 1300 0.1 mg IV glycopyrrolate
• 1325 EGD/ALA PDT begun (35 cm-40 cm treated)
• 1325-1400 Mild tachycardia, stable BP, 3L O2
• Versed 6 mg/Demerol 100 mg/Fentanyl
  100 mcg
• 1400 To RR-gt home without symptoms

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Sequence of events

• 10/8/2003 Significant nausea, emesis,
  progressive weakness
• 10/9/2003 Family notifies WP 840 AM and states
  that
• subject is nearly unconscious.
  Advised to
• call 911.
• 10/9/2003 EMT arrive 0855 and find him
  unresponsive
• - P 130, SBP 100, RR 14/min, 85 RA
• - Aniscoria, urinary incontinence noted
• - ETT placed
• - BP 64/32
• - Started on dopamine-gt MGH ED

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Sequence of events

• 10/9/2003 MGH ED
• - Hypotensive, hypoxic, Temp 100.6
• - ETT, pressors x 3, stress dose steroids, Abx
• - Chest/Head/Abd/Pelvic CT scan
• - no ICH
• - peripancreatic stranding
• - no PTX, pneumomediastinum or
  pneumoperitoneum
• - bibasilar infiltrates
• - Labs Cr 3.5, HCO3 19 ABG 87/43/7.14 (100
  FiO2), lactate 7.7
• - Tox screen doxylamine, pseudoephedrine
• - PEA arrest responding to atropine/epi/HCO3
• - TTE no effusion, nl LV/RV
• 10/9/2003 CCU
• - Continued pressor requirements, high vent
  settings
• - PEA arrest _at_8 PM
• - Pronounced 815 PM
• 10/10/2003 IRB, DSMB, FDA, DUSA (ALA) notified
  of SAE

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• Post-Mortem Examination (10/10/2003)
• BE with HGD IM carcinoma
• GE junction necrosis, congestion, acute
  inflammation c/w PDT effect
• Severe bilateral bronchopneumonia
• Cardiomegaly with mild CAD
• Nephrosclerosis (Bil)
• Osteoporosis
• Pituitary fibrosis
• Cause of death diffuse alveolar damage due to
  sepsis

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Issues discussed - DSMB

• Mechanism explaining rapid clinical deterioration
• - ?drug effect/interaction
• - abnormal metabolism
• - ?aspiration pneumonia
• - ?pituitary insufficiency
• Continuation of study
• - discontinue ALA/accutane efficacy and safety
• - ?ALA alone

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DSMB Conclusions

• Enrollment on hold pending further
• investigion by IRB
• Consideration of amending protocol depending upon
  follow-up efficacy data on
• subjects 003-005