abraxane in radiation therapy
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ABRAXANE in Radiation TherapyTRANSCRIPT
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ABRAXANE ®
Newer Dimensions in Radiation Therapy
Dr. V. Lokesh M.DAssociate Professor
Dept of Radiation OncologyKidwai Memorial Institute of Oncology
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History• NCI
– search : chemotherapeutic cancer drug in 1958 – plant species screening program > 35,000 species – The Pacific yew tree– Taxus brevifolia -antitumor activity in rodents were first reported in
1971
• Shortfall – one cancer patient– harvested – bark of three to four, 150- to 200-year-old –Tree
• Primary source of the taxane– 10-deacetylbaccatin III– renewable biomass (twigs and needles)
• European yew (Taxus baccata) • Himalayan yew (Taxus wallichiana).
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U.S. Food and Drug Administration (FDA) - Approval
• Paclitaxel for treatment – ovarian cancer : December 29, 1992– breast cancer : April 15, 1994.
• approved - semi-synthetic form in -1995
• January 7, 2005: – (Abraxane™, a trademark of American
BioScience, Inc.) – paclitaxel protein-bound particles for injectable
suspension, albumin-bound
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TAXANES: Review
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Paclitaxel • a potent cytotoxic agent
• mechanism of action – interferes with mitotic spindle function
• enhancing the rate and yield of microtubule assembly
• preventing microtubule depolymerization
– block the cell in the G2/M phase of the cell cycle
– ↑ apoptosis and tumor reoxygenation also may occur
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Microtubules • are polymers of tubulin • in dynamic equilibrium with tubulin heterodimers • composed of alpha and beta protein subunits
principal function• formation of the mitotic spindle apparatus - cell division
• vital interphase cell functions – including maintenance of shape– motility– anchorage– mediation of signals between surface receptors and the nucleus– intracellular transport - especially in neural and secretory cells]
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Eukaryotic Cytoskeleton
•Microtubules•Actin Filaments•Intermediate Filaments
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ca
AA
FFEE
CCBB
DD
Microtubules Major structural component of the mitotic spindle.
Paclitaxel • binds to & stabilizes microtubules - loss of microtubule dynamics >
impair the mitotic spindle
• inhibiting progression of cell cycle
• cell cycle arrest at the metaphase- to- anaphase transition
• ultimately, cell death by apoptosis
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• Taxol induce microtubule asters formation
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Microtubule structureMicrotubules
two proteins:
• alpha-tubulin (in blue)
• beta-tubulin (in pink)
Heterodimers
•one alpha and one beta subunit
• assemble - sturdy cylindrical tube
• Paclitaxel (in green) binds to beta-tubulin on the inner surface, stabilizing the microtubule and blocking the normal dynamics of assembly and disassembly.
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Taxanes• Highly hydrophobic (water insoluble)• To enable parentral administration
– Solvent : • Paclitaxel :
– Polyethylated Castor Oil (Cremphor EL)– Ethanol – as vehicle
• Docetaxel– Polysorbate 80 – ethanol
– Toxicities: (direct – 80% )• Hypersensitivity reactions • Prolonged & irreversible prepheral neuropathy (demyelination & Axonal
degeneration)
– Adversly affect the drug efficacy : • Entrapment of active drug in Mycellies :
– ↑ systemic drug exposure– ↓drug clearance– non linear pharmako kinetics– Lack of dose dependent anti-tumour activity
– Both CrEL and Tween 80 - leach plasticizers( they might leach the plastic IV tubing's).
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Cremophor paclitaxelCremophor paclitaxel : : Large Micelles Observed in Plasma Large Micelles Observed in Plasma
Control plasma Plasma + Taxol
LargeMicelle
Hamad and Moghimi, Expert Opin. Drug Deliv. (2008) 5(2):205-219
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Rat – peripheral nerve
• Control: Saline • Test: – Cremophor Treated– Several degenerated
Axons
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Innovation
• Need
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• Manipulation of atoms, molecules, and materials to form structures on the scale of nanometres (billionths of a metre).
• quantum mechanics : nanostructures - exhibit new properties or behaviours.
• potential quantum benefits of miniaturization - Richard Feynman 1959.
Nanoparticle Technology
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Nanoparticle Technology
Definition by size- Particles having sizes less than 0.1m (100nm)
1st generation nanoparticles: <100nm2nd generation nanoparticles: <10nm
- Lower limit of nanoparticles: ~1nm*Other names of nanoparticles
- ultrafine particles, clusters, nanocrystals, . . quantum dots - cf. colloids, aerosols, hydrosols, organosols..
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Abraxane® : ABI -007
• American BioScience, Inc., Santa Monica, California. BIOCON (India)
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• A novel – 130 nanometer particle – (1/10th - platelet, 1/20th - smallest blood vessels and 1/40th RBC)
• Protosphere™ technology : – convert insoluble drugs into soluble nanoparticles – Enhanced drug delivery
• 1st anticancer agent (Paclitaxel) – incorporate albumin technology
• Albumin – unique– A natural carrier of lipophylic molecules – Preferential drug delivery: Albumin receptor medicated drug transport
across endothelial cells (ABI- 007 4.5 fold ↑ in paclitaxel transport)
• Cremophor-free: ↓ Hypersensitivity & Nerve damage
- Half life of Abraxane is 27 hours for the dose of (260mg/m2)
Abraxane® : ABI -007
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Nab in size perspective Nab in size perspective
Human hair = 100,000 nm
Albumin = 5 nmAlbumin = 5 nmHemoglobin = 6.5 nmHemoglobin = 6.5 nm
Proteins
Red Blood Cells
RBC = 8000 nmRBC = 8000 nm
Nanoparticles
Nab-technologyNab-technology ~100nm~100nm
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Human albumin
hydrophobic hydrophobic drugdrug Size :
~ 50-150 nm
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Abraxane
Solvent based Paclitaxel
0 hr
0 hr
24 hr
Microscopic assessment at 5 mg/mL, 40 Microscopic assessment at 5 mg/mL, 40 C:C:
De et al., AACR 2008De et al., AACR 2008
Unstable: aggregate ↓ drug delivery
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Abraxane: Phase – I Trial
• MTD: 300mg/m2
• 70% higher than convetional 175mg/m2
• No - severe Hypersensitivity reaction
• No – premedication
• Administration time: 30 min v/s 90 min regular paclitaxel
• Pharmacokinetics: max AUC time curve : dose 135 – 300 mg.m2
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• Metastatic breast cancer• 300mg/m2
ORR TTPAll : 48% 26.6
weeksABI-007 as 1st Line : 64% 63.6 weeks
Findings suggested: Abraxane – may offer important advantages over standard paclitaxel
Abraxane: Phase – II Trial
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Abraxane vs. TaxolAbraxane vs. TaxolPhase 3 Clinical TrialPhase 3 Clinical Trial
Journal Clin Oncology, 2005;23.
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U.S. (FDA): Unique fast track approval • Active ingredient, paclitaxel - is identical • Paclitaxel FDA approved as Adjuvant Rx (175 mg/m2)
• Abraxane – delivers a higher dose of paclitaxel (260 mg/m2)
– Superior anti-tumor activity demonstrated in metastatic breast cancer
– Tolerability of higher Abraxane dose comparable to lower Taxol dose
• FDA approach is to use 505(b)(2) “to avoid…. studies that are not scientifically necessary”– Treatment of breast cancer after failure of
combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy.
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ABRAXANE&
RADIATION THERAPY
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Radiation Sensitizationradiation-modulating effects of ABRAXANE in
tumor and normal tissues Pre Clinical Study:• Mice - syngeneic ovarian or mammary carcinomas• nab-paclitaxel, radiation, or combination of both• 1.5 times the maximum tolerated dose for solvent-based paclitaxel• single-agent antitumor efficacy against both tumor types and acted as a
radiosensitizer• with radiation, nab-paclitaxel produced supra-additive effects when
given before radiation• Nab-paclitaxel significantly increased radiocurability by reducing
the dose yielding 50% tumor cure (TCD50) from 54.3 to 35.2 Gy.
• Tumor histology – pronounced necrotic and apoptotic cell death and mitotic arrest. – Nab-paclitaxel did not increase normal tissue radioresponse
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Current Ongoing Trials
1. UCI 05-46: A Phase II Study of AlbuminBound-Paclitaxel (AbraxaneTM) for Treatment of Recurrent or Metastatic Head and Neck Cancer With the Addition of Cetuximab (IMC-225) on Disease Progression
– To assess whether the addition of Cetuximab will re-sensitize head and neck cancer to Abraxane after progression on single agent Abraxane.
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2. Phase I Trial of ABI-007 (Abraxane) Plus Cisplatin Plus 5-Fluorouracil (APF) as Induction Chemotherapy Followed by Concurrent Chemoradiotherapy in Patients With Locally Advanced Squamous Cell Cancers of the Head and Neck (HNSCC)
– Drug: • ABI-007 Dose escalation beginning with ABI-007 75 mg/m2
day 1 + day 8, • Cisplatin 100 mg/m2 day 1, • 5-FU 1000 mg/m2/d continuous infusion x 96 hours on day
1-4, • for 3 weeks x 3 cycles.• Followed by Concurrent weekly Carboplatin (AUC 1.5) with
radiotherapy for 7 weeks..
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3. A Phase I/II Trial of Abraxane in Combination With Carboplatin, Erbitux and Intensity Modulated Radiation Therapy (IMRT)for Treatment of Locally Advanced Squamous Cancer of the Head and Neck
– Phase I: To identify the maximally tolerated dose of Abraxane given with carboplatin and Erbitux plus concurrent IMRT.
– Phase II: To evaluate the efficacy by evaluating 2-year-disease-free survival.
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Other Disease Sites for Chemoradiation with Abraxane
• Ca Pancreas
• Ca Oesophagus
• Gastric Ca
• Unresectable Metastatic Ca Prostate: Abraxane Plus Hormonal Therapy
• human Grade III astrocytoma cell line
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Proposed Concurrent RT+CTDose Schedule
• Head & Neck Ca– paclitaxel
• every 3 weeks at a dose of 100 mg/m2 concurrently with external beam radiation.
• five day infusion of Paclitaxel concurrent with radiation therapy : Paclitaxel as a continuous IV infusion of 120 mg/m(2) over 120 hours through a central venous catheter
• Paclitaxel was given every 3 weeks at a dose of 100 mg/m2 concurrently with external beam radiation -1999
• Patients received paclitaxel 60 mg/m2 by 3-hour intravenous (IV) infusion, and cisplatin 25 mg/m2 weekly on days 1, 8, 15, and 22. (Ca Oesophagus)
• ECOG (E1393) : high-dose paclitaxel (200 mg/m2) as a 24-hour infusion plus cisplatin 75 mg/m2 with G-CSF v/s low dose paclitaxel (135 mg/m2) as a 24-hour infusion, plus cisplatin 75 mg/m2 (Forastiere et al, 2001) – no difference
• s
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Radiation Therapy Committee
• Abraxane: Novel approach to Taxane delivery• A 3 hr exposure – G2/M block – lastig 24 hrs• Use 1/3 the weekly dose, 3 times/week –
maintains G2/M block
• ABRAXANE• 75 mg/m2 day 1 + day 8,• 150 mg/m2 weekly IV over 30 min, x3 q4w
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Paclitaxel PK for Abraxane are Linear
y = 3023.2e0.0089x
R2 = 0.9683
y = 3213e0.0095x
R2 = 0.9328
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
50000
100 150 200 250 300Dose (mg/m2)
Me
an
AU
Cin
f (n
g h
r/m
l)
Taxol AUC 3hr inf., ref (1)
Taxol AUC 3 hr inf., ref (2)
Taxol AUC 1hr inf., ref (3)
(1): Kearns, C. M., Pharmacotherapy, 1997(2): Taxol Package insert(3): Mross et al, Cancer Chemother Pharm 2000
TaxolTaxol Abraxane
Source: Abraxane NDA
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Cremophor Alters the Distribution PhasePK of Paclitaxel
Terminal phase-metabolism/excretion (8-72 hr)
Source: Abraxane NDA and Sparreboom et al., 2005, CCR
LargeMicelleLargeMicelle
Initial distribution
phase (0-8 hr)
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Thank You