ABRAXANE ®

Newer Dimensions in Radiation Therapy

Dr. V. Lokesh M.DAssociate Professor

Dept of Radiation OncologyKidwai Memorial Institute of Oncology

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).

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

TAXANES: Review

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

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]

Eukaryotic Cytoskeleton

•Microtubules•Actin Filaments•Intermediate Filaments

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

• Taxol induce microtubule asters formation

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.

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).

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

Rat – peripheral nerve

• Control: Saline • Test: – Cremophor Treated– Several degenerated

Axons

Innovation

• Need

• 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

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..

Abraxane® : ABI -007

• American BioScience, Inc., Santa Monica, California. BIOCON (India)

• 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

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

Human albumin

hydrophobic hydrophobic drugdrug Size :

~ 50-150 nm

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

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

• 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

Abraxane vs. TaxolAbraxane vs. TaxolPhase 3 Clinical TrialPhase 3 Clinical Trial

Journal Clin Oncology, 2005;23.

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.

ABRAXANE&

RADIATION THERAPY

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

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.

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..

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.

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

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

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

Paclitaxel PK for Abraxane are Linear

y = 3023.2e0.0089x

R2 = 0.9683

y = 3213e0.0095x

R2 = 0.9328

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100 150 200 250 300Dose (mg/m2)

Me

an

AU

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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

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)

Thank You