ABRAXANE with its safety profile will play an important role as Radiation Sensitizer in various solid tumors. The safety profile and efficacy reflects its possible beneficial effect in achieving therapeutic gain with out increasing Radiotherapy reactions. Results from various studies are awaited.
High Profile Call Girls Jaipur Vani 8445551418 Independent Escort Service Jaipur
Abraxane (nab paclitaxel) as Radiation Sensitizer
1. Exploring the Role of Nab-
paclitaxel (ABRAXANE®) as a
Radiation Sensitizer
Newer Dimensions in Radiation Therapy
Presented at National Conference AROI Nov 2012
Dr. Lokesh Viswanath M.D
Professor, Dept of Radiation Oncology
Kidwai Memorial Institute of Oncology, Bangalore
2. Radiation Sensitizer
Agents possessing significant ability to augment the
effect of radiation
– Super / sub-additive effect
– Little or non-toxic at doses used
– Minimal cytotoxic
– Selective or preferential to tumor cf normal tissue
– Counter act – determinants of radio-resistance > altering
the cancer cells radio-sensitivity
– Cell survival curve – steeper slope (eliminate shoulder or
change the slope)
• Shoulder – repair of radiation damage
• Tail – resistance to CT agents
– Lesser systemic toxicity
– Minimal or manageable enhancement of Radiation
toxicity
3. Paclitaxel Approval - U.S FDA
• Paclitaxel for treatment
– ovarian cancer : December 29, 1992
– breast cancer : April 15, 1994.
• approved - semi-synthetic form Docetaxel in -1995
• January 7, 2005:
– Abraxane™, a trademark of American BioScience, Inc unique fast track
approval for MBC
• Oct 2012 for the first-line treatment of locally advanced or metastatic non-small
cell lung cancer, in combination with carboplatin, in patients who are not
candidates for curative surgery or radiation therapy.
• 2012, Paclitaxel poliglumex
– Orphan drug status for Treatment of GBM
4. Paclitaxel
• a potent cytotoxic agent
• mechanism of action
– interferes with mitotic spindle function
– block the cell in the G2/M phase of the cell cycle
– ↑ apoptosis and tumor reoxygenation also may occur
• binds to & stabilizes microtubules - loss of microtubule
dynamics > impair the mitotic spindle
• preventing microtubule depolymerization
5. Preclinical Models
• Classic radiobiological concept: Cell Cycle dependent Radio-
sensitivity
• Radio-sensitizing effect of Paclitaxel is dependent on
– Duration of exposure
– Drug concentration
• Contribution of P53 to Paclitaxel dependent Cyto-toxicity
– Mutant P53 is more sensitive to Paclitaxel
• Theoretically Paclitaxel and RT act as non cross resistant
agent
– RT is effective in wild type P53
– Paclitaxel in mutant P53
7. Polyethylated Castor Oil - Cremphor EL
• Disadvantages of Cremphor EL – in conventional Paclitaxel
– Entrapp paclitaxel in cremophor micelles at clinically relevant
concentrations : limit ing > Px bioavailability & antitumour
activity
– inhibits Px binding with endothelial cell and albumin > inhibition
of gp60-caveolar mediated transport
– Prevent distribution of Px outside the circulation & into tissue >
↓ tumour Px concentration and low volume distribution - ↑
exposure of Px to Bone marrow - ↑ Hematological toxicity
– Cremphor EL – inhibits P glycoprotein in Hematopoietic
progenitor cells
– Inhibition of hepatic elimination
– Axonal degeneration, demyelination, irreversible sensory
neuropathy
– leach plasticizers
8. Cremophor paclitaxel :
Large Micelles Observed in Plasma
Large
Micelle
Control plasma Plasma + Taxol
Hamad and Moghimi, Expert Opin. Drug Deliv. (2008) 5(2):205-219
9. Rat – peripheral nerve
• Control: Saline • Test:
– Cremophor Treated
– Several degenerated Axons
11. Nanoparticle Technology
• potential quantum benefits of miniaturization –
Richard Feynman 1959
• Manipulation of atoms, molecules, and materials
to form structures on the scale of nanometres
(billionths of a metre).
• Particles having sizes less than 0.1m (100nm)
– 1st : <100nm
– 2nd : <10nm
12. Abraxane® : ABI -007
• Albumin bound Nano particle
• To improve Drug delivery and PK
– American BioScience, Inc., Santa Monica,
California.
– BIOCON (India)
13. Abraxane® : ABI -007
• A novel – 130 nanometer particle
– 1/10th - platelet,
– 1/20th - smallest blood vessels
– 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
14.
15.
16.
17. Therapeutic efficacy & TI of ABI 007
(Abraxane)
Trans endothelial transport of albumin is mediated by gp60
(albondin) receptor and activation of caveolin 1
•Endothelial binding ↑9.9 x
•Endothelial Trans-cytosis ↑4.2x
•↑ Endothelial binding ABI007 - ↑ anti-angiogenic activity
•↑ anti-tumour activity - ↑ enhanced intratumoral delivery
•AbI007 PK - plasma Clearance & Volume distribution – 50%
higher
• Tumor Inhibition Paclitaxel AUC at equal doses is 33% higher for
ABI007
• > 50% higher dose administration is feasible
18. SAPRC Expression
• SPARC – Tumour secreted glycoprotein – 43kDa
– High binding affinity to albumin
– Modulates cell & extracellular matrix interaction
– Key regulator of Cell proliferation, survival &
migration
• SPARC ^up-regulation in Cancer cells
• SPARC – albumin interaction
– Facilitate accumulation of albumin in Tumour
– Increase intracellular Paclitaxel – ^ effectiveness of
nab Paclitaxel
19.
20. Abraxane Stablility :
Microscopic assessment at 5 mg/mL, 40 ° C:
0 hr 24 hr
Abraxane
0 hr
Solvent Unstable: aggregate
based ↓ drug delivery
Paclitaxel
21. Cremphor base Paclitaxel -
as Radiation Sensitizer
• Review of literature
• CRT experiences in the last 2 decades - what
have we learnt ?
22. Ca Cervix – CR rates when RT is combine
with various Radiation Sensitizers
• RT alone 71%
• RT + CDDP 87%
• RT + CDDP + Paclitaxel 90%
• RT + Carbo + Docetaxel 97%
Taxanes are Good Radiation Sensitizers
Trade off : Taxnes - Acute G3Toxicities
• GI ~ 58%
• Hemat ~ 40%
• Poor Compliance ~ 20 % Discontinued
• Compliance with Abraxane – 96% (as scheduled)
23. Ca Cervix RT + Paclitaxel (as Radiation Sensitizer)
Which Scheduling may be better with RT
Once in 3 weeks PX Weekly Px Schedule
Schedule
CR - rates 70% 88-91 %
(Complete Response Rate)
Hematological 61% 11%
toxicity Gr3
2ys DFS 82%
3yr DFS 82% 70%
2yr OS 93%
3yr OS 86.6% 65%
24. Abraxane (ABI 001) – in Metastatic
Breast Cancer
what we have learnt so far ?
25. 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
26. Abraxane: Phase – II Trial
• Metastatic breast cancer
• 300mg/m2
ORR TTP
All : 48% 26.6 weeks
ABI-007 as 1st Line : 64% 63.6 weeks
Findings suggested:
Abraxane – may offer important advantages over
standard paclitaxel
28. Ca Breast : Safety profile of ABI007
ABI007 CREMPHOR BASED
260mg/m2 PACLITAXEL
175mg/m2
Tumour Response 33% 19% P 0.001
rates
TT progression 23 wk 16.9 wk P 0.006
Gr 4 Neutropenia 9% 22% P 0.001
Sensory neuropathy 10% Temporary 2% P 0.001
250mg/m2
32% (Gr3) axona
29. MBC – weekly nab Paclitaxel
median OS (mo)
• Weekly Nab Paclitaxel 150mg/m2 qw 3/4 - 33.8
• Nab Paclitaxel 300mg/m2 q3w - 27.7
• Docetaxel 100mg/m2 qw 3/4 - 26.6
Form H&N Ca TAX studies we know that Docetaxel is
better that Paclitaxel
Weekly Abraxane Schedule is Equivalent to Docetaxel
30. MTD - in Weekly schedule
Exploring What Doses of Abraxane needs to be
used for Concurrent Chemoradiation
• Paclitaxel 50mg/m2/wk when combined with
CDDP 30-60mg/m2
• Abraxane : 100mg/m2/wk In heavily pre-
treated subjects
31. Combination : is CDDP or Carbo Better ?
ORR
CDDP + Paclitaxel 29% (Ca Cx recurrence)
Carbo + Paclitaxel 53%
CDDP+5Fu+Abraxane 100% (H&N) CR -53%
Weekly CDDP v/s Weekly Carbo v/s once in 3 weeks schedule
• For Indian setting use of RT + Radiation Sensitizer - Weekly CDDP 40mg/m2
with Abraxane 75mg/m2 (50 -100) may be suitable , without enhanced RT
toxicities
32. • Giving a taxane with radiation at the present
time is, however, investigational.
34. Radiation-modulating effects of
ABRAXANE ABI 007
in tumor and normal tissues
Pre Clinical Study: Mice - syngeneic ovarian or mammary Ca
• 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.
35. • ABI 007 is also being evaluated for the
treatment of non-small cell lung cancer,
ovarian cancer, melanoma and cervical
cancers. Phase I/II trials have also been
conducted in other solid tumours, including
squamous cell cancer of the head and neck,
and pelvis.
36. Tisheret et al (2012), A Phase I/II Trial of
Concurrent Abraxane in Combination With
Carboplatin and Intensity Modulated
Radiation Therapy (IMRT) in Locally Advanced
Squamous Cancer of the Head and Neck
Rationale: favorable biodistrubition of Abraxane may allow
loco-regional treatment without increasing normal tissue
toxicity
37. LASCCHN - Abraxane CRT
• Phase I – Dose escalation study
• n=28
• Median f/u 25 mo
• Nab paclitaxel + Carbo + IMRT
• Abraxane – 50mg/m2
• G3 Gysphagia, mucositis & dermaitiis – 85%
• No DLT observed
• Control rates ~ 82%
38. L. A. Nedzi et al (2010). Phase I Study Of Nab-
paclitaxel, Cisplatin And Cetuximab With
Concurrent Radiation Therapy For Local-
regionally Advanced Head and Neck
Squamous Cell Carcinoma (HNSCC)
• n=11
• The maximum tolerated dose of weekly nab-paclitaxel given
concurrently with cisplatinum, cetuximab and 70 Gy
continuous course radiotherapy for loco-regionally
advanced HNSCC is 20mg/m2
39. 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..
41. Paclitaxel poliglumex
• 2012 FDA - Orphan drug status for Treatment of
GBM
• Phase II : Paclitaxel P (50mg/m2) + TMZ + RT
• N=25 (GBM-15), Median f/u 10.2 mo
• CR-24%, PR-16%, SD-40%
• PFS – 76%
• GBM PFS – 66.7% (Stupp 53.9%)
• AE: G3 Neutopenia – 4%, Thrombocytopenia -24%
42. Weekly Nanoparticle Albumin-Bound
Paclitaxel (Abraxane) + Weekly Cetuximab +
Radiation Therapy (IMRT, Intensity-
Modulated Radiation Therapy) in Patients
With Stage III-IVB Head and Neck Squamous
Cell Carcinoma (HNSCC)
– To establish recommended dose of weekly (Abraxane®)
given concurrently with weekly cetuximab + definitive
radiation therapy (IMRT) for patients with HNSCC.
– Memorial Sloan-Kettering Cancer Center
– Completion Date 08/01/2012
43. Current Ongoing Trials - Other Disease Sites
for Chemo-radiation with Abraxane
• Ca Pancreas – Stastically significant improved
responses reported
• Ca Oesophagus
• Gastric Ca
• Unresectable Metastatic Ca Prostate:
Abraxane Plus Hormonal Therapy
• human Grade III astrocytoma cell line
44. Abraxane as Radiation sensitizer
Other proposed Schedules:
•A minimum of 3 hr prior exposure – G2/M block –
lasting 24 hrs
•Use 1/3 the weekly dose, 3 times/week – maintains
G2/M block
•ABRAXANE
• 75 - 150 mg/m2 weekly IV over 30 min, x3 q4w
45. Summary
• Nab Paclitaxel Abraxane (ABI 007) – is one of the latest
nanoparticle molecule to be used as a Radiation sensitizer
• The results of the recently completed clinical trials are eagerly
awaited
• Preliminary reports are encouraging
• The response rates and toxicity profile of ABI 007 - potential
use as Radiation sensitizer in various Clinical setting in years to
come
• A Platin combination seems to be essential to achieve
escalated responses
• Clinical Trials in Indian setting are being encouraged:
– we are in the process of designing Chemo-radiation schedule in various
clinical settings
– The study design shall be relevant to our patients profile , radiation
toxicity tolerances and supportive care available.