Paclitaxel FDA approved as Adjuvant Rx (175 mg/m 2 )
delivers a higher dose of paclitaxel (260 mg/m 2 )
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-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 .
pronounced necrotic and apoptotic cell death and mitotic arrest.
Nab-paclitaxel did not increase normal tissue radioresponse
Current Ongoing Trials
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)
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
Unresectable Metastatic Ca Prostate: Abraxane Plus Hormonal Therapy
human Grade III astrocytoma cell line
Proposed Concurrent RT+CT Dose Schedule
Head & Neck Ca
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
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
75 mg/m2 day 1 + day 8 ,
150 mg/m2 weekly IV over 30 min, x3 q4w
Paclitaxel PK for Abraxane are Linear (1): Kearns, C. M., Pharmacotherapy, 1997 (2): Taxol Package insert (3): Mross et al, Cancer Chemother Pharm 2000 Taxol Abraxane Source: Abraxane NDA
Cremophor Alters the Distribution Phase PK of Paclitaxel Source: Abraxane NDA and Sparreboom et al., 2005, CCR Terminal phase-metabolism/excretion (8-72 hr) Initial distribution phase (0-8 hr)