nab-paclitaxel

® in

Advanced Pancreatic Cancer: Clinical Data

1

nab-paclitaxel (nab-Paclitaxel) Study in Advanced Pancreatic Cancer

2 •

nab

-Paclitaxel + gemcitabine as first-line treatment for advanced pancreatic cancer (Von Hoff; ASCO 2009) –

Von Hoff et al, JCO 2011

•

nab

-Paclitaxel in advanced pancreatic cancer patients who have progressed on gemcitabine-based therapy (Hosein/Rocha-Lima; ASCO 2010) • Paclitaxel albumin + vandetanib in patients with advanced pancreatic cancer (El-Khoueiry et al.; ASCO 2011)

3

Completed clinical studies of paclitaxel albumin in advanced/metastatic pancreatic cancer

Study design Treatment No. of pts Study endpoints Phase I/II study of paclitaxel albumin + gemcitabine as 1st-line treatment for patients with metastatic pancreatic cancer 3

Phase II, open-label study in patients with advanced, unresectable or metastatic pancreatic cancer who failed first-line treatment with gemcitabine-based therapy 1

Phase I: gemcitabine 1000 mg/m 2 followed by paclitaxel albumin 100, 125 or 150 mg/m 2 QW 3/4 Phase II: treatment at MTD

Paclitaxel albumin 100 mg/m QW 3/4 2 Phase I dose escalation study in patients with advanced, unresectable or metastatic pancreatic cancer 2 Cohort A: paclitaxel albumin 100 mg/m 2 QW 3/4 + vandetanib 100-300 mg QD Cohort B: paclitaxel albumin 260 mg/m 2 Q3W + vandetanib 100,-300 mg QD

67

19 29

Phase I: MTD + DLTs Phase II: Safety, efficacy Other: PET scan response, CA 19-9 and SPARC levels in relation to efficacy

Primary: OS rate at 6 mo Secondary: RR, PFS, safety Other: SPARC expression on pretreatment samples, CA 19-9 at baselines and every 2 cycles Primary: MTD of vandetanib in combination with paclitaxel albumin Secondary: Safety, preliminary antitumour activity 1. Hosein et al. ASCO 2010 (abstract 4120); 2. El-Khoueiry et al. ASCO 2011 (abstract 4124); 3. Von Hoff et al. J Clin Oncol 2011.

Paclitaxel albumin + gemcitabine in patients with metastatic pancreatic cancer: Phase I/II study design Open label phase I/II study in chemotherapy-naive patients with metastatic adenocarcinoma of the pancreas

Phase I:

Gemcitabine 1000 mg/m 2 Followed by paclitaxel albumin 100, 125 or 150 mg/m 2 QW 3/4 Dose escalation of paclitaxel albumin according to a standard 3+3 design

Phase II:

Accrual expanded to  42 patients Treatment at the MTD •

Study objective:

To evaluate the safety and efficacy of paclitaxel albumin + gemcitabine and the correlation of clinical response with tumoural SPARC and serum CA19-9 levels in patients with metastatic pancreatic cancer •

Study endpoints

 Safety: MTD and DLTs (Phase I); safety (incidence of treatment-related AEs and SAEs)  Efficacy: RR, PFS, OS, PET scan response, CA 19-9 and SPARC levels in relation to efficacy Von Hoff et al. J Clin Oncol 2011.

Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: dosing 1.

Weekly (days 1, 8, 15) administration of gemcitabine as a 30-minute infusion followed by paclitaxel albumin as a 30-minute infusion (repeated every 28 days) 2.

Dose levels (mg/m 2 ) Dose level 1 2 3 Paclitaxel albumin mg/m 2 100 125 150 gemcitabine mg/m 2 1000 1000 1000 3.

“3 + 3” Phase I study design with usual weekly observations; standard definitions of DLTs Von Hoff et al. J Clin Oncol 2011.

Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: eligibility criteria

Inclusion criteria Exclusion criteria

• Age  18 years • Histologically and cytologically confirmed metastatic pancreatic ductal adenocarcinoma • Prior chemotherapy for metastatic disease  Prior adjuvant 5-FU or gemcitabine as a radiation sensitizer during and up to 4 weeks after radiation therapy was permitted • Measurable disease by CT according to RECIST • Islet cell neoplasms • ECOG PS 0 or 1 • Locally advanced disease • Adequate haematological, hepatic and renal function Von Hoff et al. J Clin Oncol 2011.

Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: baseline demographics

Characteristic

Median age (range), years Female, n (%) ECOG PS, n (%) 0 1 Site of metastatic disease, n (%) Lung Liver Abdomen/peritoneal Other No of metastatic sites, n (%) 1 2  3 Baseline CA 19-9 levels, n (%) Normal* Elevated * cut-off for normal range: <37 u/mL

Paclitaxel albumin (mg/m 2 ) 100 (n=20)

62 (30 –86) 9 (45)

125 (n=44)

61 (28 –78) 25 (57)

150 (n=3)

69 (53 –72) 1 (33) 9 (45) 11 (55) 5 (25) 11 (55) 16 (80) 10 (50) 6 (30) 8 (40) 6 (30) (n=15) 2 (13) 13 (87) 22 (50) 22 (50) 18 (41) 34 (77) 38 (86) 12 (27) 2 (67) 1 (33) 1 (33) 2 (67) 2 (67) 1 (33) 8 (18) 18 (41) 18 (41) (n=37) 6 (16) 31 (84) 1 (33) 2 (67) 0 (n=2) 1 (50) 1 (50) Von Hoff et al. J Clin Oncol 2011.

Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: prior therapy Previous treatment, n (%) Chemotherapy Adjuvant therapy Adjuvant gemcitabine Adjuvant capecitabine Adjuvant 5-FU Adjuvant docetaxel Adjuvant erlotinib Median (range) time since adjuvant therapy, mo *data are for 1 patient

Paclitaxel albumin (mg/m 2 ) 100 (n=20) 125 (n=44) 150 (n=3)

3 (15) 3 (15) 1 (5) 1 (5) 2 (10) 0 0 64 (9-81) 10 (23) 10 (23) 5 (11) 4 (9) 1 (2) 2 (5) 0 12 (1-23) 1 (33) 1 (33) 0 0 0 0 1 (33) 5* Von Hoff et al. J Clin Oncol 2011.

• • • Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: safety The combination of paclitaxel albumin + gemcitabine was well tolerated The MTD was established as paclitaxel albumin 125 mg/m 2 + gemcitabine 1000 mg/m 2 both QW 3/4 – DLTs were sepsis and neutropenia Two patients in cohort 1 had dose delays and so this cohort was expanded to 20 pts

100 (n=20) Paclitaxel albumin (mg/m 2 ) 125 (n=44) 150 (n=3) Selected Grade 3/4 AEs, n (%)

Non-haematological Diarrhoea Fatigue Nausea Sensory neuropathy Vomiting Haematological Anaemia Leukopenia Neutropenia Febrile neutropenia Thrombocytopenia 3 (15) 1 (5) 0 1 (5) 0 1 (5) 4 (20) 10 (50) 2 (10) 3 (15) 1 (2) 12 (27) 1 (2) 9 (20) 3 (7) 6 (14) 24 (55) 32 (73) 1 (2) 12 (27) 0 1 (33) 0 0 0 0 1 (33) 2 (67) 0 0 Von Hoff et al. J Clin Oncol 2011.

Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: Treatment exposure Dose admin./planned Median number of Cycles Dose reduction (% pts)

nab-paclitaxel

81%

Gemcitabine

85% 6 (1-24) (20% 25% Cohort 125 mg/m²) (43% 31% Cohort 125 mg/m²) Dose delay (% pts) (70% 72% Cohort 125 mg/m²) 73% Von Hoff et al. J Clin Oncol 2011.

Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: response on CT scans Baseline

Post Rx 4.5 cm Baseline

2.5 cm

2 mo.

1.9 cm 3 mo.

resolved

resolved resolved

Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: response on CT scans Baseline: 9.10.2008 Cycle 7: 04.13.2009

Scan RECIST Total % Change Baseline Post Rx 1 19.4

15.2

Post Rx 2 Post Rx 3 12.6

10.7

Post Rx 4 10.4

Post Rx 5 9.3

Post Rx 6 Post Rx 7 9.6

7.6

-21.6

-35.1

-44.8

-46.4

-52.1

-50.5

-60.8

Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: response on CT and PET scans

RECIST TOTAL SUV - glucose 11.7 cm 36.4

Baseline 6.3 cm 5.1

One month 0.0 cm 0 3 months

Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: rapid response on PET scans

Baseline 6 weeks

Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: efficacy n, % ORR CR PR SD PD DCR PFS* OS* 1-yr OS, % * Median, months (95% CI)

Paclitaxel albumin (mg/m 2 ) 125 (n=44) All dose levels (n=67)

21 (48) 0 21 (48) 9 (20) 7 (16) 30 (68) 7.9 (5.8

–11.0) 12.2 (8.9

–17.9) 48 31 (46) 3 (4) 28 (42) 12 (18) 15 (22) 43 (64) 7.1 (5.7

–8.0) 10.3 (8.4

–13.6) Von Hoff et al. J Clin Oncol 2011.

Paclitaxel albumin + gemcitabine in patients with metastatic pancreatic cancer: survival

100 Paclitaxel albumin 125 mg/m 2 (n=44) 75 50 12.2 months 25 0 0 3 6 9 12 15 18 21 Time (months) 24 27 30

Von Hoff et al. J Clin Oncol 2011.

Paclitaxel albumin + gemcitabine in patients with metastatic pancreatic cancer: FDG PET • • • FDG PET scans were available for 55 patients Median decrease in metabolic activity at 12 weeks: – 79% (all patients) Patients with a metabolic response (defined by EORTC as absence of FDG uptake) had a significantly improved OS: – Median OS: 20.1 vs 10.3 mo, p=0.01

100 75 50 10.2 months Incomplete metabolic responses (n=38) Complete metabolic responses (n=17) p=0.01

20.1 months 25 Complete Censored 0 0 3 6 9 12 15 18 21 24 27 30 Time (months)

Von Hoff et al. J Clin Oncol 2011.

Paclitaxel albumin + gemcitabine in patients with metastatic pancreatic cancer: CA19-9 • • • Rapid CA19-9 decreases after treatment initiation CA19 9 decrease ≥50% was observed in (78%) of patients with available CA19-9 levels Median max % change in 54 patients was 91%

CA19-9 levels correlated strongly with RR, PFS, and OS CA19-9 Classification ≥50% Decrease (n = 42) <50% Decrease (n = 12)

P

-values RR, n (%) 24 (57) 2 (17) 0.021

Median PFS, mo 8.7

3.6

0.004

Median OS, mo 12.3

6.2

<0.001

D. von Hoff et al. ASCO 2009 (Poster 4525).

Paclitaxel albumin + gemcitabine in patients with metastatic pancreatic cancer: SPARC • SPARC status was evaluated in 36 patients • A significantly longer OS was reported in the high SPARC vs low SPARC group – Median OS: 17.8 vs 8.1 mo, p=0.0431

• SPARC level remained a significant predictor for OS after adjusting for clinical covariates (eg age, sex, race, baseline CA 19-9) (p=0.041) • Stromal SPARC correlated with OS (p=0.013) but SPARC in tumour cells did not (p=0.15)

100 75 50 25 8.1 months Average z score ≥0, high SPARC (n=19) Average z score <0, low SPARC (n=17) p=0.0431

17.8 months 0 0 3 6 9 12 15 18 21 24 27 30 Time (months)

NOTE: No prospective studies have evaluated SPARC as a predictive biomarker of response. Further work is required to fully establish the value of SPARC as prognostic/predictive marker, and to standardize assay methods and scoring criteria Von Hoff et al. J Clin Oncol 2011.

Preclinical Study Results

N=11 patient derived xenografts Gemcitabine nabPaclitaxel nabPaclitaxel + gemcitabine Tumor Regression 2 (18%) 4 (36%) 7 (64%) Aggregate tumor regression response in individual xenografts 22 of 90 (24%) 34 of 95 (36%) 53 of 96 (55%)

Von Hoff, J Clin Oncol 2011

Effects in Tumor Stroma

Collagen Type I Immuno-staining Treatment group

Control

Profuse Desmoplastic Stroma

Gemcitabine nabPaclitaxel

Persisting Stroma Desmoplastic Stroma Depletion

GEM + nabPtx Dilated blood vessels x3 increase in mNestin

Von Hoff, J Clin Oncol 2011

Intratumor concentration of GEM

7500

Mean Gemcitabine concentration ng/g

5000 2500

Gemcitabine alone 2.8 fold increase nabPaclitaxel + Gemcitabine

0

Von Hoff, J Clin Oncol 2011

Maximum Tolerated Dose Recommended Dose for Phase II

Gemcitabine 1000 mg/m 2 iv nabPaclitaxel 125 mg/m2 iv 1 Week 1 8 Week 2 15 Week 3 22 Days Week 4 28

Von Hoff, J Clin Oncol 2011

Paclitaxel albumin + gemcitabine in patients with metastatic pancreatic cancer: conclusions • nab-paclitaxel+ gemcitabine was generally well tolerated and demonstrated clinical activity in patients with metastatic pancreatic cancer • MTD established as 125 mg/m 2 mg/m 2 gemcitabine QW 3/4 nab-paclitaxel + 1000 • SPARC positivity (in stroma) was a significant independent predictor of OS (p=0.041) in nab-paclitaxel + gemcitabine-treated patients • Decrease in CA19-9 levels from baseline was an independent prognostic factor for OS in nab-paclitaxel + gemcitabine-treated patients Von Hoff et al. J Clin Oncol 2011.

Completed clinical studies of paclitaxel albumin in advanced/metastatic pancreatic cancer

Study design Treatment Phase II, open-label study in patients with advanced, unresectable or metastatic pancreatic cancer who failed first-line treatment with gemcitabine-based therapy 1 Paclitaxel albumin 100 mg/m 2 QW 3/4 Phase I dose escalation study in patients with advanced, unresectable or metastatic pancreatic cancer 2 Cohort A: paclitaxel albumin 100 mg/m 2 QW 3/4 + vandetanib 100-300 mg QD Cohort B: paclitaxel albumin 260 mg/m 2 Q3W + vandetanib 100,-300 mg QD No. of pts 19 29 Study endpoints Primary: OS rate at 6 mo Secondary: RR, PFS, safety Other: SPARC expression on pretreatment samples, CA 19-9 at baselines and every 2 cycles Primary: MTD of vandetanib in combination with paclitaxel albumin Secondary: Safety, preliminary antitumour activity

1. Hosein et al. ASCO 2010 (abstract 4120); 2. El-Khoueiry et al. ASCO 2011 (abstract 4124); 3. Von Hoff et al. J Clin Oncol 2011.

Paclitaxel albumin in patients with gemcitabine refractory advanced pancreatic cancer: efficacy

Best response (RECIST)

PR SD Clinical benefit rate (PR+SD) PD

n (%)

1 (5.3) 6 (31.6) 7 (36.8) 12 (63.2)

95% CI

0.1-26 12.6-56.6

16.3-61.6

38.4-83.7

Timepoint, mo

3 6 9 12

Median PFS, % (95% CI)

31.6 (12.9-52.2) 15.8 (3.9-34.9) 5.3 (0.4-21.4) 5.3 (0.4-21.4)

1.6 (1.5-3.4) OS, % (95% CI)

73.7 (47.9-88.1) 57.9 (33.2-76.3) 47.4 (24.4-67.3) 36.8 (16.5-57.5)

7.3 (2.8-15.8) 37% of patients derived clinical benefit and 21% remained on therapy for



6 months, suggesting paclitaxel albumin is active in this setting

Hosein, et al. ASCO 2010 (abstract 4120).

Paclitaxel albumin in patients with gemcitabine refractory advanced pancreatic cancer: safety

Event Haematological

Neutropenia Anaemia Thrombocytopenia Neutropenic fever

Non-haematological

Fatigue Nausea Alopecia Anorexia Hypocalcaemia Vomitting Neuropathy

Grade 1/2, n (%)

8 (42.1) 11 (57.9) 1 (5.2) 0 12 (63.1) 12 (63.1) 12 (63.1) 9 (47.4) 7 (36.8) 5 (26.3) 3 (15.8)

Grade 3/4, n (%)

5 (26.3) 1 (10.5) 0 2 (10.5) 0 0 0 1 (5.2) 0 0

Paclitaxel albumin was well tolerated in this group of patients

Hosein, et al. ASCO 2010 (abstract 4120).

A Phase II Trial of nab

‐

Paclitaxel in Patients With Advanced Pancreatic Cancer Who Have Progressed on Gemcitabine

‐

Based Therapy

Study Design / Eligibility Criteria Single-institution phase II open label trial Treatment:

nab

-P 100 mg/m2 IV over 30 minutes on days 1, 8 and 15 of a 28-day cycle Contrast CT at baseline and every 2 cycles Age > 18 Locally advanced, unresectable or metastatic pancreatic ductal carcinoma ECOG PS 0-2 Good organ function Progressed within 6 months of gemcitabine Endpoints 6-month overall survival rate Response rate by RECIST criteria / Progression-free survival Safety and tolerability CA19-9 at baseline and every 2 cycles /SPARC immunohistochemistry (IHC) on available pre-treatment tumor specimens performed at a reference lab

Hosein et al. Presented at ASCO Annual Meeting, 2010; Abstract #4120

Best Response by RECIST Criteria Partial response (PR) Stable disease (SD) Clinical benefit (PR + SD) Progressive disease (PD)

All Patients (N = 19)

n (%) 95% CI 1 (5.3) 6 (31.6) 0.1 - 26 12.6 - 56.6

7 (36.8) 12 (63.2) 16.3 - 61.6

38.4 - 83.7

CT Scan Showing Early Response in a Target Lesion in the Lung

Baseline After 2 Cycles of Therapy Hosein et al. Presented at ASCO Annual Meeting, 2010; Abstract #4120

Survival

(N = 19; Events = 17; Deaths = 11) Time Point (Months)

3 6 9 12 Median

PFS % (95% CI)

31.6 (12.9 - 52.2) 15.8 (3.9 - 34.9) 5.3 (0.4 - 21.4) 5.3 (0.4 - 21.4) 1.6 (1.5 - 3.4)

OS % (95%CI)

73.7 (47.9 - 88.1) 57.9 (33.2 - 76.3) 47.4 (24.4 - 67.3) 36.8 (16.5 - 57.5) 7.3 (2.8 - 15.8)

Hosein et al. Presented at ASCO Annual Meeting, 2010; Abstract #4120

Conclusions

nab

-P was well tolerated in patients with advanced pancreatic cancer who had progressed on gemcitabine based therapy.

37% of patients treated in this phase II trial derived clinical benefit (partial response or disease stabilization) and 21% remained on therapy for at least 6 months suggesting that

nab

-P has antitumor activity in this setting.

There was a trend towards CA19-9 being a predictor of clinical benefit, PFS and OS, but this did not reach statistical significance.

Hosein et al. Presented at ASCO Annual Meeting, 2010; Abstract #4120

Paclitaxel albumin + vandetanib in patients with advanced pancreatic cancer • Treatment – Cohort A: paclitaxel albumin 100 mg/m 2 QW 3/4 + V 100, 200 or 300 mg po QD – Cohort B: paclitaxel albumin 260 mg/m 2 Q3W + V 100, 200 or 300 mg po QD • Results – MTD of V was the maximum planned dose in each cohort (300 mg QD) – DLTs • Cohort A: 3 DLTs (1 at each dose level) – 2 patients with grade 3 rash and 1 patient with grade 4 neutropenia, grade 3 mucositis, prolonged QTc • Cohort B: No DLTs at any dose level – Preliminary efficacy results of all evaluable patients (n=22) • PR: 6 (27%), SD: 10 (45%), PD: 6 (27%) • Median PFS: 5.3 months (95% CI 3.7- 7.3) • Median OS: 8.2 months (95% CI: 6.2-11.5) • Conclusions – Both schedules were well tolerated with promising preliminary efficacy indicated El-Khoueiry et al. ASCO 2011 (abstract 4124).

NCCN guidelines V1 2012

clinical overview in pancreatic cancer

NCCN guidelines V1 2012: Treatment of locally advanced unresectable disease Good PS • Clinical trial preferred • FOLFIRINOX* • Gemcitabine* • Gemcitabine-based combination therapy* • Gemcitabine + erlotinib* • Capecitabine* • Capecitabine*  consolidation CRT (selected pts without systemic metastases) Good PS • Clinical trial preferred • FU-based chemotherapy* (if previously treated with gemcitabine-based therapy) • Gemcitabine-based chemotherapy* (if previously treated with FU-based therapy) • CRT (if not previously given and in primary site is the sole site of progression Poor PS • BSC Poor PS • Gemcitabine* • BSC *See principles of chemotherapy

NCCN guidelines V1 2012: Treatment of metastatic disease Good PS • Clinical trial preferred • FOLFIRINOX* • Gemcitabine* • Gemcitabine-based combination therapy* • Gemcitabine + erlotinib* • Capecitabine* Poor PS • Gemcitabine* • BSC *See principles of chemotherapy • Clinical trial preferred • FU-based chemotherapy* (if previously treated with gemcitabine-based therapy) • Gemcitabine-based chemotherapy* (if previously treated with FU-based therapy) • BSC • Clinical trial

NCCN guidelines V1 2012: Recurrence after resection Local recurrence • Clinical trial preferred • CRT (if not previously done) • Alternative systemic chemotherapy* • BSC Consider biopsy for confirmation Metastatic disease with/without local recurrence >6 mo since completion of primary tx <6 mo since completion of primary tx • Clinical trial preferred • Systemic therapy as previously administered* • Alternative systemic chemotherapy* • BSC • Clinical trial preferred • Switch to alternative systemic chemotherapy* • BSC *See principles of chemotherapy

NCCN guidelines V1 2012: Principles of chemotherapy

Metastatic disease

• Acceptable monotherapy: – Gemcitabine (category 1) – – FDR gemcitabine (category 2B) Capecitabine (category 2B) • Acceptable combination therapies for patients with a good PS: – Gemcitabine + erlotinib (category 1) – – FOLFIRINOX (category 1) Gemcitabine + capecitabine – – – – Gemcitabine + cisplatin (especially for patients with hereditary cancers) (category 2A) Fixed-dose rate gemcitabine, docetaxel, capecitabine (GTX regimen) (category 2B)

Gemcitabine + paclitaxel albumin (category 2B)

Fluoropyrimidine + oxaliplatin (category 2B)

Locally advanced disease

• Depending on PS, mono-

or combination systemic chemotherapy, as above,

may be considered as initial therapy prior to CRT for appropriate patients with locally advanced, unresectable disease

Category 1:

The recommendation is based on high-level evidence (e.g. randomized controlled trials) and there is uniform NCCN consensus.

Category 2A:

The recommendation is based on lower-level evidence and there is uniform NCCN consensus.

Category 2B:

The recommendation is based on lower-level evidence and there is non uniform NCCN consensus (but no major disagreement).

Category 3:

The recommendation is based on any level of evidence but reflects major disagreement.

•

Ongoing Phase III Study nab

-Paclitaxel + gemcitabine vs gemcitabine alone for advanced pancreatic cancer (Von Hoff)

A Randomized Phase III Study of Weekly nab-Paclitaxel plus Gemcitabine versus Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the Pancreas

•

Primary Objective

– To evaluate efficacy of the combination of

nab

-paclitaxel and gemcitabine versus gemcitabine alone in improving

overall survival

in patients with metastatic adenocarcinoma of the pancreas •

Secondary Objectives

– To evaluate the following: • Objective tumor response and progression-free survival (PFS) according to RECIST criteria • Safety and tolerability • Functional tumor response according to EORTC criteria • Change in serum CA19-9 and plasma SPARC levels • SPARC in tumor tissue and peripheral blood and determine its possible correlation with efficacy outcomes

Study Design R A N D O M I Z E (1:1) N = 842 Intent-To-Treat (ITT) Patients nab-Paclitaxel 125 mg/m 2 (No Premedication) + Gemcitabine 1000 mg/m 2 Weekly, 3 of 4 Weeks Gemcitabine 1000 mg/m 2 Weekly, 7 of 8 Weeks (Cycle 1) then Weekly, 3 of 4 Weeks (Cycle 2 Onward)