EORTC OSN/CTOS11

Safety of Caelyx combined with ifosfamide in previously untreated

adult patients with advanced or metastatic soft tissue sarcomas.

Final data of an EORTC phase I study.

O.S. Nielsen, P. Reichardt, D. Pink, J. Lindegaard, S. Daugaard, C. Hermans, K. Stoichkov,

M. van Glabbeke, I. Judson.

CTOS 11th Annual Meeting 2005Boca Raton, Florida

EORTC OSN/CTOS11

BACKGROUND

Caelyx (pegylated liposomal doxorubicin) 40 mg/m2 q 4 weeks seems to have the same efficacy in adult soft tissue sarcomas (STS) as doxorubicin with an improved toxicity profile (EORTC and others). It could thus be an alternative to doxorubicin and may well be easier to combine with agents such as Ifosfamide.

EORTC OSN/CTOS11

Study design Main eligibility criteria: Progression within 6 weeks, no previous

chemotherapy, PFS < 2, 18-70 years and adequate cardiac, liver, renal and haematological function.

Treatment: Caelyx as a 1 hr i.v. infusion d1 and Ifosfamide+mesna as a 4-hr i.v. infusion d1-3 every 3 weeks:

Dose level I: Caelyx 30 mg/m² + Ifosfamide 1.7 g/m² d 1-3 Dose level 2: Caelyx 30 mg/m² + Ifosfamide 2 g/m² d 1-3 Dose level 3: Caelyx 30 mg/m² + Ifosfamide 2.5 g/m² d 1-3 Dose level 4: Caelyx 30 mg/m² + Ifosfamide 3 g/m² d 1-3 Dose level 5: Caelyx 40 mg/m² + Ifosfamide 3 g/m² d 1-3

Cohorts of 3 pts/dose level. DLT 1/3 pts a new cohort added. Evaluation after 2 treatment cycles. Non-evaluable pts replaced.

Max. 6 cycles

EORTC OSN/CTOS11

ENDPOINTS

Main endpoint: Toxicity (CTC).

Occurrence of DLT: ANC < 0.5 x 109 lasting ≥ 7 days or ≥ 3 days + fever at least 38.5 oC, grade 4 thrombocytopenia, any grade 3-4 toxicity except nausea, vomiting and alopecia, and any toxicity requiring a 2 week treatment delay.

Secondary endpoint: Objective response in patients with measurable disease

(RECIST).

EORTC OSN/CTOS11

ACCRUAL

Dose level

1

Dose level

2

Dose level

3

Dose level

4

Dose level

5

Total

Aarhus 2 2 2 3 2 11 Berlin 2 6 1 3 5 17 Total 4 8 3 6 7 28

5 pts not evaluable for response (only 1 cycle of treatment)

EORTC OSN/CTOS11

Baseline characteristics

• Male/female: 12/16• Median age: 60 years (29-69)• PS: 75% PS 1• Leiomyos: 10 pts

EORTC OSN/CTOS11

RESULTS: Dose Limiting Toxicities

Dose level Toxicity Type DLT

5 Dyspnea + allergic reaction Clinical

5 Thrombocytopenia + renal insufficiency Combination

5 Febrile neutropenia Combination

5 Febrile neutropenia Combination

5 Febrile Neutropenia Combination

5 Thrombocytopenia Combination

Recommended dose level = 4: (Caelyx

30 mg/m² + Ifosfamide 3 g/m² d 1-3)

EORTC OSN/CTOS11

Hematological toxicitiesRecommended dose level 4

Grade 0 1 2 3 4 Total

Leucopenia 2 1 1 2 6

Granulocytopenia 2 1 1 2 6

Thrombocytopenia 5 1 6

Anaemia 1 5 6

EORTC OSN/CTOS11

Non-hematological toxicitiesRecommended dose level 4

Grade 0 1 2 3 4 Total

Oedema 2 2 2 6

Fatigue 4 2 6

PPE 6 6

Other skin tox 4 1 1 6

EORTC OSN/CTOS11

Efficacy evaluation

Dose level 1 2 3 4 5 Total PR 2 2

NC 3 5 2 3 3 16

PD 3 1 4

ED-PD 1 1

Uneval. 1 2 1 1 5

Total 4 8 4 6 7 28 Currently, 4 pts alive + progression free, 5 pts alive + PD. All deaths were due to progression.

EORTC OSN/CTOS11

Overall and progression free survival

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

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Failure19 28 23 18 12 9 7 4 3 1 124 28 18 10 4 2 2 1 1 0 0

OSPFS

• Median OS ~ 11 months• Median PFS ~ 6 months

EORTC OSN/CTOS11

CONCLUSIONS

• 6 DLTs were observed amongst the 7 pts treated at dose level 5. No DLT was reported at any other dose level. Therefore, dose level 4 is the recommended dose for further trial, i.e. Caelyx 30 mg/m² + Ifosfamide 3 g/m² d 1-3.

• 2 PR were observed; the estimated median PFS was ~ 6 months (equivalent to 1st line doxorubicin based therapy), and the estimated median survival approximately 11 months.

• Combined Caelyx and Ifosfamide seems to be feasible in patients with advanced soft tissue sarcomas and this combination may allow to give Ifosfamide at a dosage similar to that used when given alone.

BUT ……

• PR at dose level 5 (not level 4)!

• Caelyx is expensive!

• Hematopoietic growth factors?

• Further data needed – if possib

le.