Open-label phase II study of ZD0473 in patients with metastatic hormone-refractory prostate cancer

622

621 MECHANISMS PROSTATE

OF BISPHOSPHONATE

INDUCED

IN

APOPTOSIS

CANCER

Oades Grenvillez,

OPEN-LABEL METASTATIC

Senaratne

Siddhika’,

Clarke Ian’, Kirby Roger?, Colston

‘OGEM, St George’s Hospital Medical School, London, United Kingdom, St George’s Hospital, London, United Kingdom

ZUrology.

Cell growth and viability were measured with SRB DNA fragmentation and caspase 3 activity were based methods. Western blotting for Ras, bcl-2 and

RESULTS: The bisphosphonates pamidronate and zoledronate inhibited cell growth and viability in all three cell lines (DUl45, PC3 and LNCaP). DU145 cells treated with zoledronate were chosen as a model. Growth inhibitory effects were associated with morphological changes, induction of DNA fragmentation and a decrease in the bcl-Zibax ratio all key features of apoptotic cell death. Caspase 3 activity was demonstrated in DU 145 cells treated with zoledronate, and preincubation of these cells with caspase inhibitors attenuated the cytotoxic effects of zoledronate suggesting a caspase dependent mechanism of apoptosis. It has previously been reported that bisphosphonate induced apoptosis in myeloma cells is a result of inhibition of the mevalonate pathway and Ras prenylation, prenylated Ras being the biologically active form. We have shown that this may be an important action of bisphosphonates in prostate cancer. Bisphosphonate induced apoptosis in DU145 cells is prevented by co-treatment with famesol (which bypasses the mevalonate pathway and allows Ras prenylation). Western blot analysis has also shown a reduction in prenylated Ras in treated cells. CONCLUSION: These findings raise the possibility that the observed clinical responses of patients with prostate cancer skeletal metastasis treated with bisphosphonates may be due to inhibition of cell growth and direct induction of prostate cancer cell death. The results of ongoing trials with clodronate are eagerly awaited. The advent of newer and more potent bisphosphonates such as zoledronate may raise new strategies for combating metastatic disease in the future.

‘Velindre Plymouth.

II STUDY

OF ZD0473

IN PATIENTS WITH PROSTATE CANCER

HORMONE-REFRACTORY

Tvrrell Christooher’,

Kay’

INTRODUCTION & OBJECTIVES: Skeletal metastases are a major cause of morbidity in patients with metastatic prostate cancer. A number of clinical trials have demonstrated that bisphosphonates have clinical value in the management of these patients. Currently, the mechanisms by which these compounds exert their effects are poorly understood. We have studied the effects of these compounds on three prostate cancer cell lines: DUl45, PC3 and LNCaP. MATERIALS & METHODS: and MTS assays respectively. measured using flow cytometry bax was performed.

PHASE

Bullard Sheila*, Barber Jim’, Graham John’

Hospital, Cardiff, United Kingdom. *Plymouth Oncology Centre. United Kingdom, ?Bristol Oncology Centre. Bristol, United Kingdom

INTRODUCTION & OBJECTIVES: Hormone-refractory prostate cancer (HRPC) can be treated with cytotoxic agents, but objective response (OR) or stable disease (SD) is often not achieved with current platinum regimens. ZD0473 is a new generation platinum agent that, in preclinical studies, shows evidence of an extended spectrum of antitumour activity and overcomes resistance mechanisms. This Phase II study was designed to evaluate the response rate, duration of response, and tolerability of ZD0473 as monotherapy for patients with HRPC. A response in 2 4 out of 29 patients was required to show drug activity. MATERIALS & METHODS: patients received ZD0473 120 mgim: (I-h iv infusion on day I, q 3 weeks). Toxicity was assessed using the NCI-CTC. A CT scan was performed q 6 weeks and evaluated by an independent reviewer. RECIST response evaluation criteria were used for assessment until progression. A 2-stage recruitment was planned (recruitment to stage 2 dependent on z I out of IO OR being observed in stage I). All patients had histologically confirmed adenocarcinoma of the prostate, with measurable lymph node disease. Hormone-resistant disease was confirmed by serological, radiographical or symptomatic progression. Patients had not received flutamide or bicalutamide within the previous 4 or 6 weeks, respectively. RESULTS: To date, I7 patients (median age 64 years [range 56-831; WHO performance status O/l) have been recruited. A total of 59 cycles of ZDO473 have been administered (median per patient of 4 [range I-61); the dose was reduced in 3 patients. Fourteen patients were evaluable for tolerability. The main dose-limiting toxicities attributed, or possibly attributed, to ZD0473 included grade (G) 4 neutropenia (2 episodes), G3 neutropenia (6) and G3 thrombocytopenia (13). There were no G4 episodes of non-haematological toxicity; G3 included constipation, nausea, fatigue and dehydration (I episode of each). There was no evidence of oto-, neuro- or nephrotoxicity. Three patients died (I 2,20 and 40 weeks from the end of treatment); no deaths were treatment-related, Of I3 patients evaluated for activity, 4 had a partial response (PR). All 4 PRs had a reduction in prostate-specific antigen (PSA) 50%. Seven additional patients had SD on radiographical assessment, sustained for 3 months in 5 patients, whilst 2 patients had disease progression. CONCLUSION: Early data indicate that ZD0473 has manageable tolerability at a dose of 120 mg/m’. The objective of a response in 4 patients has been achieved. and this, in addition to the reduction in PSA. suggests that ZD0473 is active in patients with HRPC with metastatic lymph node involvement.

624

623 DOCETAXEL PROSTATE

COMBINATION

IN

PHOSPHATE

IN

PATIENTS

WITH

WITH

ESTRAMUSTINE

HORMONE

CHEMOTHERAPY WITH A WEEKLY ADMINISTRATION OF DOCETAXEL FOR METASTATIC HORMONE REFRACTORY PROSTATE CANCER (HRPC). EVALUATION OF TOLERANCE, QUALITY OF LIFE (QOL), AND CLINICAL BENEFIT

REFRACTORY

CANCER (HRPC): A PHASE II STUDY

Gravis Gwenaelle’, Bladou Frank*, Salem Naji’, Macquar Genevieve’, Serment Gerard’. Camerlo Jacques’. Maranin Dominique’, Viens Patrice’

Oncology,

Hospital S. Bernardo,

INTRODUCTION are active

drugs

efficacy

& OBJECTIVES:

Docetaxel

in patients with HRPC. This trial was designed

& METHODS:

Eligibility

(Hopkins classification)

HRPC, progressive

age range

ECOG-PS

65-91

patients.

(70%)

mgiday

years,

Patients

included

phosphate

to evaluate

20 patients

disease manifested

O-2. Bone metastases

received

the

for 5 days, and metilprednisolone

with

D2

by a rising PSA,

were present in l4/20

every 21 days estramustine

before and until the end of treatment;

phosphate

I6 mgiday, per OS, starting

on day 2, docetaxel60

280

8 days

IV one hour

mgima,

All patients started G-CSF on day 5.

infusion.

RESULTS: treatment

A total was well

anaemia,

of I I7 cycles tolerated,

vomiting,

in cycles

response.

alopecia;

(median

with

grade

and grade

or dose reductions.

In 6 patients

(30%)

PSA

(20%)

by >75%,

also

in 4 patients

>25%;

2 patients

(IO%)

progressed

CONCLUSION: reduce

and estramustine

and safety of this combination.

MATERIALS

delay

’ 13, lnstitut Paoli-Calmettes. Marseille, France

Setubal, Portugal

We conclude

PSA. diminish

European

5.8) were l-2 toxicity

3 dermatologic

Nineteen

Urology Supplements

toxicity.

patients

levels

decreased

(20%)

by >SO%,

Overall, including

There

was no

were evaluable

by >90%,

for

in 4 patients

in 3 patients

(15%)

by

and were asymptomatic.

that this combination

measurable

administrated. (NCIC-CTG),

disease

and improve

is well tolerated quality

1 (2002) No. 1, pp. 158

of life.

and can

Marseille,

France,

213, CHRU

Hopital

Salvator.

INTRODUCTION & OBJECTIVES: In this phase II study we investigated the clinical benefit, tolerability, and impact on Quality of Life (QoL) of docetaxel (D) in patients with metastatic HRPC. MATERIALS & METHODS: Twenty-three patients with progressive and symptomatic metastatic HRPC were enrolled. To decrease toxicity in elderly patients. D was administered weekly at 35 mgim? 1.V for 6 consecutive weeks (=I cycle). followed by 2 weeks rest for a maximum of 24 weeks (4 cycles). Activity was measured by clinical benefit and evaluated by analgesic consumption. pain intensity and Karnofsky Performance Status (KPS). Clinical benefit required a sustained (4. weeks) improvement in at least one parameter without worsening in any others. Other measures included QoL using the EORTC QLQC30, changes in PSA level and tumoural response for evaluable patients. RESULTS: Thirteen out of 23 patients had been previously treated with chemotherapy. Pain measurement (analgesic consumption and KPS) was evaluated before D, each week during D infusion and at the end of treatment. Pain response wa’i observed for 45% of patients with no significant modification for KPS (median KPS: 80%). Patients QoL was measured before treatment, at day I of each cycle and at the end of treatment. Patients compliance in completion of questionnaires was high (92%). Compared to baseline, all EORTC QLQC30 scores improved after 2 cycles of D (p=O.O07 for pain score and p=O.O04 for constipation score). In subsequent cycles. results showed a deterioration of fatigue, dyspnea and physical functioning scores at the last QL evaluation (p=O.OOS, p=O.O12 and p=O.O4 respectively) compared to baseline. 42% of patients achieved at least a 50% decrease in PSA level. Toxicity was mild: mucositis grade IV: I patient, alopecia grade 111: 4 patients. asthenia grade III: I patient, painimyalgia grade III: 3 patients. diarrhea grade III: I patient, hepatitic toxicity grade III: I patient, nails changes: 3 patients. No patients experienced hematologic toxicity grade > 11. CONCLUSION: Weekly D: decreased pain intensity well tolerated. These preliminary results show activity clinical benefit.

and improved QoL and was of weekly D as measured by