A Pitoval, Multicentre, Randomised, Double-Blind, Placebo-Controlled Study of Marimastat as a Maintenance Therapy in Patients with Inoperable Gastric Adenocarcinoma

A Pitoval, Multicentre, Randomised, Double-Blind, Placebo-Controlled Study of Marimastat as a Maintenance Therapy in Patients with Inoperable Gastric Adenocarcinoma

Introduction

The treatment of the gastric adenocarcinoma, especially the inoperable gastric adenocarcinoma, is problematic and most of chemotherapies are ineffective. Marimastat (BB-2516) is an inhibitor of the family of enzymes known as matrix metalloproteinases. Theses enzymes are believed to be responsible for the breakdown of extracellular matrix and the disruption of tissue architecture that accompanies malignant growth and metastasis. Preclinical studies have shown that in animal models of malignancy, matrix metalloproteinase inhibitors can restrict the growth and regional spread of solid tumors, inhibit metastatic spread and block the process of tumor neovascularisation.

Primary objective

To compare the effect of marimastat versus placebo on overall survival of patients with inoperable gastric adenocarinoma

Secondary

To asses the effect of marimastat on time to disease progression

To assess safety and tolerability

To assess quality of life

To characterise pharmacokinetic parameters further

Organization

St. Gretschel, M.D.

Universit�tsklinikum Charit� der Humboldt-Universit�t Berlin
Campus Berlin-Buch
Klinik f�r Chirurgie und Chirurgische Onkologie
Lindenberger Weg 80
13122 Berlin

Tel.: 030-9417-1400
Fax: 030-9417-1404

Inclusion criteria

histologically- or cytologically-confirmed gastric adenocarcinoma
locally advanced or metastatic disease which is considered inoperable
If non-curative surgical resection has been performed:
There must be histological or radiological confirmation of residual malignant disease
If chemotherapy has not been administered entry into the study must occur withn 4 weeks of the surgery
If chemotherapy has been given:
Received first-line chemotherapy which contained 5-fluorouracil,
documented response or stable disease following chemotherapy
last dose of chemotherapy must be at least 2 weeks ago, but no more than 6 weeks ago
Age >/= 18 years
Signed, informed consent to take part in the study
Life expectancy >/= 3 months
ECOG score 0 or 1

Exclusion criteria

primary cancer under investigation is oesophageal, either squamous or adenocarcinoma
previous or concurrent malignancy, with the exception of curatively resected basal cell carcinoma
Received any investigational agent in the 4 weeks before the start of the study, with the exception of trial chemotherapy regimes
Received more than one regimen of cytotoxic chemotherapy
Received any other anti-neoplastic therapy. This includes hormonal therapy (specifically gastrin antagonists) radiotherapy, immunotherapy or biological therapy
open surgery within 2 weeks, or laparoscopy within 1 week prior to randomisation, or planned elective surgery
Granulocytes </= 0.5 x 10⁹/l (</= 500/�l)
Platelets </= 50 x 10⁹/l (</=50000/�l)
Serum creatinine >/= 1.5 times the upper limit of normal
AST/ALT >/=1.5 times upper limits of normal
Bilirubin >/= 2 times upper limits of normal
Previously received marimastat (BB-2516) or batimastat
Any acute illness within one week of the start of the study, or any other illness judged by the Investigator as likely to interfere with study outcome or th preclude prolonged marimastat administration
pregnant or lactating women, women of child-bearing potential who have not had a negative pregnancy test prior to minimisation, men or women of child-producing potential unwilling to use a medically-approved method of contraception while participating in this study.

Study design

Study completion is defined as the time when 85% of patients in either group have died, or 18 months following the enrolement of the last patient, whichever occurs first. Study completion for each individual patient is defined as completion of all study assessments up to an including 18 months. Marimastat and placebo will be supplied in capsules, marimastat 10 mg or placebo will be taken orally twice daily, with or after morning and evening meals.

The following procedures will be performed prior to and during treatment as specified:

	Screening	Day 0	Week 6	Months 3,6,9,12,15,18 Early termination and Extended treatment*	Follow-up: 1 month after last dose	Follow-up: every 3 months
Patient consent	X
Medical history and height	X
Physical exam and ECOG	X		X	X	X
Vital signs and weight	X		X	X	X
Haematology	X		X	X	X
Biochemistry	X		X	X	X
Urinalysis	X		X	X	X
CT-scan: abdomen/pelvis	X		X^a	X^a
CT scan or USS of liver	X^b		X^a	X^a
Quality of life		X	X	X	X
Minimisation	<----->
Plasma for PK assay		X^c	X^c	X^{c(month 3 only)}
Marimastat/placebo	<-------------------------------->
Concominant therapies	<---------------------------------------------------------------->
Adverse events	<---------------------------------------------------------------->
Study drug compliance			X	X
Survival information			X	X	X	X

*every 3 months until the last patient completes 18 months of treatment

^aif clinical suspicion of relapse

^bif previous LFTs/CT scans/US were abnormal

^cpre-dose

Coordination

P. M. Schlag, M.D., PhD

St. Gretschel, M.D.

Universit�tsklinikum Charit� der Humboldt-Universit�t Berlin
Campus Berlin-Buch
Klinik f�r Chirurgie und Chirurgische Onkologie
Lindenberger Weg 80
13122 Berlin

Tel.: 030-9417-1400
Fax: 030-9417-1404