ST1968 Intravenous (Weekly) in Solid Tumors

Phase I Dose Finding and Pharmacokinetic Study of the Intravenous Camptothecin ST1968 in Patients With Solid Tumors

ST1968 is a novel camptothecin derivative which interacts with topoisomerase I-DNA complex, inducing S-Phase specific cytotoxicity. It is endowed with a potent antitumor activity and an increased Therapeutic Index with respect to the clinically used analogues (i.e.irinotecan and topotecan) in some xenograft models (ovary, colon, head & neck, cervix). Anti-tumor activity has been also noted in platinum resistant ovarian cell xenografts and in topoisomerase I mutant prostate cell lines. The acceptable toxicity profile in animals and the activity in camptothecin-resistant cell lines make ST1968 a good candidate for clinical trials.

Study Overview

• Status: Completed
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: ST1968

Detailed Description

Multicenter, open label, uncontrolled Phase I pharmacokinetic trial to determine the Maximum Tolerated Dose (MTD) of ST1968 given intravenously (I.V.) once every week for 2 consecutive weeks every 3 weeks and the MTD of ST1968 given I.V. once every 3 weeks. A starting dose of 1.5mg/m2 given as a flat dose of 2.5mg is defined, given once on Day 1, Day 8 every 21 Days (D1, D8 Q21D schedule), over 2 h. Starting dose for the Day 1 every 21 Days (D1 Q21D schedule) has to be determined from the MTD of D1, D8 Q21D schedule.

Plasma, urine pharmacokinetics in all patients (minimum of 3 pts for each cohort) during the first cycle of treatment and in at least 6 patients at the Recommended Dose (RD).

During the study any hints of anti-tumor activity will also be evaluated by RECIST criteria.

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histological/cytological diagnosis of solid tumors for which therapy of proven efficacy does not exist.
• Preferably measurable disease
• ECOG performance status ≤ 1.
• Age ≥ 18 years.
• Ongoing toxicity associated with prior anticancer therapy ≤ grade 1 (NCI-CTCAE V3.0).
• Maximum of 2 prior chemotherapy lines for advanced disease (not including neoadjuvant or adjuvant chemotherapy)
• Adequate hematological, liver and renal function
• Hemoglobin ≥ 9 g/dl; ANC ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L;
• Serum bilirubin ≤ upper normal limit (UNL). ALT, AST ≤ UNL but ≤ 2.5 x UNL in case of liver metastases; alkaline phosphatase (liver isoenzyme fraction) ≤ UNL or ≤ 1.5xULN in case of liver metastases; albumin within normal limits;
• Creatinine ≤1.5 mg/dl or calculated creatinine clearance ≥ 60 ml/min.
• Life expectancy of at least 3 months
• Capacity of understanding the nature of the trial and giving written informed consent.

Exclusion Criteria:

• Less than 4 weeks since last chemotherapy, radiotherapy or prior investigational therapy. Less than 2 weeks since last hormone or immunotherapy or signal transduction therapy.
• Active infection.
• Presence of cirrhosis or chronic hepatitis
• Presence of serious cardiac (congestive heart failure, angina pectoris, myocardial infarction within one year prior to study entry, uncontrolled hypertension or arrhythmia), neurological or psychiatric disorder.
• Presence of uncontrolled intercurrent illness or any condition which in the judgement of the investigator would place the subject at undue risk or interfere with the results of the study.
• Symptomatic brain metastases (this does not include primary brain tumors) or leptomeningeal disease.
• Pregnancy or lactation or unwillingness to use adequate method of birth control

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ST1968; ST1968 once a week for 2 weeks every 3 weeks (protocol amendment: once every 3 weeks --------------------------------------------------------------------------------	Drug: ST1968; ST1968 once a week for 2 weeks every 3 weeks (protocol amendment: once every 3 weeks; Other Names: Namitecan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) of ST1968 given I.V. once every week for 2 consecutive weeks every 3 weeks and MTD of ST1968 given I.V. once every 3 weeks	2/6 patients with a Dose Limiting Toxicity (DLT) at the first cycle (21 days)	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events, physical examination and laboratory tests (hematology and biochemistry) as a measure of safety and tolerability	safety assessments (routine physical examinations and laboratory evaluations) and severity of adverse events based on the NCI-Common Terminology Criteria for Adverse Events V. 3.0 (NCI-CTCAE)	21 days of each cycle of therapy
Tumor response	objective tumor response based on RECIST criteria	4 weeks
Tmax, Cmax, AUC0-24, AUC-last, T1/2,CL	full blood and urine PK	21 days

Collaborators and Investigators

• Sponsor: sigma-tau i.f.r. S.p.A.
• Collaborators: Southern Europe New Drug Organization
• Investigators: Study Chair: Dagmar Hess, MD, Kantonsspital St. Gallen, 9700 St. Gallen - Switzerland

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: June 12, 2012
• First Submitted That Met QC Criteria: December 10, 2012
• First Posted (Estimate): December 12, 2012

Study Record Updates

• Last Update Posted (Estimate): December 12, 2012
• Last Update Submitted That Met QC Criteria: December 10, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: Solid tumors; Camptothecin; ST1968; Topoisomerase I
• Additional Relevant MeSH Terms: Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Namitecan
• Other Study ID Numbers: ST1968-DM-06-001