Solid Tumors
Conditions
Keywords
ST1968, Camptothecin, Solid tumors, Topoisomerase I
Brief summary
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.
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.
Interventions
DRUGST1968
ST1968 once a week for 2 weeks every 3 weeks (protocol amendment: once every 3 weeks
Sponsors
Southern Europe New Drug Organization
sigma-tau i.f.r. S.p.A.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 21 days | 2/6 patients with a Dose Limiting Toxicity (DLT) at the first cycle (21 days) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events, physical examination and laboratory tests (hematology and biochemistry) as a measure of safety and tolerability | 21 days of each cycle of therapy | 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) |
| Tumor response | 4 weeks | objective tumor response based on RECIST criteria |
| Tmax, Cmax, AUC0-24, AUC-last, T1/2,CL | 21 days | full blood and urine PK |
Outcome results
None listed