TLD-1, a Novel Liposomal Doxorubicin, in Patients With Advanced Solid Tumors
Rekrutierend
NCT-Nummer:
NCT03387917
Studienbeginn:
November 2018
Letztes Update:
22.11.2023
Wirkstoff:
TLD-1, Caelyx
Indikation (Clinical Trials):
Neoplasms
Geschlecht:
Alle
Altersgruppe:
Erwachsene (18+)
Phase:
Phase 1
Sponsor:
Swiss Group for Clinical Cancer Research
Collaborator:
-
Studienleiter
Dagmar Hess, MD Study ChairCantonal Hospital of St. Gallen
Anastasios Stathis, MD Study DirectorIOSI, Ospedale San Giovanni
Markus Jörger, Prof Study DirectorCantonal Hospital of St. Gallen
Kontakt
Jana Musilova Kontakt: Phone: +41 31 389 91 91 E-Mail: trials@sakk.ch» Kontaktdaten anzeigen
Detailed Description: Despite impressive progress in the fields of surgical and immunological cancer therapies, most late-stage cancer treatments still heavily depend on conventional chemotherapeutics, which are often effective but also toxic, resulting in severe adverse effects limiting the dose and duration of therapy. Consequently, there remains a high unmet medical need for new innovative systemic treatments with an improved risk-benefit-profile. Doxorubicin is a potent anthracycline used as a systemic treatment against several solid tumor including breast, ovarian and bladder cancer, small cell lung cancer and various types of sarcoma. However, Doxorubicin use is often limited due to hematological and non-hematological toxicity including cumulative cardiotoxicity with myocardial damage. Cardiotoxicity has been substantially mitigated through the introduction of liposomal formulations such as Myocet and Caelyx/Doxil. Both products are associated with substantially lower rates of cardiac dysfunction during or post-treatment. Whereas Myocet's clinical use remains limited due to the intricate "bedside" reconstitution process, Caelyx has been associated with a high incidence of Palmar-Plantar Erythrodysesthesia (PPE) (also called hand-foot-syndrome), likely due to its long plasma half-life. The development of TLD-1 (Talidox) aimed at combining the cardio-preserving properties of the liposomal delivery system with shorter blood circulation time in order to reduce the risk of PPE. Even though the pathophysiology of PPE is not yet fully understood, studies analyzing the correlation of dose and pharmacokinetic parameters with PLD toxic effects revealed that the severity of PPE correlated significantly with plasma half-life (t1/2). Given its performance in preclinical trials, TLD-1 bears the potential for an improved benefit/risk profile compared to established liposomal doxorubicin formulations including Caelyx. This first-in-human phase-I trial will evaluate the safety and will establish the maximal tolerated dose (MTD) and recommended phase II dose of TLD-1, and characterize specific dose limiting toxicities (DLT) of TLD-1. Moreover, the trial shall yield information on adverse events profile, pharmacokinetics and preliminary efficacy.
Key inclusion criteria for dose escalation part: - Final protocol until amendment 2: Patients with either histologically or cytologically confirmed advanced or recurrent solid tumor who failed standard therapy or for whom no effective standard therapy is available - From Amendment 3 on: Patients with histologically or cytologically confirmed advanced malignant tumors of the breast, ovary, uterine or sarcoma who failed standard therapy or for whom no effective standard therapy is available. - Patients may have received up to 3 prior lines of palliative systemic chemotherapy - Patients with brain metastases must have undergone definitive treatment (surgery and/or radiation) at least 1 month prior to starting study drug and be documented as having stable disease by imaging and are on stable doses of steroids for at least 2 weeks. - Adequate bone marrow, renal and hepatic function Key inclusion criteria for comparative PK part: - Patients with either histologically or cytologically confirmed advanced or recurrent breast or ovarian cancer of all histologies - Histologically-confirmed ovarian, fallopian tube or primary peritoneal cancer (collectively referred to herein as 'ovarian cancer') that is either platinum-resistant (disease progression within 6 months of the last receipt of platinum-based chemotherapy) or refractory (lack of response or disease progression while receiving the most recent platinum-based therapy). - Patients with ovarian cancer may have received up to 3 lines of prior cytotoxic chemotherapy, but maximum 1 of them in the platinumresistant/ refractory setting. Confirmed high-grade serous, endometrioid, or carcinosarcoma histotypes are permitted. - Patients with advanced or recurrent breast cancer may have received up to 2 prior lines of palliative cytotoxic chemotherapy. - Patients with brain metastases must have undergone definitive treatment (surgery and/or radiation) at least 1 month prior to starting study drug and be documented as having stable disease by imaging and be on stable doses of steroids for at least 2 weeks. - Adequate bone marrow, renal and hepatic function Key exclusion criteria for dose escalation and comparative PK part: - Significant cardiac disease or abnormality - Patients who have received prior anthracyclines at a cumulative dose that exceeds 250mg/m2 for non-liposomal doxorubicin, 300mg/m2 for liposomal doxorubicin or 400mg/m2 for epirubicin and/or are refractory (during 3 months) to anthracyclines or have experienced allergic reactions or severe toxicity (grade 3 or 4) under anthracyclines - Prior systemic chemotherapy/treatment for adjuvant/metastatic disease, radiotherapy, immunotherapy, or investigational agents within 28 days 5 half- life periods of previous therapy before registration.
Primary outcome: 1. Dose-limiting toxicity (DLT) (Time Frame - at 3 weeks) 2. Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: volume of distribution [Vd] (Time Frame - 2 months) 3. Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Area under curve [AUC] (Time Frame - 2 months) 4. Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Area under curve [Cmax] (Time Frame - 2 months) 5. Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Terminal half life [t½] (Time Frame - 2 months) 6. Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Clearance (CL) (Time Frame - 2 months) 7. Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Ratio of unencapsulated to encapsulated drug over time for Caelyx and TLD-1 (Time Frame - 2 months)Secondary outcome: 1. Adverse Events (AEs) (Time Frame - at 7 months) 2. Objective tumor response (OR) (Time Frame - at 7 months) 3. Time to treatment failure (TTF) (Time Frame - at 7 months) 4. Population pharmacokinetics (PK) of TLD-1: clearance (CL) (Time Frame - at 2 months) 5. Population pharmacokinetics (PK) of TLD-1: volume of distribution (Vd) (Time Frame - at 2 months) 6. Population pharmacokinetics: Area Under the Curve [AUC] (Time Frame - at 2 months) 7. Population pharmacokinetics: Maximum Plasma Concentration [Cmax] (Time Frame - at 2 months)
Experimental: TLD-1Duration of treatment
1 cycle: 21 days
1 cycle: 28 days (only comparative PK part, in cycle 1 or 2)
until progression or occurrence of unacceptable toxicity or withdrawal, but
maximum 9 cycles for patients previously not treated with anthracyclines
maximum 6 cycles for patients previously treated with anthracyclines.
Dose: i.v., according to DL on day 1 of each cycle or tentative MTD Experimental: Caelyx (only for comparative PK part)Duration of treatment
1 cycle: 28 days
Caelyx is given only in one cycle (cycle 1 or 2)
Dose: i.v., 40mg/m2
TLD-1 (Talidox):TLD-1 is a new liposomal formulation of the anthracycline doxorubicin. Caelyx:Caelyx is a liposomal formulation of the anthracycline doxorubicin
Quelle: ClinicalTrials.gov
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