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JOURNAL ONKOLOGIE – STUDIE

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 Chair
Cantonal Hospital of St. Gallen
Anastasios Stathis, MD
Study Director
IOSI, Ospedale San Giovanni
Markus Jörger, Prof
Study Director
Cantonal Hospital of St. Gallen

Kontakt

Studienlocations
(3 von 5)

Istituto Oncologico della Svizzera Italiana
6500 Bellinzona
SwitzerlandRekrutierend» Google-Maps
Ansprechpartner:
Anastasios Stathis, MD
Phone: +41 91 811 89 31
E-Mail: anastasios.stathis@eoc.ch
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Studien-Informationen

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.

Ein-/Ausschlusskriterien

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.

Studien-Rationale

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)

Studien-Arme

  • Experimental: TLD-1
    Duration 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

Geprüfte Regime

  • 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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