TLD-1, a Novel Liposomal Doxorubicin, in Patients With Advanced Solid Tumors

NCT ID: NCT03387917

Last Updated: 2024-12-02

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-11-12
• Study Completion Date: 2023-12-22

Brief Summary

TLD-1 is a novel liposomal formulation of doxorubicin (PEG surface) that compared favorably to conventional liposomal formulations of doxorubicin including Caelyx® in preclinical in vivo models. Particle features including size, charge distribution, lipid composition and drug release add up to a considerably altered particle behavior compared to Caelyx®, potentially explaining the lack of hand-foot-syndrome in respective animal models. Preclinical evaluation confirmed TLD-1 to be a promising new and innovative formulation of doxorubicin with promising activity and good tolerability.

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.

Conditions

Advanced Solid Tumors

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

TLD-1

Intervention Type: DRUG

TLD-1 is a new liposomal formulation of the anthracycline doxorubicin.

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

Group Type: EXPERIMENTAL

Caelyx

Intervention Type: DRUG

Caelyx is a liposomal formulation of the anthracycline doxorubicin

Interventions

TLD-1

TLD-1 is a new liposomal formulation of the anthracycline doxorubicin.

Intervention Type: DRUG

Caelyx

Caelyx is a liposomal formulation of the anthracycline doxorubicin

Intervention Type: DRUG

Other Intervention Names

Talidox

Eligibility Criteria

Inclusion Criteria

• 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

• 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

Exclusion Criteria

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Swiss Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Dagmar Hess, MD

Role: STUDY_CHAIR

Cantonal Hospital of St. Gallen

Anastasios Stathis, MD

Role: STUDY_DIRECTOR

IOSI, Ospedale San Giovanni

Markus Jörger, Prof

Role: STUDY_DIRECTOR

Cantonal Hospital of St. Gallen

Locations

Istituto Oncologico della Svizzera Italiana

Bellinzona, , Switzerland

Inselspital Bern

Bern, , Switzerland

Kantonsspital Graubünden

Chur, , Switzerland

Kantonsspital St. Gallen

Sankt Gallen, , Switzerland

Kantonsspital Winterthur

Winterthur, , Switzerland

Countries

Switzerland

References

Mc Laughlin AM, Hess D, Michelet R, Colombo I, Haefliger S, Bastian S, Rabaglio M, Schwitter M, Fischer S, Eckhardt K, Hayoz S, Kopp C, Klose M, Sessa C, Stathis A, Halbherr S, Huisinga W, Joerger M, Kloft C. Population pharmacokinetics of TLD-1, a novel liposomal doxorubicin, in a phase I trial. Cancer Chemother Pharmacol. 2024 Sep;94(3):349-360. doi: 10.1007/s00280-024-04679-z. Epub 2024 Jun 15.

Reference Type: DERIVED

PMID: 38878207 (View on PubMed)

Colombo I, Koster KL, Holer L, Haefliger S, Rabaglio M, Bastian S, Schwitter M, Eckhardt K, Hayoz S, Mc Laughlin AM, Kloft C, Klose M, Halbherr S, Baumgartner C, Sessa C, Stathis A, Hess D, Joerger M. TLD-1, a novel liposomal doxorubicin, in patients with advanced solid tumors: Dose escalation and expansion part of a multicenter open-label phase I trial (SAKK 65/16). Eur J Cancer. 2024 Apr;201:113588. doi: 10.1016/j.ejca.2024.113588. Epub 2024 Feb 2.

Reference Type: DERIVED

PMID: 38377773 (View on PubMed)

Other Identifiers

SAKK 65/16

Identifier Type: -

Identifier Source: org_study_id