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

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ClinicalTrials.gov Identifier: NCT03387917
Recruitment Status : Recruiting
First Posted : January 2, 2018
Last Update Posted : September 7, 2022
Sponsor:
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research

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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: TLD-1 Drug: Caelyx Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: The trial uses an accelerated titration design (ATD) up to the occurrence of the first DLT, followed by a modified continual reassessment method (mCRM) for dose escalation part and randomized cross-over design for the comparative PK part
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: TLD-1, a Novel Liposomal Doxorubicin, in Patients With Advanced Solid Tumors: A Multicenter Open-label Single-arm Phase I Trial
Actual Study Start Date : November 12, 2018
Estimated Primary Completion Date : October 2023
Estimated Study Completion Date : October 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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
Drug: TLD-1
TLD-1 is a new liposomal formulation of the anthracycline doxorubicin.
Other Name: Talidox

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
Drug: Caelyx
Caelyx is a liposomal formulation of the anthracycline doxorubicin




Primary Outcome Measures :
  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 Measures :
  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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03387917


Contacts
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Contact: Jesus Glaus Garzon, PhD +41 31 389 91 91 trials@sakk.ch

Locations
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Switzerland
Istituto Oncologico della Svizzera Italiana Recruiting
Bellinzona, Switzerland, 6500
Contact: Anastasios Stathis, MD    +41 91 811 89 31    anastasios.stathis@eoc.ch   
Principal Investigator: Anastasios Stathis, MD         
Inselspital Bern Terminated
Bern, Switzerland, CH-3010
Kantonsspital Graubünden Recruiting
Chur, Switzerland, 7000
Contact: Sara Bastian, MD    +41 81 256 68 84    sara.bastian@ksgr.ch   
Principal Investigator: Sara Bastian, MD         
Kantonsspital St. Gallen Recruiting
St. Gallen, Switzerland, 9007
Contact: Dagmar Hess, MD    +41 71 494 11 11    dagmar.hess@kssg.ch   
Principal Investigator: Dagmar Hess, MD         
Kantonsspital Winterthur Recruiting
Winterthur, Switzerland, 8401
Contact: Ursina Zürrer, MD    +41 52 266 25 83    ursina.zuerrer@ksw.ch   
Principal Investigator: Ursina Zürrer, MD         
Sponsors and Collaborators
Swiss Group for Clinical Cancer Research
Investigators
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Study Chair: Dagmar Hess, MD Cantonal Hospital of St. Gallen
Study Director: Anastasios Stathis, MD IOSI, Ospedale San Giovanni
Study Director: Markus Jörger, Prof Cantonal Hospital of St. Gallen
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Responsible Party: Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier: NCT03387917    
Other Study ID Numbers: SAKK 65/16
First Posted: January 2, 2018    Key Record Dates
Last Update Posted: September 7, 2022
Last Verified: September 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Swiss Group for Clinical Cancer Research:
Advanced Solid Tumors
doxorubicin
TLD-1
phase I
Talidox
Liposomal
Additional relevant MeSH terms:
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Neoplasms
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents