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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 : November 14, 2018
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 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 tolerability, adverse events profile, pharmacokinetics and preliminary efficacy.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
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
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 : March 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: TLD-1

Duration of treatment

  • 1 cycle: 21 days,
  • 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
Drug: TLD-1
TLD-1 is a new liposomal formulation of the anthracycline doxorubicin.
Other Name: Talidox




Primary Outcome Measures :
  1. Dose-limiting toxicity (DLT) [ Time Frame: at 3 weeks ]

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 ]


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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

Inclusion Criteria:

  • Written informed consent according to Swiss law and ICH/GCP regulations, before registration and prior to study-specific screening procedures.
  • 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
  • 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 months 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.
  • Measurable or evaluable disease (according to RECIST v1.1).
  • Age ≥ 18 years
  • ECOG performance status ≤ 1
  • Bone marrow function:

    • Neutrophil count ≥ 1.5 x 109/L
    • Platelet count ≥ 100 x 109/L
    • Hemoglobin ≥ 90g/L
  • Hepatic function:

    • Bilirubin ≤ 1.5 x ULN
    • AST/ALT ≤ 2.5 x ULN or ≤ 5 × ULN in the presence of liver metastasis
  • enal function:

    o eGFR ≥ 60 ml/min/1.73m2 according to the CKD-EPI formula

  • Cardiac function: Left ventricular Ejection Fraction (LVEF) ≥ 50% as determined by either echocardiography (ECHO) or radionuclide angiocardiography (MUGA)
  • Female patients must not be pregnant or breast-feeding and must meet one of the following conditions:

    • Women with child-bearing potential are using effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and during 6 months after the last dose of study drug. Women of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) pregnancy test result
    • Postmenopausal for at least 1 year
    • Post hysterectomy and/or post bilateral ovariectomy
  • Men agree not to father a child and not to donate sperm during trial treatment and during 6 months after the last dose of study drug and the patient should be instructed that their female partner should use an additional form of contraception for the duration of the study and continue this use for 6 months after the last dose of study drug.

Exclusion Criteria:

  • Known symptomatic CNS or leptomeningeal metastases, indicative of symptomatic disease
  • Patients with malignant primary brain tumors
  • Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this trial except cervical carcinoma in situ, treated basal cell carcinoma or any cancer curatively treated > 3 years prior to registration
  • Prior systemic chemotherapy/treatment for metastatic disease, radiotherapy, immunotherapy, or investigational agents within 28 days before registration

Exceptions:

  • Patients with prior single fraction palliative radiotherapy within 2 weeks before registration
  • Patients treated prior with nitrosoureas or mitomycin within 6 weeks before registration
  • Patients with prostate cancer must have discontinued anti-androgens (e.g. bicalutamide, nilutamide) for at least 6 weeks prior to registration; chemical castration with luteinizing hormone-releasing hormone analogues can be continued.

    • 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 time) to anthracyclines or have experienced allergic reactions or severe toxicity (grade 3 or 4) under anthracyclines
    • Concurrent or recent treatment with any other experimental drug within 28 days of registration [exception: participation in SAKK 96/12 and 63/12 (Biobank)]
    • Concomitant use of other anti-cancer drugs or radiotherapy except for local pain control
    • Patients who have not recovered to CTCAE (version 4.03) grade ≤ 1 from all side effects of prior therapies except for residual toxicities, such as alopecia, which do not pose an ongoing medical risk.
    • Peripheral neuropathy ≥ CTCAE grade 2
    • Significant cardiac disease or abnormality, including any one of the following:
  • QTcF interval >470 msec for female >450 msec for male
  • Congenital long QT syndrome.
  • History of sustained ventricular tachycardia, ventricular fibrillation or torsades de pointes.
  • Presence of atrial fibrillation with tachyarrhythmia (ventricular response rate > 100 bpm).
  • Bradycardia (heart rate < 50 bpm).
  • Complete left bundle branch block.
  • Bifascicular block (complete right bundle branch block and anterior or posterior left hemiblock).
  • Myocardial infarction, acute coronary syndrome (including unstable angina), coronary revascularization procedures, or coronary arterial bypass grafting within 6 months prior to starting study drug.
  • Congestive heart failure of New York Heart Association class III or IV

    • Uncontrolled hypertension (sustained systolic blood pressure > 150 mmHg and/or diastolic > 100 mmHg despite antihypertensive therapy)
    • Known history of
  • human immunodeficiency virus (HIV)
  • active/chronic Hepatitis C
  • active Hepatitis B Virus infection
  • or any active systemic infection requiring intravenous (iv) antimicrobial treatment.

Patients with a history of recurring or chronic infections may be included in the trial but caution should be exercised and an infectious disease expert should be consulted before enrollment in the trial.

  • Uncontrolled intercurrent illness that would unduly increase the risk of toxicity or limit compliance with trial requirements in the opinion of the Investigator
  • Any concomitant drugs contraindicated for use with the trial drugs according to protocol
  • Requires treatment with strong CYP3A inhibitors (such as fluconazole, ketoconazole, and clarithromycin) and strong CYP3A inducers (such as rifampin, carbamazepine, phenytoin, St. John's wort) and strong inducers/inhibitors of CYP2D6 at least 5 days prior to registration (Link to shortlist: http://medicine.iupui.edu/flockhart/)
  • Known hypersensitivity to trial drug or to any component of the trial drug
  • Any other serious underlying medical, psychiatric, psychological, familial or geographical conditions or circumstances, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.

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
Contact: Katrin Eckhardt, PhD +41 31 389 91 91 trials@sakk.ch

Locations
Switzerland
Universitaetsspital Basel Recruiting
Basel, Switzerland, 4031
Contact: Andreas Wicki, MD    +41 61 265 50 74    andreas.wicki@usb.ch   
Principal Investigator: Andreas Wicki, MD         
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 Recruiting
Bern, Switzerland, CH-3010
Contact: Manuela Rabaglio, MD    +41 31 632 43 70    manuela.rabaglio@insel.ch   
Principal Investigator: Manuela Rabaglio, MD         
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: Markus Joerger, MD    +41 71 494 11 11    markus.joerger@kssg.ch   
Principal Investigator: Markus Joerger, MD         
Sponsors and Collaborators
Swiss Group for Clinical Cancer Research
Investigators
Study Director: Markus Joerger, MD Cantonal Hospital of St. Gallen
Study Director: Anastasios Stathis, MD IOSI, Ospedale San Giovanni

Responsible Party: Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier: NCT03387917     History of Changes
Other Study ID Numbers: SAKK 65/16
First Posted: January 2, 2018    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: November 2018

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:
Doxorubicin
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action