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Trial record 96 of 2030 for:    doxil

Treatment of Metastatic Soft Tissue Sarcoma (STS) Patients (FIBROSARC USA) (FIBROSARC USA)

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ClinicalTrials.gov Identifier: NCT03420014
Recruitment Status : Recruiting
First Posted : February 2, 2018
Last Update Posted : May 7, 2019
Sponsor:
Information provided by (Responsible Party):
Philogen S.p.A.

Brief Summary:

The present study is an open-label, randomized, controlled, two-arm multi-center study of the efficacy of L19TNF treatment in combination with doxorubicin versus doxorubicin alone in metastatic or unresectable soft-tissue sarcoma patients.

In the study, 114 patients will be randomized in a 1:1 ratio to receive doxorubicin treatment (Arm 1) or L19TNF treatment in combination with doxorubicin (Arm 2).

The primary objective of the trial is to evaluate if L19TNF in combination with doxorubicin (Arm 2) given for unresectable or metastatic soft tissue sarcoma improves efficacy measured as progression free survival, as compared to doxorubicin alone (Arm 1).

Anti-cancer activity will be assessed every 6 weeks during therapy and every 12 weeks thereafter.


Condition or disease Intervention/treatment Phase
Unresectable or Metastatic Soft Tissue Sarcoma Drug: Doxorubicin Combination Product: L19TNF plus doxorubicin Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 114 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Study Comparing the Efficacy of the Combination of Doxorubicin and the Tumor-targeting Human Antibody-cytokine Fusion Protein L19TNF to Doxorubicin Alone as First-line Therapy in Patients With Advanced or Metastatic Soft Tissue Sarcoma
Actual Study Start Date : December 27, 2018
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : September 2021


Arm Intervention/treatment
Active Comparator: Arm 1: Doxorubicin
Patients will receive a fixed dose doxorubicin, administered as a 15 ± 5 minutes i.v. infusion.
Drug: Doxorubicin
75 mg/m2 doxorubicin will be administered once every 3 weeks (Day 1 of every 21-days cycle).

Experimental: Arm 2: L19TNF plus doxorubicin

Patients will receive a fixed dose of L19TNF in combination with a fixed dose doxorubicin.

Doxorubicin will be administered as a 15 ± 5 minutes i.v. infusion on day 1 of each 21-day cycle followed by at least 30 minutes pause before starting infusion of L19TNF.

Combination Product: L19TNF plus doxorubicin
13 μg/kg L19TNF will be administered on day 1, 3 and 5 of every 21-days cycle in combination with 60 mg/m2 doxorubicin on day 1 of every 21-days cycle.




Primary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: From randomization up to week 72 ]
    Progression-free survival PFS in a time-to-event analysis in the L19TNF plus Doxorubicin control group (Arm 2) versus the Doxorubicin alone treatment group (Arm 1).


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: From week 1 up to week 72, every 6 weeks; from week 73 up to week 144, every 12 weeks; ]
    Overall survival (OS) in the L19TNF plus Doxorubicin treatment group (Arm 2) versus Doxorubicin alone (Arm 1) will be evaluated in time to event analysis.

  2. Overall response rate (ORR) [ Time Frame: 1) From week 1 up to week 18, every 6 weeks; 2) from week 19 up to week 72, every 12 weeks (Maintenance); 3) EoT: at week 22/23 (only Induction) and at week 72 (Maintenance); 4) Follow-up: from week 22/23 (EoT) up to week 72, every 12 weeks. ]
    Overall Response Rate (ORR) assessed by BIRC, i.e. rate of CR and PR of L19TNF plus Doxorubicin treatment group (Arm 2) versus Doxorubicin alone (Arm 1).

  3. Duration of response (DOR) [ Time Frame: 1) From week 1 up to week 18, every 6 weeks; 2) from week 19 up to week 72, every 12 weeks (Maintenance); 3) EoT: at week 22/23 (only Induction) and at week 72 (Maintenance); 4) Follow-up: from week 22/23 (EoT) up to week 72, every 12 weeks. ]
    Duration of Response (DOR) assessed by BIRC in the L19TNF plus Doxorubicin treatment group (Arm 2) versus Doxorubicin alone (Arm 1).

  4. Progression-free survival (PFS) rate [ Time Frame: 1) From week 1 up to week 18, every 6 weeks; 2) from week 19 up to week 72, every 12 weeks (Maintenance); 3) EoT: at week 22/23 (only Induction) and at week 72 (Maintenance); 4) Follow-up: from week 22/23 (EoT) up to week 72, every 12 weeks. ]
    PFS rate of L19TNF plus Doxorubicin treatment group (Arm 2) versus Doxorubicin alone (Arm 1).

  5. Overall survival (OS) rates [ Time Frame: From week 1 up to week 144. ]
    Overall survival (OS) rates in the L19TNF plus Doxorubicin treatment group (Arm 2) versus Doxorubicin alone (Arm 1).

  6. Number of patients with adverse events (AEs). [ Time Frame: From week 1 up to week 72. ]
  7. Percentage of participants with worst on-study hematological and chemistry abnormalities. [ Time Frame: From week 1 up to week 72. ]
  8. Percentage of participants with Electrocardiogram (ECG) and Echocardiogram (ECHO) abnormality findings. [ Time Frame: From week 1 up to week 72, every 6 weeks. ]
  9. Number of Participants With Clinically Significant Abnormalities in Vital Signs (Systolic and Diastolic Blood Pressure, Temperature, Heart Rate). [ Time Frame: From week 1 up to week 72. ]
  10. Number of Participants With Clinically Significant Physical Examination Abnormalities (General Appearance, Skin, Eyes, Ears-Nose-Throat, Breast, Head and Neck, Lungs, Heart, Abdomen, Lymph Nodes, Musculoskeletal) [ Time Frame: From week 1 up to week 72. ]
  11. Human anti-fusion protein antibodies (HAFA) levels against L19TNF. [ Time Frame: At day 1 of week 1 and week 2; at day 1 from week 4 up to week 18, every 3 weeks; at week 22-23 (EoT); at week 23-24 (first follow-up visit) ]
  12. Maximum drug concentration [Cmax]. [ Time Frame: At day 1, 2 ,3 and 5 of week 1 ]
    Pharmacokinetics assessment of L19TNF through blood sampling.

  13. Time to reach maximum drug concentration [Tmax]. [ Time Frame: At day 1, 2 ,3 and 5 of week 1 ]
    Pharmacokinetics assessment of L19TNF through blood sampling.

  14. Terminal half-life [t1/2]. [ Time Frame: At day 1, 2 ,3 and 5 of week 1 ]
    Pharmacokinetics assessment of L19TNF through blood sampling.

  15. Area under the drug concentration-time curve, extrapolated to infinity [AUC]. [ Time Frame: At day 1, 2 ,3 and 5 of week 1 ]
    Pharmacokinetics assessment of L19TNF through blood sampling.

  16. Maximum drug concentration [Cmax]. [ Time Frame: At day 1, 2 ,3 and 5 of week 1 ]
    Pharmacokinetics assessment of doxorubicin through blood sampling.

  17. Time to reach maximum drug concentration [Tmax]. [ Time Frame: At day 1, 2 ,3 and 5 of week 1 ]
    Pharmacokinetics assessment of doxorubicin through blood sampling.

  18. Terminal half-life [t1/2]. [ Time Frame: At day 1, 2 ,3 and 5 of week 1 ]
    Pharmacokinetics assessment of doxorubicin through blood sampling.

  19. Area under the drug concentration-time curve, extrapolated to infinity [AUC]. [ Time Frame: At day 1, 2 ,3 and 5 of week 1 ]
    Pharmacokinetics assessment of doxorubicin through blood sampling.



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients may be included in the study only if they meet all of the following criteria:

  1. Age 16 - 75 years. Patients under 18 years, should be fully grown (prove of fused growth plates).
  2. Patients with histological evidence of advanced unresectable and/or metastatic high-gradesoft tissue sarcoma (grade 2 - 3 according to the FNLCC grading system) not amenable to curative treatment with surgery or radiotherapy. The following tumor types are included:

    • Malignant fibrous histiocytoma (undifferentiated pleomorphic sarcoma)
    • Myxoid and round cell liposarcoma, pleomorphic liposarcoma or dedifferentiated liposarcoma
    • Myxofibrosarcoma intermediate and high-grade
    • Fibrosarcoma
    • Leiomyosarcoma
    • Angiosarcoma
    • Unclassified sarcoma NOS

    The following tumor types will not be included:

    • GIST
    • Mixed mesodermal tumor
    • Synovial sarcoma
    • Malignant peripheral nerve sheath tumor
    • Epithelioid sarcoma
    • Embryonal rhabdomyosarcoma
    • Chondrosarcoma
    • Malignant mesothelioma
    • Neuroblastoma
    • Osteosarcoma
    • Ewing's sarcoma / primitive neuroectodermal tumor
    • Desmoplastic small round cell tumor
    • Alveolar soft part sarcoma
    • Pleomorphic rhabdomyosarcoma
    • Alveolar rhabdomyosarcoma
  3. Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria 1.1. If only 1 lesion is present at screening, this lesion should not have been irradiated during previous treatments.
  4. Life expectancy of at least 3 months in the judgment of the investigator.
  5. ECOG ≤ 2.
  6. Documented negative test for HIV-HBV-HCV. For HBV serology: the determination of HBsAg, anti-HBsAg-Ab and anti-HBcAg-Ab is required. In patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), negative serum HBV-DNA is required. For HCV: HCV-RNA or HCV antibody test. Subjects with a positive test for HCV antibody but no detection of HCV-RNA indicating no current infection are eligible.
  7. Female patients: negative serum pregnancy test for women of childbearing potential (WOCBP)* within 14 days of starting treatment. WOCBP must agree to use, from the screening to six months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' ClinicalTrial Facilitation Group (www.hma.eu/ctfg.html) and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence.

    Male patients: Male subjects able to father children must agree to use two acceptable methods of contraception throughout the study (e.g. condom with spermicidal gel). Double-barrier contraception is required.

    * Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy).

  8. Informed consent signed and dated to participate in the study.
  9. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

Patients will be excluded from participating in this study if they meet 1 or more of the following criteria:

  1. Prior therapy (except surgery and radiation) for unresectable or metastatic malignant soft tissue sarcoma.
  2. Previous treatment with anthracycline-containing chemotherapy.
  3. Radiotherapy within 4 weeks prior to therapy.
  4. Known history of allergy to TNFα, anthracyclines or other intravenously administered human proteins/peptides/antibodies.
  5. Absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L and haemoglobin (Hb) < 9.0 g/dl.
  6. Chronically impaired renal function as expressed by creatinine clearance < 60 mL/min.
  7. Inadequate liver function (ALT, AST, ALP or total bilirubin ≥ 2.5 x ULN)
  8. Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.
  9. History within the last year of cerebrovascular disease and/or acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
  10. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
  11. Clinically significant cardiac arrhythmias or requiring permanent medication.
  12. Abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator. Subjects with current, or a history of QT/QTc prolongation would be excluded. In particular:

    • patients with a marked prolongation of QT/QTc interval (e.g., repeated demonstration of QTc >480 milliseconds using Fredricia's QT correction formula) are excluded;
    • patients with a history of risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of prolonged QT syndrome) are excluded;
    • patients who require the use of concomitant medications that prolong the QT/QTc interval are excluded.
  13. Uncontrolled hypertension, despite optimal therapy.
  14. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification).
  15. Severe diabetic retinopathy such as severe non-proliferative retinopathy and proliferative retinopathy.
  16. Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery) within 4 weeks of administration of study treatment.
  17. Pregnancy or breast-feeding.
  18. Requirement of chronic administration of corticosteroids or other immunosuppressant drugs. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
  19. Presence of active and uncontrolled infections or other severe concurrent disease which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
  20. Known active or latent tuberculosis (TB).
  21. Concurrent malignancies other than Soft Tissue Sarcoma, unless the patient has been disease-free for at least 2 years.
  22. Growth factors or immunomodulatory agents within 7 days prior to the administration of study treatment.
  23. Serious, non-healing wound, ulcer or bone fracture.
  24. Allergy to study medication or excipients in study medication.
  25. Concurrent therapy with anticoagulants.
  26. Concurrent use of other anti-cancer treatments or agents other than study medication.
  27. Any recent live vaccination within 4 weeks prior to treatment or plan to receive vaccination during the study.

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): NCT03420014


Contacts
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Contact: Teresa Hemmerle, PhD +39 057717816 regulatory@philogen.com
Contact: Serena Bettarini, Dr +39 057717816 regulatory@philogen.com

Locations
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United States, Arizona
Mayo Clinic Hospital Recruiting
Phoenix, Arizona, United States, 85054
Contact: Mahesh Seetharam, MD         
United States, California
Sarcoma Oncology Research Center (SORC) Cancer Center of Southern California Recruiting
Santa Monica, California, United States, 90403
Contact: Sant P Chawla, MD         
United States, Florida
Mayo Clinic Hospital Recruiting
Jacksonville, Florida, United States, 32224
Contact: Steven Attia, MD    904-953-7292    Attia.steven@mayo.edu   
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Scott Okuno, MD         
Sponsors and Collaborators
Philogen S.p.A.
Investigators
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Principal Investigator: Scott H. Okuno, M.D. Mayo Clinic Rochester MN

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Responsible Party: Philogen S.p.A.
ClinicalTrials.gov Identifier: NCT03420014     History of Changes
Other Study ID Numbers: PH-L19TNFDOX2-02/17
First Posted: February 2, 2018    Key Record Dates
Last Update Posted: May 7, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Doxorubicin
Liposomal doxorubicin
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action