Phase III Evaluation of Onfekafusp Alfa and Doxorubicin Versus Doxorubicin Monotherapy in Advanced or Metastatic Soft Tissue Sarcoma
- Trial ID
- 2024-512789-32-00
- Protocol
- PH-L19TNFDOX2-03/16
- Sponsor
- Philogen S.p.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III study is to evaluate whether the combination of **L19TNF** and doxorubicin extends **progression free survival (PFS)** in patients with advanced or metastatic soft tissue sarcoma, compared to doxorubicin alone. This is clinically relevant as prolonging PFS can potentially improve patient outcomes by delaying disease progression and maintaining quality of life.
Secondary objectives include assessing the efficacy of the treatment through various measurements:
- **Overall survival (OS)**
- **Median Progression Free Survival (mPFS)**
- **Median Overall Survival (mOS)**
- **Overall Response Rate (ORR)**, consisting of complete response (CR) and partial response (PR), and Best Overall Response Rate (BORR)
Participants
The clinical trial involves participants diagnosed with **unresectable or metastatic soft tissue sarcoma**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants are required to have histological evidence of advanced unresectable and/or metastatic high-grade soft tissue sarcoma, specifically grade 2 or 3 according to the FNCLCC grading system, and must not be amenable to curative treatment with surgery or radiotherapy. The trial excludes individuals with specific sarcoma subtypes such as Osteosarcoma, Chondrosarcoma, Ewing Sarcoma/Primitive Neuroectodermal Tumor (PNET), Kaposi’s Sarcoma, Dermatofibrosarcoma protuberans, and Gastrointestinal Stromal Tumors (GIST). Participants must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria 1.1, and a life expectancy of at least three months. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are expected to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. Lifestyle considerations such as diet and physical activity are not specified in the trial details.
Plans and Procedures
The clinical trial is a **Phase III** study designed to evaluate the efficacy of combining **doxorubicin** with the tumor-targeting human antibody-cytokine fusion protein **L19TNF** compared to doxorubicin alone in patients with advanced or metastatic **soft tissue sarcoma**. The trial employs a randomized, double-blind, controlled design to ensure unbiased results. The primary objective is to assess whether the combination therapy prolongs progression-free survival (PFS) compared to doxorubicin alone. The trial is expected to conclude by December 31, 2025, with recruitment having commenced on October 10, 2017.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological evidence of high-grade soft tissue sarcoma, measurable lesions, and a life expectancy of at least three months. Following the screening, participants will be randomized to receive either the combination therapy or doxorubicin alone. Regular follow-up visits will be scheduled to monitor the safety and efficacy of the treatment, including assessments of adverse events, laboratory parameters, and physical examinations. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected duration of participant involvement is up to 72 weeks, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or any other reason deemed appropriate by the investigator. The trial will adhere to rigorous safety monitoring, with secondary endpoints focusing on the safety profile of the combination therapy, including adverse events and standard laboratory assessments.
Treatment
The clinical trial involves the administration of **Fibromun**, a **solution for injection/infusion** containing the active substance **onfekafusp alfa**. This investigational medication is provided by PHILOGEN SPA and is classified as a protein of other origin. Fibromun is administered via **intravenous infusion**. The dosing regimen for Fibromun is calculated based on body weight, with a maximum daily dose of 13 µg/kg and a cumulative maximum dose of 468 µg/kg over a treatment period of up to 72 weeks. The administration schedule and participant compliance are closely monitored to ensure adherence to the protocol.
In addition to Fibromun, the trial includes the use of **Doxorubicin 2 mg/ml Solution for Injection**, a standard-of-care therapy provided by PFIZER LIMITED. The active substance in this formulation is **doxorubicin hydrochloride**, a chemical compound classified under anthracyclines and related substances. Doxorubicin is administered as a **solution for infusion**, with a maximum daily dose of 75 mg/m² and a total maximum dose of 450 mg/m² over a treatment period of up to 18 weeks. The administration of doxorubicin follows established guidelines for dosage and infusion rates, with compliance monitored throughout the study.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)**. This endpoint will measure the length of time during and after the treatment that a patient lives with advanced or metastatic soft tissue sarcoma without the disease worsening. The trial aims to compare the efficacy of the combination of doxorubicin and the tumor-targeting human antibody-cytokine fusion protein L19TNF against doxorubicin alone. The assessment of PFS will be conducted using standardized criteria to ensure consistency and reliability in the measurement of disease progression.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age 18 - 75 years.
- Patients must have histological evidence of advanced unresectable and/or metastatic high-grade soft tissue sarcoma (grade 2 – 3 according to the FNCLCC grading system) not amenable to curative treatment with surgery or radiotherapy and for which doxorubicin treatment is considered appropriate. Participants with Osteosarcoma, Chondrosarcoma, Ewing Sarcoma/ Primitive Neuroectodermal Tumor (PNET), Kaposi’s Sarcoma, Dermatofibrosarcoma protuberans, and Gastrointestinal Stromal Tumors (GIST) will be excluded
- Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria 1.1. This lesion should not have been irradiated during previous treatments.
- Life expectancy of at least 3 months.
- ECOG ≤ 2.
- Documented negative test for HIV-HBV-HCV. For HBV serology: the determination of HBsAg and anti-HBcAg-Ab is required. In patients with serology documenting previous exposure to HBV, 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.
- Female patients: negative serum pregnancy test at screening for women of childbearing potential (WOCBP)*. WOCBP must agree to use, from the screening to six months following the last administration of L19TNF and/or Doxorubicin, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial 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 from the screening to four months following the last administration of L19TNF and/or Doxorubicin (e.g. condom with spermicidal gel). Double-barrier contraception is required.
- Informed consent signed and dated to participate in the study
- Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures. * 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)
Exclusion Criteria
- Prior therapy (except surgery and radiation) for unresectable or metastatic malignant soft tissue sarcoma.
- Previous treatment with anthracycline-containing chemotherapy.
- Radiotherapy within 4 weeks prior to therapy
- Known history of allergy to TNFα, anthracyclines or other intravenously administered human proteins/peptides/antibodies.
- Previous therapy with recombinant TNF.
- Absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L and haemoglobin (Hb) < 9.0 g/dl.
- Chronically impaired renal function as expressed by creatinine ≥ 2.0 x ULN.
- Inadequate liver function (ALT, AST, ALP or total bilirubin ≥ 2.5 x ULN).
- Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.
- History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
- Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
- Clinically significant cardiac arrhythmias or requiring permanent medication.
- Uncontrolled hypertension, despite optimal therapy.
- Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification).
- Severe diabetic retinopathy such as severe non-proliferative retinopathy and proliferative retinopathy.
- Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery) within 4 weeks of administration of study treatment.
- Pregnancy or breast-feeding.
- 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.
- 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.
- Known active or latent tuberculosis (TB).
- Concurrent malignancies other than Soft Tissue Sarcoma, unless the patient has been disease-free for at least 2 years.
- Growth factors or immunomodulatory agents within 7 days prior to the administration of study treatment.
- Serious, non-healing wound, ulcer or bone fracture.
- Allergy to study medication or excipients in study medication.
- Deep vein thrombosis, pulmonary embolism or other acute vascular events within 6 months.
- Anticoagulation therapy with P2Y12 antagonists (e.g., clopidogrel, ticagrelor) and vitamin K antagonists (e.g., phenprocoumon, warfarin)
- Concurrent use of other anti-cancer treatments or agents other than study medication.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 10 Oct 2017 | 12 |
 Germany | Not Recruiting | 10 Oct 2017 | 59 |
 Italy | Not Recruiting | 10 Oct 2017 | 7 |
 Poland | Not Recruiting | 10 Oct 2017 | 6 |
 Spain | Not Recruiting | 10 Oct 2017 | 34 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Fibromun | Test | SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS INFUSION | 13 | 72 | PRD97068 |
Doxorubicin 2 mg/ml Solution for Injection. | Other | SOLUTION FOR INJECTION | SOLUTION FOR INFUSION | 75 | 18 | PRD631907 |