Evaluation of Onfekafusp Alfa and Dacarbazine in Advanced or Metastatic Soft-Tissue Sarcoma Post-Two Systemic Therapies
- Trial ID
- 2024-512704-20-00
- Protocol
- PH-L19TNFSARC-03/18
- Sponsor
- Philogen S.p.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the anti-tumor activity of **L19TNF** in combination with **dacarbazine** (DTIC) for patients with unresectable or metastatic soft-tissue sarcoma. The focus is on determining whether this combination therapy prolongs progression-free survival (PFS) after at least two lines of systemic therapy for advanced or metastatic disease, compared to DTIC alone. This is clinically relevant as it addresses the need for more effective treatment options in a patient population with limited therapeutic alternatives.
Secondary objectives include: - Demonstrating statistical superiority of L19TNF combined with DTIC in prolonging overall survival (OS) compared to DTIC alone. - Assessing the efficacy of the combination therapy by evaluating endpoints such as progression-free survival (PFS) at various time points, objective response rate (ORR), and overall survival (OS) at 12, 24, and 36 months. - Evaluating the safety profile of L19TNF in combination with DTIC by monitoring adverse events, serious adverse events, drug-induced liver injury, and other safety parameters. - Assessing the quality of life of patients receiving the combination therapy compared to those receiving DTIC alone, focusing on health-related quality of life (HRQoL).
Participants
The clinical trial involves participants diagnosed with **unresectable and/or metastatic soft-tissue sarcoma** who have experienced failure of at least two prior systemic therapy regimens. The study population includes both male and female subjects aged between 18 to 80 years. Participants are required to have a histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic soft tissue sarcoma, specifically Grade 2 - 3 according to the FNCLCC grading system. Individuals with bone sarcomas, including Ewing sarcoma, Kaposi's sarcoma, and gastrointestinal stromal tumors (GIST), are excluded from the study. The trial does not involve a vulnerable population. Participants must have a life expectancy of at least three months and an ECOG performance status of 0 to 2. They should have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria v.1.1. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. Key inclusion criteria include a documented negative test for HIV, HBV, and HCV, and for women of childbearing potential, a negative serum pregnancy test at screening is required. Both male and female participants must agree to use effective contraception methods during the study and for a specified period after the last administration of the study drugs.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of the tumor-targeting human antibody-cytokine fusion protein **L19TNF** in combination with **dacarbazine** for patients with unresectable or metastatic soft-tissue sarcoma who have failed at least two prior systemic therapy regimens. This is a randomized, controlled, double-blind study, with participants being randomly assigned to receive either the combination therapy or **dacarbazine** alone. The trial is expected to last until June 2025, with recruitment having started in June 2020. The primary endpoint is progression-free survival (PFS) according to RECIST v.1.1, while the secondary endpoint is overall survival (OS).
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, histological confirmation of disease, and previous treatment history. The screening visit will also include assessments like computed tomography to measure lesions, and laboratory tests to ensure the absence of infections such as HIV, HBV, and HCV. Following the screening, eligible participants will be enrolled and randomized into the study arms. Regular follow-up visits will be scheduled to monitor treatment response, manage any adverse events, and ensure compliance with the study protocol. The end-of-study visit will occur after the completion of the treatment period or upon early termination, where final assessments will be conducted to evaluate the overall health status and treatment outcomes.
Participant involvement is expected to last up to 48 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant disease progression, unacceptable toxicity, or withdrawal of consent. Participants are required to comply with scheduled visits, treatment plans, and other study procedures to remain in the trial. The study aims to provide valuable insights into the potential benefits of the combination therapy for this patient population, contributing to the advancement of treatment options for advanced soft-tissue sarcoma.
Treatment
The clinical trial involves the administration of two experimental medications. The first medication is **Dacarbazine**, marketed under the name Dacarbazine medac 1000 mg. It is provided as a **powder for solution for infusion**. The active substance, dacarbazine, is a chemical compound classified under the ATC code L01AX04. The medication is administered via **intravenous infusion**. The dosage is calculated based on body surface area, with a maximum daily dose of 1000 mg/m² and a total maximum dose of 16000 mg/m² over a treatment period of up to 48 weeks. Dacarbazine is an alkylating agent used in the treatment of soft-tissue sarcoma.
The second experimental medication is **Fibromun**, which contains the active substance **onfekafusp alfa**. This medication is available as a **solution for injection/infusion** and is also administered through **intravenous infusion**. The dosing is based on body weight, with a maximum daily dose of 13 µg/kg and a total maximum dose of 364 µg/kg over a treatment period of up to 48 weeks. Onfekafusp alfa is a protein-based therapeutic agent, specifically a tumor-targeting human antibody-cytokine fusion protein, designed to enhance anti-tumor activity in patients with advanced or metastatic soft-tissue sarcoma.
In this study, the primary objective is to evaluate the efficacy of L19TNF (Fibromun) in combination with dacarbazine (DTIC) compared to dacarbazine alone in prolonging progression-free survival (PFS) in patients with unresectable or metastatic soft-tissue sarcoma who have undergone at least two lines of systemic therapy. The trial does not consider neoadjuvant and adjuvant therapies as prior lines of therapy. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**, as defined by the RECIST v.1.1 criteria. This endpoint will evaluate the duration during which patients with advanced or metastatic soft-tissue sarcoma remain free from disease progression after receiving the investigational treatment L19TNF in combination with Dacarbazine (DTIC), compared to DTIC alone. The secondary efficacy endpoint will focus on **Overall Survival (OS)**, which will measure the time from randomization until death from any cause.
Data collection for these endpoints will be conducted at specified intervals throughout the trial, with assessments scheduled according to the study protocol. The trial will involve the use of computed tomography to ensure accurate measurement of tumor size and progression, adhering to the RECIST v.1.1 guidelines. The analysis of these efficacy parameters will be performed using appropriate statistical methods to determine the treatment's impact on PFS and OS, providing insights into the potential benefits of the investigational therapy for patients with advanced or metastatic soft-tissue sarcoma.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female, 18 to 80 years of age.
- Histologically or cytologically confirmed advanced unresectable or metastatic soft tissue sarcoma (STS), Grade 2 - 3 according to the FNCLCC grading system. Participants with bone sarcomas including Ewing sarcoma, Kaposi's sarcoma and gastrointestinal stromal tumors (GIST) will be excluded.
- Subjects who received at least two prior systemic therapies (e.g., anthracyclines, taxanes, ifosfamide, gemcitabine, trabectedin, pazopanib, eribulin) for advanced or metastatic disease including at least one prior therapy based on anthracyclines as monotherapy or in combination. Neoadjuvant and adjuvant therapies can be considered as a prior line of treatment if the time to recurrence from completion of treatment was ≤ 12 months. Previous therapy with anthracyclines is not compulsory in situations of contraindications to this class of drugs. All previous therapies must have completed ≥ 3 weeks (21 days) prior to study treatment start.
- Evidence of disease progression after prior line of therapy advanced or metastatic disease.
- Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria v.1.1. If only one lesion is present at screening this lesion should not have been irradiated during previous treatments.
- Life expectancy of at least 3 months in the judgment of the investigator.
- 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 (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.
- 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 DTIC, 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 six months following the last administration of L19TNF and/or DTIC (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)
- Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
- Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
Exclusion Criteria
- Anti-cancer treatment with radiation therapy (with the exception of radiation of single lesions for palliative reasons, e.g. pain management which then are not taken as indicator lesions for iRECIST response), chemotherapy, targeted therapies, immunotherapy, or other antitumor therapies within 3 weeks prior to study treatment start.
- Subjects who participated in an investigational drug or device study within 3 weeks prior to study treatment start.
- Previous treatment with TNF or L19TNF or DTIC.
- Known history of allergy to intravenously administered human proteins/peptides/antibodies and any other constituent of the product.
- Absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L and hemoglobin (Hb) < 9.0 g/dl, with the exception of values lower than these due to cytologically or histologically proven marrow metastasis, which will not constitute exclusion criteria.
- Chronically impaired renal function as expressed by creatinine clearance < 60 mL/min or serum creatinine > 1.5 ULN.
- Inadequate liver function (ALT or AST ≥ 3 x ULN, ALP or GGT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5 x ULN). For patients with metastatic lesions in the liver ALT, AST, GGT or ALP ≥ 5 x ULN.
- Any severe concomitant condition which in the opinion of investigators 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 cerebrovascular disease and/or 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.
- Abnormalities observed during baseline ECG and echocardiogram investigations that are considered as clinically significant by the investigator.
- Uncontrolled hypertension.
- Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification).
- Severe non-proliferative diabetic retinopathy or proliferative diabetic 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.
- 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.
- Protected adults (i.e., persons referred to as adults who are under legal protection measure or unable to express their consent) or persons under the protection of justice.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 22 Jun 2020 | 20 |
 Germany | Not Recruiting | 22 Jun 2020 | 30 |
 Italy | Not Recruiting | 22 Jun 2020 | 13 |
 Poland | Not Recruiting | 22 Jun 2020 | 15 |
 Spain | Not Recruiting | 22 Jun 2020 | 20 |
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 | INTRAVENIOUS INFUSION | 13 | 48 | PRD97068 |
Dacarbazine medac 1000 mg, powder for solution for infusion | Other | POWDER FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1000 | 48 | PRD507001 |