Clinical trial NCT04650984: A Study Comparing the Efficacy of L19TNF+Doxorubicin vs Doxorubicin Alone as First-line Therapy in Patients With Advanced or Metastatic Soft Tissue Sarcoma
Official title: A Phase III 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Soft Tissue Sarcoma
Lead sponsor: Philogen S.p.A.
Sponsor class: INDUSTRY
First posted: 2020-12-03
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 advanced or metastatic soft-tissue sarcoma patients.

In the study, 102 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).

Detailed description: Phase III, open label, randomized, controlled study in subjects with advanced or metastatic soft tissue sarcoma. In the study, 102 patients will be enrolled and parallel assigned in a 1:1 fashion to one of two different arms, as follows:

* ARM 1: Patients will receive 75 mg/m2 doxorubicin once every 3 weeks (reference treatment).
* ARM 2: Patients will receive 13 µg/kg L19TNF on days 1, 3 and 5 every 3 weeks in combination with 60 mg/m2 doxorubicin (once every 3 weeks).

Anti-cancer activity will be assessed every 6 weeks during therapy and every 12 weeks thereafter. Median PFS, PFS rates at 3, 6, 9, 12 and 18 months, mOS, OS rate at 12 and 18 months and ORR will be calculated.

Safety assessment will be performed on an ongoing basis during study participation, including standard laboratory assessments. The incidence of AEs will be summarized by severity in all patients with at least one study drug intake.

Eligibility criteria: Inclusion Criteria:

1. Patients aged 18-75 years.
2. 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
3. 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.
4. Life expectancy of at least 3 months.
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 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 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.
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:

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. Previous therapy with recombinant TNF.
6. Absolute neutrophil count (ANC) \< 1.5 x 109/L, platelets \< 100 x 109/L and haemoglobin (Hb) \< 9.0 g/dl.
7. Chronically impaired renal function or creatinine ≥ 2.0 x ULN.
8. Inadequate liver function (ALT, AST, ALP or total bilirubin ≥ 2.5 x ULN.
9. Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.
10. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
11. Heart insufficiency (\> Grade II, New York Heart Association (NYHA) criteria).
12. Clinically significant cardiac arrhythmias or requiring permanent medication.
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. Deep vein thrombosis, pulmonary embolism or other acute vascular events within 6 months.
26. Anticoagulation therapy with P2Y12 antagonists (e.g., clopidogrel, ticagrelor) and vitamin K antagonists (e.g., phenprocoumon, warfarin).
27. Concurrent use of other anti-cancer treatments or agents other than study medication.

Primary outcomes:
measure: Median Progression free survival (mPFS)
timeFrame: From randomization up to week 72
Secondary outcomes:
measure: PFS rate
timeFrame: At 3, 6, 9, 12, 18 months after randomization
measure: Overall Response Rate (ORR)
timeFrame: At 3, 6, 9, 12, 18 months after randomization
measure: Overall survival (OS)
timeFrame: At 12 months and 18 months after randomization
measure: Median Overall survival (mOS)
timeFrame: At 12 months and 18 months after randomization
measure: Adverse Events
timeFrame: From week 1 up to week 72
measure: HAFA assessment
timeFrame: 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)
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Institut Bergonié
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Lyon
country: France
facility: Centre Léon Bérard
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow
city: Berlin
country: Germany
facility: Charité- Universitätsmedizin Berlin
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt
city: Hamburg
country: Germany
facility: Universitätsklinik Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: Heidelberg University Hospital
city: Köln
country: Germany
facility: Uniklinik Köln
city: Mainz
country: Germany
facility: Universitätsmedizin der J.-G. Universität Mainz
city: München,
country: Germany
facility: Klinik rechts der Isar
city: Münster
country: Germany
facility: Universitaetsklinikum Muenster
city: Candiolo
country: Italy
facility: IRCCS Fondazione del Piemonte per l'Oncologia Istituto per la Ricerca e la Cura del Cancro di Candiolo
state: Torino
city: Bologna
country: Italy
facility: Bologna University, Chemotherapy Unit, IRCCS Istituto Ortopedico Rizzoli, Department of DIMES
city: Orbassano
country: Italy
facility: AOU San Luigi Gonzaga
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
city: Gdynia
country: Poland
facility: Szpital Pomorski Im. PCK
city: Warsaw
country: Poland
facility: Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie Warszawa
city: El Palmar
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
state: Murcia
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: Madrid
country: Spain
facility: Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Zaragoza
country: Spain
facility: Hospital Miguel Servet
Study officials:
References: