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 Metastatic Leiomyosarcoma

Philogen S.p.A.7 sites in 1 country114 target enrollmentDecember 27, 2018

ConditionsLeiomyosarcoma

InterventionsDoxorubicin L19TNF plus doxorubicin

DrugsDoxorubicin

Overview

Phase: Phase 2
Intervention: Doxorubicin
Conditions: Leiomyosarcoma
Sponsor: Philogen S.p.A.
Enrollment: 114
Locations: 7
Primary Endpoint: Progression free survival (PFS)
Status: Recruiting
Last Updated: 2 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

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 leiomyosarcoma patients.

Detailed Description

In the study, 122 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 metastatic leiomyosarcoma 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.

Registry

clinicaltrials.gov

Start Date

December 27, 2018

End Date

December 2025

Last Updated

2 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

Philogen S.p.A.

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Patients may be included in the study if they meet all of the following criteria:
•Age ≥ 16 years. Patients under 18 years, should be fully grown (proof of fused growth plates).
•Patients with histological evidence of stage IV metastatic high-grade leiomyosarcoma (grade 2 - 3 according to the Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system) not amenable to curative treatment with surgery or radiotherapy.
•Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by Response Evaluation Criteria In Solid Tumors (RECIST) v.1.
•If only 1 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.
•Documented negative test for HIV, HBV and 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 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' 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 throughout the study (e.g., condom with spermicidal gel). Double-barrier contraception is required.
•Informed consent signed and dated to participate in the study.

Exclusion Criteria

•Patients will be excluded from participating in this study if they meet one or more of the following criteria:
•Prior therapy (except surgery and radiation) for unresectable or metastatic malignant soft tissue sarcoma (STS).
•Patients with primary tumor localized to the extremities and a single resectable synchronous distant metastatic lesion.
•Patients eligible for neoadjuvant preoperative treatment.
•Previous treatment with anthracycline-containing chemotherapy.
•Radiotherapy within 4 weeks prior to start of therapy.
•Known history of allergy to TNFα, anthracyclines or other intravenously (IV) administered human proteins/peptides/antibodies.
•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 clearance \< 60 mL/min or serum creatinine \> 1.5 ULN.
•Inadequate liver function (ALT, AST, GGT, ALP or total bilirubin ≥ 1.5 x ULN) or total bilirubin ≥ 1.5 x ULN).

Arms & Interventions

Arm 1: Doxorubicin

Patients will receive a fixed dose doxorubicin, administered as a 15 ± 5 minutes i.v. infusion.

Intervention: Doxorubicin

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.

Intervention: L19TNF plus doxorubicin

Outcomes

Primary Outcomes

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 Outcomes

Percentage of participants with worst on-study hematological and chemistry abnormalities.(From week 1 up to week 72.)
Overall response rate (ORR)(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 survival (OS) rates(From week 1 up to week 144.)
Number of patients with adverse events (AEs).(From week 1 up to week 72.)
Percentage of participants with Electrocardiogram (ECG) and Echocardiogram (ECHO) abnormality findings.(From week 1 up to week 72, every 6 weeks.)
Number of Participants With Clinically Significant Abnormalities in Vital Signs (Systolic and Diastolic Blood Pressure, Temperature, Heart Rate).(From week 1 up to week 72.)
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)(From week 1 up to week 72.)
Maximum drug concentration [Cmax].(At day 1, 2 ,3 and 5 of week 1)
Overall survival (OS)(From week 1 up to week 72, every 6 weeks; from week 73 up to week 144, every 12 weeks;)
Duration of response (DOR)(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.)
Progression-free survival (PFS) rate(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.)
Human anti-fusion protein antibodies (HAFA) levels against L19TNF.(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))
Time to reach maximum drug concentration [Tmax].(At day 1, 2 ,3 and 5 of week 1)
Terminal half-life [t1/2].(At day 1, 2 ,3 and 5 of week 1)
Area under the drug concentration-time curve, extrapolated to infinity [AUC].(At day 1, 2 ,3 and 5 of week 1)