Phase II Randomized Trial of Trabectedin Versus Gemcitabine in Metastatic or Locally Advanced Leiomyosarcoma Post-Anthracycline Chemotherapy
- Trial ID
- 2024-513820-40-00
- Sponsor
- Italian Sarcoma Group
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **growth modulation index (GMI)** in patients with metastatic or locally advanced leiomyosarcoma who have been pre-treated with anthracycline-based chemotherapy. The comparison is between those treated in the second line with **Trabectedin** or **Gemcitabine**. The GMI is calculated as the ratio of time to progression with the nth line of therapy to the time to progression with the n-1th line. A GMI greater than 1.33 is considered indicative of therapeutic activity in phase II trials. This measure is clinically relevant as it provides insight into the efficacy of second-line treatments in prolonging disease control.
Secondary objectives include: - Evaluating the **Overall Response Rate (ORR)** determined by RECIST, version 1.1, in patients treated with Trabectedin compared to those treated with Gemcitabine. - Assessing **overall survival (OS)** in the same patient groups. - Measuring **Progression Free Survival (PFS)** and the **Progression Free Survival Rate (PFSR)** at 6 months. - Determining the **duration of response (DOR)** per RECIST, version 1.1. - Evaluating the **GMI2**, calculated as the ratio of time to progression in the third line to the second line in patients who crossed over after progression. - Assessing the **safety and tolerability** of Trabectedin compared to Gemcitabine. - Exploratory objectives include identifying gene mutations associated with response or resistance to treatment and clinical outcomes, and evaluating specific subgroup activity of Trabectedin based on age, sex, site of disease, ECOG performance status, and first-line anthracycline-based chemotherapy regimen.
Participants
The clinical trial involves participants diagnosed with **metastatic or locally advanced leiomyosarcoma**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically documented diagnosis of leiomyosarcoma and must have completed any previous anticancer treatments at least 21 days prior to the first dose of the study drug. The trial does not include a vulnerable population. Participants must have adequate bone marrow, liver, and renal function, and a left ventricular ejection fraction of at least 50%. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial. Key inclusion criteria include having received previous first-line systemic treatment with anthracycline-based chemotherapy for advanced disease and being suitable to receive gemcitabine or trabectedin therapy. Participants must have measurable or evaluable disease according to RECIST 1.1 criteria and evidence of progression within six months before study entry. The trial population was selected based on these criteria, ensuring that participants are suitable for the study's objectives.
Plans and Procedures
The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the efficacy of **trabectedin** versus **gemcitabine** in patients with metastatic or locally advanced **leiomyosarcoma** who have been pretreated with conventional chemotherapy. The trial aims to compare the growth modulation index (GMI) in patients treated with these agents. The study is expected to last until January 18, 2026, with recruitment having commenced on January 18, 2022. Participants will be involved in the study for a maximum treatment period of 99 weeks, with the possibility of early termination if adverse events occur or if the patient withdraws consent.
The sequence of study visits includes an initial screening visit to confirm eligibility based on inclusion criteria such as histologically documented diagnosis of leiomyosarcoma, completion of previous anticancer treatments at least 21 days prior, and adequate organ function. Following the screening, participants will undergo regular follow-up visits to monitor treatment response and safety, with assessments conducted according to RECIST 1.1 criteria. The end-of-study visit will evaluate the overall response rate, progression-free survival, and other secondary endpoints. Participants will be monitored for adverse events throughout the trial, and any significant toxic effects may lead to early withdrawal from the study.
Inclusion criteria require participants to be at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or less. Female participants of childbearing potential must have a negative pregnancy test before each chemotherapy cycle and agree to use effective contraception. The trial excludes individuals with a history of thromboembolic events within the past 12 months. The primary endpoint is the comparison of GMI, with secondary endpoints including overall response rate, overall survival, and progression-free survival. The trial also explores gene mutations associated with treatment response and clinical outcomes.
Treatment
The clinical trial involves the administration of **Gemcitabine**, marketed as Gemcitabina Accord, which is provided as a 100 mg/ml concentrate for solution for infusion. This pharmaceutical form is a **solution for infusion** and is administered via the **intravenous** route. The maximum daily dose is 1000 mg/m², with the same maximum total dose amount. The treatment period is set for a maximum of 99 days. The product is manufactured by Accord Healthcare S.L.U. and is not a pediatric formulation. The active substance, gemcitabine, is of chemical origin and is classified under the ATC code L01BC05.
Another experimental medication used in the trial is **Trabectedin**, available under the brand names Yondelis and Trabectedina Teva. Yondelis is provided as a powder for concentrate for solution for infusion, available in 0.25 mg and 1 mg dosages. Trabectedina Teva is similarly available in 0.25 mg and 1 mg dosages. Both forms are administered as a **solution for infusion** via the **intravenous** route. The maximum daily dose for trabectedin is 2.6 mg, with the same maximum total dose amount, and the treatment period is also set for a maximum of 99 days. Trabectedin is manufactured by Pharma Mar, S.A. and TEVA B.V., and is classified under the ATC code L01CX01. The active substance is of chemical origin and is not formulated for pediatric use.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data. Compliance with the dosing schedule and administration is monitored throughout the trial to ensure adherence to the protocol. The trial aims to compare the efficacy of trabectedin versus gemcitabine in patients with metastatic or locally advanced leiomyosarcoma pretreated with conventional chemotherapy.
Efficacy
The efficacy of the clinical trial will be assessed by comparing the **Growth Modulation Index (GMI)** in patients treated with Trabectedin or Gemcitabine for locally relapsed or metastatic leiomyosarcoma pretreated with anthracycline-based chemotherapy. The GMI is defined as the ratio of time to progression with the nth line (TTPn) of therapy to the TTPn-1 with the n-1th line. A GMI greater than 1.33 is considered indicative of activity in phase II trials. Specifically, the GMI will be calculated as the ratio between TTPTrabectedin/Gemcitabine and TTPfirst line.
Secondary endpoints include evaluating the Overall Response Rate (ORR) determined by RECIST, version 1.1, overall survival (OS), Progression Free Survival (PFS), and Progression Free Survival Rate (PFSR) at 6 months. Additionally, the duration of response (DOR) per RECIST, version 1.1, will be assessed. The trial will also evaluate GMI2, calculated as the ratio of TTPthird line and TTPsecond line in patients who crossed over after progression to the second line. Safety and tolerability of Trabectedin compared to Gemcitabine will be evaluated. Exploratory objectives include identifying gene mutations associated with response or resistance to treatment and clinical outcomes, with evaluations based on subgroups such as age, sex, site of disease, ECOG performance status, and type of first-line anthracycline-based chemotherapy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients with histologically documented diagnosis of leiomyosarcoma
- Patients with diagnosis of unresectable or metastatic leiomyosarcoma
- Patients who received previous first line systemic treatment with Anthracycline-based chemotherapy for advanced disease.
- Patients suitable to receive gemcitabine or Trabectedin therapy
- Measurable or evaluable disease with RECIST 1.1 criteria.
- Evidence of progression according RECIST 1.1 during the 6 months before study entry
- Availability of the following dates (DD/MM/AAAA): start date of the first line treatment, date of the last radiological assessment showing RECIST1.1 PR or SD; date of the last radiological assessment showing RECIST 1.1 PD.
- Age ≥18 years
- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
- All previous anticancer treatments must have completed ≥ 3 weeks (21 days) prior to first dose of study drug.
- The patient has resolution of adverse events, with the exception of alopecia, and of all clinically significant toxic effects of prior loco-regional therapy, surgery, radiotherapy or systemic anticancer therapy to ≤ Grade 1, by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
- Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted at screening and repeated within 7 days prior to start of treatment: a. Hemoglobin ≥ 9 g/dl b. Absolute neutrophil count (ANC) ≥1,500/mm3 c. Platelet count≥100000/mm3 d. Total bilirubin ≤ upper limit of normal (ULN) () e. Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal. f. Alkaline phosphatase ≤ 2.5 x ULN (consider hepatic isoenzymes 5-nucleotidase or gamma glutamyl transpeptidase (GGT) if the elevation could be osseous in origin). g. PT-INR/PTT < 1.5 x ULN (Patients who are being therapeutically anticoagulated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists). h. Serum creatinine ≤ 1.5 x ULN or creatinine clearance estimated of ≥30 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test : Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a / [serum creatinine (mg/dL) x 72]. a where F=0.85 for females and F=1 for males Albumin > 25 g/l i. Albumin ≥ 25 g/l j. Creatine phosphokinase (CPK) ≤ 2.5 x ULN
- Left Ventricular Ejection Fraction ≥ 50% and/or above lower institutional limit of normality
- Female patients of child-bearing potential must have negative pregnancy test within 7 days before initiation each cycle of chemotherapy. Post-menopausal women must be amenorhoic for at least 12 months to be considered of non-childbearing. potential. Male and female patients of reproductive potential must agree to employ an effective method of birth control during the trial and thereafter, at the end of study treatment, for 3 months in female patients of childbearing potential and for 6 months in men in fertile age
- No history of arterial and/or venous thromboembolic event within the previous 12 months.
- The patient or legal representative must be able to read and understand the informed consent form and must have been willing to give written informed consent prior to any study specific procedure. The subject may also provide an optional consent for the biological/translational sub-study associated. However, the subject may participate in the main trial without participating in biological/translational.
Exclusion Criteria
- Prior treatment with Trabectedin and/or Gemcitabine
- Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
- History of other malignancies (except basal cell carcinoma or cervical carcinoma in situ, adequately treated), unless in remission from 5 years or more and judged of negligible potential of relapse.
- Persistent toxicities(≥CTCAE grade 2) with the exception of alopecia, caused by previous anticancer therapies
- Metastatic brain or meningeal tumors (unless the patient is > 6 months from definitive therapy, does not require corticosteroid treatment, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry)
- Active viral hepatitis(HBV or HCV infection). Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
- Patients with any severe and/or uncontrolled medical conditions such as unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months, serious uncontrolled cardiac arrhythmia, uncontrolled hyperlipidemia, cirrhosis, chronic or persistent active hepatitis or severely impaired lung function. In particular for history of cardiac disease: congestive heart failure ≥ NYHA class 2; active coronary artery disease (myocardial infarction more than 6 months prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry),superior vena cava syndrome, extensive bilateral lung disease on High Resolution CT sca
- Medical history of hemorrhage or a bleeding event ≥ Grade 3 (NCI-CTCAE v 5.0) within 4 weeks prior to the initiation of study treatment
- Active clinically serious infections (> grade 2 NCI-CTCAE version 5.0).
- Previous treatment with radiation therapy within 14 days of first day of study drug dosing
- Major surgery within 4 weeks prior to study entry
- Concomitant use of known strong CYP3A inhibitors (eg. Ketoconazole, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil)
- Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil).
- Patients undergoing renal dialysis or with ClCr <30 ml/min or Creatinine >1,5 mg/dL
- Pregnant or breast feeding patients
- Patients with severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 18 Jan 2022 | 100 |
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 |
|---|---|---|---|---|---|---|
Gemcitabina Accord 100 mg/ml concentrato per soluzione per infusione. | Comparator | CONCENTRATO PER SOLUZIONE PER INFUSIONE | INTRAVENOUS | 1000 | 99 | PRD3332928 |
Trabectedina Teva 1 mg polvere per concentrato per soluzione per infusione | Test | POLVERE PER CONCENTRATO PER SOLUZIONE PER INFUSIONE | INTRAVENOUS | 2.6 | 99 | PRD9755010 |
Gemcitabina Accord 100 mg/ml concentrato per soluzione per infusione. | Comparator | CONCENTRATO PER SOLUZIONE PER INFUSIONE | INTRAVENOUS | 1000 | 99 | PRD3332927 |
Gemcitabina Accord 100 mg/ml concentrato per soluzione per infusione. | Comparator | CONCENTRATO PER SOLUZIONE PER INFUSIONE | INTRAVENIOUS INFUSION | 1000 | 99 | PRD3332926 |
Trabectedina Teva 0,25 mg polvere per concentrato per soluzione per infusione | Test | POLVERE PER CONCENTRATO PER SOLUZIONE PER INFUSIONE | INTRAVENOUS | 2.6 | 99 | PRD9755009 |
Yondelis 0.25 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 2.6 | 99 | PRD342793 |
Gemcitabina Accord 100 mg/ml concentrato per soluzione per infusione. | Comparator | CONCENTRATO PER SOLUZIONE PER INFUSIONE | INTRAVENOUS | 1000 | 99 | PRD3332925 |
Yondelis 1 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 2.6 | 99 | PRD343315 |