A Randomized & Observational phase II trial comparing the activity of TrabectedIn vs gemCitabine in patients with metastatic or locally advanced LEiomyosarcoma pretreated with conventional chemotherapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Italian Sarcoma Group

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02]

Trial duration

29 Oct 2021 → ongoing

Decision date (initial)

2024-06-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Pharma Mar S.A.

External identifiers

EU CT number

2024-513820-40-00

EudraCT number

2020-000741-13

ClinicalTrials.gov

NCT04383119

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others

Compare the growth modulation index (GMI) in patients treated in second line with Trabectedin or Gemcitabine for locally relapsed/metastatic leiomyosarcoma pre-treated with anthracycline-based chemotherapy. The growth modulation index (GMI) is the ratio of time to progression with the nth line (TTPn) of therapy to the TTPn−1 with the n-1th line. GMI >1.33 is considered as a sign of activity in phase II trials. Specifically, GMI will be calculated as the ratio between TPTrabectedin/Gemcitabine and TTPfirst line.

Secondary objectives 7

1. To evaluate Overall Response Rate (ORR) determined by RECIST, version 1.1 in patients with advanced leiomyosarcoma treated with Trabectedin compared to patients treated with Gemcitabine.
2. To evaluate overall survival (OS) in patients with advanced leiomyosarcoma treated with Trabectedin compared to patients treated with Gemcitabine.
3. To evaluate Progression Free Survival (PFS) and Progression Free Survival Rate (PFSR) at 6 months in patients with advanced leiomyosarcoma treated with Trabectedin compared to patients treated with Gemcitabine.
4. To evaluate duration of response (DOR) per RECIST, version 1.1 in patients with advanced leiomyosarcoma treated with Trabectedin compared to patients treated with Gemcitabine.
5. To evaluate GMI2 calculated as the ratio of TTPthird line and TTPsecond line in the subset of patients who crossed over after progression to second line
6. To evaluate the safety and tolerability of Trabectedin compared to Gemcitabine
7. Exploratory objectives will be to identify gene mutations that may be associated to response/resistance to the treatment and to clinical outcomes parameters. Moreover, to generate hypotheses regarding specific subgroup activity of Trabectedin, patients will be also exploratory evaluated according to the following subgroups: - age (<65 vs. ≥65) - sex (males vs. females) - site of disease (uterine LMS and non-uterine LMS) - ECOG performance status (0 vs. ≥1). -First line anthracycline based chemotherapy (single agent vs. combined chemotherapy)

Conditions and MedDRA coding

Metastatic or locally advanced leiomyosarcoma

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Patients with histologically documented diagnosis of leiomyosarcoma
2. Patients with diagnosis of unresectable or metastatic leiomyosarcoma
3. Patients who received previous first line systemic treatment with Anthracycline-based chemotherapy for advanced disease.
4. Patients suitable to receive gemcitabine or Trabectedin therapy
5. Measurable or evaluable disease with RECIST 1.1 criteria.
6. Evidence of progression according RECIST 1.1 during the 6 months before study entry
7. 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.
8. Age ≥18 years
9. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
10. All previous anticancer treatments must have completed ≥ 3 weeks (21 days) prior to first dose of study drug.
11. 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
12. 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
13. Left Ventricular Ejection Fraction ≥ 50% and/or above lower institutional limit of normality
14. 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
15. No history of arterial and/or venous thromboembolic event within the previous 12 months.
16. 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 17

1. Prior treatment with Trabectedin and/or Gemcitabine
2. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
3. 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.
4. Persistent toxicities(≥CTCAE grade 2) with the exception of alopecia, caused by previous anticancer therapies
5. 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)
6. 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.
7. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
8. 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
9. 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
10. Active clinically serious infections (> grade 2 NCI-CTCAE version 5.0).
11. Previous treatment with radiation therapy within 14 days of first day of study drug dosing
12. Major surgery within 4 weeks prior to study entry
13. 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)
14. 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).
15. Patients undergoing renal dialysis or with ClCr <30 ml/min or Creatinine >1,5 mg/dL
16. Pregnant or breast feeding patients
17. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Compare the growth modulation index (GMI) in patients treated with Trabectedin or Gemcitabine for locally relapsed/metastatic leiomyosarcoma pretreated with anthracycline-based chemotherapy. GMI is the ratio of time to progression with the nth line (TTPn) of therapy to the TTPn−1 with the n-1th line. GMI >1.33 is considered as a sign of activity in phase II trials (Penel Ann Oncology). GMI will be calculated as the ratio between TTPTrabectedin/Gemcitabine and TTPfirst line.

Secondary endpoints 7

1. To evaluate Overall Response Rate (ORR) determined by RECIST, version 1.1 in patients with advanced leiomyosarcoma treated with Trabectedin compared to patients treated with Gemcitabine.
2. To evaluate overall survival (OS) in patients with advanced leiomyosarcoma treated with Trabectedin compared to patients treated with Gemcitabine
3. To evaluate Progression Free Survival (PFS) and Progression Free Survival Rate (PFSR) at 6 months in patients with advanced leiomyosarcoma treated with Trabectedin compared to patients treated with Gemcitabine
4. To evaluate duration of response (DOR) per RECIST, version 1.1 in patients with advanced leiomyosarcoma treated with Trabectedin compared to patients treated with Gemcitabine.
5. To evaluate GMI2 calculated as the ratio of TTPthird line and TTPsecond line in the subset of patients who crossed over after progression to second line
6. To evaluate the safety and tolerability of Trabectedin compared to Gemcitabine
7. Exploratory objectives will be to identify gene mutations that may be associated to response/resistance to the treatment and to clinical outcomes parameters. Patients will be also exploratory evaluated according to the following subgroups: - age (<65 vs. ≥65) - sex (males vs. females) - site of disease (uterine LMS and non-uterine LMS) - ECOG performance status (0 vs. ≥1). -First line anthracycline based chemotherapy (single agent vs. combined chemotherapy)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Italian Sarcoma Group

Sponsor organisation

Italian Sarcoma Group

Address

Via Luigi Carlo Farini 31

City

Bologna

Postcode

40124

Country

Italy

Scientific contact point

Organisation

Italian Sarcoma Group

Contact name

ISG Clinical Trials Office

Public contact point

Organisation

Italian Sarcoma Group

Contact name

ISG Clinical Trials Office

Locations

1 EU/EEA country · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications