Phase II study on trabectedin in adults and young adults HEY1-NOCA2 positive skeletal and extra-skeletal mesenchymal chondrosarcoma (MCS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Italian Sarcoma Group

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Sep 2021 → ongoing

Decision date (initial)

2024-07-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Pharma Mar S.A.

External identifiers

EU CT number

2024-514319-85-00

EudraCT number

2019-003733-41

ClinicalTrials.gov

NCT04305548

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Diagnosis, Efficacy, Therapy

The primary objective of this study is to explore the activity of trabectedin from 2nd to 4th line, in patients aged  16 years with advanced HEY1-NOCA2 positive MCS pre-treated with anthracycline-based chemotherapy. Therefore, with reference to a study population of patients with progressive by RECIST v1.1, locally advanced or metastatic, HEY1-NCOA2 positive MCS pre- treated with one, two or three lines of medical treatment, the primary end-point of the study will be to assess: Overall tumour Response Rate, according to RECIST v 1.1

Secondary objectives 2

1. The activity of trabectedin in advanced MCS will be also evaluated according to Choi criteria. In addition, trabectedin efficacy will be investigated by means of progression-free survival (PFS), clinical benefit rate (RECIST CR + PR + SD > 6 months), overall survival (OS) and duration of response. The toxicity profile of trabectedin will be also evaluated.
2. Tumour transcriptional pattern and immunological profile of recruited patients will be evaluated and correlated with the response.

Conditions and MedDRA coding

Advanced rearranged mesenchymal chondrosarcoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Age ≥ 16 years old
2. Histological centrally confirmed diagnosis of skeletal or extra-skeletal MCS with the documented presence of HEY1-NCOA2 fusion (a paraffin embedded tumour block is required for centralized review)
3. Locally advanced disease (i.e. surgical resection of local disease unfeasible radically or unaccepted by the patient or amenable to become less demolitive or feasible or easier after cytoreduction) and/or metastatic disease
4. Measurable or evaluable disease with RECIST v1.1
5. Evidence of progression by RECIST v1.1 during the 6 months before study entry
6. Patients must be pre-treated with at least one prior chemotherapy treatment containing anthracyclines for the advanced phase of disease and with a maximum of 3 lines
7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
8. Adequate bone marrow function (Blood transfusions to reach the baseline requested Hb level are not allowed)
9. Adequate organ function
10. Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation each cycle of chemotherapy. Post-menopausal women must be amenorrhoeic 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 throughout the study and thereafter, at the end of study treatment, for 3 months in female patients of childbearing potential and for 5 months in men in fertile age
11. Cardiac ejection fraction ≥50% as measured by echocardiogram
12. No history of arterial and/or venous thromboembolic event within the previous 12 months
13. The patient or legal representative must be able to read and understand the informed consent form (ICF) and must have been willing to give written informed consent and any locally required authorisation before any study-specific procedures, including screening evaluations, sampling, and analyses.

Exclusion criteria 18

1. Other primary malignancy with <5 years clinically assessed disease free interval, except basal cell skin cancer, cervical carcinoma in situ or other neoplasm judged to entail a low risk of relapse
2. Previous treatment with radiation therapy within 14 days of first day of study drug dosing, or patients who have not recovered from adverse events due to agents previously administered
3. Previous radiotherapy to 25% of the bone marrow
4. Major surgery within 2 weeks prior to study entry
5. Participation in another clinical study with an investigational product, which last dose was taken less than 4 weeks prior to the start of the treatment.
6. Persistent toxicities (≥ NCI CTCAE v5.0 grade 2) with the exception of alopecia, caused by previous anticancer therapies.
7. Pregnancy or breast feeding
8. Grade III/IV cardiac problems as defined by the New York Heart Association Criteria (i.e. congestive heart failure, myocardial infarction within 6 months of study)
9. Medical history of arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within 6 months prior to the initiation of study treatment
10. Known brain metastasis
11. Known chronic liver disease (i.e. chronic active hepatitis and cirrhosis)
12. Known diagnosis of human deficiency virus (HIV) infection
13. Active or chronic hepatitis B or C requiring treatment with antiviral therapy
14. 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
15. Evidence of any other serious or unstable illness, or medical, psychological, or social condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject’s participation in the study or evaluation of the study results
16. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
17. Any other factors, that, at judgment of investigator, could affect the safety of the patients according to the available trabectedin safety data
18. Expected non-compliance to medical regimens

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall tumour Response Rate, according to RECIST v 1.1

Secondary endpoints 9

1. Choi Response Rate
2. Overall Survival (OS)
3. Progression Free Survival (PFS)
4. Clinical Benefit Rate
5. Duration of response
6. Safety
7. Exploration of transcriptomic and genomic profile of responsive versus unresponsive tumors. Genomic, mRNA, miRNA expression pattern of a sizable number of responsive and unresponsive tumors will be analyzed and compared.
8. Evaluation of efficacy of liquid biopsy (measure of HEY1-NCOA2 fusion in cell free DNA/RNA) in anticipating response/progression under treatment.
9. Validazione dei target trascrizionali HEY1-NCOA2 coinvolti nella risposta MCS alla trabectedina mediante esperimenti in vitro.

Investigational products

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

Test 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

Silvia Stacchiotti

Public contact point

Organisation

Italian Sarcoma Group

Contact name

Gianluca Ignazzi

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Country notifications

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

Application history

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