Clinical Study in Adult and Young Adult Patients With Advanced Desmoplastic Small Round Cell Tumor (DSRCT) ISG-TULIPS

This is an Italian and Spanish multicentric, prospective, phase II single-arm, open-label, investigator-initiated clinical study that will be conducted within the Italian Sarcoma Group (ISG) and the Spanish Sarcoma Groups (GEIS), aiming at exploring the activity of lurbinectedinin combination with irinotecan, until progression or unacceptable toxicity, in a population of =/>15 years old patients with histologically and molecularly confirmed (EWSR1-WT1 translocation positive), advanced (locally advanced or metastatic) DSRCT, from 2nd to 4th line, following progression to anthracycline-based chemotherapy.

The primary end-point of the study will be the overall response rate (ORR) by RECIST v1.1 in the study population. Secondary end-points will be PFS, DoR, OS, safety and changes in QoL.

Patients will be evaluated for the primary end-point if have completed at least one cycle of lurbinectedin and irinotecan and have at least one post-baseline radiologic disease assessment. Patients with documented early progression disease (PD) or who die due to PD before the first scheduled tumor assessment will also be included in the analysis.

Patients will be followed for follow up visits every 6 months for 2 years.

Inclusion criteria

• Histological centrally confirmed diagnosis of DSRCT with the documented presence of EWSR1-WT1 translocation.
• Age ≥ 15 years.
• Locally advanced (i.e. radical surgical resection of local disease unfeasible or surgery declined by the patient or surgery deemed to become less demolitive and / or easier after cytoreduction) and/or metastatic disease.
• Measurable disease by RECIST v1.1.
• Clinical or objective disease progression after the last administration of the last standard therapy, or have stopped standard therapy due to intolerability within 6 months from enrollment.
• At least one prior chemotherapy based on anthracycline (considering chemotherapy administered for primary tumour) and no more than 3 prior chemotherapy lines.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2.
• Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤ 7 days before inclusion in the trial), defined as the following:

• platelet count ≥ 100 × 109/L, hemoglobin ≥ 9.0 g/dL, white blood cells ≥ 3.0 × 109/L and absolute neutrophil count (ANC) ≥ 2.0 × 109/L,
• aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × the upper limit of normal (ULN), even in the presence of liver metastases,
• total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ ULN,
• International Normalized Ratio (INR) < 1.5 (except if patient is on oral anticoagulation therapy),
• calculated creatinine clearance (CrCL) ≥ 30 mL/minute (using Cockcroft-Gault formula),
• creatine phosphokinase (CPK) ≤ 2.5 × ULN,
• albumin ≥ 3.0 g/dL.
• Cardiac ejection fraction ≥50% as measured by echocardiogram.
• Recovery to grade ≤ 1 or to baseline from any adverse event (AE) derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or fatigue grade ≤ 2).
• No history of arterial and/or venous thromboembolic event within the previous 12 months.
• Females of childbearing potential must have a negative pregnancy test (preferable by serum or, if serum test unavailable, urine beta-HCG) within 7 days before treatment start.
• 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 a highly effective method of birth control (Acceptable methods of contraception are described in Appendix 5) throughout the study and thereafter, at the end of study treatment, and for at least 7 months from the patient's last lurbinectedin administration in female patients of childbearing potential and for at least 4 months in men in fertile age after the last lurbinectedin administration.
• 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

• Prior treatment with lurbinectedin or trabectedin, Ecubectedin (PM 14) or PM54.
• Known hypersensitivity to irinotecan or lurbinectedin or any of their components of the drugs products (excipients).
• 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.
• History or presence of unstable angina, myocardial infarction, or clinically significant valvular heart disease within 12 months of the study.
• Grade III/IV cardiac problems as defined by the New York Heart Association Criteria (i.e. congestive heart failure, myocardial infarction within 12 months of study).
• Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment within 12 months of study.
• Myopathy or any clinical situation that causes significant and persistent elevation of CPK (> 2.5 × ULN in two different determinations performed one week apart).
• Severe and/or uncontrolled medical disease (i.e. uncontrolled diabetes, chronic renal disease, or active uncontrolled infection).
• Known active brain metastasis.
• Known chronic liver disease (i.e. chronic active hepatitis and cirrhosis).
• Diagnosis of human deficiency virus (HIV), hepatitis C virus (HCV) infection or active hepatitis B (to be excluded during the screening period).
• Any past or present chronic inflammatory colon and/or liver disease, past intestinal obstruction, pseudo or sub-occlusion or paralysis.
• Evident symptomatic pulmonary fibrosis or interstitial pneumonitis, pleural or cardiac effusion rapidly increasing and/or necessitating prompt local treatment within seven days.
• Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.
• Known active COVID-19 disease (this includes positive test for SARS-CoV-2 in nasopharyngeal/oropharyngeal swabs or nasal swabs by PCR).
• Prior bone marrow and/or stem cell transplantation, and allogenic transplant.
• Last dose of systemic cytotoxic therapy or investigational therapy within 21 days from enrollment.
• Prior treatment with any form of radiation therapy within 14 days from enrollment.
• Major surgery within 3 weeks prior to study entry and minor surgery within 1 week prior to study entry.
• Use of strong inducers of CYP3A activity within two weeks prior to the first infusion of lurbinectedin (Appendix 6).
• Expected limitation of the patient's ability to comply with the treatment or follow-up protocol.
• Subjects who have current active hepatic or biliary disease (with exception of patients with asymptomatic gallstones, liver metastasis or stable chronic liver disease per Investigator assessment).
• Subjects who have known Gilbert's syndrome.
• Patient has received a live or liver attenuated vaccines within 30 days before the first dose of study intervention. Killed vaccines are allowed.