Inclusion Criteria:
1. Voluntarily signed and dated written informed consent prior to any specific-study
procedure.
2. Age ≥ 18 years.
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
4. Life expectancy ≥ 3 months.
5. Histologically or cytologically confirmed diagnosis of advanced disease of any of
the following tumor types:
For the Lurbinectedin Escalation Group and the Irinotecan Escalation Group:
1. Glioblastoma.
2. Soft-tissue sarcoma (excluding gastrointestinal stromal tumors [GIST]).
3. Endometrial carcinoma.
4. Epithelial ovarian carcinoma (including primary peritoneal disease and/or
fallopian tube carcinomas and/or endometrial adenocarcinomas) regardless of
platinum sensitivity.
5. Mesothelioma.
6. Gastroenteropancreatic neuroendocrine tumors (GEP-NET).
7. Small cell lung cancer (SCLC).
8. Pancreatic adenocarcinoma.
9. Gastric carcinoma.
10. Colorectal carcinoma (CRC).
For the Intermediate Escalation Group:
1. Endometrial carcinoma.
2. SCLC.
3. Other solid tumors may be included, if appropriate, after discussion between
the Investigators and the Sponsor.
For the Phase II expansion stage:
1. Glioblastoma.
2. Soft tissue sarcoma (including synovial sarcoma),
3. Endometrial carcinoma.
4. SCLC.
5. Neuroendocrine tumors.
- - Group 1: Poorly differentiated grade 3 NEC (Ki-67 >20%) according to the
2019 WHO classification of tumors of the digestive system, of
gastroenteropancreatic origin or unknown primary site (lung primary tumors
will be excluded).
- - Group 2: Well differentiated grade 2 (Ki-67 3-20%) or grade 3 (Ki-67
21-55%) GEP-NETs according to the 2019 WHO classification of tumors of the
digestive system.
6. The number of prior lines of therapy allowed per patient will be as follows:
For the Phase I Escalation Stage:
No more than two prior lines of cytotoxic-containing chemotherapy regimens for
advanced disease. For the Phase II Lurbinectedin Expansion Stage:
- - For SCLC, one prior line of platinum-containing chemotherapy with/without
antibodies against programmed cell death protein-1 (PD-1) or programmed death
ligand-1 (PD-L1).
- - For NENs,
- In Group 1 (patients with poorly differentiated NEC of
gastroenteropancreatic origin or unknown primary site, excluding lung
primary tumors), one prior line of platinum-based chemotherapy; and.
- - In Group 2 (patients with well differentiated GEP-NETs), no more than
three prior lines of systemic therapy (that may include somatostatin
analogues, chemotherapy, everolimus and/or sunitinib).
- - For all other tumor types, no more than two prior lines of cytotoxic-containing
chemotherapy regimens for advanced disease.
There is no limit for prior targeted therapy, hormonal therapy and immunotherapy
(such as nivolumab).
7. Phase II expansion stage: Tumor-specific cohort(s) at the RD:
1. Measurable disease according to Response Evaluation Criteria in Solid Tumors
(RECIST) v.1.1. For patients with glioblastoma: Measurable disease according to
RECIST v.1.1 and Response Assessment in Neuro-Oncology (RANO) criteria.
2. Documented disease progression per RECIST v.1.1 during or immediately after
last therapy according to any of the aforementioned criteria. For patients with
glioblastoma: Documented disease progression per RECIST v.1.1 and RANO
criteria.
8. At least three weeks since the last anticancer therapy, (including immunotherapy,
investigational drugs and radiotherapy), and at least six weeks since nitrosoureas
and mitomycin C (systemic).
For biological/investigational anticancer therapies given orally, the aforementioned
period of at least three weeks could be changed for one of at least five half-lives
(whichever occurred first), provided that the therapy is given as single agent and
not combined with other drugs. If this is not the case, this exception will not be
acceptable.
For patients with glioblastoma: at least 12 weeks since the end of radiotherapy,
except if:
1. The patient has a new lesion outside of the radiotherapy field, or. 2. The patient has undergone brain surgery to remove the tumor before study entry,
and progressive disease has been confirmed histologically.
Note: washout periods will be referred to the day of first cycle administration (Day
1), not to the day of registration (Day 0).
9. Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤ 7 days
before inclusion in the trial):
1. Platelet count ≥ 100 × 10^9/L, hemoglobin ≥ 9.0 g/dL and absolute neutrophil
count (ANC) ≥ 2.0 × 10^9/L.
2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × the
upper limit of normal (ULN), even in the presence of liver metastases.
3. Alkaline phosphatase (ALP) ≤ 2.5 × ULN (≤ 5 × ULN if disease-related/in the
case of liver metastases).
4. Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ ULN.
5. International Normalized Ratio (INR) < 1.5 (except if patient is on oral
anticoagulation therapy).
6. Calculated creatinine clearance (CrCL) ≥ 30 mL/minute (using Cockcroft-Gault
formula).
7. Creatine phosphokinase (CPK) ≤ 2.5 × ULN.
8. Albumin ≥ 3.0 g/dL*
10. Recovery to grade ≤ 1 or to baseline from any adverse event (AE) derived from
previous treatment (excluding alopecia and/or cutaneous toxicity and/or peripheral
neuropathy and/or fatigue grade ≤ 2).
- - Albumin transfusion to increase the blood level in order to fulfill the
inclusion criterion is strictly forbidden.
Exclusion Criteria:
1. Concomitant diseases/conditions:
1. History or presence of unstable angina, myocardial infarction, congestive heart
failure, or clinically significant valvular heart disease within the previous
year.
2. Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing
treatment.
3. Myopathy or any clinical situation that causes significant and persistent
elevation of CPK (> 2.5 × ULN in two different determinations performed one
week apart).
4. Ongoing chronic alcohol consumption or cirrhosis with Child-Pugh score B or C.
Known Gilbert disease.
5. Active uncontrolled infection.
6. Known human immunodeficiency virus (HIV) or known hepatitis C virus (HCV)
infection or active hepatitis B.
7. Any past or present chronic inflammatory colon and/or liver disease, past
intestinal obstruction, pseudo or sub-occlusion or paralysis.
8. Evident symptomatic pulmonary fibrosis or interstitial pneumonitis, pleural or
cardiac effusion rapidly increasing and/or necessitating prompt local treatment
within seven days.
9. Any other major illness that, in the Investigator's judgment, will
substantially increase the risk associated with the patient's participation in
this study. 10. Active Coronavirus disease (COVID-19).
11. Hypersensitivity to any of the study drugs or their excipients.
2. Prior treatment with lurbinectedin, trabectedin (Yondelis®) or topoisomerase I
inhibitors (irinotecan, topotecan, etc.). Prior topoisomerase inhibitors (e.g.,
irinotecan) are only allowed in patients with colorectal carcinoma or NENs.
3. Prior bone marrow or stem cell transplantation, or radiation therapy in more than
35% of bone marrow.
4. Known brain metastases or leptomeningeal disease involvement. Glioblastoma lesions
(primary or locally advanced) are eligible. Exception: patients with brain
metastases are eligible provided they are radiologically stable, i.e. without
evidence of progression for at least 4 weeks by repeat imaging (note that the repeat
imaging should be performed during study screening), clinically stable and without
requirement of steroid treatment (patients taking steroids in the process of already
being tapered within two weeks prior to screening are allowed). Brain CT-scan or MRI
results must be provided at baseline.
5. Women who are pregnant or breast feeding and fertile patients (men and women) who
are not using an effective method of contraception. Women of childbearing potential
(WOCBP) must agree to use an effective contraception method to avoid pregnancy
during the course of the trial (and for at least six months after the last
infusion). Fertile male patients must agree to refrain from fathering a child or
donating sperm during the trial and for four months after the last infusion.
6. Limitation of the patient's ability to comply with the treatment or follow-up
protocol.
