| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Selected Advanced Solid Tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
-Phase I escalation stage: To determine the maximum
tolerated dose (MTD) and the recommended dose (RD) of
lurbinectedin in combination with irinotecan in patients
with selected advanced solid tumors.
- Phase II expansion stage: To obtain information on the
clinical antitumor activity of this combination in patients
with selected advanced solid tumors. |
|
| E.2.2 | Secondary objectives of the trial |
-To determine the MTD and the RD of lurbinectedin in combination with
irinotecan with or without primary prophylaxis with G-CSF in patients
with SAST [if dose-limiting toxicities of the combination without G-CSF
prophylaxis are exclusively related to neutropenia].
-To characterize the safety profile and feasibility of this combination in
patients with SAST.
-To characterize the pharmacokinetics(PK) of this combination and to
detect major drug-drug PK interactions.
-To obtain preliminary information on the clinical antitumor activity of
this combination in non-heavily pretreated selected solid tumor patients.
-To evaluate PGx in tumor samples of patients exposed to lurbinectedin
and irinotecan in order to identify potential biomarkers of response
and/or resistance to the combination of lurbinectedin and irinotecan.
-To evaluate PGt in germline DNA by the presence or absence of
mutations or polymorphisms that may explain individual variability in
main PK parameters. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The aim of pharmacogenomic component of this study is to identify and validate putative molecular biomarkers associated with the clinical outcome of patients treated with lurbinectedin combined with irinotecan.These molecular markers would help to select future pacients who might preferentially benefit from the lurbinectedin and irinotecan combination,thus contributing to a more individualizaed medicine
The aim of the pharmacogenetic component of this study is to explore genetic factors that may help explain individual variability in main PK parameters |
|
| E.3 | Principal inclusion criteria |
1)Voluntarily signed and dated written informed consent prior to any specific-study procedure
2)Age ≥18years
3)ECOG performance status ≤1
4)Life expectancy ≥3 months
5)Histologically or cytologically confirmed diagnosis of advanced disease of any of the following tumor types:
- Lurbinectedin Escalation Group and Irinotecan Escalation Group:
a)Glioblastoma
b)Soft-tissue sarcoma (excluding GIST)
c)Endometrial carcinoma
d)Epithelial ovarian carcinoma (including primary peritoneal disease and/or fallopian tube carcinomas and/or endometrial adenocarcinomas) regardless of platinum sensitivity
e)Mesothelioma
f)GEP-NET
g)SCLC
h)Pancreatic adenocarcinoma
i)Gastric carcinoma
j)CRC
- Intermediate Escalation Group:
a)Endometrial carcinoma
b)SCLC
c)Other solid tumors may be included, if appropriate, after discussion between the Investigators and the Sponsor
For the Phase II expansion stage:
a)Glioblastoma
b)Soft tissue sarcoma (including synovial sarcoma)
c)Endometrial carcinoma
d)SCLC
e)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:
-Phase I Escalation Stage: No more than 2 prior lines of cytotoxic-containing chemotherapy regimens for advanced disease
-Phase II Lurbinectedin Expansion Stage:
•For SCLC, 1 prior line of platinum-containing chemotherapy with/without antibodies against PD-1 or PD-L1
•For NENs, in Group 1 (patients with poorly differentaited 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 3 prior lines of systemic therapy
(that may include somatostatin analogues, chemotherapy, everolimus and/or sunitinib)
•For all other tumor types, no more than 2 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:
a)Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. For patients with glioblastoma: Measurable disease according to RECISTv.1.1 and Response Assessment in Neuro-Oncology (RANO) criteria
b)Documented disease progression per RECISTv.1.1 during or immediately after last therapy according to any of the aforementioned criteria. For patients with glioblastoma: Documented disease progression per RECISTv.1.1 and RANO criteria
8)At least 3 weeks since the last anticancer therapy (including immunotherapy, investigational drugs and radiotherapy), and at least 6 weeks since nitrosoureas and mitomycin C (systemic). For biological/investigational anticancer therapies given orally, the aforementioned period of at least 3 weeks could be changed for one of at least 5 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:
a)The patient has a new lesion outside of the radiotherapy field, or
b)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 (Day1), not to the day of registration (Day0)
9)Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤7 days before inclusion in the trial):
a) Platelet count ≥100×10^9/L, hemoglobin ≥9.0g/dL and absolute neutrophil count (ANC) ≥2.0×10^9/L
b)AST and ALT ≤3.0×ULN, even in the presence of liver metastases
c)Alkaline phosphatase (ALP) ≤2.5×ULN (≤5 × ULN if disease-related/in the case of liver metastases)
d)Total bilirubin ≤1.5×ULN or direct bilirubin ≤ULN
e)INR <1.5 (except if patient is on oral anticoagulation therapy)
f)Calculated creatinine clearance (CrCL) ≥30 mL/minute (using Cockcroft-Gault formula)
g)Creatine phosphokinase (CPK) ≤2.5×ULN
h)Albumin ≥3.0 g/dL*
10)Recovery to grade ≤1 or to baseline from any 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 |
|
| E.4 | Principal exclusion criteria |
1)Concomitant diseases/conditions:
a)History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within the previous year
b)Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment
c) Myopathy or any clinical situation that causes significant and persistent elevation of CPK (> 2.5 × ULN in two different determinations performed one week apart)
d) Ongoing chronic alcohol consumption or cirrhosis with Child-Pugh score B or C. Known Gilbert disease
e) Active uncontrolled infection
f) Known human immunodeficiency virus (HIV) or known hepatitis C virus (HCV) infection or active hepatitis B
g) Any past or present chronic inflammatory colon and/or liver disease, past intestinal obstruction, pseudo or subocclusion or paralysis
h) Evident symptomatic pulmonary fibrosis or interstitialpneumonitis, pleural or cardiac effusion rapidly increasing and/or necessitating prompt local treatment within seven days
i) Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.
j) Active COVID-19 disease
k) 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 *
6) Limitation of the patient's ability to comply with the treatment or follow-up protocol
* 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I Escalation Stage: Determination of MTD and RD
Phase II Expansion Stage: Efficacy |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Safety
Pharmacokinetics
Efficacy (Secondary Endpoint in the Phase I Escalation Stage)
Pharmacogenomics
Pharmacogenetics |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalating of lurbinectedin or irinotecan given with irinotecan/lurbinectedin respectively |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Switzerland |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| When all treated patients in Phase I escalation stage or in each expansion cohorts have had at least 12 months survival follow-up. Patients in the expansion cohorts for second-line SCLC and synovial sarcoma in the Lurbinectedin Escalation Group will be followed for at least 18 months after the inclusion of the last treated patient in each cohort. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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