Clinical and Pharmacokinetic Study of Lurbinectedin in Combination with Irinotecan in Patients with Advanced Solid Tumors

Austria, France, Germany, Italy, Switzerland, United States (ICTRP)

ICTRP Trial ID
EUCTR2015-003602-16 (ICTRP)

Official title (approved by ethics committee)
Phase I/II, Multicenter, Open-label, Clinical and Pharmacokinetic Study of Lurbinectedin in Combination with Irinotecan in Pretreated Patients with Selected Advanced Solid Tumors (BASEC)

Academic title
Phase I/II, Multicenter, Open-label, Clinical and Pharmacokinetic Study of Lurbinectedin in Combination with Irinotecan in Pretreated Patients with Selected Advanced Solid Tumors. - NA (ICTRP)

Public title
Clinical and Pharmacokinetic Study of Lurbinectedin in Combination with Irinotecan in Patients with Advanced Solid Tumors (ICTRP)

Disease under investigation
Selected Advanced Solid Tumors
MedDRA version: 21.1Level: LLTClassification code 10065147Term: Malignant solid tumorSystem Organ Class: 100000004864;Therapeutic area: Diseases [C] - Cancer [C04] (ICTRP)

Intervention under investigation

Product Name: Lurbinectedina
Product Code: [PM01183]
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: lurbinectedina
CAS Number: 497871-47-3
Current Sponsor code: PM01183
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-

Product Name: Irinotecan
Product Code: [NA]
Pharmaceutical Form: Concentrate for solution for injection/infusion
INN or Proposed INN: IRINOTECAN CLORIDRATO TRIIDRATO
CAS Number: 97682-44-5
Current Sponsor code: NA
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

(ICTRP)

Type of trial
Interventional clinical trial of medicinal product (ICTRP)

Trial design
Controlled: no Randomised: no Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1 (ICTRP)

Inclusion/Exclusion criteria
Gender:
Female: yes
Male: yes

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: NENs grade 3 (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 P-NETs grade 2 (Ki-67 3-20%) or low grade 3 (Ki-67 21-55%) 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 NENs of gastroenteropancreatic origin or unknown primary site, excluding lung primary tumors), progression
to first-line platinum-based chemotherapy; and in Group 2 (patients with well differentiated P-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 (excluding immunotherapy that must be at least 2 weeks, provided that is not combined with chemotherapy), including investigational drugs and radiotherapy, and at least 6 weeks since nitrosoureas and mitomycin C (systemic).

Please refer to the synopsis and Protocol for the complete information.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 215
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this ag (ICTRP)

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 (this includes positive test for SARS-CoV-2 in nasopharyngeal/oropharyngeal swabs or nasal swabs by PCR)

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

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


Primary and secondary end points
Main Objective: -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.;Secondary Objective: -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.

Please refer to the synopsis or Protocol for complete info.;Primary end point(s): Phase I Escalation Stage: Determination of MTD and RD

Phase II Expansion Stage: Efficacy;Timepoint(s) of evaluation of this end point: Along the study (ICTRP)

Secondary end point(s): Safety
Pharmacokinetics
Efficacy (Secondary Endpoint in the Phase I Escalation Stage)
Pharmacogenomics
Pharmacogenetics;Timepoint(s) of evaluation of this end point: Along the study (ICTRP)

Registration date
17.03.2022 (ICTRP)

Incorporation of the first participant
18.08.2022 (ICTRP)

Secondary sponsors
not available

Additional contacts
Clinical trials, clinicaltrials@pharmamar.com, +34918466003, Pharma Mar S.A. (ICTRP)

Secondary trial IDs
PM1183-A-014-15, NCT02611024, 2015-003602-16-FR (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003602-16 (ICTRP)