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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pharma Mar S.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Apr 2016 → 2 Jul 2025

Decision date (initial)

2024-08-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pharma Mar S.A.

External identifiers

EU CT number

2024-515394-10-00

EudraCT number

2015-003602-16

ClinicalTrials.gov

NCT02611024

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacogenomic, Therapy, Safety, Pharmacogenetic, Efficacy

Phase I escalation stage: To determine the maximum tolerated dose (MTD) and the 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 objectives 6

1. 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].
2. To characterize the safety profile and feasibility of this combination in patients with SAST.
3. To characterize the pharmacokinetics(PK) of this combination and to detect major drug-drug PK interactions.
4. To obtain preliminary information on the clinical antitumor activity of this combination in non-heavily pretreated selected solid tumor patients.
5. 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.
6. To evaluate PGt in germline DNA by the presence or absence of mutations or polymorphisms that may explain individual variability in main PK parameters.

Conditions and MedDRA coding

Selected Advanced Solid Tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

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
6. Histologically or cytologically confirmed diagnosis of advanced disease of any of the following tumor types: - 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
7. Histologically or cytologically confirmed diagnosis of advanced disease of any of the following tumor types: 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
8. 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 cytotoxiccontaining chemotherapy regimens for advanced disease
9. The number of prior lines of therapy allowed per patient will be as follows: -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 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 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 cytotoxiccontaining chemotherapy regimens for advanced disease There is no limit for prior targeted therapy, hormonal therapy and immunotherapy (such as nivolumab)
10. 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
11. 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)
12. 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* *Albumin transfusion to increase the blood level in order to fulfill the inclusion criterion is strictly forbidden
13. 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).

Exclusion criteria 6

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 * * 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I Escalation Stage: Determination of MTD and RD
2. Phase II Expansion Stage: Efficacy

Secondary endpoints 5

1. Safety
2. Pharmacokinetics
3. Efficacy (Secondary Endpoint in the Phase I Escalation Stage)
4. Pharmacogenomics
5. Pharmacogenetics

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pharma Mar S.A.

Sponsor organisation

Pharma Mar S.A.

Address

Avenida De Los Reyes 1, Poligono Industrial La Mina Poligono Industrial La Mina

City

Colmenar Viejo

Postcode

28770

Country

Spain

Scientific contact point

Organisation

Pharma Mar S.A.

Contact name

Clinical Development Oncology Unit

Public contact point

Organisation

Pharma Mar S.A.

Contact name

Clinical Development Oncology Unit

Third parties 5

Locations

3 EU/EEA countries · 16 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 21 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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