Public Title: Study of Lurbinectedin in Combination with Doxorubicin versus Doxorubicin Alone as First-line Treatment in Participants with Metastatic Leiomyosarcoma

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

12 Dec 2023 → ongoing

Decision date (initial)

2024-01-04

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Pharma Mar S.A.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Efficacy, Safety, Pharmacokinetic, Therapy

The primary objective of this III study is to evaluate whether the combination of lurbinectedin plus doxorubicin given as first line treatment for metastatic leiomyosarcoma (LMS) prolongs the progression-free survival (PFS) by Independent Review Committee(IRC) when compared to doxorubicin administered as a single agent.

Secondary objectives 1

1. To determine whether there is a difference between lurbinectedin plus doxorubicin in combination versus doxorubicin alone in terms of: Overall survival (OS) (key secondary endpoint). PFS by Investigator Assessment (IA). Overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 by IRC and IA. Duration of response (DoR) by IRC and IA. Clinical Benefit Rate (CBR=objective response plus stable disease ≥ 6 months) by IRC and IA according to the RECIST v.1.1. PFS on next-line therapy (PFS2) by IA. To evaluate: Treatment safety profile according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5. Patient-reported outcomes (PRO). Subgroup analyses. Pharmacokinetics (PK) of lurbinectedin and/or doxorubicin and its metabolite doxorubicinol in patients treated in the Experimental arms (lurbinectedin plus doxorubicin combination) and in the Control arm (doxorubicin alone). PK/pharmacodynamic (PD) correlations in patients treated in the experimental arms (lurbinectedin plus doxorubicin combination), if any. To explore the efficacy and safety/tolerability between lurbinectedin arms in case that both arms are significantly better than the control arm in the primary endpoint. To conduct an exploratory pharmacogenomic (PGx) analysis in tumor and blood samples from patients who consented to be included in a substudy to identify potential biomarkers of response and/or resistance to lurbinectedin plus doxorubicin combination compared to doxorubicin alone

Conditions and MedDRA coding

Metastatic leiomyosarcoma

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Voluntary signed and dated written informed consent of the patient, obtained before any study-specific procedure.
2. 2. Age ≥ 18 years.
3. 3. Histologically confirmed diagnosis of metastatic LMS, in patients not candidates for curative resection.
4. 4. Radiologically measurable disease according to the RECIST v.1.1.
5. 5. No previous systemic therapy for metastatic disease (i.e., first-line setting) and no previous anthracyclines. Note: Prior chemotherapy (without anthracycline) in the context of adjuvant or neoadjuvant therapy is allowed. Prior line/s of hormone therapy in the adjuvant/metastatic setting are also allowed.
6. 6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
7. 7. Adequate hematological, renal, metabolic and hepatic function: a) Hemoglobin ≥ 9.0 g/dL [patients may have received prior red blood cell (RBC) transfusion]; absolute neutrophil count (ANC) ≥ 2.0 x 109/L, and platelet count ≥ 100 x 109/L. b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x upper limit of normal (ULN). c) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN if total bilirubin is > ULN. d) Albumin ≥ 3.0 g/dL. e) Calculated creatinine clearance (CrCL) ≥ 30 mL/min (using Cockcroft and Gault’s formula). f) Left ventricular ejection fraction (LVEF) > 50% assessed by multiple-gated acquisition scan (MUGA), echocardiography (ECHO) or cardiac magnetic resonance imaging (MRI).
8. 8. Wash-out periods: a) At least three weeks since last prior systemic treatment. b) At least three weeks since last prior major surgery and one week since last prior minor surgery (port placement is excluded from this wash-out period). c) At least two weeks since last prior radiotherapy.
9. 9. Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to seven months after treatment discontinuation. Valid methods to determine the childbearing potential, adequate contraception and requirements for WOCBP partners are described in APPENDIX 2. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose.

Exclusion criteria 11

1. 1. Prior treatment with anthracyclines, lurbinectedin or trabectedin.
2. 10. Women who are pregnant or breast feeding and fertile patients (men and women) who are not using a highly effective method of contraception.* * Women of childbearing potential (WOCBP) must agree to use a highly effective contraception method to avoid pregnancy during the course of the trial (and for at least seven 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. Valid methods to determine childbearing potential, adequate contraception and requirements of WOCBP partners are described in APPENDIX 2.
3. 2. Known low grade leiomyosarcoma (i.e., grade I).
4. 3. Known hypersensitivity to any of the components of the i.v. formulation of lurbinectedin or doxorubicin.
5. 4. Concomitant diseases/conditions: a) History of cardiac disease: myocardial infarction or angina within the last year prior to enrollment; severe valvular disease; or symptomatic arrhythmia despite ongoing treatment. b) Patients with any immunodeficiency, including those known to be infected by human immunodeficiency virus (HIV). c) Known chronic active hepatitis or cirrhosis. For Hepatitis B, this includes positive tests for both Hepatitis B surface antigen and quantitative Hepatitis B polymerase chain reaction (PCR). For Hepatitis C, this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR. d) Active uncontrolled infection. e) Any other major illness (including severe cardiovascular disease) or risk factors that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this study.
6. 5. Use of strong inducers of CYP3A activity within two weeks prior to the first infusion of lurbinectedin.
7. 6. Prior irradiation of a RECIST v.1.1 target lesion if only one target lesion is available, unless progression of this lesion has been confirmed.
8. 7. Known myopathy (history of resolved steroid-induced myopathy is allowed).
9. 8. History of malignancies other than LMS within 3 years prior to enrollment, except for malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, non-muscle-invasive urothelial carcinomas, ductal carcinoma in situ, or stage I uterine cancer. Prior malignancies should have received curative treatment and should remain in remission. The Investigator should ensure, based on histology and/or clinical information, that the current metastatic sites are leiomyosarcoma and not recurrence of the original malignancy.
10. 9. Limitation of the patient’s ability to comply with the treatment or to follow-up the protocol.
11. 11. Patients in whom rapid tumor shrinkage is needed (e.g., when a tumor is close to a critical structure).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. 1. PFS by IRC is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death).
2. 2. If the patient is lost to follow-up before disease progression (PD), PFS will be censored at the date of last tumor assessment.
3. 3. If the patient receives further antitumor therapy before PD, PFS will be censored at the last tumor assessment performed before the start of new antitumor therapy. In the event of a patient with at least two missing visits before PD, PFS will be censored at the date of the last prior tumor assessment.

Secondary endpoints 15

1. 2A PFS by IA is defined as the time from the date of registration to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death).
2. 3. ORR by IRC and IA is defined as the percentage of patients with a response, either complete (CR) or partial (PR), according to the RECIST v.1.1.
3. 4. Duration of response (DoR) by IRC and IA will be calculated from the date of first documentation of response per RECIST v.1.1 (CR or PR, whichever comes first) to the date of documented PD or death. The censoring rules defined for PFS will be used for DoR.
4. 5. Clinical Benefit Rate (CBR) by IRC and IA is defined as objective response plus stable disease (SD) ≥ 6 months according to the RECIST v.1.1.
5. 6. PFS on next-line therapy (PFS2) by IA is defined as the time from the date of randomization to the date of progression on next line treatment or death (regardless of the cause of death), whichever occurs first. In case of no event, follow-up of the patient will be censored at the date of last news.
6. 1. Key secondary endpoint: • Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact (in this case, survival will be censored on that date).Other Secondary Endpoints:
7. 7. Treatment safety profile: AEs, serious adverse events (SAEs) and laboratory abnormalities will be coded by the Medical Dictionary for Regulatory Activities (MedDRA), graded according to the NCI-CTCAE v.5 and analyzed. Dose delays or reductions required due to treatment-related AEs, and reasons for treatment discontinuations will also be assessed.
8. 8. Patient-reported outcomes (PRO): To measure the quality of life of patients, the EORTC QLQ-C30 questionnaire will be analyzed.
9. 9 Subgroup analyses: Subgroup analyses of efficacy and safety profiles in the Experimental arms and the Control arm will be performed.
10. 10. Plasma PK of lurbinectedin, doxorubicin and its metabolite doxorubicinol will be evaluated using a sparse sampling scheme. Details will be given in a population PK analysis plan, and results will be presented in a separate report.
11. 11. PK/PD correlation: Population PK correlations of exposure to lurbinectedin, doxorubicin and its metabolite doxorubicinol with safety will be explored. Details will be given in specific population PK/PD analysis plans, and results will be presented in separate reports.
12. 2B If the patient is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment. If the patient receives further antitumor therapy before PD, PFS will be censored at the last tumor assessment performed before the start of new antitumor therapy.
13. 12A Pharmacogenomics (PGx): The mutational status and the expression levels of potential predictive factors of response and/or resistance to lurbinectedin and doxorubicin treatment, or to doxorubicin alone will be analyzed from available tumor and/or blood samples obtained before, during and at the end of treatment (either during the EOT visit, or as soon as possible during the follow-up period).
14. 12B Their correlation with the clinical response and outcome after treatment will be assessed. This analysis will be performed in those patients who signed the ICF for the PGx substudy.
15. 2C In the event of a patient with at least two missing visits before PD, PFS will be censored at the date of the last prior tumor assessment otherwise

Investigational products

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

Test 2

Comparator 1

Auxiliary 4

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 7

Locations

9 EU/EEA countries · 64 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 74 files

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

Application history

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