“Phase I/II, Multicenter, Open-label, Clinical and Pharmacokinetic Study of Lurbinectedin (PM01183) in Combination with Pembrolizumab in Patients with Relapsed Small Cell Lung Cancer (the LUPER study).”

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Dr.Antonio Calles Blanco

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Jul 2020 → 20 May 2025

Decision date (initial)

2024-07-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

PharmaMar S.A. · MERCK SHARP & DOHME SA

External identifiers

EU CT number

2024-514206-31-00

EudraCT number

2019-002261-35

ClinicalTrials.gov

NCT04358237

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

Stage I: To determine the MTD and the recommended stage II dose (RD) of PM01183 in combination with pembrolizumab in patients with relapsed SCLC.
Stage II: To assess the efficacy of PM01183 in combination with pembrolizumab in terms of ORR, according to RECIST 1.1, in patients with relapsed SCLC.

Secondary objectives 7

1. Stage I: (1) to obtain preliminary information on the clinical antitumor activity of this combination in patients with relapsed SCLC.
2. Stage I: (2) to determine the MTD and the RD of PM01183 in combination with pembrolizumab with mandatory primary prophylaxis with G-CSF in patients with relapsed SCLC (if DLTs of this combination are exclusively related to neutropenia).
3. Stage II: to further characterize the antitumor activity of this combination as per RECIST 1.1 in terms of: o Clinical benefit (ORR or stable disease lasting over 3 months [stable disease (SD) ≥3 months]). o Duration of response (DOR). o Progression-free survival (PFS). o Overall survival (OS).
4. Both Stages: (1) To characterize the safety profile and feasibility of PM01183 in combination with pembrolizumab in patients with relapsed SCLC.
5. Both Stages: (2) To characterize the plasma pharmacokinetics (PK) of PM01183 in this combination and to detect major drug-drug PK interactions.
6. Both Stages: (3) to perform a pharmacogenetic (PGt) analysis.
7. Both Stages: (4) to perform a pharmacogenomic (PGx) analysis in tumor samples of patients exposed to PM01183 and pembrolizumab in order to assess potential markers of response and/or resistance.

Conditions and MedDRA coding

Small cell lung cancer (SCLC).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of SCLC whose disease has progressed after first-line chemotherapy-based regimen will be enrolled in this study.
2. At least 4 weeks since the last anticancer therapy.
3. Male participants: a male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 190 days after the last dose of study treatment and refrain from donating sperm during this period.
4. Female participants: a female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 7 months after the last dose of study treatment.
5. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
6. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1. Evaluation of ECOG PS is to be performed within 7 days prior to the date of allocation.
8. Have adequate organ function as defined in the following table (Table 1). Specimens must be collected within 10 days prior to the start of study treatment.
9. Recovery to NCI-CTCAE grade ≤1 or to baseline from any AE derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or peripheral sensory neuropathy and/or asthenia, all grade ≤2 and/or correctable electrolyte abnormality with supplementation).
10. Patients included in the expansion cohort at the RD (stage I) and all patients included in the stage II must have: a) Measurable disease according to RECIST 1.1; and b) Documented disease progression during or immediately after last therapy according to any of the aforementioned criteria.

Exclusion criteria 23

1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
2. Has had prior treatment with or exposure to: a) PM01183. b) T-cell or other cell-based or biologic therapies. c) Experimental anti-tumor vaccines; therapies that target any T-cell costimulation or checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PDL2, anti-CD137, or anti CTLA-4 antibody, including ipilimumab; or other medicines specifically targeting T-cells.
3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
4. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
5. Has had radiotherapy (RT) in more than 35% of the bone marrow
6. Has a history of previous bone marrow and/or stem cell transplantation and allogenic transplant.
7. Has an impending need for RT (e.g., painful bone metastasis and/or risk of spinal cord compression).
8. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
9. Has any of the following concomitant diseases/conditions: a) History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within last year. b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment. c) History of idiopathic, pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis or evidence of active pneumonitis on screening chest CT-scan. History of radiation pneumonitis in radiation field (fibrosis) is permitted, as long as it is asymptomatic and no steroids are needed. d) Known history of active neurologic paraneoplastic syndrome. e) Myopathy or any clinical situation that causes significant and persistent elevation of CPK (>2.5 x ULN in two different determinations performed one week apart). f) Limitation of the patient’s ability to comply with the treatment or follow-up protocol. g) 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. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
12. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
13. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate 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 for at least 14 days prior to first dose of study treatment. Brain CT-scan or MRI results must be provided at baseline.
14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, PM01183 and/or any of their excipients.
15. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Exception: patients with vitiligo or resolved childhood asthma/atopy; patients who require intermittent use of bronchodilators or local steroid injections; and patients with hypothyroidism stable on hormone replacement or Sjögren's syndrome will not be excluded from the study.
16. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
17. Has an active infection requiring systemic therapy.
18. Has a known history of Human Immunodeficiency Virus (HIV).
19. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
20. Has a known history of active tuberculosis (Mycobacterium tuberculosis).
21. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
22. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
23. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 7 months after the last dose of trial treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 11

1. Stage I: (1) Determination of MTD and RD: • The MTD will be the lowest dose level explored during dose escalation at which more than one third of evaluable patients develop a DLT in Cycle 1. • The RD will be the highest dose level explored at which less than one third of evaluable patients develop a DLT during Cycle 1.
2. Stage I: (1 cont.) If the DLTs of the PM01183 and pembrolizumab combination without G-CSF prophylaxis are exclusively related to neutropenia, the MTD and RD will also be determined with primary G-CSF prophylaxis.
3. Stage I: (2) DLTs are defined as any adverse events (AEs) and laboratory abnormalities related to the study treatment during the first cycle of treatment and fulfilling at least one of the criteria outlined below.
4. Stage I: (2 cont.) • Grade 4 neutropenia (absolute neutrophil count [ANC] <0.5 x 109/L) lasting >3 days. • Grade 3 neutropenia (ANC: 0.5-1.0 x 109/L) lasting >7 days. • Febrile neutropenia of any duration or neutropenic sepsis. • Grade 4 thrombocytopenia (platelet count <25 x 109/L) or grade 3 with any major bleeding episode requiring a platelet transfusion. • Grade 4 alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) increase, or grade 3 increase lasting >14 days.
5. Stage I: (2 cont.2) • Grade ≥2 ALT or AST increase concomitantly with total bilirubin increase ≥2.0 x upper limit of normal (ULN) and normal alkaline phosphatase (AP). • Grade ≥3 creatine phosphokinase (CPK) increase.
6. Stage I: (2 cont. 3) • Any other grade 3/4 non-hematological AE that is suspected to be related to study drug(s), except nausea/vomiting (unless the patient is receiving an optimal anti- emetic regimen), hypersensitivity reactions, extravasations, grade 3 asthenia lasting less than one week, and non-clinically relevant isolated biochemical abnormalities (e.g., isolated increase in gamma-glutamyltransferase [GGT]).
7. Stage I: (2 cont. 4) Delay in the administration of Cycle 2 of the combination exceeding 15 days of the theoretical date (i.e., Day 22), due to any AEs related to the study drug(s).
8. Stage II: The primary objective of this stage is to assess the antitumor activity of PM01183 combined with pembrolizumab in terms of ORR, defined as the percentage of evaluable patients with a confirmed response, either complete (CR) or partial (PR).
9. Stage II: (cont.) The ORR will be assessed using the RECIST 1.1 on a set of measurable lesions identified at baseline as target lesions or as non-target lesions (if any), and followed until PD by an appropriate method (e.g., helical computed tomography [CT]-scan, magnetic resonance imaging [MRI]).
10. Stage II: (cont. 2) Radiological tumor assessment will be performed at baseline, and every 2 cycles from the onset of the study treatment until evidence of PD. If an objective response is observed, according to the RECIST 1.1, it must be confirmed by the same method at least 4 weeks after the date of the first documentation of response.
11. Stage II: (cont. 3) The date of response, the date of radiological or clinical PD, and the date of death will be registered and documented, as appropriate.

Secondary endpoints 6

1. Both stages: Safety:AEs will be graded according to the NCI-CTCAE v.5. Additionally, treatment compliance, in particular dose reduction requirements, skipped doses and/or cycle delays due to AEs, will be described.
2. Both stages:Efficacy: preliminary antitumor activity will be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable)
3. Both stages: Pharmacokinetics: PK parameters will be evaluated in plasma by standard noncompartmental methods (compartmental modeling may be performed if appropriate).
4. Both stages:Pharmacogenetics: analyze germline DNA for the presence or absence of mutations or polymorphisms in genes relevant for the metabolism and/or transport of PM01183 that may help explain individual variability in main PK parameters.
5. Pharmacogenomics:The mutational status of factors involved in DNA repair mechanisms, or related to the mechanism of action of PM01183 or pembrolizumab, will be evaluated from available prior paraffin-embedded tumor tissue samples obtained at diagnosis or relapse. mRNA and/or protein expression levels of these factors might be also analyzed, if relevant. Potentially whole exome sequencing will also be analyzed. Their correlation with the clinical response and outcome after treatment
6. Biomarker research: Both stages: Molecular assessments may be performed with the material derived from plasma samples, using both hypothesis-driven and discovery-based approaches, in order to explore potential molecular patterns correlating with sensitivity/resistance to the treatment.

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Dr.Antonio Calles Blanco

Sponsor organisation

Dr.Antonio Calles Blanco

Address

Calle Del Doctor Esquerdo 46

City

Madrid

Postcode

28007

Country

Spain

Scientific contact point

Organisation

Dr.Antonio Calles Blanco

Contact name

Alicia Garcia

Public contact point

Organisation

Dr.Antonio Calles Blanco

Contact name

Melissa Fernandez (International Trial Lead)

Locations

1 EU/EEA country · 5 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 10 files

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

Application history

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