WO2024133947A1

WO2024133947A1 - Lurbinectedin and cyp3a4 inhibitor combination

Info

Publication number: WO2024133947A1
Application number: PCT/EP2023/087758
Authority: WO
Inventors: Rubin LUBOMIROV; Salvador FUDIO MUÑOZ
Original assignee: Pharma Mar, S.A.
Priority date: 2022-12-23
Filing date: 2023-12-22
Publication date: 2024-06-27

Abstract

Described are combination therapy for the treatment of cancer comprising lurbinectedin and a strong CYP3A4 inhibitor.

Description

Lurbinectedin and CYP3A4 inhibitor combination

FIELD OF THE INVENTION

The present invention relates to therapeutic treatment of cancers, particularly dosing schedules useful in the treatment of cancer. In particular, the present invention relates to combination therapy using lurbinectedin and a strong CYP3A4 inhibitor.

BACKGROUND OF THE INVENTION

Lurbinectedin (LRB), also known as PM01 183 and initially called tryptamicidin, is a synthetic alkaloid with antineoplastic activity, and the subject of WO 03/01427. Lurbinectedin is a selective inhibitor of oncogenic transcription, induces DNA double-strand break generating apoptosis, and modulates the tumour microenvironment. For example, by inhibiting active transcription in tumourassociates macrophages, lurbinectedin downregulates IL-6, IL-8, CCL2, and VEGF.

The chemical structure of lurbinectedin is represented as follows:

It is a selective inhibitor of the oncogenic transcription programs on which many tumours are particularly dependent. Together with its effect on cancer cells, lurbinectedin inhibits oncogenic transcription in tumour-associated macrophages, downregulating the production of cytokines that are essential for the growth of the tumour. Transcriptional addiction is an acknowledged target in those diseases, many of them lacking other actionable targets.

Lurbinectedin received US approval in 2020 and is marketed in the US for the treatment of adult patients with metastatic small cell lung cancer (SOLO) with disease progression on or after platinum-based chemotherapy. The recommended dosage is 3.2 mg/m2 every 21 days by intravenous infusion. In 2021 , lurbinectedin also received marketing authorization in the United Arab Emirates, Canada, Australia and Singapore.

Lurbinectedin is extensively metabolized by the cytochrome P450 enzymes, primarily CYP3A4. Thus, strong inhibitors of this enzyme may alter the plasma concentration of lurbinectedin. However, these inhibitors can affect to the effect of lurbinectedin against cancer treatment. There is a need for reducing lurbinectedin plasma clearance while maintaining a therapeutically effect of the drug against cancer.

SUMMARY OF THE INVENTION

The present inventors have surprisingly determined dosing regimens of lurbinectedin and a strong CYP3A4 inhibitor effective in the treatment of cancer.

Accordingly, a first aspect of the present invention is to provide lurbinectedin for use in the treatment of cancer in a patient in need thereof, wherein said treatment comprises administering to the patient lurbinectedin in combination with a strong CYP3A4 inhibitor, wherein lurbinectedin is administered at a dose of about 1.2 mg/m² during each administration cycle.

In a further aspect, there is provided lurbinectedin and a strong CYP3A4 inhibitor for use in the treatment of cancer in a patient in need thereof, wherein said treatment comprises administering to the patient lurbinectedin in combination with a strong CYP3A4 inhibitor, wherein lurbinectedin is administered at a dose of about 1.2 mg/m² during each administration cycle.

In a further aspect, there is provided lurbinectedin for use in the treatment of cancer in a patient in need thereof, said treatment comprises: i) administering to the patient one or more administration cycles of lurbinectedin in combination with a strong CYP3A4 inhibitor in a first phase, wherein the dose of lurbinectedin is about 1.2 mg/m²; and ii) administering to the patient one or more administration cycles of lurbinectedin alone in a second phase.

In a further aspect, there is provided lurbinectedin and a strong CYP3A4 inhibitor for use in the treatment of cancer in a patient in need thereof, said treatment comprises i) administering to the patient one or more administration cycles of lurbinectedin in combination with a strong CYP3A4 inhibitor in a first phase, wherein the dose of lurbinectedin is about a dose of about 1 .2 mg/m² ; and ii) administering to the patient one or more administration cycles of lurbinectedin alone in a second phase.

In a further aspect, there is provided lurbinectedin for use in the treatment of cancer in a patient in need thereof, said treatment comprises i) administering to the patient one or more administration cycles of lurbinectedin alone in a first phase; and ii) administering to the patient one or more administration cycles of lurbinectedin in combination with a strong CYP3A4 inhibitor in a second phase, wherein the dose of lurbinectedin in the second phase is about 1 .2 mg/m².

In a further aspect, there is provided lurbinectedin and a strong CYP3A4 inhibitor for use in the treatment of cancer in a patient in need thereof, said treatment comprises i) administering to the patient one or more administration cycles of lurbinectedin alone in a first phase; and ii) administering to the patient one or more administration cycles of lurbinectedin in combination with a strong CYP3A4 inhibitor in a second phase, wherein the dose of lurbinectedin in the second phase is about 1 .2 mg/m². In a further aspect, there is provided a method of treatment of cancer, the method comprising administering to a patient need thereof lurbinectedin in combination with a strong CYP3A4 inhibitor, wherein lurbinectedin is administered at a dose of about 1 .2 mg/m² during each administration cycle, thereby treating the cancer.

In a further aspect, there is provided the use of lurbinectedin in the manufacture of a medicament for the treatment of cancer, wherein said treatment comprises administering to a patient need thereof lurbinectedin in combination with a strong CYP3A4 inhibitor, wherein lurbinectedin is administered at a dose of about 1.2 mg/m² during each administration cycle.

In a further aspect, there is provided the use of lurbinectedin and a strong CYP3A4 inhibitor in the manufacture of a medicament for the treatment of cancer, wherein said treatment comprises administering to a patient need thereof, lurbinectedin in combination with a strong CYP3A4 inhibitor, wherein lurbinectedin is administered at a dose of about 1.2 mg/m² during each administration cycle.

In a further aspect, there is provided a pharmaceutical package comprising lurbinectedin, optionally, together with instructions for its use in combination with a strong CYP3A4 inhibitor, wherein lurbinectedin is administered at a dose of about 1.2 mg/m² during each administration cycle.

In a further aspect, there is provided lurbinectedin for use in a treatment of cancer in a patient in need thereof, wherein the treatment comprises:

(1) administering to the patient an effective amount of a strong CYP3A4 inhibitor;

(2) discontinuing the administration of the strong CYP3A4 inhibitor; and

(3) administering to the patient a standard recommended dose of lurbinectedin at least four, five, six, seven, eight, nine, ten, eleven or twelve days after the last administration of the strong CYP3A4 inhibitor, wherein the standard recommended dose of lurbinectedin is not used for co-administration with the strong CYP3A4 inhibitor to the patient.

In a further aspect, there is provided a method of treating cancer to a patient in need thereof, wherein the method comprises:

(2) discontinuing the administration of the strong CYP3A4 inhibitor; and (3) administering to the patient a standard recommended dose of lurbinectedin at least four, five, six, seven, eight, nine, ten, eleven or twelve days after the last administration of the strong CYP3A4 inhibitor, wherein the standard recommended dose of lurbinectedin is not used for co-administration with the strong CYP3A4 inhibitor to the patient.

In a further aspect, there is provided the use of lurbinectedin in the manufacture of a medicament for the treatment of cancer, wherein the treatment comprises:

(2) discontinuing the administration of the strong CYP3A4 inhibitor; and

(3) intravenously administering to the patient a standard recommended dose of 3.2 mg/m2 per administration cycle of lurbinectedin at least four days after the last administration of the strong CYP3A4 inhibitor, optionally, the treatment further comprises:

(4) intravenously administering to the patient lurbinectedin at a standard recommended dose of 3.2 mg/m2 per administration cycle at least four days before the initial administration of the strong CYP3A4 inhibitor, wherein each of the administration cycle of lurbinectedin is 21 days.

(1) administering to the patient an effective amount of a strong CYP3A4 inhibitor; (2) discontinuing the administration of the strong CYP3A4 inhibitor; and

In a further aspect, there is provided the use of lurbinectedin in the manufacture of a medicament for the treatment of cancer in a patient in need thereof, wherein the treatment comprises:

(2) discontinuing the administration of the strong CYP3A4 inhibitor; and

(4) intravenously administering to the patient lurbinectedin at a standard recommended dose of 3.2 mg/m2 per administration cycle at least four days before the initial administration of the strong CYP3A4 inhibitor,

The following embodiments apply to all aspects of the present invention.

In an embodiment, the dose of about 1 .2 mg/m² is 1 .2 mg/m² ± 0.4 mg/m².

In an embodiment, the dose is about 1 .3 mg/m². In an embodiment, the dose is about 1 .4 mg/m².

In an embodiment, the dose is about 1 .5 mg/m². In an embodiment, the dose is about 1 .6 mg/m².

In an embodiment, the dose is about 1 .1 mg/m². In an embodiment, the dose is about 1 .0 mg/m².

In an embodiment, the dose is about 0.9 mg/m². In an embodiment, the dose is about 0.8 mg/m².

In an embodiment, the dose is 0.8 mg/m², 0.9 mg/m², 1.0 mg/m², 1.1 mg/m², 1.2 mg/m², 1.3 mg/m², 1.4 mg/m², 1.5 mg/m², or 1 .6 mg/m². In an embodiment, after discontinuation of the strong CYP3A inhibitor, the dose of lurbinectedin is increased. In an embodiment, after discontinuation of the strong CYP3A inhibitor, the dose of lurbinectedin is increased to the dose used before starting the strong CYP3A inhibitor. In an embodiment, after discontinuation of the strong CYP3A inhibitor, the dose of lurbinectedin is increased to the standard recommended dose of 3.2 mg/m² (adjustable in accordance with any applicable dose reductions taking into account adverse events).

In an embodiment, after discontinuation of the strong CYP3A inhibitor for 5 half-lives of the inhibitor, the dose of lurbinectedin is increased. In an embodiment, after discontinuation of the strong CYP3A inhibitor for 5 half-lives of the inhibitor, the dose of lurbinectedin is increased to the dose used before starting the strong CYP3A inhibitor. In an embodiment, after discontinuation of the strong CYP3A inhibitor for 5 half-lives of the inhibitor, the dose of lurbinectedin is increased to the standard recommended dose of 3.2 mg/m² (adjustable in accordance with any applicable dose reductions taking into account adverse events).

In an embodiment, the time period after discontinuation of the strong CYP3A inhibitor may be about 5 half-lives of the inhibitor. In a further embodiment, the time period may be about 3 to about 7 half-lives, about 4 to about 6 half-lives, about 4 half-lives, about 5 half-lives or about 6 half-lives.

In an embodiment, after discontinuation of the strong CYP3A inhibitor for 5 half-lives of the inhibitor, increase the lurbinectedin dose to the dose used before starting the inhibitor.

In an embodiment of the invention, lurbinectedin is administered as 1 hour intravenous infusion during each administration cycle.

In another embodiment of the invention, lurbinectedin is administered on day 1 (D1) of each administration cycle.

In a further embodiment of the invention, lurbinectedin may be administered every 3 weeks (q3wk).

In an embodiment of the invention, each administration cycle is 21 consecutive days.

In a further embodiment, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or more than 30 administration cycles are administered.

In a particular embodiment, up to 3 administration cycles are administered.

In another embodiment of the invention, the strong CYP3A4 inhibitor is orally or intravenously administered during each administration cycle.

In a further embodiment, the strong CYP3A4 inhibitor is administered 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 times per day during each administration cycle. In another embodiment, the strong CYP3A4 inhibitor is administered up to 14 consecutive days during each administration cycle.

In a preferred embodiment, the strong CYP3A4 inhibitor is administered during 12 consecutive days during each administration cycle.

In an embodiment, lurbinectedin is administered after the administration of the strong CYP3A4 inhibitor.

In another embodiment, the strong CYP3A4 inhibitor is administered within a period comprised up to four, five, six, seven or eight days before the administration of lurbinectedin infusion during each administration cycle, preferably up to four days before. In another embodiment, the strong CYP3A4 inhibitor is administered within a period comprised up to four, five, six, seven, eight, nine, ten, eleven or twelve days after the administration of lurbinectedin infusion during each administration cycle, preferably up to seven days after. In another embodiment, the strong CYP3A4 inhibitor is administered within a period comprised between four days before and seven days after the administration of lurbinectedin infusion during each administration cycle.

In an embodiment, lurbinectedin is administered in combination with a strong CYP3A4 inhibitor, wherein lurbinectedin is administered at a dose of about 1.2 mg/m² on day 1 of each administration cycle; and wherein the strong CYP3A4 inhibitor is administered within a period comprised between four days before and seven days after the administration of lurbinectedin infusion during each administration cycle; and wherein each administration cycle is 21 days.

Lurbinectedin and the strong CYP3A4 inhibitor may be co-administered concurrently, separately or sequentially. Separate or sequential administration of lurbinectedin and the strong CYP3A4 inhibitor may be within three days of each other.

In a further embodiment, the method further comprises administration of granulocyte-colony stimulating factor (G-CSF).

In a further embodiment, G-CSF may be administered on day 1 of an administration cycle.

In a further embodiment, a patient may receive primary prophylaxis with G-CSF starting 24-72 hours after day 1 of an administration cycle, and for five days.

In a further embodiment, G-CSF may be administered during one or more subsequent administration cycles.

In an embodiment, lurbinectedin is administered in combination with a strong CYP3A4 inhibitor, wherein lurbinectedin is administered at a dose of about 1.2 mg/m² on day 1 of each administration cycle; and wherein the strong CYP3A4 inhibitor is administered within a period comprised between four days before and seven days after the administration of lurbinectedin infusion during each administration cycle; wherein the method further comprises administration of granulocyte-colony stimulating factor (G-CSF); wherein G-CSF may be administered on day 1 of an administration cycle or wherein a patient may receive primary prophylaxis with G-CSF starting 24-72 hours after day 1 of an administration cycle, and for five days; optionally wherein G-CSF is administered during one or more subsequent administration cycles; optionally wherein each administration cycle is between 3 to 4 weeks or is 21 days.

In a further embodiment, the strong CYP3A4 inhibitor can be a mixture of compounds selected from the group of: cobicistat with atazanavir and darunavir; danoprevir and ritonavir; elvitegravir and ritonavir, indinavir and ritonavir; lopinavir and ritonavir; paritaprevir and ritonavir and ombitasvir and dasabuvir; paritaprevir and ritonavir and ombitasvir; paritaprevir and ritonavir and dasabuvir; saquinavir and ritonavir; tipranavir and ritonavir.

In a further embodiment, the strong inhibitor is selected from cobicistat, grapefruit juice, troleandomycin, itraconazole, posaconazole, ketoconazole, voriconazole, clarithromycin, ritonavir, telithromycin, nelfinavir, atazanavir, indinavir, boceprevir, ceritinib, clarithromycin, idelalisib, nefazodone, nelfinavir, and telaprevir.

In a preferred embodiment, the strong CYP3A4 inhibitor is selected from the group of lopinavir and ritonavir; itraconazole, posaconazole, ketoconazole, voriconazole, clarithromycin, ritonavir, telithromycin, nelfinavir, atazanavir, inidinavir, boceprevir, and telaprevir.

In a particular embodiment, the strong CYP3A4 inhibitor is itraconazole (ITZ).

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows dose-normalized mean total lurbinectedin (LRB) plasma concentration-time profile by treatment (pharmacokinetic (PK) evaluable population).

Figure 2 shows dose-normalized mean unbound lurbinectedin plasma concentration-time profile by treatment (PK evaluable population).

Figure 3 shows dose-normalized mean lurbinectedin metabolite M1 plasma concentration-time profile by treatment (PK evaluable population).

Figure 4 shows dose-normalized mean lurbinectedin metabolite M4 plasma concentration-time profile by treatment (PK evaluable population).

Figure 5 shows mean itraconazole (ITZ) and hydroxyl-ITZ plasma concentration-time profiles (PK evaluable population).

DETAILED DESCRIPTION OF THE INVENTION In the present application, a number of general terms and phrases are used, which should be interpreted as follows.

The term “treating” as used herein, unless otherwise indicated, means reversing, attenuating, alleviating or inhibiting the progress of the disease or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment” as used herein, unless otherwise indicated, refers to the act of treating as “treating” is defined immediately above.

“Patient” includes humans, non-human mammals (e.g. dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g. birds, and the like), preferably humans.

In addition, any drug referred to herein may be in crystalline or amorphous form either as free compounds or as solvates (e.g. hydrates) and it is intended that all forms are within the scope of the present invention. Methods of solvation are generally known within the art.

Cytochrome CYP450 (Drug Metabolism, the importance of cytochrome P450 3A4, Medsafe NZ, March 2014) proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This enzyme is involved in the metabolism of approximately half the drugs in use today, including acetaminophen, codeine, cyclosporin A, diazepam, erythromycin, and chloroquine. The enzyme also metabolizes some steroids and carcinogens.

CYP3A4 (CYP isoform) is mainly located in the liver and small intestine and is the most abundant cytochrome in these organs. In disease states, the inherent variability of CYP3A4 mediated drug metabolism is potentially exacerbated by many factors including alterations in hepatic haemodynamics, hepatocellular function, nutrition, circulating hormones, as well as drug-drug interactions.

In the present invention, the expression “CYP3A4 inhibitor” means an agent which inhibits CYP3A4 mediated metabolism. Further information on CYP3A4 inhibitors can be found at (Drug development and drug interactions, table of substrates, inhibitors and inducers, FDA website, dated on 24 August 2022).

For the purposes of the present intention, the CYP3A4 are strong inhibitors. The US Food and Drug Administration (FDA) proposed that CYP3A (including CYP3A4) inhibitors be classified based on the magnitude of change in plasma area under the curve (AUC) of oral midazolam or other sensitive CYP3A substrate. For instance, if the ratio AUCinhibited/AUCcontroi (AUCR) of oral midazolam (or other sensitive CYP3 A substrate) is > 5, the inhibitor is considered a strong CYP3A inhibitor. If the ratio is > 2 < 5, the inhibitor is classified as moderate and, finally, if the ratio is > 1 .25 < 2, it is considered a weak inhibitor.

To determine whether an agent is a strong CYP3A4 inhibitor, see the FDA “Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry” U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) dated January 2020.

Notwithstanding the definition above, the following agents are considered “strong CYP3A4 inhibitors” for the purposes of the present invention: a) combination of compounds selected form: cobicistat with atazanavir and darunavir; danoprevir and ritonavir; elvitegravir and ritonavir; indinavir and ritonavir; lopinavir and ritonavir; paritaprevir and ritonavir and ombitasvir and dasabuvir; paritaprevir and ritonavir and ombitasvir; paritaprevir and ritonavir and dasabuvir; saquinavir and ritonavir; tipranavir and ritonavir; and b) a compound selected from: cobicistat, grapefruit juice, troleandomycin, itraconazole, posaconazole, ketoconazole, voriconazole, clarithromycin, ritonavir, telithromycin, nelfinavir, atazanavir, indinavir, boceprevir, ceritinib, clarithromycin, idelalisib, nefazodone, nelfinavir, and telaprevir.

The expression “administration cycle” refers to a period of treatment, wherein a single cancer drug or a combination of drugs are administered and usually followed by a period of rest. In the present invention, a treatment cycle is a period of four weeks, preferably three weeks, more preferably 21 consecutive days.

The expression “phase” in the present invention, refers to a period of treatment comprising various administration cycles.

In the present invention, it has been identified that lurbinectedin should be administered at a lowered dose of 1.2 mg/m² when lurbinectedin is administered in conjunction with a strong CYP3A4 inhibitor. It is possible that lurbinectedin will be administered over multiple administration cycles and that some cycles will correspond with administered in conjunction with a strong CYP3A4 inhibitor and other cycles will not. In this situation, lurbinectedin may be administered at a lowered dose of 1.2 mg/m² when lurbinectedin is administered in conjunction with a strong CYP3A4 inhibitor; and lurbinectedin may be administered at its standard recommended dose when it is not administered in conjunction with a strong CYP3A4 inhibitor. This standard recommended dose may be 3.2 mg/m² (adjustable in accordance with any applicable dose reductions taking into account adverse events).

To provide a more concise description, some of the quantitative expressions given herein are not quantified with the term “about”. It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. “Lurbinectedin” or PM01183 is a new synthetic alkaloid that which binds the DNA minor groove causing spatial distortion of DNA and protein complexes and leading to the formation of DNA double-strand breaks (DSBs), thus inducing apoptosis and delaying progression through the cell cycle S/G2 phase. Lurbinectedin has the following structure:

Lurbinectedin has a negative COMPARE analysis when compared against other 98 standard anticancer agents in the standard National Cancer Institute (NCI) panel of 36 cell lines. Thus, its mechanism of action is likely to differ significantly from the other drugs. It only showed a positive correlation (S-rank > 0.8) with trabectedin.

In vitro, lurbinectedin demonstrated cytotoxic effects against a broad selection of tumour-derived cell lines with half maximal inhibitory concentration (IC50) values in the low to very low nanomolar range (approximately median IC50 of 1 E-10 M).

Further information regarding the clinical development of PM01183 (lurbinectedin) can be found in:

-Elez, ME. et. al. Clin. Cancer Res. 2014, 20(8), 2205-2214;

-50^th ASCO Annual Meeting, May 30 - June 3, 2014, Chicago, IL, Abstract 5505;

- 26^th EORTC - 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; November 18-21 , 2014, Barcelona, Spain, published in Eur. J. Cancer 2014, 50 (Suppl.6), pages 13-14, Abs. No. 23.

- 51^th ASCO Annual Meeting, May 29 - June 2, 2015, Chicago, IL, Abstract No. TPS2604 and Abstract Nr. 7509, published in J. Clin. Oncol. 33, 2015 (suppl);

- 54^th ASCO Annual Meeting, June 1-5, 2018, Chicago, IL, Abstract No. 11519, published in J. Clin. Oncol. 36, 2018 (suppl);

- Cruz, C. et al. J. Clin. Oncol. 2018, 36(31), 3134-3143; - 54^th ASCO Annual Meeting, June 1-5, 2018, Chicago, IL, Abstract No. 8570, published in J. Clin. Oncol. 36, 2018 (suppl).

Further information may be found in Xie et al Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity, Oncoimmunology, 2019, Vol. 8, No. 11 , e1656502 (9 pages).

The preferred route of administration is parenteral administration including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, intracerebral, intraventricular, intrathecal, intravaginal or transdermal. The preferred mode of administration is left to the discretion of the practitioner, and will depend in part upon the site of the medical condition. The preferred mode of administration is left to the discretion of the practitioner, and will depend in part upon the site of the medical condition. In a more preferred embodiment, lurbinectedin according to the present invention is administered intravenously.

In specific embodiments, it can be desirable to administer lurbinectedin locally to the area in need of treatment. In one embodiment, administration can be by direct injection at the site (or former site) of a cancer, tumour or neoplastic or preneoplastic tissue.

In a particular embodiment, lurbinectedin for use in the treatment of cancer, may be administered by infusion and with an infusion time of up to 24 hours, 1 to 12 hours, 1 to 6 hours and most preferably 1 hour. In embodiments, dosing may be -5 minutes to +20 minutes of the stated infusion time.

In an embodiment, lurbinectedin may be administered on day 1 of the administration cycle. A window of +/- 2 days may be allowed for administration on day 1 of the cycle which comprises the administration of lurbinectedin in combination with the strong CYP3A4 inhibitor.

In case of lurbinectedin administration delay (< 2 days), the strong CYP3A4 inhibitor may be administered during a 14 consecutive days.

In another embodiment, the strong CYP3A4 inhibitor is administered within a period comprised up to four, five, six, seven or eight days before the administration of lurbinectedin infusion during each administration cycle, preferably up to four days before. In another embodiment, the strong CYP3A4 inhibitor is administered within a period comprised up to four, five, six, seven, eight, nine, ten, eleven or twelve days after the administration of lurbinectedin infusion during each administration cycle, preferably up to seven days after. In another embodiment, the strong CYP3A4 inhibitor is administered within a period comprised between four days before and seven days after the administration of lurbinectedin infusion during each administration cycle. In another embodiment, the strong CYP3A4 inhibitor is administered before lurbinectedin. A particular administration of the strong inhibitor is within a period comprised between four days before and seven days after the lurbinectedin intravenous infusion during each administration cycle, and wherein each administration cycle is 21 days.

In a preferred embodiment, the strong CYP3A4 inhibitor is itraconazole and it is orally administered once daily at a dose about 200 mg during 12 consecutive days during each administration cycle.

In another preferred embodiment, the strong CYP3A4 inhibitor is itraconazole and it is orally administered once daily at a dose about 200 mg during 14 consecutive days during each administration cycle in case of lurbinectedin administration delay.

In an embodiment, lurbinectedin is administered at a dose of about 1.2 mg/m² by intravenous infusion and itraconazole is orally administered at a dose about 200 mg during each administration cycle, wherein each administration cycle is 21 days.

In a particular embodiment, lurbinectedin is administered at a dose of about 1.2 mg/m² by intravenous infusion on day 1 of each administration cycle and itraconazole is orally administered at a dose about 200 mg within a period comprised between four days before and seven days after the lurbinectedin intravenous infusion during each administration cycle, wherein each administration cycle is 21 days.

In a preferred embodiment, the treatment of the invention comprises i) administering to the patient one or more administration cycles of lurbinectedin in combination with itraconazole in a first phase, wherein the dose of lurbinectedin is about 1.2 mg/m² and, ii) administering to the patient one or more administration cycles of lurbinectedin alone in a second phase.

In an embodiment, the dose of lurbinectedin alone in the second phase is about 3.2 mg/m².

In a preferred embodiment, in the one or more administration cycles of the first phase i), itraconazole is orally administered at a dose about 200 mg during 12 consecutive days within a period comprised between four days before and seven days after the lurbinectedin intravenous infusion.

In an embodiment, the treatment of the invention, optionally, comprises an additional third phase of administering lurbinectedin alone at a dose of about 3.2 mg/m².

In another embodiment, the patient may also receive antiemetic prophylaxis before each treatment infusion, preferably 1 before, more preferably 45 minutes before, more preferably 30 minutes before. Antiemetic prophylaxis comprises corticosteroids and 5HT3 antagonists. Preferably, the corticosteroid is dexamethasone and the 5HT3 antagonist is ondansetron. Aprepritant or any other NK-1 antagonist or P-antagonist, except rolapitant, are forbidden during lurbinectedin treatment.

The patient may also receive prophylactic medication before getting treatment by infusion as described in the present invention. Prophylactic medication includes corticosteroids and 5-HT3 receptor antagonists. Particular corticosteroids include dexamethasone. Particular 5-HT3 receptor antagonists include ondansetron. Particular dosages include dexamethasone 8 mg i.v. (or an equivalent dose of another i.v. corticosteroid) and ondansetron 8 mg i.v. (or an equivalent dose of another i.v. 5-HT3 receptor antagonist). Prophylactic medication can be administered on Day 1 of each administration cycle. In addition, further prophylactic medication may be administered as needed. An example includes metoclopramide or equivalent, which in embodiments may be administered every eight hours. After Day 1 and Day 8 of each cycle, extended oral corticosteroids (for example dexamethasone not exceeding 20 mg/days) and/or 5-HT3 receptor antagonists (for example oral (or i.v.) ondansetron 4-8 mg (or equivalent)) may be administered.

The patient may also receive granulocyte-colony stimulating factor G-CSF. An example of G-CSF is nonpegylated filgrastim. By way of example, in cycle 1 , patients may receive primary prophylaxis with G-CSF starting 24-72 hours after Day 1 of Cycle 1 , and during five days. In embodiments, primary G-CSF prophylaxis for further cycles may also be administered using the same regimen. G-CSF prophylaxis may also be administered according to physician discretion.

The present invention has identified dosing regimens useful in the treatment of cancer.

The combination of the present invention have been found to be useful in the treatment of cancer preferably advanced solid tumors selected from endometrial carcinoma, small cell lung cancer, soft tissue sarcoma (particularly leiomyosarcoma), glioblastoma, pancreatobiliary adenocarcinoma, mesothelioma, colorectal adenocarcinoma, ovarian carcinoma, epidermoid carcinoma.

The patient may have progressed, including wherein the patient has progressed from first line therapy. The patient may be pre-treated. The patient may be heavily pre-treated. The patient may be progressive.

The patients may have previously undergone surgery.

The patients may have previously received radiotherapy.

The patients may have received four prior lines and four lines of chemotherapy for advanced disease.

The pharmaceutical compositions can be prepared using methodology well known in the pharmaceutical art. For example a composition intended to be administered by injection can be prepared by combining lurbinectedin with water, or other physiologically suitable diluent, such as phosphate buffered saline, so as to form a solution. A surfactant can be added to facilitate the formation of a homogeneous solution or suspension.

Preferred compositions comprising lurbinectedin of the invention may include:

• Pharmaceutical compositions comprising lurbinectedin and a disaccharide. Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosaccharose, isotrehalose, furanose, melibiose, gentiobiose, and mixtures thereof.

• Lyophilised pharmaceutical compositions comprising lurbinectedin and a disaccharide. Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosaccharose, isotrehalose, furanose, melibiose, gentiobiose, and mixtures thereof.

The ratio of lurbinectedin to the disaccharide in embodiments of the present invention is determined according to the solubility of the disaccharide and, when the formulation is freeze dried, also according to the freeze-dryability of the disaccharide. It is envisaged that this lurbinectedin:disaccharide ratio (w/w) can be about 1 :10 in some embodiments, about 1 :20 in other embodiments, about 1 :50 is still further embodiments. It is envisaged that other embodiments have such ratios in the range from about 1 :5 to about 1 :500, and still further embodiments have such ratios in the range from about 1 :10 to about 1 :500.

The composition comprising lurbinectedin may be lyophilized. The composition comprising lurbinectedin is usually presented in a vial which contains a specified amount of such compound.

Lurbinectedin may be a lyophilized powder for concentrate for solution for infusion, as 4 mg/vial. Before use, the 4-mg vial may be reconstituted with 8 mL of sterile water for injection, to give a solution containing 0.5 mg/mL of lurbinectedin. For administration to patients as i.v. infusion, reconstituted vials may be diluted with glucose 50 mg/mL (5%) or sodium chloride 9 mg/mL (0.9%) solution for infusion.

The full composition of the PM01183 4 mg vial and the reconstituted solution per mL may be as disclosed in Table 1 :

Table 1. Composition of the PM01183 vial.

In a preferred embodiment, a pharmaceutical package comprises lurbinectedin, together with instructions for its use in combination with a strong CYP3A4 inhibitor, wherein lurbinectedin is administered at a dose of about 1.2 mg/m² during each administration cycle and the strong CYP3A4 inhibitor is administered 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 times per day during 12 consecutive days during each administration cycle.

In a more preferred embodiment, a pharmaceutical package comprises lurbinectedin, together with instructions for its use in combination with itraconazole, wherein lurbinectedin is administered at a dose of about 1.2 mg/m² during each administration cycle and itraconazole is orally administered at a dose of of about 200 mg (two capsules of 100 mg) once daily during 12 consecutive days during each administration cycle.

The invention will now be described further with reference to the following example:

EXAMPLE

Prospective, open-label, two-way crossover, phase lb drug-drug interaction study in patients with advanced solid tumors.

STUDY OBJECTIVES

Phase I

Primary Objective:

To assess the effect of itraconazole on lurbinectedin total plasma exposure in patients with advanced solid tumors.

Secondary Objectives:

• To assess the effect of itraconazole on lurbinectedin unbound plasma exposure.

• To assess the effect of itraconazole on lurbinectedin major metabolites (i.e., M1 and M4).

• To assess the effect of itraconazole on the safety profile of lurbinectedin.

• To collect and store a blood sample for germline DNA extraction for future pharmacogenetic (PGt) analysis of variations on genes that may influence exposure and response (i.e., disposition, metabolism and safety) to lurbinectedin.

STUDY DESIGN

Prospective, open-label, two-way crossover, phase lb drug-drug interaction study in patients with advanced solid tumors. The study will include a pre-treatment (screening) phase (within 14 days before the first lurbinectedin or itraconazole administration) followed by a treatment phase consisting of two lurbinectedin cycles, one cycle in combination with itraconazole and one cycle as single agent (in different order depending on the study sequence), and one additional third cycle of lurbinectedin as a single agent for patients who meet the continuation criteria and obtain a clinical benefit after the first two cycles, and then follow-up of adverse events if any.

Phase lb

Patients will receive a maximum of three cycles: two consecutive cycles of lurbinectedin, one cycle with and one cycle without itraconazole co-administration (in different order depending on the study Sequence 1 or Sequence 2 of treatment), followed by a third cycle with lurbinectedin alone (this last optional for patients with clinical benefit). Lurbinectedin will be administered as a 1-hour (-5/+20 min) intravenous (i.v.) infusion on Day 1 every three weeks (q3wk) via a central or peripheral vein. This study will consist of two parts: Part A and B. The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on acceptability of the PK and safety results from the first three patients of Part A. Once, Part A was completed, given the favourable safety results, the dose of lurbinectedin was increased to 0.9 mg/m2 in Part B when administered with itraconazole.

The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole.

STUDY POPULATION

Inclusion criteria

1) Voluntarily signed and dated written informed consent prior to any specific study procedure.

2) Male or female with age >18 years.

3) Life expectancy > 3 months.

4) Pathologically confirmed diagnosis of advanced solid tumors [except for primary central nervous system (CNS) tumors], for which no standard therapy exists.

5) Recovery to grade < 1 from drug-related adverse events (AEs) of previous treatments, excluding alopecia and grade 1 asthenia or fatigue, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v.5).

6) Eastern Cooperative Oncology Group (ECOG) performance status (PS) score <1 .

7) Laboratory values within fourteen days prior to Day 1 of Cycle 1 : a) Absolute neutrophil count (ANC) > 2.0 x 109/L, platelet count > 120 x 109/L and hemoglobin > 9.0 g/dL (patients may be transfused as clinically indicated prior to study entry). b) Platelet count >100 x 109/L, hemoglobin > 9.0 g/dL and absolute neutrophil count (ANC) >1.5 x 109/L. c) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 x the upper limit of normal (ULN) d) Serum total bilirubin <1 .0 x ULN or direct bilirubin <ULN; If total bilirubin is > 1 .0 x ULN, but < 1 .5 x ULN, direct bilirubin must be < 1 .0 x ULN. e) Albumin >3.5 g/dL. f) Alkaline phosphatase (AP) <2.5 x ULN. g) Calculated creatinine clearance (CrCL) >30 mL/minute (using Cockcroft and Gault's formula). h) Creatine phosphokinase (CPK) <2.5 x ULN.

8) Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to six months after treatment discontinuation. 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

1) Concomitant diseases/conditions: a) History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular disease within last year. b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment. c) Known cirrhosis, alcohol induced steatosis, or chronic active hepatitis. For hepatitis B, this includes positive test for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR or HVB- DNA+). For hepatitis C, this includes positive test for both Hepatitis C antibody and quantitative Hepatitis C by PCR (or HVC-RNA+). d) History of obstructive cholestatic liver disease (suitable for stenting procedure) or biliary sepsis in the past 2 months. e) Known of active COVID-19 disease (this includes positive test for SARS-CoV-2 in nasopharyngeal/oropharyngeal swabs or nasal swabs by PCR).

2) Symptomatic, progressive or corticosteroids-requiring documented brain metastases or leptomeningeal disease involvement. Patients with asymptomatic documented stable brain metastases not requiring corticosteroids during the last four weeks are allowed.

3) Use of (strong or moderate) inhibitors or inducers of CYP3A4 activity within three weeks prior to Day 1 of Cycle 1 .

4) Use of CYP3A4 substrates such as HMG-CoA reductase inhibitors atorvastatin, lovastatin and simvastatin for which concomitant administration with strong CYP3A4 inhibitor is contraindicated.

5) Treatment with any investigational product within the 30 days before Day 1 of Cycle 1 .

6) Women who are pregnant or breast-feeding and fertile patients (men and women) who are not using an effective method of contraception.

7) Psychiatric illness/social situations that would limit compliance with study requirements.

STUDY POPULATION

Expected number of patients

A total of 14 patients were included and treated: 3 patients enrolled in Part A and 1 1 patients enrolled in Part B (five in sequence 1 and six in sequence 2). In part A, all patients were assigned to Sequence 1 , while in Part B patients were randomly assigned at a 1 :1 ratio to sequence 1 (TR) or sequence 2 (RT).

Disease characteristics

Primary tumors comprised ovarian carcinoma (n=4; 28.6%; one patient in Part A and three patients in Sequence 2 of Part B), lung (n=3; 21 .4%; one patient in Sequence 1 and two patients in Sequence 2, all of them of Part B), endometrial carcinoma (n=2; 14.3%, both in Sequence 1 of part B), colon adenocarcinoma, epidermoid carcinoma, leiomyosarcoma, mesothelioma and pancreatobiliary adenocarcinoma (n=1 ; 7.1 % each).

The median number of sites involved at baseline was 3 (range, 1-5), with 50.0% of patients having >3 disease sites. Lung and lymph nodes (n=9; 64.3% each), liver (n=4; 28.6%), bone, peritoneum and pleura (n=3; 21.4% each), and adrenal and CNS (n=2; 14.3% each) were the most common disease sites. The median time from disease diagnosis to first infusion was 3.4 years (range, 1 .0- 13.8 years).

Data shown in Table 2 are n (%) of treated patients by study part (Part A: Sequence 1 vs. Part B: Sequence 1 +2) and sequence (Sequence 1 S1 [TR] vs. Sequence 2 S2 [RT]), except for median (range).

Table 2. Disease characteristics of treated patients

^a Lung (n=3) included: NSCLC (n=2) and SCLC (n=1).

CNS: central nervous system; NSCLC: non-small cell lung cancer; RT: reference-test (ITZ + lurbinectedin in Cycle 2); S1 : Sequence 1 ; S2: Sequence 2; SCLC: small cell lung cancer; TR: test- reference (ITZ + lurbinectedin in Cycle 1).

STUDY DRUG

Formulation

PM01183

PM01183 drug product is provided as a lyophilized powder for concentrate for solution for infusion in 4-mg vials.

Before use, the 4-mg vial should be reconstituted with 8 mL of sterile water for injection to give a solution containing 0.5 mg/mL of PM01183. For administration to patients as an i.v. infusion, reconstituted vials should be diluted either with glucose 50 mg/mL (5%) solution or sodium chloride 9 mg/mL (0.9%) solution for infusion.

The full composition of the PM011834-mg vials and the reconstituted solution per mL is shown in Table 3.

Table 3. Composition of PM01183 vials.

Strong CYP3A4 inhibitor: itraconazole

Commercially available itraconazole capsules (with strengths of 100 mg). Treatment schedule

Lurbinectedin PM01183 is administered at a dose of 0.8 mg/m2 in patients of Part A and 0.9 mg/m2 in patients of Part B a 1-hour i.v. infusion (-5/+20 min), on Day 1 every 3 weeks (q3wk) over a minimum of 100 mL dilution on 5% glucose or 0.9% sodium chloride via a central line (or a minimum of 250 mL dilution if a peripheral line is used).

Itraconazole at a fixed dose of 200 mg (two capsules of 100 mg) orally administered once daily in the morning after breakfast during 12 consecutive days, and self-administered from Day -4 (i.e. four days before lurbinectedin infusion) until Day 8 (i.e. seven days after lurbinectedin infusion).

On Day 1 (i.e. days of lurbinectedin infusion) itraconazole will be given immediately prior to the start of the lurbinectedin infusion (i.e. between 15 min and 1 min before). In case of lurbinectedin delay (< 2 days), itraconazole could be administered during a maximum of 14 days.

In sequence 1 (TR), itraconazole was given to the patient on Day -5 with a -2/+1 day time window. In sequence 2 (RT), itraconazole was given to the patient on Day -5 of Cycle 2 with a -2/+1 day time window.

Administration route and dose

Phase lb

Part A: All patients will receive itraconazole plus lurbinectedin in Cycle 1 and lurbinectedin alone in Cycles 2 and 3 (this last cycle being optional for patients with clinical benefit).

Part B: Patients will be randomly assigned to the corresponding sequences:

1. Sequence 1 (TR) (same used in Part A):

□ Cycle 1 : Itraconazole + lurbinectedin

□ Cycle 2: Lurbinectedin alone

□ Cycle 3: Lurbinectedin alone (optional)

2. Sequence 2 (RT):

□ Cycle 1 : Lurbinectedin alone

□ Cycle 2: Itraconazole + lurbinectedin

□ Cycle 3: Lurbinectedin alone (optional)

Cycles administered and dose intensity A total of 36 cycles (nine in Part A, and 27 in Part B, 13 in Sequence 1 [TR] and 14 in Sequence 2 [RT]) were administered to the 14 treated patients. Overall, the median number of cycles per patient was 3 (range, 1-3 cycles), with seven patients (50.0%) having received 3 cycles who continued treatment with lurbinectedin under Compassionate Use Agreement.

Three patients were treated in Part A with a median number of 3 cycles per patient (range, 3-3 cycles); no patients needed to be replaced in Part A.

In Part B, five patients were treated in Sequence 1 (TR) with a median number of 3 cycles per patient (range, 2-3 cycles). In this sequence, one patient was replaced because he was not evaluable for primary endpoint as the itraconazole self-administration was not according to the Summary of Product Characteristics (SmPC). Six patients were treated in Sequence 2 (RT) with a median of 3 cycles per patient (range, 1-3 cycles). Two patients were replaced in Sequence 2: one patient because this patient did not receive a second cycle, and the other patient because the itraconazole self-administration was not according to the SmPC.

In all treated patients, median time on treatment was 10.8 weeks (range, 4.3-11 .3 weeks. Median cumulative dose was 7.2 mg/m² (range, 3.2-8.2 mg/m²), median dose intensity was 0.8 mg/m²/week (range, 0.5-1.1 mg/m^2/week), and median relative dose intensity was 98.3% (range, 77.9-100.1 %) (Table 4).

The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A was 0.8 mg/m². Once, Part A was completed, given the favorable safety profile and to ensure an exposure similar to that obtained when lurbinectedin was administered alone, it was agreed to increase the dose of lurbinectedin to 0.9 mg/m² when was co-administered with itraconazole in Part B.

Table 4. Treatment exposure by study part and sequence.

Prophylactic medication

All patients received standard antiemetic prophylaxis before each treatment infusion (i.e. 30±5 minutes before lurbinectedin administration), as follows: • Dexamethasone 8 mg i.v. or equivalent, maximum 20 mg/day. If feasible, the medication and dose administered in Cycle 1 should be maintained in Cycle 2.

• 5-HT3 antagonists, ie. Ondansetron 8 mg i.v. and no more than 16 mg.

Other possible prophylactic medications:

• Treatment with 5-HT3 antagonists and/or dexamethasone could be extended orally, i.e with 4 to 8 mg/day for three consecutive days, and/or 10 mg of metoclopramide orally every eight hours, at the Investigator’s criteria if required.

• Aprepitant or any other NK-1 antagonist or related substance P-antagonists (except for rolapitant) are forbidden in patients treated with lurbinectedin.

Allowed medications/therapies • Therapies for preexisting and treatment-emergent medical conditions, including pain management and local management of mucositis/stomatits. Blood products and transfusions, as clinically indicated.

Bisphosphonates.

• In case of nausea or vomiting, secondary prophylaxis and/or symptomatic treatment for emesis according to American Society of Clinical Oncology (ASCO) guidelines (taking into account the aforementioned limit of corticosteroids per day).

• Erythropoietin use according to ASCO guidelines.

• Low molecular weight heparin (LMWH) and/or any other anticoagulants, as clinically indicated. Oral anticoagulants must be carefully monitored.

• Secondary prophylaxis or therapeutic use of G-CSF.

• Palliative limited field bone RT (e.g. for pain control outside the thoracic wall).

• Megestrol acetate for appetite stimulation.

• Contraceptives.

Prohibited medications/therapies

• Concomitant administration of any other antineoplastic therapy.

• Other investigational agents.

• Inmunopressive therapies other than corticosteroids for antiemetic prophylaxis or pain control, or low-dose replacement in patients requiring this approach.

• Aprepitant or any other NK-1 antagonist or related substance P-antagonists (except for rolapitant).

• Primary prophylaxis and/or treatment with colony- stimulating factors (G-CSF) during Cycle 1 .

• CYP3A4 inhibitors such as ketoconazole, fluconazole, voriconazole, telithromycin, clarithromycin, erythromycin, nafcillin, aprepitant, fosaprepritant, verapamil, modafinil, nefazodone, or grapefruit juice.

• CYP3A enzyme inducers and/or inhibitors (unless strictly necessary and when there is no therapeutic alternative treatments).

• Use of any prescription or non-prescription herbal and/or dietary supplements within 14 days prior to the first dose of medication and until 31 days after the last administration of lurbinectedin, unless the Investigators, with the Sponsor agreement, consider it will not interfere with study procedures of patient safety.

Drug-Drug interactions

In vitro studies with human microsomes showed that CYP3A4 is the major CYP isoform involved in the metabolism of PM01 183, followed by CYP2E1 , CYP2D6 and CYP2C9. The estimated contribution of the other CYP isoenzymes to the PM01183 metabolism is considered to be negligible. Therefore, concomitant drugs which induce or inhibit any of these cytochromes, especially CYP3A4, should be carefully monitored or avoided, whenever is possible.

A significant interaction with aprepitant is suggested by available available phase II data from ovarian cancer patients and phase I data from the PM1 183-A- 008-13 study. PM01183 clearance was reduced by 33%, approximately, in the presence of aprepitant. Although all patients eventually recovered, the use of aprepitant is currently forbidden in all Phase II and III lurbinectedin studies.

EVALUABILITY OF PATIENTS

Phase lb

Part A: An evaluable patient for Part A should have completed sufficient study procedures until Day 8 of Cycle 1 (i.e., most itraconazole administration and PK assessments).

Part B: An evaluable patient forthe main objective of the study (e.g., assessment of lurbinectedin PK) should have provided sufficient and interpretable PK parameters (e.g., AUCo-t should cover at least 80% of AUCo-~) of Cycle 1 and 2. Evaluable patients should have received the first two complete cycles regardless dose delays or reductions.

For Part A and Part B, the compliance of itraconazole will be confirmed based on a patient’s diary, the drug accountability and the expected individual plasma concentration at the steady state.

Adverse events

An overall analysis of treatment-related (or with unknown relationship) AEs are provided in this section by study part, according to worst grade per treatment (ITZ + LRB vs. LRB alone) (Table 5) and by sequence, according to worst grade per patient (Sequence 1 [Part A + Part B] vs. Sequence 2 [Part B]) (Table 6), with special emphasis on those with grade > 3 AEs.

Table 5. Treatment-related adverse events (including cases with unknown relationship) by study part (regardless of sequence), worst grade per treatment.

Table 6. Treatment-related adverse events (including cases with unknown relationship) by sequence, worst grade per patient.

In Part A, one patient treated with ITZ + LRB and two with LRB alone had at least one AE related to treatment (or with unknown relationship). In Part A, in the combination of ITZ plus lurbinectedin, only one event of treatment-related grade 1 fatigue (related to both) during Cycle 1 was reported. No grade > 3 AEs related to treatment (or with unknown relationship) were observed while patients were in treatment with the combination of ITZ + LRB. In part A, in lurbinectedin alone, two episodes of grade 4 neutropenia in two patients (66.7%) were reported. In addition, one patient had grade 3 ALT increased (SAE) related to lurbinectedin that led to dose reduction in Cycle 3.

In Part B, in the combination of ITZ + LRB, all treatment- related events were grade 1/2. In LRB alone, the most common treatment-related (or with unknown relationship) AEs were blood and lymphatic system disorders (mainly neutropenia, n=5, 45.5% of patients, all grade > 3 neutropenia), gastrointestinal disorders (mainly nausea, n=5, 45.5%, all grade 1/2; and vomiting, n=3, 27.3%, one of them reaching grade 3), and general disorders and administration site conditions (fatigue, n=2, 18.2%, all grade 1/2).

In Part A (Sequence 1) and Part B (Sequences 1 +2), no grade > 3 AEs related to treatment (or with unknown relationship) were observed while patients were in treatment with the combination of ITZ plus lurbinectedin.

In the analysis by sequence, seven patients (7/8: 87.5% of patients) had 22 treatment-related AEs (or with unknown relationship) in Sequence 1 (Part A+B), reaching grade > 3 in four patients while were on treatment with LRB alone. Four patients (4/6: 66.7%) had ten treatment-related AEs (or with unknown relationship) in Sequence 2 (Part B), reaching grade > 3 in three patients treated with LRB alone.

EVALUATION CRITERIA Primary endpoint

Plasma exposure to lurbinectedin: Plasma dose-normalized Cmax and AUCo - of lurbinectedin will be compared between Cycle 1 and Cycle 2. Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.

Phase lb

Secondary endpoints

• Secondary PK parameters: a) Differences in dose-normalized total AUCo-t and Cmax and in Cl, V_ss and ti/2 of lurbinectedin between Cycle 1 and Cycle 2 will be explored. b) Differences in dose-normalized unbound AUC_u,o -~, AUCu.o t and Cmax and in CL, Vss, and ti/2,u of lurbinectedin between Cycle 1 and Cycle 2 will be explored. c) Differences in ratios between total AUCo-, AUCo-t and Cmax, of main lurbinectedin metabolites relative to parent drug between Cycle 1 and Cycle 2 will be explored. Additional PK parameters will be calculated if deemed appropriate.

• Plasma protein binding: A similar model used for the primary endpoint will be fit to the data with dose-normalized AUC_U as the dependent variable.

• Safety: patients will be evaluable for safety if they have received at least one partial infusion of lurbinectedin. Adverse effects (AEs), serious adverse events (SAEs) and laboratory abnormalities will be graded according to the NCI-CTCAE v.5. The safety profile of patients will be monitored throughout the treatment and up to 31 days (±10 days) after the last treatment infusion (EOT), or until the patient starts a new antitumor therapy, until the continuation of treatment outside this study under a Compassionate Use Agreement or until the date of death, whichever occurs first. Additionally, treatment compliance, in particular dose reductions requirements and/or treatment delays due to AEs, and reasons for treatment discontinuation will also be described.

• Pharmacogenetics: the presence or absence of pharmacogenetic polymorphisms in genes relevant for lurbinectedin disposition (distribution, metabolism and excretion) from a single blood sample collected at any time during the trial (but preferably at the same time as the pre-treatments PK sample on Day 1 of Cycle 1), which will be stored to explain individual variability in main PK parameters in future analyses.

Pharmacokinetic (PK) Analysis All of the 14^th (3 in Part A and 11 in Part B) treated patients in the study were sampled for pharmacokinetic assessment. Pharmacokinetic samples for measurement of lurbinectedin concentrations were collected for 361 hours after the start of lurbinectedin infusion during the lurbinectedin alone administration cycle and the lurbinectedin plus itraconazole (ITZ) administration cycle.

ITZ and its metabolite hydroxyl-ITZ exposure assessment at steady state, aiming to assure the adequate treatment compliance, were performed using sparse pharmacokinetic sampling for 25 hours after the last ITZ administration during the Day 1 of the lurbinectedin plus ITZ treatment cycle. An additional PK sample was collected on Day 8 of the cycle.

■ Total plasma lurbinectedin pharmacokinetics

Co-administration of multiple oral doses of ITZ, increased the dose-normalized mean plasma concentrations of total plasma lurbinectedin throughout most of the PK sampling interval. (Figure 1)

■ Unbound plasma lurbinectedin pharmacokinetics

Co-administration of multiple oral doses of ITZ, increased the dose-normalized mean plasma concentrations of unbound plasma lurbinectedin throughout most of the PK sampling interval. (Figure 2)

■ Total plasma metabolite Ml (l’,3 -dihydroxy-lurbinectedin) pharmacokinetics

Co-administration of multiple oral doses of ITZ, almost completely suppresses the lurbinectedin transformation to M1 in most of the patients. (Figure 3)

■ Total plasma metabolite M4 (PM030047, N-desmethyl-lurbinectedin) pharmacokinetics

Co-administration of multiple oral doses of itraconazole, almost completely inhibited the conversion of lurbinectedin to M4 (PM030047, A/-desmethyl-lurbinectedin) compared to lurbinectedin administered alone. (Figure 4).

■ Itraconazole and hydroxyl-ITZ pharmacokinetics

The individual and mean steady-state plasma concentration-time profile of itraconazole and its metabolite (hydroxyl-ITZ) after multiple-dose oral administration of 200 mg daily during 12 days shows that the steady state was archived (Figure 5).

Statistical Analysis of Comparative Pharmacokinetic Exposure of Lurbinectedin (LRB) Coadministered with or without itraconazole (ITZ) A mixed-effects model was fitted to the data with log-transformed PK parameters as dependent variable, treatment (ITZ + LRB or LRB alone), period (Cycle 1 or 2) and sequence as fixed effects, and patient (nested in the sequence) as a random effect. The estimated least square means and intra-subject variability from the mixed-effects model were used to construct 90% Cis for the difference in means on the log scale between treatments (ITZ + LRB or LRB alone). The adjusted mean differences and the 90% Cis were exponentiated to obtain estimates of the ratio of adjusted geometric means (Test/Reference) and 90% Cis for the ratios.

■ Total plasma lurbinectedin exposure

Inferential statistical analysis was performed on the log-transformed total plasma lurbinectedin PK parameters with lurbinectedin alone as the reference treatment. Results show that the coadministration with ITZ is associated with significant increase in systemic exposure of lurbinectedin. The Cmax was increased by approximately 15%, and ITZ co-administration was associated with a 2.4-fold and 2.7-fold increase in AUCo-t and AUCo-, respectively. Total lurbinectedin CL decreased by 63% and ti/2was 2.2-fold longer. These changes in lurbinectedin CL, ti/2 and systemic exposure were statistically significant, as the 90% confidence intervals did not contains the 100% (Table 7).

Table 7. Statistical comparison of total plasma lurbinectedin PK parameters between lurbinectedin alone and co-administered with ITZ (PK evaluable population).

Terminology: ^a Dose-normalized PK parameter; ^b Ratio = least-squares geometric mean ratio; AUC: area under the concentration-time curve; CL: clearance; Cmax: maximum plasma concentration; CV: coefficient of variation; n: number of patient with PK parameter included; RT: reference-test (ITZ + lurbinectedin in Cycle 2); ti/2: terminal half-life; TR: test- reference (ITZ + lurbinectedin in Cycle 1); Vss, volume of distribution at steady state.

■ Unbound plasma lurbinectedin exposure

Inferential statistical analysis was performed on the log-transformed unbound plasma lurbinectedin PK parameters with lurbinectedin alone as the reference treatment. Results show that the co-administration with ITZ is associated with significant increase in systemic exposure of unbound lurbinectedin associated with a 2.2-fold and 2.4-fold increase in AUCo-t and AUCo-, respectively. Unbound lurbinectedin CL decreased by 58% and ti/2 was 2-fold longer. These changes in unbound lurbinectedin CL, ti/2 and systemic exposure were statistically significant, as the 90% confidence intervals did not contains the 100% (Table 8).

Table 8. Statistical comparison of total plasma lurbinectedin PK parameters between lurbinectedin alone and co-administered with ITZ (PK evaluable population).

■ Total plasma metabolite M1 (T,3'-dihydroxy-lurbinectedin) / parent ratio (MPR)

A formal inferential statistical analysis cannot be performed on the log-transformed metabolite/parent ratio (MPR) for M1 plasma PK exposure parameters with lurbinectedin alone as the reference treatment, because during ITZ co-administration cycle almost all PK samples in all patients, except one, were below the limit of quantification. These findings suggest that ITZ coadministration almost completely inhibit the conversion of lurbinectedin to its metabolite M1 .

■ Total plasma metabolite M4 (PM030047, N-desmethyl-lurbinectedin) /parent ratio (MPR)

Inferential statistical analysis was performed on the log-transformed metabolite/parent ratio for M4 plasma PK exposure parameters with lurbinectedin alone as the reference treatment. Results from statistical analysis show that the co-administration with ITZ did not modify the M4 metabolite/parent ratio for Cmax, however was associated to a statistically significant reduction in the M4 metabolite/parent ratio for AUCo-t (Table 9). These changes suggest that ITZ co- administration reduced by 69% the conversion of lurbinectedin to its metabolite M4.

Table 9. Statistical comparison of metabolite M4/parent ratio (MPR) in plasma between lurbinectedin alone and co-administered with ITZ (PK evaluable population).

Results

The Phase 1 b drug-drug interaction study was conducted in patients with advanced solid tumors in two parts (Part A and Part B). This study allowed to characterize the pharmacokinetics of total and unbound lurbinectedin (LRB) administered alone and in combination with a strong CYP3A4 inhibitor such as itraconazole (ITZ). Co-administration with itraconazole increased the systemic exposure of total lurbinectedin Cmax by 15%, and by approximately 2.4-fold for AUCo-t and by 2.7-fold for AUCo-, and reduced clearance (CL) by 63% and prolonged elimination half-life (ti/2) by 2.2-fold.

Moreover, co-administration with itraconazole, produced statistically significant modifications in the unbound plasma lurbinectedin PK parameters of similar extent, by increasing the systemic exposure of unbound lurbinectedin by approximately 2.2-fold for AUCo-t and by 2.4-fold for AUCo and reducing clearance (CL) by 58% and prolonging elimination half-life (ti/2) by 2-fold.

Furthermore, co-administration with itraconazole, almost completely inhibited the conversion of lurbinectedin to M1 (1 ',3'-dihydroxy-lurbinectedin) and to M4 (PM030047, A/-desmethyl- lurbinectedin) compared to lurbinectedin administered alone.

The magnitude of these changes showed a clinically relevant effect of itraconazole co- administration on lurbinectedin pharmacokinetics.

The most common treatment-related (or with unknown relationship) adverse events (AEs) were neutropenia, nausea, vomiting and fatigue. Considering the sample size of patients analyzed, some differences were observed between both sequences in terms of treatment-related adverse events (AEs), with 87.5% of patients in Sequence 1 (Part A and B) and 66.7% in Sequence 2 (Part B) who had treatment-related AEs or with unknown relationship. In addition, the most common grade 4 hematological toxicity was observed in Sequence 1 . Two treatment-related serious adverse events (SAEs) consisted of grade 3 ALT increased and grade 3 rhabdomyolysis were also observed in Sequence 1 .

Based on the total plasma value Ratio ITZ+ LRB/LRB for AUC₀.«, PK parameter (2.73) obtained or the factor value of CL (0.37), the recommended dose obtained for lurbinectedin in combination with itraconazole is about 1 .2 mg/m².

In conclusion, co-administration with multiple doses of a strong CYP3A inhibitor (ITZ) has not been associated with worst safety profile compared with lurbinectedin administered alone and safety profile of lurbinectedin administered alone at dose of 3.2 mg/m² was consistent with that reported in previous phase II and phase III trials with the same administration regimen in patients with advanced cancer.

Claims

1. Lurbinectedin for use in the treatment of cancer in a patient in need thereof, wherein said treatment comprises administering to the patient lurbinectedin in combination with a strong CYP3A4 inhibitor, wherein lurbinectedin is administered at a dose of about 1 .2 mg/m² during each administration cycle.

2. Lurbinectedin for use according to claim 1 , wherein lurbinectedin is administered as 1-hour intravenous infusion during each administration cycle.

3. Lurbinectedin for use according to claim 1 or 2, wherein lurbinectedin is administered on day 1 of each administration cycle.

4. Lurbinectedin for use according to any of the previous claims, wherein the strong CYP3A4 inhibitor is administered up to four, five, six, seven or eight days before the administration of lurbinectedin.

5. Lurbinectedin for use according to any of the previous claims, wherein the strong CYP3A4 inhibitor is administered up to four, five, six, seven, eight, nine, ten, eleven or twelve days after the administration of lurbinectedin.

6. Lurbinectedin for use according to any of the previous claims, wherein the strong CYP3A4 inhibitor is administered within a period comprised between four days before and seven days after the administration of lurbinectedin.

7. Lurbinectedin for use according to any of the previous claims, wherein the method further comprises administration of granulocyte-colony stimulating factor (G-CSF).

8. Lurbinectedin for use according to claim 7, wherein G-CSF is administered on day 1 of an administration cycle; or wherein the patient receives primary prophylaxis with G-CSF starting 24- 72 hours after day 1 of an administration cycle, and for five days.

9. Lurbinectedin for use according to claim 7 or claim 8, wherein G-CSF is administered during the first administration cycle; optionally wherein G-CSF during one or more subsequent administration cycles.

10. Lurbinectedin for use according to any of the previous claims, wherein the strong CYP3A4 inhibitor is selected from the group of cobicistat with atazanavir and darunavir; danoprevir and ritonavir; elvitegravir and ritonavir; indinavir and ritonavir; lopinavir and ritonavir; paritaprevir and ritonavir and ombitasvir and dasabuvir; paritaprevir and ritonavir and ombitasvir; paritaprevir and ritonavir and dasabuvir; saquinavir and ritonavir; tipranavir and ritonavir; cobicistat; grapefruit juice; troleandomycin; itraconazole; Posaconazole; ketoconazole; voriconazole; clarithromycin; ritonavir; telithromycin; nelfinavir; atazanavir; indinavir; boceprevir; ceritinib; clarithromycin; idelalisib; nefazodone; nelfinavir; and telaprevir.

11. Lurbinectedin for use according to claim 10, wherein the strong CYP3A4 inhibitor is selected from the group of itraconazole, posaconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, lopinavir, saquinavir, nelfinavir, ritonavir, atazanavir, indinavir, boceprevir, and telaprevir.

12. Lurbinectedin for use according to claim 10 or 11 , wherein the strong CYP3A4 inhibitor is itraconazole.

13. Lurbinectedin for use according to any of the previous claims, wherein lurbinectedin is administered in combination with a strong CYP3A4 inhibitor, wherein lurbinectedin is administered at a dose of about 1.2 mg/m² on day 1 of each administration cycle; and wherein the strong CYP3A4 inhibitor is administered within a period comprised between four days before and seven days afterthe administration of lurbinectedin infusion during each administration cycle; and wherein each administration cycle is 21 days.

14. Lurbinectedin for use according to any of the previous claims, wherein said treatment of cancer includes administration cycles where lurbinectedin is administered without administration of a strong CYP3A4 inhibitor.

15. Lurbinectedin for use according to claim 14, wherein in said administration cycles which do not include administration of a strong CYP3A4 inhibitor, lurbinectedin is administered according to its standard regimen, optionally wherein lurbinectedin is administered at a dose of 3.2 mg/m² during each administration cycle.

16. Lurbinectedin for use according to any of the previous claims, wherein after combination administration of lurbinectedin and a strong CYP3A4 inhibitor during a first phase; lurbinectedin is administered alone for one or more cycles during a second phase; wherein lurbinectedin may be administered according to one or more of claims 1 to 13 during the first phase.

17. Lurbinectedin for use according to any of the previous claims, wherein after discontinuation of the strong CYP3A inhibitor, the patient continues treatment with lurbinectedin, and wherein the dose of lurbinectedin is increased.

18. Lurbinectedin for use according to claim 17, wherein dose of lurbinectedin is increased to the dose used before starting the inhibitor.

19. Lurbinectedin for use according to claim 17 or claim 18, wherein the dose of lurbinectedin is increased to the standard recommended dose of 3.2 mg/m² (adjustable in accordance with any applicable dose reductions taking into account adverse events).

20. Lurbinectedin for use according to any one of claims 17 to 19, wherein after discontinuation of the strong CYP3A inhibitor is after discontinuation of the strong CYP3A inhibitor after about 5 half-lives.

21 . Lurbinectedin for use according to any of the previous claims, wherein the cancer is advanced solid tumors selected from endometrial carcinoma, small cell lung cancer, soft tissue sarcoma, glioblastoma, pancreatobiliary adenocarcinoma, mesothelioma, colorectal adenocarcinoma, ovarian carcinoma, epidermoid carcinoma; preferably small cell lung cancer.

22. Lurbinectedin for use in the treatment of cancer in a patient in need thereof, said treatment comprises: i. administering to the patient one or more administration cycles of lurbinectedin in combination with a strong CYP3A4 inhibitor in a first phase, wherein the dose of lurbinectedin is about 1.2 mg/m²; and ii. administering to the patient one or more administration cycles of lurbinectedin alone in a second phase, wherein lurbinectedin may be administered according to any one of claims 15 to 20.

23. Lurbinectedin for use in the treatment of cancer in a patient in need thereof, said treatment comprises: i. administering to the patient one or more administration cycles of lurbinectedin alone in a first phase, wherein lurbinectedin may be administered according to claim 15; and ii. administering to the patient one or more administration cycles of lurbinectedin in combination with a strong CYP3A4 inhibitor in a second phase, wherein the dose of lurbinectedin is about 1 .2 mg/m².

24. Lurbinectedin for use according to claims 22 or 23, wherein said treatment comprises an additional third phase of administering lurbinectedin alone.

25. A pharmaceutical package comprising lurbinectedin, together with instructions for its use in combination with a strong CYP3A4 inhibitor according to any one of claims 1 to 24.

26. Lurbinectedin for use in a treatment of cancer in a patient in need thereof, wherein the treatment comprises:

27. Lurbinectedin for use according to claim 26, wherein the treatment further comprises administering to the patient the standard recommended dose of lurbinectedin at least four, five, six, seven, eight, nine, ten, eleven or twelve days before the initial administration of the strong CYP3A4 inhibitor.

28. Lurbinectedin for use according to claim 26 or 27, wherein lurbinectedin is administered intravenously, such as by intravenous infusion, preferably by 1-hour intravenous infusion.

29. Lurbinectedin for use according to any one of claims 26 to 28, wherein the standard recommended dose is 3.2 mg/m² per administration cycle.

30. Lurbinectedin for use according to any one of claims 26 to 29, wherein the treatment does not comprise co-administration of lurbinectedin together with the effective amount of the strong CYP3A4 inhibitor.

31 . Lurbinectedin for use according to any one of claims 26 to 29, wherein the treatment further comprises co-administering to the patient a reduced dose of lurbinectedin together with the effective amount of the strong CYP3A4 inhibitor, wherein the reduced dose is lower than the standard recommended dose.

32. Lurbinectedin for use according to claim 31 , wherein the reduced dose is about 1 .2 mg/m² per administration cycle.

33. Lurbinectedin for use according to claim 31 , wherein the reduced dose is 1.0. 1.1. 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 mg/m², preferably 1.6 mg/m², per administration cycle.

34. Lurbinectedin for use according to any one of claims 31 to 33, wherein the effective amount of the strong CYP3A4 inhibitor is administered up to four, five, six, seven or eight days before the administration of the reduced dose of lurbinectedin.

35. Lurbinectedin for use according to any one of claims 31 to 34, wherein the effective amount of the strong CYP3A4 inhibitor is administered up to four, five, six, seven, eight, nine, ten, eleven or twelve days after the administration of the reduced dose of lurbinectedin.

36. Lurbinectedin for use according to any one of claims 31 to 35, wherein the strong CYP3A4 inhibitor is administered within a period of four days before and seven days after the administration of lurbinectedin.

37. Lurbinectedin for use according to any one of claims 26 to 36, wherein the treatment includes one or more administration cycles where lurbinectedin and the effective amount of the strong CYP3A4 inhibitor are not co-administered.

38. Lurbinectedin for use according to any one of claims 26 to 36, wherein each administration cycle is 21 days.

39. Lurbinectedin for use in a treatment of cancer in a patient in need thereof, wherein the treatment comprises:

(2) discontinuing the administration of the strong CYP3A4 inhibitor; and

(3) intravenously administering to the patient a standard recommended dose of 3.2 mg/m² per administration cycle of lurbinectedin at least four days after the last administration of the strong CYP3A4 inhibitor, optionally, the treatment further comprises:

(4) intravenously administering to the patient lurbinectedin at a standard recommended dose of 3.2 mg/m² per administration cycle at least four days before the initial administration of the strong CYP3A4 inhibitor, wherein each of the administration cycle of lurbinectedin is 21 days.

40. Lurbinectedin for use according to claim 39, wherein the treatment does not comprise coadministering to the patient lurbinectedin together with the effective amount of the strong CYP3A4 inhibitor.

41 . Lurbinectedin for use according to claim 39, wherein the treatment further comprises coadministering to the patient a reduced dose of 1 .6 mg/m² per administration cycle of lurbinectedin together with the effective amount of the strong CYP3A4 inhibitor.

42. Lurbinectedin for use according to any one of claims 26 to 41 , wherein the treatment further comprises administering to the patient a granulocyte-colony stimulating factor (G-CSF).

43. Lurbinectedin for use according to claim 42, wherein G-CSF is administered on the same day of the administration of lurbinectedin; or wherein the patient receives primary prophylaxis with G- CSF starting 24-72 hours after the administration of lurbinectedin and for five days.

44. Lurbinectedin for use according to claim 42 or claim 43, wherein G-CSF is administered during the first administration cycle; optionally wherein G-CSF is administered during one or more subsequent administration cycles.

45. Lurbinectedin for use according to any one of claims 26 to 44, wherein the strong CYP3A4 inhibitor is selected from the group of cobicistat with atazanavir and darunavir; danoprevir and ritonavir; elvitegravir and ritonavir; indinavir and ritonavir; lopinavir and ritonavir; paritaprevir and ritonavir and ombitasvir and dasabuvir; paritaprevir and ritonavir and ombitasvir; paritaprevir and ritonavir and dasabuvir; saquinavir and ritonavir; tipranavir and ritonavir; cobicistat; grapefruit juice; troleandomycin; itraconazole; Posaconazole; ketoconazole; voriconazole; clarithromycin; ritonavir; telithromycin; nelfinavir; atazanavir; indinavir; boceprevir; ceritinib; clarithromycin; idelalisib; nefazodone; nelfinavir; and telaprevir.

46. Lurbinectedin for use according to claim 45, wherein the strong CYP3A4 inhibitor is selected from the group of itraconazole, posaconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, lopinavir, saquinavir, nelfinavir, ritonavir, atazanavir, indinavir, boceprevir, and telaprevir.

47. Lurbinectedin for use according to claim 46, wherein the strong CYP3A4 inhibitor is itraconazole.

48. Lurbinectedin for use according to claim 47, wherein itraconazole is administered orally to the patients, preferably at a dose of 200 mg once daily.

49. Lurbinectedin for use according to any one of claims 26 to 48, wherein the cancer is advanced solid tumors selected from endometrial carcinoma, small cell lung cancer, soft tissue sarcoma, pancreatobiliary adenocarcinoma, mesothelioma, colorectal adenocarcinoma, ovarian carcinoma, epidermoid carcinoma; preferably small cell lung cancer.

50. Lurbinectedin for use according to any one of claims 26 to 49, wherein the patient has been or is being treated with a platinum-based chemotherapy.

51 . Lurbinectedin for use according to any one of claims 26 to 50, wherein the cancer is metastatic small cell lung cancer (SOLO) with disease progression on or after platinum-based chemotherapy.

52. A pharmaceutical package comprising lurbinectedin, together with instructions for its use in combination with a strong CYP3A4 inhibitor according to any one of claims 26 to 51 .

53. A pharmaceutical package comprising a strong CYP3A4 inhibitor, together with instructions for its use in combination with lurbinectedin according to any one of claims 26 to 51 .