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Doxorubicin

Liposomal doxorubicin

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Enzyme Inhibitors

lurbinectedin (PM01183) is presented as powder for concentrate for solution for infusion with two strengths, 1-mg and 4-mg vials.

lurbinectedin (PM01183)

Commercially available presentations of vials containing doxorubicin will be provided as appropriate.

Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM01183 in Combination with Fixed Doxorubicin in Non- Heavily Pretreated Patients with Selected Advanced Solid Tumors to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of PM01183 in combination with doxorubicin, to characterize the safety profile and feasibility of this combination, to characterize the pharmacokinetics (PK) of this combination, to obtain preliminary information on the clinical antitumor activity,to explore the feasibility, safety and efficacy of a potential improvable dose of this combination in selected tumor types \[i.e. small cell lung cancer (SCLC) and endometrial cáncer\] and to evaluate the pharmacogenomics (PGx) in tumor samples of patients exposed to PM01183 and doxorubicin at the RD in order to assess potential markers of response and/or resistance.

The study has currently met its primary end point and is now recruiting patients to be treated at the RD expansion cohort of selected tumor types, specifically: endometrial adenocarcinomas, neuroendocrine tumors, and small-cell lung cancer (SCLC).

Study Escalating Doses of PM01183 in Combination With Fixed Doxorubicin in Patients With Specific Advanced Unresectable Solid Tumors

Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM01183 in Combination With Doxorubicin in Non-heavily Pretreated Patients With Selected Advanced Solid Tumors

A minimum of three patients will be included at each DL. If no patients experience a DLT during Cycle 1, the dose will be escalated. If one of three patients experiences a DLT, three additional patients will be included at that level. If \>1 evaluable patient during dose escalation at a given DL experience a DLT during Cycle 1, that DL will be considered the MTD and dose escalation will be terminated, except if all DLTs are related to neutropenia exclusively, in which case dose escalation may be resumed as originally planned in a new cohort of patients but with compulsory primary G-CSF prophylaxis.

The DL immediately below the MTD, or DL4 if the MTD is not yet defined during dose escalation before the last DL (i.e., DL4) is reached, was to be initially expanded up to a minimum of nine evaluable patients. If less than three among the first nine evaluable patients treated within the expansion cohort experience a DLT during Cycle 1, this DL will be the RD.

DLT,dose-limiting toxicity Patients enrolled into this study were originally not allowed to receive primary G-CSF prophylaxis. However, the finding of dose-limiting febrile neutropenia in two patients treated at dose level I in the present study (see below) suggested that increasing doses of the DOX/PM01183 combination might require primary G-CSF prophylaxis to decrease the risk of febrile neutropenia. Therefore, a separate dose escalation was established to define the MTD and the RD of the DOX/PM01183 combination with compulsory primary G-CSF prophylaxis.

Tumor response was evaluated according to the RECIST v.1.1 for target lesions and assessed by computed tomography (CT) scans or magnetic resonance imagings (MRIs): Progressive disease (PD) is declared when there is an increase in sum of target disease ≥ 20%, stable diease (SD) when the change is \> -30% and ≤ 20%, partial response (PR) when there is a decrease in sum of target disease ≥ 30%, and complete response (CR) when all lesions have disappeared or all lesions have disapeared and all nodal disease is \< 10 mm each.

The duration of overall response was measured from the time measurement criteria are met for complete response (CR)/ PR, whichever is first recorded, until the first date in which progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started) or the date of death. In absence of disease progression or death, the duration of response was censored on the date of last tumor evaluation.

Progression-free survival (PFS) is defined as the time from the date of first infusion of study treatment to the date of progression or death (due to any cause). If progression or death has not occurred at the time of the analysis, the PFS was censored on the date of last tumor evaluation.

Overall survival (OS) is defined as the time from the date of first infusion of study treatment to the date of death (due to any cause). Patients with no documented death were censored at the last date they are known to be alive

PharmaMar

All 120 patients treated in this study were evaluable for safety

73 patients treated in Cohort A (DOX \[mg/m2\] plus PM01183 \[mg FD\]) were evaluable for safety

Cohort A

Patients with SCLC 2nd line received the following on Day 1 q3wk (three weeks = one treatment cycle), administered: DOX 40 mg/m2 immediately followed by PM01183: 2.0 mg/m2.

Cohort B: SCLC 2nd Line

Patients with endometrial cancer received the following on Day 1 q3wk (three weeks = one treatment cycle), administered: DOX 40 mg/m2 immediately followed by PM01183: 2.0 mg/m2.

Cohort B: Endometrial

DOX: 50 mg/m² q3wk immediately followed by PM01183. The dose escalation scheme was: 3.0, 3.5, 5.0, 6.0, 7.0 mg FD

Patients with SCLC 2nd line received the following on Day 1 q3wk (three weeks = one treatment cycle), administered: DOX 40 mg/m2 Immediately followed by PM01183: 2.0 mg/m2.

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

ECOG PS, Eastern Cooperative Oncology Group performance status PS 0 Fully active able to carry on all pre-disease performance without restriction PS 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature PS 2 Ambulatory and capable of all selfcare but unable to carry out any work activities up and about more than 50% of waking hours PS 3 Capable of only limited selfcare confined to bed or chair more than 50% of waking hours PS 4 Completely disabled cannot carry on any selfcare; totally confined to bed or chair PS 5 Dead

ECOG PS

ET-GEP, neuroendocrine-gastroenteropancreatic tumor; SCLC, small cell lung cancer; STS, soft tissue sarcoma; HCC, hepatocellular carcinoma

Tumor type

Lines of prior anticancer therapies

Body surface area

Time from diagnosis to first infusion

Time from last progressive disease to first infusion

Time to progression of last prior therapy

Sites of disease at baseline

Agents of prior anticancer therapies

Pharma Mar S.A.

PM01183

All participants who received at least one complete cycle study treatments without Primary G-CSF Prophylaxis

Patients Without Primary G-CSF Prophylaxis

All participants who received at least one complete cycle study treatments with Primary G-CSF Prophylaxis

Patients With Primary G-CSF Prophylaxis

Fifty-seven of the 61 patients treated in this cohort without primary G-CSF prophylaxis were evaluable for DLTs Eleven of the 12 patients treated with primary G-CSF prophylaxis in this cohort were evaluable for DLTs.

Maximum Tolerated Dose (MTD)

Fifty-seven of the 61 patients treated in this cohort without primary G-CSF prophylaxis were evaluable for DLTs

Recommended Dose (RD)

DOX 50 mg/m2 plus PM01183 3.5 mg FD without primary G-CSF prophylaxis

Cohort A: Dose I Without Primary G-CSF Prophylaxis

DOX 50 mg/m2 plus PM01183 3.0 mg FD without primary G-CSF prophylaxis

Cohort A: Dose II Without Primary G-CSF Prophylaxis

DOX 50 mg/m2 plus PM01183 3.5 mg FD and the Investigators and the Sponsor decided to amend the study's eligibility criteria, which originally did not establish a maximum age limit for the patients, in order to restrict accrual to patients aged between 18 and 75 years, both inclusive

Cohort A: Dose I Without Primary G-CSF Proph and Age Limit

DOX 50 mg/m2 plus PM01183 4.0 mg FD without primary G-CSF prophylaxis

Cohort A: Dose III Without Primary G-CSF Prophylaxis

DOX 50 mg/m2 plus PM01183 5.0 mg FD without primary G-CSF prophylaxis

Cohort A: Dose IV Without Primary G-CSF Prophylaxis

DOX 50 mg/m2 plus PM01183 3.5 mg FD. Patients enrolled into this study were originally not allowed to receive primary G-CSF prophylaxis.

However, the finding of dose-limiting febrile neutropenia in two patients treated at dose level I (DOX 50 mg/m2 plus PM01183 3.5 mg FD) in the present study suggested that increasing doses of the DOX/PM01183 combination might require primary G-CSF prophylaxis to decrease the risk of febrile neutropenia. Therefore, a separate dose escalation was established to define the MTD and the RD of the DOX/PM01183 combination with compulsory primary G-CSF prophylaxis

Cohort A: Dose I With Primary G-CSF Prophylaxis

DOX 50 mg/m2 plus PM01183 4.0 mg FD Patients enrolled into this study were originally not allowed to receive primary G-CSF prophylaxis.

However, the finding of dose-limiting febrile neutropenia in two patients treated at dose level I (DOX 50 mg/m2 plus PM01183 3.5 mg FD) in the present study suggested that increasing doses of the DOX/PM01183 combination might require primary G-CSF prophylaxis to decrease the risk of febrile neutropenia. Therefore, a separate dose escalation was established to define the MTD and the RD of the DOX/PM01183 combination with compulsory primary G-CSF prophylaxis

Cohort A: Dose III With Primary G-CSF Prophylaxis

DOX 50 mg/m2 plus PM01183 5.0 mg FD Patients enrolled into this study were originally not allowed to receive primary G-CSF prophylaxis.

However, the finding of dose-limiting febrile neutropenia in two patients treated at dose level I (DOX 50 mg/m2 plus PM01183 3.5 mg FD) in the present study suggested that increasing doses of the DOX/PM01183 combination might require primary G-CSF prophylaxis to decrease the risk of febrile neutropenia. Therefore, a separate dose escalation was established to define the MTD and the RD of the DOX/PM01183 combination with compulsory primary G-CSF prophylaxis

Cohort A: Dose IV With Primary G-CSF Prophylaxis

DOX \[mg/m2\] plus PM01183 \[mg/m2\] Patient accrual into Cohort B started after the RD for the DOX/PM01183 combination had been defined in Cohort A. The dose evaluated in Cohort B was based on this RD, but the DOX dose was decreased to 40 mg/m2 and the PM01183 dose was changed to a BSA-based dose of 2.0 mg/m2 in order to improve the feasibility of this combination in patients with SCLC treated as second-line therapy and in patients with endometrial cancer. In accordance with the findings obtained in Cohort A, no patients in Cohort B received primary G-CSF prophylaxis.

Cohort B: DOX [mg/m2] Plus PM01183 [mg/m2]

Patients evaluable for the primary endpoint (evaluable for DLT): 5 patients were not evaluable in Cohort A and 1 patient in Cohort B.

Number of Participants With Dose-limiting Toxicities

DOX: 50 mg/m² q3wk immediately followed by PM01183. The dose escalation scheme was: 3.0, 3.5, 5.0, 6.0, 7.0 mg FD

lurbinectedin (PM01183): lurbinectedin (PM01183) is presented as powder for concentrate for solution for infusion with two strengths, 1-mg and 4-mg vials.

Doxorubicin: Commercially available presentations of vials containing doxorubicin will be provided as appropriate.

Patients with SCLC 2nd line received the following on Day 1 q3wk (three weeks = one treatment cycle), administered: DOX 40 mg/m2 immediately followed by PM01183: 2.0 mg/m2.

lurbinectedin (PM01183): lurbinectedin (PM01183) is presented as powder for concentrate for solution for infusion with two strengths, 1-mg and 4-mg vials.

Doxorubicin: Commercially available presentations of vials containing doxorubicin will be provided as appropriate.

Patients with endometrial cancer received the following on Day 1 q3wk (three weeks = one treatment cycle), administered: DOX 40 mg/m2 immediately followed by PM01183: 2.0 mg/m2.

lurbinectedin (PM01183): lurbinectedin (PM01183) is presented as powder for concentrate for solution for infusion with two strengths, 1-mg and 4-mg vials.

Doxorubicin: Commercially available presentations of vials containing doxorubicin will be provided as appropriate.

Cohort A: 1 patient of 73 was not evaluable: extensive bone marrow involvement

Best Overall Tumor Response

Cohort A: 26 patients showed response to treatment Events: 26 (100.0%) Cohort B SCLC: 10 patients showed response to treatment Events: 10 (100.0%) Cohort B: Endometrial: 8 patients showed response to treatment Events: 4 (50.0%)

Duration of Response

Cohort A: 1 patient was not evaluable: extensive bone marrow involvement Events: 66 (91.7%) Cohort B: SCLC Events: 28 (100.0%) Cohort B: Endometrial: Events: 14 (73.7%)

Progression-free Survival

Cohort A: Events: 15 (20.5%); Cohort B: SCLC: Events: 22 (78.6%); Cohort B: Endometrial Events: 11 (57.9%)

Overall Survival

Patients with SCLC 2nd line received the following on Day 1 q3wk (three weeks = one treatment cycle), administered: DOX 40 mg/m2 immediately followed by PM01183: 2.0 mg/m2.

lurbinectedin (PM01183): lurbinectedin (PM01183) is presented as powder for concentrate for solution for infusion with two strengths, 1-mg and 4-mg vials.

Doxorubicin: Commercially available presentations of vials containing doxorubicin will be provided as appropriate.

SCLC, small cell lung cancer

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study Escalating Doses of PM01183 in Combination With Fixed Doxorubicin in Patients With Specific Advanced Unresectable Solid Tumors	NCT01970540	Endometrial Ade... Neuroendocrine ... Small-cell Lung...	lurbinectedin (... Doxorubicin	18 Years - 75 Years	PharmaMar
Study Escalating Doses of PM01183 in Combination With Fixed Doxorubicin in Patients With Specific Advanced Unresectable Solid Tumors	NCT01970540	Endometrial Ade... Neuroendocrine ... Small-cell Lung...	lurbinectedin (... Doxorubicin	18 Years - 75 Years	PharmaMar

Spots Global Cancer Trial Database for endometrial adenocarcinomas