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

Time frame: During the first cycle of treatment, up to 28 days

Population: 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.

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.

Time frame: During the first cycle of treatment, up to 28 days

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

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.

Time frame: During the first cycle of treatment, up to 28 days

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

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.

Time frame: Tumor assessments were done every six weeks up to study completion

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

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.

Time frame: Time from the time measurement criteria are met for complete response, whichever is first recorded, until the first date in which progressive disease is objectively documented or the date of death, assessed up to 72 months

Population: 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%)

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

Time frame: Time from the date of first administration to the date of death (of any cause), assessed up to 72 months

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

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.

Time frame: Time from the date of first administration to the date of PD or death (of any cause), whichever came first, assessed up to 72 months

Population: 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%)