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 Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
122
lurbinectedin (PM01183) is presented as powder for concentrate for solution for infusion with two strengths, 1-mg and 4-mg vials.
Commercially available presentations of vials containing doxorubicin will be provided as appropriate.
Hospital Universitari Vall D'Hebron
Barcelona, Spain
Centro Oncológico Md Anderson International España
Madrid, Spain
Hospital Ramón Y Cajal
Madrid, Spain
Hospital Universitario Fundación Jiménez
Madrid, Spain
Hospital Universitario Madrid Sanchinarro
Madrid, Spain
Fundación Instituto Valenciano de Oncología
Valencia, Spain
UCLH (University College London Hospitals)
London, United Kingdom
Maximum Tolerated Dose (MTD)
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
Recommended Dose (RD)
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
Number of Participants With Dose-limiting Toxicities
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
Best Overall Tumor Response
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
Duration of Response
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
Progression-free Survival
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
Overall Survival
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
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