Phase I Study of Lurbinectedin (PM01183) in Combination With Paclitaxel, With or Without Bevacizumab, in Selected Advanced Solid Tumors

Study Overview
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Brief Summary
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Clinical trial of PM01183 in combination with paclitaxel, with or without bevacizumab, in patients with solid tumors

Detailed Description
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Clinical trial to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of PM01183 in combination with weekly paclitaxel, with or without bevacizumab. Once a recommended dose is defined for the PM01183 and weekly paclitaxel combination, the feasibility of adding bevacizumab to this combination will be explored in a selected cohort of patients to characterize the safety profile and feasibility of this combination, to obtain preliminary information on antitumor activity, to obtain preliminary information on quality of life (QoL), to characterize the pharmacokinetics (PK) of this combination and to detect major drug-drug PK interactions and PK(pharmacokinetic)/PD(pharmacodynamic) correlation and to conduct an exploratory pharmacogenomic(PGx) analysis in patients with selected advanced solid tumors.

Official Title
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Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of Lurbinectedin (PM01183) in Combination With Weekly Paclitaxel, With or Without Bevacizumab, in Patients With Selected Advanced Solid Tumors

Conditions
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Breast Cancer, Ovarian Cancer, Gynecological Cancer, Head and Neck Carcinoma, Non-small Cell Lung Cancer, Small Cell Lung Cancer, Non-squamous Cell Lung Cancer

Intervention / Treatment
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* Drug: PM01183 + paclitaxel +/- bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily signed and dated written informed consent Age between 18 and 75 years old (both inclusive) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 1 Life expectancy ≥ 3 months. Patients with a histologically/cytologically confirmed diagnosis of advanced and/or unresectable disease of any of the following tumors: Breast cancer Epithelial ovarian cancer or gynecological cancer Head and neck squamous cell carcinoma Non-small cell lung cancer Small cell lung cancer Platinum-refractory germ-cell tumors. Adenocarcinoma or carcinoma of unknown primary site Adequate bone marrow, renal, hepatic, and metabolic function Recovery to grade ≤ 1 or to baseline from any Adverse Event (AE) derived from previous treatment (excluding alopecia of any grade). Pre-menopausal women must have a negative pregnancy test before study entry and agree to use a medically acceptable method of contraception throughout the treatment period and for at least six weeks after treatment discontinuation Exclusion Criteria: Prior treatment with PM01183 or weekly paclitaxel or nanoalbumin-paclitaxel Patients who have previously discontinued paclitaxel-based regimes due to drug related toxicity. Known hypersensitivity to bevacizumab or any component of its formulation Patients who have previously discontinued bevacizumab-containing regimes due to drug-related toxicity. More than three prior lines of chemotherapy Less than three months since last taxane-containing therapy. Wash-out period: Less than three weeks since the last chemotherapy-containing regimen Less than three weeks since the last radiotherapy dose Less than four weeks since last monoclonal antibody-containing therapy Concomitant diseases/conditions: Unstable angina, myocardial infarction, valvular heart disease, encephalopathy, ischemic attacks, hemorrhagic or ischemic cerebrovascular accident (CVA) or ongoing pulmonary embolism within last year, arrhythmia, hepatopathy, uncontrolled infection, hemoptysis or oxygen requiring dyspnea, known HIV infection, bleeding risk, muscular problems, peripheral neuropathy, Symptomatic or progressive brain metastases or leptomeningeal disease. Men or pre-menopausal women who are not using an effective method of contraception as previously described; actively breast feeding women. Patients who have pelvic irradiation with doses ≥ 45 Grays (Gy). History of previous bone marrow and/or stem cell transplantation. Confirmed bone marrow involvement

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>PM01183 + paclitaxel +/- bevacizumab | Drug: PM01183 + paclitaxel +/- bevacizumab<br>* PM01183: 1 mg and 4 mg vials. Powder for concentrate for solution for infusion paclitaxel: 6 mg/ml concentrate for solution for infusion bevacizumab: 25 mg/ml concentrate for solution for infusion Once a recommended dose is defined for the PM01183 and weekly paclitaxel combination, the feasibility of adding bevacizumab to this combination will be explored in a prospectively selected cohort of patients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | The MTD will be the lowest level at which one third or more evaluable patients experience a DLT in Cycle 1. DLTs are defined as AEs or laboratory abnormalities related to the study drugs occurred during Cycle 1. | The MTD was followed mainly during Cycle 1 through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (cycle duration: 3 weeks) | 
| Recommended Dose (RD) | The RD will be the highest DL explored with less than one third of the patients experiencing a DLT during Cycle 1. DLTs are defined as AEs or laboratory abnormalities related to the study drugs occurred during Cycle 1. | The RD was followed mainly during Cycle 1 through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (cycle duration: 3 weeks) | 
| Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | DLTs are defined as AEs or laboratory abnormalities related to the study drugs occurred during Cycle 1. | DLT was followed mainly during Cycle 1 through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (cycle duration: 3 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Tumor Response | Best overall response:Best response recorded from the start of the study treatment until the end of treatment Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to<10 mm Partial Response (PR):At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression) Stable Disease (SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum diameters while on study Treatment failure (TF):symptomatic deterioration or death due to progression | Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks) | 
| Progression-free Survival | Progression-free survival (PFS) was 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 had not occurred at the time of the analysis, the PFS was censored. | Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks) | 
| Duration of Response (DR) | Duration of response (DR) was defined as the time from the date when the response criteria (PR or CR, whichever was reached first) were fulfilled, to the first date when PD, recurrence or death was documented | Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks) | 
| Quality of Life (QoL) | Change from baseline to last cycle. European Organization for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL scale scores. The EORTC QLQ-C15-PAL is an abbreviated 15-item version of the EORTC QLQ-C30 (version 3.0) developed for palliative care. Wilcoxon signed ranks test repeat-measure analyses of variance were used to measure the change value from baseline value. Data has to be analysed following the corresponding EORTC manual http://www.eortc.be/qol/files/SCManualQLQ-C15-PAL.pdf and the overall quality of life assessment is contained in 0 to 100 where a higher value represents a better state. | Through study completion, an average of 5 cycles for PM1183 in cohort A and 9.5 cycles in cohort B were observed (1 cycle =3 weeks) |