A Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or Unselected Metastatic Breast Cancer

Study Overview
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Brief Summary
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A Clinical Trial of PM01183 in Metastatic Breast Cancer to assess the antitumor activity of PM01183 ,to evaluate whether the presence of a known germline mutation in BRCA 1/2 predicts response to PM01183 in Metastatic Breast Cancer (MBC) patients, to evaluate the safety profile of this PM01183 to analyze the pharmacokinetics (PK) and PK/PD (pharmacokinetic/pharmacodynamic) correlations and to evaluate the pharmacogenomic (PGx) expression profile in tumor samples.

Detailed Description
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A Multicenter Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or Unselected Metastatic Breast Cancer to assess the antitumor activity of PM01183 in terms of overall response rate (ORR), duration of response (DR),clinical benefit [ORR or stable disease lasting over three months (SD > 3 months)], progression free survival (PFS), and one-year overall survival (1y-OS) and to evaluate whether the presence of a known germline mutation in BRCA 1/2 predicts response to PM01183 in MBC patients, to explore the activity of PM01183 in specific breast cancer subpopulations according to hormonal receptor status, HER-2 overexpression, number and/or type of prior therapies, or according to other available histological/molecular classifications, to evaluate the safety profile of this PM01183 administration schedule [Day 1 every three weeks (q3wk)] in this patient population, to analyze the pharmacokinetics (PK) of PM01183 in this patient population, to explore PK/PD (pharmacokinetic/ pharmacodynamic) correlations, if applicable and to evaluate the pharmacogenomic (PGx) expression profile of selected putative markers potentially predictive of response to PM01183, in tissues from tumor samples.

Official Title
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A Multicenter Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or Unselected Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: PM01183


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women ≥ 18 and ≤ 75 years of age. Voluntary signed informed consent form (ICF). Proven diagnosis of metastatic breast cancer (MBC). At least one, but no more than three, prior chemotherapy regimens for MBC. Patients with known HER-2 overexpressing MBC must have failed at least one prior trastuzumab-containing regimen for metastatic disease. Disease evaluable for response by specific appropriate criteria. No or minimal disease-related symptoms not affecting patient daily activities. Adequate major organ function (normal or minimal alteration in liver, kidney, hematological, metabolic and cardiac function) Wash out periods prior to Day 1 of Cycle 1: At least three weeks since the last chemotherapy (six weeks in some particular cases) and At least four weeks since the last radiotherapy (RT) > 30 Gy) and At least one week since the last hormonal therapy and At least two weeks since the last biological/investigational therapy Minimal or no ongoing toxicity from immediately prior therapy according to specific appropriate criteria. Mild ongoing toxicity is allowed in case of alopecia, skin toxicity, fatigue and/or finger numbness or tumbling. Patients of child-bearing potential must agree to use a medically approved contraception method until at least six weeks after the last study drug administration. Known deleterious germline mutation of BRCA1/2 (Patients in Cohorts A and A1) Prior treatment with PARP inhibitors (Patients in Cohort A1) Exclusion Criteria: Prior treatment with PM01183 or trabectedin. Extensive prior RT. Prior or concurrent malignant disease unless cured for more than five years. Exceptions are breast cancer in the other breast. Uncommon or rare subtypes of breast cancer. Symptomatic or progressive brain metastases. Bone-limited and exclusively metastases. Relevant diseases or clinical situations which may increase patient's risk: History of cardiac disease. Moderate breathing difficulties or oxygen requirement Active uncontrolled infection. Unhealed wound or presence of any external drainage. Chronically active viral hepatitis. Immunocompromised patients, including those known to be infected by human immunodeficiency virus (HIV). Known muscular disease or functional alteration Pregnant or breastfeeding women. Impending need for immediate RT for symptomatic relief. Limitation of the patient's ability to comply with the treatment or to follow-up the protocol.

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

Sexes Eligible for Study
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Female

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: PM01183<br> | Drug: PM01183<br>* PM01183 drug product (DP) is presented as a lyophilized powder for concentrate for solution for infusion with two strengths: 1 mg/vial and 4 mg/vial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | The overall response rate is defined as the percentage of patients with a confirmed response, either complete response (CR) or partial response (PR), according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1. Per RECIST v1.1 for target lesions and assessed by MRI: CR, Disappearance of all target lesions; PR >=30% decrease in the sum of the longest diameter of target lesions. | Minimum 10-12 months if negative results and up to 26-28 months if study is to be complete the targeted enrollment | 
| Overall Response | Overall Response Rate (ORR) in the population evaluable for efficacy according to RECIST v.1.1. ORR was defined as the percentage of patients with a confirmed response, either CR or PR, according to the RECIST v.1.1 for target lesions and assessed by MRI: CR, complete response: Disappearance of all target lesions; PD, progressive disease: 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; PR, partial response: >=30% decrease in the sum of the longest diameter of target lesions; SD, stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; TF, treatment failure. | Minimum 10-12 months if negative results and up to 26-28 months if study is to be complete the targeted enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Duration of response (DoR), defined as the time between the date when the response criteria (PR or CR, whichever was first reached) were fulfilled to the first date when disease progression (PD), recurrence or death was documented. According to the RECIST v.1.1 for target lesions and assessed by MRI: CR, complete response: Disappearance of all target lesions; PD, progressive disease: 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; PR, partial response: >=30% decrease in the sum of the longest diameter of target lesions. | Minimum 10-12 months if negative results and up to 26-28 months if study is to be complete the targeted enrollment | 
| Duration of Response Rate at 6 Months | Duration of response (DoR), defined as the time between the date when the response criteria (PR or CR, whichever was first reached) were fulfilled to the first date when disease progression (PD), recurrence or death was documented. According to the RECIST v.1.1 for target lesions and assessed by MRI: CR, complete response: Disappearance of all target lesions; PD, progressive disease: 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; PR, partial response: >=30% decrease in the sum of the longest diameter of target lesions. | Time between the response criteria date and the date when disease progression, recurrence or death was documented, up to 6 months | 
| Duration of Response Rate at 12 Months | Duration of response (DoR), defined as the time between the date when the response criteria (PR or CR, whichever was first reached) were fulfilled to the first date when disease progression (PD), recurrence or death was documented. According to the RECIST v.1.1 for target lesions and assessed by MRI: CR, complete response: Disappearance of all target lesions; PD, progressive disease: 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; PR, partial response: >=30% decrease in the sum of the longest diameter of target lesions. | Time between the response criteria date and the date when disease progression, recurrence or death was documented, up to 12 months | 
| Clinical Benefit Rate | Clinical benefit, defined as the percentage of patients with ORR or SD lasting over three months (SD >3 months). The overall response rate is defined as the percentage of patients with a confirmed response, either complete response (CR) or partial response (PR), according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1. Per RECIST v1.1 for target lesions and assessed by MRI: CR, Disappearance of all target lesions; PR >=30% decrease in the sum of the longest diameter of target lesions. SD, stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | Minimum 10-12 months if negative results and up to 26-28 months if study is to be complete the targeted enrollment | 
| Progression-free Survival (PFS) | Progression-free survival (PFS) is defined as the period of time from the date of first infusion to the date of progression disease, death (due to any cause), or last tumor evaluation. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 36 months | 
| Progression-free Survival at 3 Months | Progression-free survival (PFS), defined as the period of time from the date of first infusion to the date of PD, death (due to any cause), or last tumor evaluation. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Time from the date of first infusion to the date of PD, death (due to any cause), or last tumor evaluation, up to 3 months | 
| Progression-free Survival at 6 Months | Progression-free survival (PFS), defined as the period of time from the date of first infusion to the date of PD, death (due to any cause), or last tumor evaluation. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Time from the date of first infusion to the date of PD, death (due to any cause), or last tumor evaluation, up to 6 months | 
| Progression-free Survival at 12 Months | Progression-free survival (PFS), defined as the period of time from the date of first infusion to the date of PD, death (due to any cause), or last tumor evaluation. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Time from the date of first infusion to the date of PD, death (due to any cause), or last tumor evaluation, up to 12 months | 
| Overall Survival (OS) | Overall survival (OS) will be defined as time from the date of first infusion to the date of death or last contact | 36 months | 
| Overall Survival Rate at 12 Months | Overall survival (OS), defined as the time from the date of first infusion to the date of death or last contact | Time from the date of first infusion to the date of death or last contact, up to 12 months | 
| Overall Survival Rate at 18 Months | Overall survival (OS), defined as the time from the date of first infusion to the date of death or last contact. | Time from the date of first infusion to the date of death or last contact, up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, PM01183, lurbinectedin, Pharma Mar