Clinical trial NCT01525589: A Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or Unselected Metastatic Breast Cancer
Official title: A Multicenter Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or Unselected Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: Breast cancer
PM01183
lurbinectedin
Pharma Mar
Lead sponsor: PharmaMar
Sponsor class: INDUSTRY
First posted: 2012-02-03
Enrollment: 111
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Minimum 10-12 months if negative results and up to 26-28 months if study is to be complete the targeted enrollment
measure: Overall Response
timeFrame: Minimum 10-12 months if negative results and up to 26-28 months if study is to be complete the targeted enrollment
Secondary outcomes:
measure: Duration of Response
timeFrame: Minimum 10-12 months if negative results and up to 26-28 months if study is to be complete the targeted enrollment
measure: Duration of Response Rate at 6 Months
timeFrame: Time between the response criteria date and the date when disease progression, recurrence or death was documented, up to 6 months
measure: Duration of Response Rate at 12 Months
timeFrame: Time between the response criteria date and the date when disease progression, recurrence or death was documented, up to 12 months
measure: Clinical Benefit Rate
timeFrame: Minimum 10-12 months if negative results and up to 26-28 months if study is to be complete the targeted enrollment
measure: Progression-free Survival (PFS)
timeFrame: 36 months
measure: Progression-free Survival at 3 Months
timeFrame: 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
measure: Progression-free Survival at 6 Months
timeFrame: 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
measure: Progression-free Survival at 12 Months
timeFrame: 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
measure: Overall Survival (OS)
timeFrame: 36 months
measure: Overall Survival Rate at 12 Months
timeFrame: Time from the date of first infusion to the date of death or last contact, up to 12 months
measure: Overall Survival Rate at 18 Months
timeFrame: Time from the date of first infusion to the date of death or last contact, up to 18 months
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford Women's Cancer Center
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Weill Cornell Medical College - New York Presbyterian Hospital
state: New York
city: Philadelphia
country: United States
facility: Abramson Cancer Center - Hospital of the University of Pennsylvania at Perelman Center for Advanced Medicine
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: A Coruna
country: Spain
facility: Complexo Hospitalario Universitario A Coruña
state: A Coruña
city: Santiago de Compostela
country: Spain
facility: Complexo Hospitalario Universitario de Santiago
state: A Coruña
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
Study officials:
References:
citation: Fernandez-Teruel C, Lubomirov R, Fudio S. Population Pharmacokinetic-Pharmacodynamic Modeling and Covariate Analyses of Neutropenia and Thrombocytopenia in Patients With Solid Tumors Treated With Lurbinectedin. J Clin Pharmacol. 2021 Sep;61(9):1206-1219. doi: 10.1002/jcph.1886. Epub 2021 Jun 9.
citation: Cruz C, Llop-Guevara A, Garber JE, Arun BK, Perez Fidalgo JA, Lluch A, Telli ML, Fernandez C, Kahatt C, Galmarini CM, Soto-Matos A, Alfaro V, Perez de la Haza A, Domchek SM, Antolin S, Vahdat L, Tung NM, Lopez R, Arribas J, Vivancos A, Baselga J, Serra V, Balmana J, Isakoff SJ. Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy. J Clin Oncol. 2018 Nov 1;36(31):3134-3143. doi: 10.1200/JCO.2018.78.6558. Epub 2018 Sep 21.