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

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.

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.