Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM060184 in Combination With Gemcitabine in Selected Patients With Advanced Solid Tumors

Inclusion Criteria

• Voluntarily signed and dated written informed consent prior to any specific study procedure.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 1 (see APPENDIX 1).
• Life expectancy ≥ 3 months.
• Patients with a histologically/cytologically confirmed diagnosis of advanced disease of any of the following tumors that progressed to standard therapy or for whom no standard therapy exists:
• Breast cancer non-candidate for hormone therapy alone.
• Epithelial ovarian cancer (including primary peritoneal disease and/or fallopian tube carcinomas and/or endometrial adenocarcinomas).
• Locally advanced or metastatic head and neck cancer.
• Non-small cell lung cancer (NSCLC).
• Germ cell tumors (GCTs).
• Biliary tract adenocarcinoma.
• Adenocarcinoma or carcinoma of unknown primary site (UKPS).
• Cervix carcinoma.
• Gastrointestinal stromal tumor (GIST).
• Urothelial cancer.
• Expansion cohort at the RD: All patients must have:
• Measurable disease according to RECIST v.1.1 (or Choi criteria and/or EORTC metabolic response criteria for solid tumors, in the case of GIST); or
• Evaluable disease by serum markers in the case of ovarian cancer [Gynecologic Cancer Intergroup (GCIG) specific criteria]; and
• Documented disease progression during or immediately after last therapy according to any of the aforementioned criteria.
• Wash-out periods: at least three weeks since the last anticancer therapy, including radiation therapy (RT) in more than 35% of the bone marrow; at least three weeks since the last biological/investigational therapy [excluding monoclonal antibodies (MAbs)]; at least four weeks since the last MAb-containing therapy; and at least six weeks since nitrosoureas and mitomycin C (systemic). In the case of hormonesensitive breast cancer progressing while on hormone therapy, the latter must be either stopped up to one week before or continued without changes during the trial.
• Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤ 7 days before inclusion in the study):
• Platelet count ≥ 100 x 109/l, hemoglobin ≥ 9.0 g/dl and ANC ≥ 1.0 x 109/l.
• AST and ALT ≤ 3.0 x ULN, independently of the presence of liver metastases.
• AP ≤ 2.5 x ULN (≤ 5 x ULN if disease-related).
• Total bilirubin ≤ 1.5 x ULN.
• International Normalized Ratio (INR) < 1.5 (except if patient is on oral anticoagulation therapy).
• Calculated creatinine clearance (CrCl) ≥ 50 ml/minute (using Cockcroft and Gault's formula; see APPENDIX 2).
• Albumin ≥ 2.5 g/dl.
• Recovery to grade ≤ 1 from any AE derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or asthenia).
• Left ventricular ejection fraction (LVEF) by echocardiography (ECHO) or multiplegated acquisition (MUGA) within normal range (according to institutional standards).
• Women of childbearing potential must have a negative serum or urine pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six weeks after discontinuation of treatment. Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and/or double barrier.

Exclusion Criteria

• Concomitant diseases/conditions:
• History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within last year.
• Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment.
• Known chronic active hepatitis or cirrhosis
• Active uncontrolled infection [i.e., antibiotic, antifungal or antiviral intervention indicated or surgical procedure (i.e., pleural or deep abscess drainage) conducted within 15 days prior to inclusion].
• Known human immunodeficiency virus (HIV) infection.
• Current or prior history of grade ≥ 2 peripheral sensory and/or motor neuropathy.
• Prior treatment with oxaliplatin.
• Limitation of the patient's ability to comply with the treatment or follow-up protocol.
• Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.
• Symptomatic, progressive or corticosteroids-requiring documented brain metastases or leptomeningeal disease involvement.
• Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding.
• Patients who have had RT in more than 35% of the bone marrow.
• Treatment with any investigational product within 30 days before the first infusion.
• Prior treatment with PM060184.
• Prior treatment with gemcitabine-containing therapy for advanced disease (adjuvant therapy is allowed, provided not more than six cycles were administered and relapse occurred more than six months after the last drug administration), and/or:
• Patients who have previously discontinued gemcitabine-containing regimens due to gemcitabine-related toxicity.
• Known hypersensitivity to gemcitabine or any component of the formulation.