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

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

Prospective, open-label, dose-ranging, uncontrolled phase I study with escalating doses of PM060184 in combination with gemcitabine in selected patients with advanced solid tumors.

The study objectives are:

To determine the MTD and the RD of PM060184 in combination with gemcitabine in selected patients with advanced solid tumors.

To characterize the safety profile and feasibility of this combination in this study population.

To characterize the pharmacokinetics of this combination and to detect major drug-drug PK interactions.

To obtain preliminary information on the clinical antitumor activity of this combination.

Inclusion Criteria:

1. Voluntarily signed and dated written informed consent prior to any specific study procedure.

2. Age ≥ 18 years.

3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 1 (see APPENDIX 1).

4. Life expectancy ≥ 3 months.

5. 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.

6. 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.

7. 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.

8. 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.

9. Recovery to grade ≤ 1 from any AE derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or asthenia).

10. Left ventricular ejection fraction (LVEF) by echocardiography (ECHO) or multiplegated acquisition (MUGA) within normal range (according to institutional standards).

11. 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:

1. 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.

2. Symptomatic, progressive or corticosteroids-requiring documented brain metastases or leptomeningeal disease involvement.

3. 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.

4. Patients who have had RT in more than 35% of the bone marrow.

5. Treatment with any investigational product within 30 days before the first infusion.

6. Prior treatment with PM060184.

7. 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.

8. Known hypersensitivity to gemcitabine or any component of the formulation.