Safety and Efficacy of Quisinostat, a Histone Deacetylase Inhibitor, in Combination With Chemotherapy

1. Signed patient's information sheet and informed consent form to participate in the study.
2. Histological confirmed diagnosis of serous epithelial ovarian, primarily peritoneal or fallopian tube carcinoma.
3. Females aged ≥ 18 years.
4. Patients must have an ECOG status of 0 or 1.
5. Patients must have received only 1 prior line of platinum and Paclitaxel based chemotherapy.
6. Tumor progression observed not less than 1 month and no more than 6 months after completion of the planned number of cycles of first line platinum/Paclitaxel based chemotherapy (Carboplatin in the dose AUC5-6 or Cisplatin in the dose ≥ 75 mg/m2, in combination with paclitaxel for 6 q3-4 wk cycles) and indications for undergoing the second line chemotherapy.
7. The patients must have at least one measurable lesion according to RECIST 1.1 criteria.
8. Tissue block from archived material at diagnosis must be available and be submitted for predictive biomarker analysis.
9. Patient's ability to carry out visits and study procedures and to comply with the protocol.

10. Requirements for laboratory parameters determined below:

    Hematology: Absolute neutrophil count:

    Platelets:

    Hemoglobin: ≥ 1,500/mm3 (1.5 x 109 cells/L)

    • 100,000/mm3 (100 x 109 cells/L)
    • 9.0 g/dl Liver function: Total bilirubin: ≤ 1.5x upper limit of normal (ULN)

    Aspartate aminotransferase (AST) and alanine aminotransferase (ALT):

    Alkalinephosphatase:

    • 2.5x ULN, or ≤ 5.0 x ULN in the case of liver metastasis
    • 5.0 x ULN Renal function: Serum creatinine: ≤2 mg/dL Coagulation panel: Activated partial thromboplastin time (aPTT): ≤ 1.5 x ULN
11. The expected survival time not less than 6 months.
12. Women of childbearing potential (not sterile or in menopause less than 2 years) must be practicing an effective method of birth control during the whole period of the study and 6 months after the last administration of the investigational product. Effective methods include usage of a condom or diaphragm (barrier method) with spermicide.

Exclusion Criteria:

1. Patients previously treated with an HDAC inhibitor. Patients, who have been treated with Valproate for convulsions can be included, however only if the treatment has taken place > 30 days before the screening.
2. Have received treatment for ovarian cancer with any other prior chemotherapy than platinum (Carboplatin (AUC 5-6) or Cisplatin (≥ 75 mg/m2)) and paclitaxel (175-200 mg/m2) q3-4 wk for 6 cycles. Additional first line chemotherapy or prior treatment with additional investigational anticancer therapy is also an exclusion criterion.
3. Presence of specific toxicities of ≥ I grade, according to the NCI-CTCAE v.4.3, related to any prior anti-cancer therapy (excluding alopecia)
4. Patients with subsequent debulking operation (after first line chemotherapy) or radiotherapy due to the disease recurrence.
5. Patients who have undergone lower pelvis radiotherapy.
6. Patients with active or uncontrolled infection.
7. Patients with antibodies to human immunodeficiency virus (HIV), or hepatitis C virus (HCV), active hepatitis B virus (HBsAg).
8. History of other malignancies with the exception of basal cell carcinoma of the skin or cervical cancer in situ, that had undergone surgical removal or treatment within ≥ 5 years before the screening.
9. Patients with known cerebral metastases or clinical signs of cerebral metastases.
10. Have a history of severe hypersensitivity reaction to carboplatin, paclitaxel or agents within the histone deacetylase inhibitor group.
11. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess during the year prior to inclusion.

12. Clinically significant cardiovascular diseases including:

    • Myocardial infarction within 12 months before screening
    • Unstable angina within 12 months before screening
    • Congestive heart failure Class III or IV according to the New York Heart Association criteria (NYHA)
    • Clinically significant ventricular arrhythmia including ventricular tachycardia, ventricular fibrillation, history of cardiac arrest, atrioventricular block (Mobitz II or III), use of cardiostimulator
    • QTc interval > 470 ms (ECG) (calculated according to Fredericia formula), or a diagnosis of long QTc syndrome
    • Hypotension (systolic blood pressure \< 86 mm Hg) or bradycardia with a heart rate of \< 50 beats per minute (ECG) except when caused by medications (e.g. beta-blockers)
    • Uncontrolled arterial hypertension (systolic arterial pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg)
13. Pregnancy and lactation
14. Drug or alcohol abuse at the moment of screening or in the past which according to the opinion of the Investigator makes the patient unsuitable for participation in the study
15. Inability to read or write; inability to understand and comply with the procedures of the study protocol; failure to comply with the treatment, which, in opinion of the Investigator, may affect the results of the study or the patient's safety and prevent the patient from further participation in the study; any other associated medical or serious mental conditions that make the patient unsuitable for participation in the clinical study, limit the validity of informed consent or may affect the patient's ability to participate in the study