Know Cancer

forgot password

A Randomized, Double-blind, Placebo Controlled, Multicenter Phase II Study to Assess the Efficacy and Safety of Sorafenib Added to Standard Treatment With Topotecan in Patients With Platinum-resistant Recurrent Ovarian Cancer

Phase 2
18 Years
Open (Enrolling)
Ovarian Cancer

Thank you

Trial Information

A Randomized, Double-blind, Placebo Controlled, Multicenter Phase II Study to Assess the Efficacy and Safety of Sorafenib Added to Standard Treatment With Topotecan in Patients With Platinum-resistant Recurrent Ovarian Cancer

Ovarian cancer continues to be a leading cause of cancer-related deaths in women and is the
leading cause of deaths attributed to gynecologic malignancies. Because ovarian cancer is
usually asymptomatic in its early stages, the disease often has spread outside of the pelvic
region at the time of diagnosis and requires debulking surgery followed by systemic
chemotherapy. First-line chemotherapy involves platinum-based treatments, including the
widely adopted regimens of cisplatin/paclitaxel, carboplatin/paclitaxel, and single-agent
carboplatin. Although these regimens yield relatively satisfactory tumor response rates, the
majority of patients experience disease recurrence and receive additional treatments. For
such patients, a number of antitumor agents with novel mechanisms of action (topotecan,
gemcitabine, pegylated liposomal doxorubicin, docetaxel, etoposide) have been applied, in
addition to retreatment with platinum, with the goal of re-establishing remission or disease
control, minimizing disease-related symptoms, improving quality of life, and extending
patient survival. Of these agents, topotecan (Hycamtin®; GlaxoSmithKline) is one of the
best-characterized agents in the recurrent setting.

Topotecan is an S-phase 1-dependent cytotoxic agent that targets the topoisomerase I enzyme
and exhibits broad activity in solid tumors and is approved for the treatment of recurrent
ovarian cancer in US and in most western countries.

Data from preclinical and clinical studies reported in the last 2 years demonstrate the
importance of several proangiogenic factors in the tumorigenesis and prognosis of ovarian
cancer, suggesting possible new targets for antiangiogenic therapy. Once-daily oral
treatment with Sorafenib produces broad spectrum antitumor efficacy in preclinical tumor
models including also xenograft models of ovarian carcinoma. Preliminary antitumor activity
has been reported in single ovarian cancer patients in several phase I and phase II studies.

Most promising strategy in the therapy of advanced and recurrent ovarian cancer seems to be
the combination of cytotoxic agents and targeted therapies. Furthermore an oral therapy to
achieve and maintain long term tumor control seems to be very attractive.

Therefore Sorafenib and Topotecan would make a rational therapeutic strategy for combination
in recurrent ovarian cancer.

Inclusion Criteria:

1. Patients with histologically confirmed epithelial ovarian cancer, primary peritoneal
carcinomatosis or fallopian tube cancer

2. Patients must have platinum resistant (relapse-free interval < 6 months of a
platinum-containing primary or secondary therapy) or platinum refractory (progression
during primary or secondary platinum treatment) disease defined by measurable disease
according to RECIST or elevated CA-125 level according the GCIG-criteria.

Definition of relapse: Demonstration of measurable or non-measurable tumour according
to RECIST criteria by an imaging procedure (where applicable before relapse surgery)
or increase in the tumour marker CA-125 to twice the upper laboratory value of normal
for the hospital or histological confirmation of tumour relapse by biopsy or surgery.

3. No more than 2 prior treatment regimens for recurrent epithelial ovarian cancer.

4. Elevated CA-125-value before study entry in order to assess the response according
the GCIG-criteria (see below). Patients without elevated CA-125 may be enrolled if
they show a measurable or not-measurable disease (according RECIST) evaluated by
imaging techniques (measurable disease - at least one unidimensionally measurable
lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan) or
histologically or cytologically confirmed relapse

5. ECOG Performance Status of 0 or 1

6. ≥ 18 years age

7. The patient must be recovered from a prior operation. The operation must be performed
at least 4 weeks prior to start of study drug,

8. Adequate bone marrow, liver and renal function as assessed by the following
laboratory requirements to be conducted within 7 days prior to screening

- Hemoglobin ≥ 9.0 g/dl

- Leucocyte count ≥ 3.000/micro liter

- Absolute neutrophil count (ANC) major than 1.500/micro liter

- Platelet count ≥ 100.000/micro liter

- PT-INR/PTT < 1.5 x upper limit of normal [Patients who are being therapeutically
anticoagulated with an agent such as coumadin or heparin will be allowed to
participate provided that no prior evidence of underlying abnormality in these
parameters exists].

- Total bilirubin < 1,0 times the upper limit of normal

- ALT and AST < 2,5 x upper limit of normal (< 5 x upper limit of normal for
patients with liver involvement of their cancer); Alkaline phosphatase < 4 x ULN

- Calculated creatinine clearance ≥ 50 ml/min or serum creatinine ≤ 1,2 x upper
limit of institutional values (according to Cockcroft and Gault)

9. Life expectancy of at least 12 weeks

10. Signed and dated written informed consent before the start of specific protocol

Exclusion Criteria:

1. History of cardiac disease: congestive heart failure >NYHA class 2; active coronary
artery disease (CAD) or myocardial infarction within the past 6 months (MI more than
6 months prior to study entry is allowed); cardiac arrhythmias requiring
anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled
arterial hypertension with systolic blood pressure >160 mmHg or diastolic blood
pressure > 90 mm Hg despite optimal treatment

2. Previous or concurrent cancer that is distinct in primary site or histology from the
cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal
cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively
treated > 5 years prior to study entry

3. Prior radiological or clinical evidence of CNS metastases including previously
treated, resected, or asymptomatic brain lesions or leptomeningeal involvement by
head CT scan or MRI

4. Known or suspected hypersensitivity reaction to topotecan or any ingredient of
topotecan or sorafenib or any ingredient of sorafenib

5. Active clinically serious infections (> grade 2 NCI-CTC version 3.0)

6. History of HIV infection or chronic hepatitis B or C

7. History of organ allograft

8. Patients with history of colon perforation

9. Patients with history of colitis or neutropenia colitis

10. Patients with evidence or history of bleeding diathesis

11. Serious non healing wound, fracture or ulcer

12. Patients undergoing renal dialysis

13. Patients unable to swallow oral medications

14. Significant disease which, in the investigator's opinion, would exclude the patient
from the study

15. Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results

16. Patients with seizure disorder requiring medication (such as steroids or

17. Medical or psychological conditions that would not permit the subject to complete the
study or sign informed consent

18. Any condition that is unstable or could jeopardize the safety of the patient and
their compliance in the study

19. Legal incapacity or limited legal capacity

20. Participation in another clinical study with experimental therapy within the 30 days
before start of treatment

21. Subjects housed in an institution on official or legal orders.

Excluded therapies and medications, previous and concomitant:

22. Patients with prior therapy containing topotecan

23. Patients with prior therapy containing Avastin or other VEGFR TK1

24. Any other anticancer chemotherapy or immunotherapy or investigational drug therapy
outside of this trial during the study or within 4 weeks prior to study entry.

25. Radiotherapy during study or within 4 weeks prior to start of study drug and prior
radiotherapy of > 25% of the bone marrow (exception: palliative radiotherapy of
non-target lesions or pain therapy or local bone irradiation)

26. Autologous bone marrow transplant or stem cell rescue within 4 months of study

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Primary objective: Determination of the progression-free survival (PFS) of patients treated with topotecan and sorafenib versus topotecan and placebo

Outcome Description:

The primary target value of this study is the comparison of the median progression-free survival time between the two study arms. Progression-free survival time (PFS) of a patient is defined as the time in months from start of the first therapy cycle until PD or death is observed

Outcome Time Frame:

18 months

Safety Issue:


Principal Investigator

Jalid Sehouli Sehouli, Professor

Investigator Role:

Principal Investigator

Investigator Affiliation:

Charité Campus Virchow-Klinikum, Berlin


Germany: Federal Institute for Drugs and Medical Devices

Study ID:

TRIAS 2009



Start Date:

January 2010

Completion Date:

December 2013

Related Keywords:

  • Ovarian Cancer
  • Ovarian Neoplasms