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Phase II, Multicenter, Prospective, Single Arm, Open Labeled Clinical Trial Investigating Pazopanib, a Multi-targeted Tyrosine Kinase Inhibitor (TKI) of VEGFR-1, -2, -3, PDGFR-α and -β and c-Kit in Patients With Platinum-resistant Advanced Ovarian Cancer.

Phase 2
18 Years
Open (Enrolling)
Platinum-resistant Advanced Ovarian Cancer

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Trial Information

Phase II, Multicenter, Prospective, Single Arm, Open Labeled Clinical Trial Investigating Pazopanib, a Multi-targeted Tyrosine Kinase Inhibitor (TKI) of VEGFR-1, -2, -3, PDGFR-α and -β and c-Kit in Patients With Platinum-resistant Advanced Ovarian Cancer.

Ovarian cancer is considered a chemo-responsive neoplasm, with initial response rates to
systemic chemotherapy exceeding 80% when integrated with primary cytoreductive surgery
Despite this, over 50% of women diagnosed with epithelial ovarian cancer eventually go on to
die from their disease. Six major trials published over the past 15 years report that the
median PFS for patients with advanced disease ranges between 16 and 23 months while the
median OS lies between 31 and 65 months.The majority of patients who achieve a Complete
Response with first-line chemotherapy ultimately develop recurrent disease. These patients
can be subdivided into platinum-sensitive or platinum-resistant groups. In
platinum-sensitive patients, disease recurrence occurs more than 6 months after cessation of
initial platinum-containing chemotherapy. Platinum-based therapies are typically used to
retreat these patients, in light of clinically meaningful responses observed in these
patients following a second platinum-based treatment.Currently, there is no optimal
treatment strategy for platinum-resistant patients whose disease recurs within 6 months of
completing initial platinum-based chemotherapy.Despite a wide range of available treatments,
prolonged survival has not been shown in this setting, and ORR is generally less than 20%.
As resistant-disease is not curable, the goals of treatment for these patients include
palliation of symptoms and improvements in quality of life. Platinum-resistance is therefore
a significant clinical problem for which improved treatment regimens are needed. In this
regard, molecular targeted therapeutic agents herald a new era for cancer treatment. In the
setting of epithelial ovarian cancer, a growing body of evidence supports the use of
anti-angiogenic agents.Platinum-resistant ovarian cancer patients are often treated with
sequential lines of single-agent chemotherapy. Commonly used agents include topotecan,
pegylated liposomal doxorubicin (PLD), weekly paclitaxel and gemcitabine.Topotecan is
topoisomerase I inhibitor well established as therapy for recurrent ovarian cancer, with
demonstrated efficacy in platinum-resistant populations. PLD is licensed in the US and
Europe for use in ovarian cancer after failure of platinum chemotherapy and is recommended
by the NCCN as a treatment option in this setting. PLD and topotecan have been compared in a
Phase III study of 474 patients with tumours that were recurrent or refractory to
platinum-based chemotherapy. In the subgroup of patients with platinum-resistant tumours
treated with PLD (n=130), the ORR was 12.3%, and median PFS and OS were 2.1 and 8.2 months,
respectively. The 124 platinum-resistant patients who received topotecan achieved median PFS
and OS of 3.1 months and 9.5 months, respectively, which were not significantly different
from the PLD group. For platinum-resistant patients, outcomes were not significantly
different between treatment groups so whatever treatment option is acceptable.In a recent
study in platinum-resistant recurrent ovarian cancer patients, topotecan monotherapy showed
and ORR of 19% and 9% when used as conventional or weekly schedule, respectively.
Angiogenesis is known to play a critical role in the growth of ovarian tumours and may
represent an important target. For example, several studies have demonstrated that increased
microvessel density in primary ovarian tumours is associated with VEGF expression and
predicted worsened survival rates. Likewise, circulating VEGF levels were significantly
higher in ovarian cancer subjects with an advanced stage at diagnosis, poorly-differentiated
tumours, or increased levels of ascites as compared to subjects with an early stage,
well-differentiated tumour(s), and less ascites. Tumour-derived VEGF may play a role in
ascites formation. Angiogenesis has been shown to be a negative predictive factor for
overall survival and disease-free survival in women with advanced ovarian cancer 18.
Blockade or inhibition of VEGF (eg, using bevacizumab) or VEGFR (using TKIs) have been shown
to be effective in Phase II studies in ovarian cancer. For example, single-agent bevacizumab
has shown a 16-21% overall tumour response rate (ORR) in two studies of previously treated
patients with ovarian cancer.Pazopanib is a potent, multi-targeted tyrosine kinase inhibitor
(TKI) of VEGFR-1, -2, -3, PDGFR-α and -β and c-Kit. Pazopanib has shown evidence of
antitumor activity in clinical studies of ovarian cancer. VEG104450 is a Phase II study of
pazopanib in subjects with ovarian, fallopian tube, or primary peritoneal cancers who had
responded to first-line chemotherapy and who were at high risk of clinical recurrence (as
evidenced by rising CA-125 levels). 36 subjects were enrolled, of which 22 (61%) had a
sensitive platinum relapse and a previous chemotherapy regimen. Final results obtained
recently indicate the following:10 out of 36 (28%) subjects experienced a CA-125 response to
pazopanib with responses occurring shortly after start of pazopanib administration (median
time to response 29 days) with a median duration of response of 113 days 21.Taking into
account theses results, pazopanib is one of the promising antiangiogenic therapies to be
studied against ovarian cancer

Inclusion Criteria:

1. Subjects must provide written informed consent prior to performance of study-specific
procedures or assessments, and must be willing to comply with treatment and

2. Age ≥ 18 years

3. The patient has histologically or cytologically confirmed epithelial ovarian cancer,
primary peritoneal carcinoma, fallopian tube cancer

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

5. The patient has completed at least 4 CYCLES OF one and up to two platinum-containing
regimens (involving cisplatin or carboplatin),for the management of this condition.
Treatment may have included intraperitoneal therapy, consolidation or extended
therapy administered after surgical or nonsurgical assessment.

6. The patient must have a platinum-free interval of ≤ 6 months after the final dose of
primary or subsequent platinum-based therapy.

Patients must have platinum-resistant disease,(defined as progression within <6
months from completion of a minimum of 4 platinum therapy cycles. The date should be
calculated from the last administered dose of platinum therapy.

7. The patient has at least one unidimensionally measurable target lesion (≥ 20 mm or ≥
10 mm by spiral computed tomography [CT] or magnetic resonance imaging [MRI]), as
defined by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines V 1.1.

8. Previously archived tumor tissue from either the primary or metastatic tumor
(paraffin block or 10 unstained slides) should be collected prior to administration
of the first dose of study therapy and stored at a secure central laboratory.

9. Adequate organ system function

10. Women of child bearing potential should be using an effective method of contraception
(complete abstinence, any intrauterine device (IUD) with published data showing that
the lowest expected failure rate is < 1 % per year; or any other methods with
published data showing that the lowest expected failure rate is less than 1 % per
year) before entry into the study and throughout the same and for 6 months after
ending the study. Women of childbearing potential must have a negative test serum or
urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta human
chorionic gonadotropin [β-HCG]) within 7 days prior to randomization.

11. Able to swallow oral compound.

12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests and other study procedures.

Exclusion Criteria:

1. Other malignancy within the last 5 years, except for adequately treated carcinoma in
situ of the cervix or squamous carcinoma of the skin, or adequately controlled
limited basal cell skin cancer.

2. Previous treatment with >2 anticancer regimens for ovarian cancer

3. Prior treatment with any antiangiogenic treatment (i.e. Bevacizumab)

4. Patients with platinum-refractory disease defined as those patients progress during
platinum-based therapy.

5. History or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS
metastases, are asymptomatic, and have had no requirement for steroids or
anti-seizure medication for 6 months prior to first dose of study drug. Screening
with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging
[MRI]) is required only if clinically indicated or if the subject has a history of
CNS metastases.

6. Clinically significant gastrointestinal abnormalities that may increase the risk for
gastrointestinal bleeding including, but not limited to:

- Active peptic ulcer disease

- Known intraluminal metastatic lesion/s with risk of bleeding

- Inflammatory bowel disease (e.g. ulcerative colitis, Chrohn's disease), or other
gastrointestinal conditions with increased risk of perforation

- History of bowel obstruction, including sub-occlusive disease, related to the
underlying disease and history of abdominal fistula, gastrointestinal
perforation, or intra-abdominal abscess within 28 days prior to beginning study

- active episodes of intestinal pseudo-obstruction

7. Clinically significant gastrointestinal abnormalities that may affect absorption of
investigational product including, but not limited to:

- Malabsorption syndrome

- Major resection of the stomach or small bowel.

- Grade 3 diarrhoea

8. Presence of uncontrolled infection.

9. Corrected QT interval (QTc) > 480 msecs using Bazett's formula

10. History of any one or more of the following cardiovascular conditions within the past
6 months:

- Cardiac angioplasty or stenting

- Myocardial infarction

- Unstable angina

- Coronary artery bypass graft surgery

- Symptomatic peripheral vascular disease

- Class II, III or IV congestive heart failure, as defined by the New York Heart
Association (NYHA

11. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg
or diastolic blood pressure (DBP) of ≥ 90mmHg] instead an anti-hypertensive

Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior
to study entry. BP must be assessed using the following recommendations:

Once a patient has had an elevated blood pressure reading (> 140/80mmHg) this should
be confirmed with another measurement, done locally if possible, either by the
patients local doctor, or by home monitoring if available. Patients should continue
to have their blood pressure monitored, at least weekly, until it becomes controlled
(i.e. ≤ 140/80mmHg on 2 separate occasions, at least one week apart).
Anti-hypertension medication changes, such as initiation of therapy, dose increases
of existing therapies, or addition of other anti-hypertensive agents, should be done
if the blood pressure remains high at 2 consecutive readings, at least 24 hours
apart. Please, refer to guidance regarding the management of hypertension for the
patient's local doctor for further information.

12. History of cerebrovascular accident including transient ischemic attack (TIA),
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6

Note: Subjects with recent DVT who have been treated with therapeutic
anti-coagulating agents for at least 6 weeks are eligible

13. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
placement not considered to be major).

14. Prior minor surgery within 7 days prior to first dose of study drug

15. Evidence of active bleeding or bleeding diathesis.

16. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels

17. Hemoptysis within 6 weeks of first dose of study drug.

18. Any serious and/or unstable pre-existing medical, psychiatric, or other condition
that could interfere with subject's safety, provision of informed consent, or
compliance to study procedures.

19. Unable or unwilling to discontinue use of prohibited medications for at least 14 days
or five half-lives of a drug (whichever is longer) prior to the first dose of study
drug and for the duration of the study.

20. Treatment with any of the following anti-cancer therapies:

radiation therapy, surgery or tumor embolization within 14 days prior to the first
dose of pazopanib OR chemotherapy, immunotherapy, biologic therapy, investigational
therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is
longer) prior to the first dose of pazopanib

21. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
progressing in severity, except alopecia.

22. Women who are pregnant or breast-feeding

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The primary efficacy endpoint for this study is Clinical Benefit Rate

Outcome Description:

Clinical Benefit Rate defined as the percentage of patients with Complete Response plus Partial Response plus Stable Disease ≥ 8 weeks by RECIST v1.1

Outcome Time Frame:

average 30 months

Safety Issue:


Principal Investigator

Ana Oaknin, MD

Investigator Role:

Study Chair

Investigator Affiliation:

H Vall d'Hebron


Spain: Spanish Agency of Medicines

Study ID:




Start Date:

December 2010

Completion Date:

December 2015

Related Keywords:

  • Platinum-resistant Advanced Ovarian Cancer
  • platinum
  • resistant
  • advanced
  • ovarian
  • cancer
  • Ovarian Neoplasms