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A Phase II Randomized Multicentre Study Evaluating the Efficacy of Pazopanib+Best Supportive Care (BSC) Versus BSC Alone in Metastatic and/or Locally Advanced Unresectable GIST, Resistant to Imatinib and Sunitinib

Phase 2
18 Years
90 Years
Open (Enrolling)

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Trial Information

A Phase II Randomized Multicentre Study Evaluating the Efficacy of Pazopanib+Best Supportive Care (BSC) Versus BSC Alone in Metastatic and/or Locally Advanced Unresectable GIST, Resistant to Imatinib and Sunitinib

Complete resection, with or without associated anticancer therapy, is the standard treatment
of GIST. Even though the prognosis of advanced GIST has been tremendously improved by the
introduction of tyrosine kinase inhibitors (TKI-imatinib, sunitinib...), the vast majority
of patients will develop secondary resistance to these agents. The therapeutic options for
patients with advanced GIST with resistance (or intolerance) to imatinib and sunitinib
remain very limited. Some new molecules are currently being evaluated in patients with
metastatic or locally advanced - imatinib-resistant disease. Nilotinib, for instance, has
been evaluated in phase I/II trials and compassionate use programs with a median
progression-free survival (PFS) close to 3 months and a median overall survival close to 8.5
months. A phase III trial comparing nilotinib vs. best supportive care (BSC) +/- imatinib or
sunitinib (investigators choice) has just been completed and results are pending. Another
molecule, Sorafenib, has been evaluated in 4th line treatment in compassionate use studies,
with a median PFS close to 5 months and a median overall survival of 10-13 months. There are
currently no recognized standard options after failure of 2nd line treatment, and the
recently updated guidelines from the NCCN or ESMO (2009) suggest the possible reintroduction
of TKI in an attempt to control the progression of sensitive cell clones.

Pazopanib is a broad spectrum TKI targeting KIT, PDGFR and VEGFR which has been tested in
phase II trials in advanced sarcomas and has demonstrated promising antitumor activity.
Whether pazopanib would be useful in patients with GIST is not known.

In the present study, we propose to analyze the antitumor activity of pazopanib in patients
with GIST refractory to imatinib and sunitinib. The drug will be tested against BSC in a
randomized setting, with possible crossing-over to the no-treatment arm.

Inclusion Criteria:

1. Age ≥ 18 years.

2. Histologically confirmed, unresectable, metastatic and/or locally advanced GIST.

3. Progression or intolerance after treatment with at least imatinib (400 mg and 600/800
mg/d) then sunitinib at either 50mg/d on a 4w/6w schedule or 37.5mg/d continuous
dosing. Intolerance is defined as documented grade 3 or higher toxicity requiring
treatment interruption as documented in patient record.

4. Measurable disease according to RECIST v1.1.

5. Performance status ≤ 2 (WHO).

6. Left Ventricular Ejection Fraction (LVEF) in accordance with local standards.

7. Adequate organ system functions as defined below:

- Haematologic parameters

- Absolute neutrophil count (ANC) ≥ 1.5 G/L

- Haemoglobin ≥ 9 g/dL

- Platelets ≥ 100 G/L

- Prothrombin time (PT) or international normalized ratio (INR) ≤ 1.2 X upper
limit of normal (ULN) NB: Subjects receiving anticoagulation therapy are
eligible if INR is stable and within the recommended range.

- Partial thromboplastin time (PTT) ≤ 1.2 X ULN

- Hepatic parameters

- Total bilirubin ≤ 1.5 X ULN

- AST and ALT ≤ 2.5 X ULN

- Renal parameters

- Serum creatinine ≤ 1.5 mg/dL (133 µmol/L) or, if greater than 1.5 mg/dL:
calculated creatinine clearance ≥ 50 mL/min

- Urine Protein to Creatinine ratio (UPC) < 1. If UPC ≥ 1, subjects must have
a 24-hour urine protein value <1g to be eligible.

- Biochemical parameters

- Kaliemia ≥ 1 X lower limit of normal (LLN)

8. a) Females of non-childbearing potential (i.e., physiologically incapable of becoming

b) Females of childbearing potential provided that they are not pregnant or
lactating, including any female who has had a negative serum pregnancy test within 2
weeks prior to the first dose of study treatment, preferably as close to the first
dose as possible, and who agrees to use adequate contraception.

9. Affiliation with a health insurance company.

10. Subjects must provide written informed consent

Exclusion Criteria:

1. Prior malignant disease (other than GIST) within 3 years prior to entry, with the
exception of in situ breast cell carcinoma or in situ carcinoma of the cervix or
basocellular carcinoma or spinocellular carcinoma or bladder neoplasm, treated at
least 6 months before and with no evidence of relapse.

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

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

- radiation therapy, surgery or tumour embolisation within 14 days prior to the
first dose of pazopanib OR

- chemotherapy, biological therapy or investigational therapy within 14 days or
five half-lives of a drug (whichever is longer) prior to the first dose of

The analgesic radiation therapy is allowed (the irradiated lesions won't be chosen as
target lesions during the evaluation)

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

5. Other uncontrolled severe medical conditions.

6. Presence of uncontrolled infection.

7. Clinically significant gastrointestinal abnormalities

- that may increase the risk for gastrointestinal bleeding.

- that may affect absorption of investigational product.

8. Poorly controlled hypertension [defined as systolic blood pressure (SBP) ≥ 140 mmHg
or diastolic blood pressure (DBP) ≥ 90 mmHg].

NB: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
study entry. BP must be re-assessed on two occasions at > 1 hour interval; on each of
these occasions, the mean (of 3 readings) SBP / DBP values from each BP assessment
must be <140/90 mmHg for the subject to be eligible to the study.

9. History of any cardiovascular pathology within the past 6 months.

10. Corrected QT interval (QTcB) > 480 msec using Bazett's formula.

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

NB: Subjects with recent DVT treated with therapeutic anti-coagulating agents at
least 6 weeks before inclusion are eligible.

12. 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 are not considered to be major).

13. Evidence of active bleeding or bleeding diathesis.

14. Haemoptysis within 8 weeks before inclusion.

15. Platelet transfusion in the past 7 days.

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

17. Concomitant bilirubin and AST/ALT elevations above ULN.

18. Treatment with anti-vitamin K (LMWH are allowed).

19. Inability or unwillingness to discontinue 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. Inability to swallow.

21. Pregnant or lactating woman

22. Impossibility to comply with protocol constraints

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Outcome Time Frame:

Within 16 months after the first inclusion, from the date of randomisation until the date of the first documented progression or death from any cause

Safety Issue:


Principal Investigator

Jean-Yves BLAY, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Centre Léon Bérard, LYON, FRANCE


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:




Start Date:

March 2011

Completion Date:

March 2014

Related Keywords:

  • GIST
  • GIST
  • Resistant
  • Pazopanib
  • Tyrosine kinase inhibitor
  • Best supportive care
  • Progression-free survival
  • Overall survival
  • Objective response rate
  • Best response
  • Tolerance profile
  • Gastrointestinal Stromal Tumors