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GISTPhase 2PAZOGISTNCT01323400

Efficacy of Pazopanib in Gastrointestinal Stromal Tumors (GIST)

A Phase 2 study testing Pazopanib in people with GIST, run by Centre Leon Berard at 13 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to evaluate the antitumor activity of pazopanib in patients with metastatic and/or locally advanced unresectable Gastrointestinal Stromal Tumors (GIST) resistant to imatinib and sunitinib. This is a phase II, randomized, multicentre study. Read more about this study

Who is it for?
Ages 18 to 90 years
Conditions the study is for
GIST
What is being tested?
Pazopanib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
81 participants
Where
13 sitesFrance
Study dates
Mar 2011to Feb 2016
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 90 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age ≥ 18 years.
  • Histologically confirmed, unresectable, metastatic and/or locally advanced GIST.
  • 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.
  • Measurable disease according to RECIST v1.1.
  • Performance status ≤ 2 (WHO).
  • Left Ventricular Ejection Fraction (LVEF) in accordance with local standards.
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  • 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)
  • a) Females of non-childbearing potential (i.e., physiologically incapable of becoming pregnant).
  • 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.
  • Affiliation with a health insurance company.
  • Subjects must provide written informed consent

Who cannot join

  • 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.
  • 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.
  • 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 pazopanib.
  • The analgesic radiation therapy is allowed (the irradiated lesions won't be chosen as target lesions during the evaluation)
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  • Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 followed and/or progressing in severity, except alopecia.
  • Other uncontrolled severe medical conditions.
  • Presence of uncontrolled infection.
  • Clinically significant gastrointestinal abnormalities
  • that may increase the risk for gastrointestinal bleeding.
  • that may affect absorption of investigational product.
  • 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.
  • History of any cardiovascular pathology within the past 6 months.
  • Corrected QT interval (QTcB) > 480 msec using Bazett's formula.
  • History of cerebrovascular accident, including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT), within the past 6 months.
  • NB: Subjects with recent DVT treated with therapeutic anti-coagulating agents at least 6 weeks before inclusion are eligible.
  • 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).
  • Evidence of active bleeding or bleeding diathesis.
  • Haemoptysis within 8 weeks before inclusion.
  • Platelet transfusion in the past 7 days.
  • Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
  • Concomitant bilirubin and AST/ALT elevations above ULN.
  • Treatment with anti-vitamin K (LMWH are allowed).
  • 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.
  • Inability to swallow.
  • Pregnant or lactating woman
  • Impossibility to comply with protocol constraints

Trial locations and contacts

13 sites in 1 country.

13 sites in 1 country

France13 sites

  • Institut Bergonié

    Bordeaux

  • Centre Georges François Leclerc

    Dijon

  • Centre Oscar Lambret

    Lille

  • Centre Léon Bérard

    Lyon, F-69008

  • Hôpital de la Timone

    Marseille

  • Institut Paoli Calmette

    Marseille

  • Centre Alexis Vautrin

    Nancy

  • Institut de Cancérologie de l'Ouest

    Nantes

  • Hôpital St Antoine

    Paris

  • Hôpital Tenon

    Paris

  • CHU de Reims

    Reims

  • Institut Cancerologie Neuwirth

    Saint-Priest-en-Jarez

  • Institut Gustave Roussy

    Villejuif

Other trials in France

About this study

Official title: 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

The purpose of this study is to evaluate the antitumor activity of pazopanib in patients with metastatic and/or locally advanced unresectable Gastrointestinal Stromal Tumors (GIST) resistant to imatinib and sunitinib. This is a phase II, randomized, multicentre study.

Read the detailed description

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.

Conditions
GIST
Being tested
Pazopanib, Best supportive care
Keywords
GIST, Resistant, Pazopanib, Tyrosine kinase inhibitor, Best supportive care, Progression-free survival, Overall survival, Objective response rate, Best response, Tolerance profile

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PazopanibDrug

    Pazopanib is administered orally at 800 mg/day (one dose every morning). A dose modification is possible in case of documented toxicity, according to specific algorithms.

  • Best supportive careOther

    Best supportive care according to the investigator's judgment (chemotherapy, immunotherapy, hormone therapy are not allowed).

    Non-targeted radiation therapy is tolerated, as antalgic strategy. Surgery is tolerated in case of emergency.

Study groups in NCT01323400
Study groupRoleWhat they receive
PazopanibExperimentalPazopanib (800 mg/day) + Best supportive care according to the investigator's judgement. Pazopanib treatment is started on the day after randomization until radiological progression according to RECIST or until documented toxicity. In case of radiological progression, pazopanib may be continued (if the investigator wishes so) if a clinical benefit (pain reduction, 1 point increase in performance status) is observed.
Receives: Drug: Pazopanib; Other: Best supportive care
Best supportive careOtherBest supportive care according to the investigator's judgment. Upon progression, compassionate treatment by pazopanib is possible according to eligibility criteria.
Receives: Other: Best supportive care

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-free survival

    Measured: 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

Secondary outcomes (8)

  1. Overall survival

    Measured: Within 16 months after the first inclusion, from the date of randomisation until the date of death from any cause

  2. Objective tumour response rate (RECIST v.1.1) at 4 months

    Measured: 4 months after randomisation

  3. Best response (RECIST v.1.1) obtained during the study

    Measured: Within 16 months after the first inclusion

  4. Tolerance profile (NCI-CTCAE v.4.0)

    Measured: Within 16 months after the first inclusion

  5. Pattern of progression-free survival in the different molecular subtypes

    Measured: 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

  6. Intra and inter-patient variability of the Cmin of pazopanib

    Measured: After 4 weeks, 10 weeks, 16 weeks of pazopanib treatment and at time of progression

  7. Progression-free survival in patients not randomly assigned to pazopanib, but receiving pazopanib on a compassionate basis after progression

    Measured: Within 16 months after the first inclusion, from the date of the first pazopanib administration until the date of the first documented progression or death from any cause

  8. Overall survival in patients not randomly assigned to pazopanib, but receiving pazopanib on a compassionate basis after progression

    Measured: Within 16 months after the first inclusion, from the date of the first pazopanib administration until the date of death from any cause

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Mar 2011 (estimated)
  2. Study startMar 2011
  3. Primary completionApr 2014
  4. Study completionFeb 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
81 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01323400
Sponsor's protocol ID
PAZOGIST
Acronym
PAZOGIST
Status last verified
Feb 2016
First submitted
10 Mar 2011
Last updated
25 Feb 2016
Results posted
No
Data monitoring committee
No
Individual data sharing
No

Publications

  • Blay JY, Bonvalot S, Casali P, Choi H, Debiec-Richter M, Dei Tos AP, Emile JF, Gronchi A, Hogendoorn PC, Joensuu H, Le Cesne A, McClure J, Maurel J, Nupponen N, Ray-Coquard I, Reichardt P, Sciot R, Stroobants S, van Glabbeke M, van Oosterom A, Demetri GD; GIST consensus meeting panelists. Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO. Ann Oncol. 2005 Apr;16(4):566-78. doi: 10.1093/annonc/mdi127.

    PubMed 15781488

  • Casali PG, Jost L, Reichardt P, Schlemmer M, Blay JY; ESMO Guidelines Working Group. Gastrointestinal stromal tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008 May;19 Suppl 2:ii35-8. doi: 10.1093/annonc/mdn080. No abstract available.

    PubMed 18456761

  • Demetri GD, Benjamin RS, Blanke CD, Blay JY, Casali P, Choi H, Corless CL, Debiec-Rychter M, DeMatteo RP, Ettinger DS, Fisher GA, Fletcher CD, Gronchi A, Hohenberger P, Hughes M, Joensuu H, Judson I, Le Cesne A, Maki RG, Morse M, Pappo AS, Pisters PW, Raut CP, Reichardt P, Tyler DS, Van den Abbeele AD, von Mehren M, Wayne JD, Zalcberg J; NCCN Task Force. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw. 2007 Jul;5 Suppl 2:S1-29; quiz S30.

    PubMed 17624289

  • Reichardt P, Blay JY, Mehren Mv. Towards global consensus in the treatment of gastrointestinal stromal tumor. Expert Rev Anticancer Ther. 2010 Feb;10(2):221-32. doi: 10.1586/era.09.171.

    PubMed 20131998

  • Montemurro M, Schoffski P, Reichardt P, Gelderblom H, Schutte J, Hartmann JT, von Moos R, Seddon B, Joensuu H, Wendtner CM, Weber E, Grunwald V, Roth A, Leyvraz S. Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib. Eur J Cancer. 2009 Sep;45(13):2293-7. doi: 10.1016/j.ejca.2009.04.030. Epub 2009 May 19.

    PubMed 19467857

  • Sleijfer S, Ray-Coquard I, Papai Z, Le Cesne A, Scurr M, Schoffski P, Collin F, Pandite L, Marreaud S, De Brauwer A, van Glabbeke M, Verweij J, Blay JY. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol. 2009 Jul 1;27(19):3126-32. doi: 10.1200/JCO.2008.21.3223. Epub 2009 May 18.

    PubMed 19451427

  • Freedman LS. Tables of the number of patients required in clinical trials using the logrank test. Stat Med. 1982 Apr-Jun;1(2):121-9. doi: 10.1002/sim.4780010204.

    PubMed 7187087

  • Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004 Sep 15;22(18):3813-25. doi: 10.1200/JCO.2004.05.140.

    PubMed 15365079

  • Mazur MT, Clark HB. Gastric stromal tumors. Reappraisal of histogenesis. Am J Surg Pathol. 1983 Sep;7(6):507-19. doi: 10.1097/00000478-198309000-00001.

    PubMed 6625048

  • Schaldenbrand JD, Appelman HD. Solitary solid stromal gastrointestinal tumors in von Recklinghausen's disease with minimal smooth muscle differentiation. Hum Pathol. 1984 Mar;15(3):229-32. doi: 10.1016/s0046-8177(84)80184-7.

    PubMed 6421716

  • Nilsson B, Bumming P, Meis-Kindblom JM, Oden A, Dortok A, Gustavsson B, Sablinska K, Kindblom LG. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden. Cancer. 2005 Feb 15;103(4):821-9. doi: 10.1002/cncr.20862.

    PubMed 15648083

  • DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000 Jan;231(1):51-8. doi: 10.1097/00000658-200001000-00008.

    PubMed 10636102

  • Emile JF. [GIST: definition, physiopathology]. J Chir (Paris). 2008;145 Suppl 3:6S1-3. French.

    PubMed 19060840

  • Hirota S, Ohashi A, Nishida T, Isozaki K, Kinoshita K, Shinomura Y, Kitamura Y. Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology. 2003 Sep;125(3):660-7. doi: 10.1016/s0016-5085(03)01046-1.

    PubMed 12949711

  • Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R, Hibbard MK, Chen CJ, Xiao S, Tuveson DA, Demetri GD, Fletcher CD, Fletcher JA. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 2001 Nov 15;61(22):8118-21.

    PubMed 11719439

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Pazopanib in people with GIST, run by Centre Leon Berard at 13 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 13 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free survival (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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01323400, which also lists 26 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2016.

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