Clinical Trials /

Phase I/II Study of Pazopanib+ Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme

NCT02331498

Description:

A phase I/II study of pazopanib in combination with temozolomide in patients with newly diagnosed glioblastoma multiforme after surgery and RT-CT (PAZOGLIO study)

Related Conditions:
  • Conventional Glioblastoma Multiforme
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I/II Study of Pazopanib+ Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme
  • Official Title: A Phase I/II Study of Pazopanib in Combination With Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme After Surgery and RT-CT

Clinical Trial IDs

  • ORG STUDY ID: 2012/49
  • NCT ID: NCT02331498

Conditions

  • Glioblastoma Multiforme

Interventions

DrugSynonymsArms
PazopanibA Pazopanib

Purpose

A phase I/II study of pazopanib in combination with temozolomide in patients with newly diagnosed glioblastoma multiforme after surgery and RT-CT (PAZOGLIO study)

Detailed Description

      Glioblastoma (GBM), the most common and most malignant primary brain tumor, represents a
      major medical challenge considering its extremely poor prognosis (Wen 2008). Current standard
      of care includes maximal surgical resection, followed by concomitant radio-chemotherapy
      (temozolomide - TMZ) (RT-CT) followed by 6 months of maintenance TMZ, with a median overall
      survival (mOS) of 14.6 vs. 12.1 months with RT alone (Stupp 2005). Non operable GBM,
      represents around 30% of cases of GBM, with a poorer prognosis, a median PFS of 3-4 months
      and a median OS between 6-9 months (Chinot 2007, Stupp 2009), with concomitant RT-CT
      treatment. Therefore, innovative treatment strategies are urgently needed and new treatment
      combinations evaluated in phase I studies are highly encouraged (Wen 2011).

      Since GBM is one of the most vascularised cancers, antiangiogenic agents have been tested and
      used firstly in recurrent GBM. Among them, Bevacizumab, a humanized monoclonal antibody
      against vascular endothelial growth factor (VEGF), has shown high response rate between 19%
      and 62% in several Phase 2 and multiple retrospective studies, alone or in combination with
      chemotherapy (Chamberlain 2011). Two randomized phase III trials, AVAGLIO and RTOG 0825,
      investigating the efficacy of Bevacizumab added or not to the Stupp protocol in patients with
      newly diagnosed GBM, have been presented at the annual meeting of the American Society of
      Clinical Oncology (ASCO 2013). While both studies exhibited a significant progression-free
      survival (PFS) improvement (RTOG 0825:10.7 vs. 7.3m, p=0.007; AVAGLIO: 10.6 vs. 6.2m,
      p<0.0001), there was no gain in overall survival.

      Other antiangiogenic agents have been studied in GBM patients (Sathornsumetee 2009, Van Meir
      2010, Wick 2011), with encouraging results but still insufficient when used as single agents.
      Among them, pazopanib is thought to be promising. It is an orally tyrosine kinase inhibitor
      with potently inhibition of VEGFR-1, -2, -3, c-kit and PDGFR-α, -β (Castaneda 2009, Schutz
      2011). Interestingly, these 2 PDGFR subtypes are overexpressed in malignant gliomas (Verhaak
      2010). Furthermore, pazopanib is already validated in patients with advanced renal cell
      carcinoma and soft-tissue sarcomas (Sleijfer 2009, Sternberg 2010).

      A phase II trial evaluated efficacy and safety of pazopanib in 35 patients with recurrent GBM
      (Iwamoto 2010). Two patients had a partial radiographic response by standard bidimensional
      measurements, whereas 9 patients (6 at the 8-week point and 3 only within the first month of
      treatment) had decreased contrast enhancement, vasogenic edema, and mass effect but <50%
      reduction in tumor. The median PFS was 12 weeks and mOS was 35 weeks. Pazopanib was
      reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR
      agents and with unexpected toxicity.

      Given the emerging concern that pure anti-VEGF inhibition may promote malignant glial cell
      invasiveness (Keunen 2011), we consider essential to combine a multitargeted antiangiogenic
      agent, such as pazopanib, with the current standard treatment. TMZ was chosen not only
      because it represents the current standard of care but because of its very good penetration
      in the brain parenchyma and its low hepatic metabolism, making very unlikely the occurrence
      of a pharmacokinetic interaction with pazopanib (Friedman 2000). Indeed, phase I trials of
      TMZ in combination with molecules such as RAD001, cilengitide, gefitinib or irinotecan showed
      no need for dose modification of TMZ. Similarly, the Phase I trials of pazopanib association
      with paclitaxel or FOLFOX6 have been conducted up to a dose of 800 mg daily, the recommended
      dose of pazopanib in monotherapy, with standard doses of chemotherapy (Tan 2010, Brady 2009).
      Finally, the study of the toxicity profile of pazopanib and TMZ does not suggest a specific
      limiting dose escalation adverse event, except perhaps asthenia, thrombocytopenia or ALAT
      elevation. However, considering the high level of potential toxicity when an ITK is
      administered with radiations, pazopanib should not be administered in the induction phase of
      the Stupp protocol.

      Therefore, based on a strong synergy rational, the study coordinator aims to evaluate the
      safety and efficacy of pazopanib in combination with TMZ in the maintenance phase of the
      Stupp protocol. The study coordinator hopes that this strategy could significantly improve
      the poor prognosis of these patients.

      This study is a multicenter Phase I/II trial, which aims to determine the Recommended Phase 2
      Dose (RP2D) of pazopanib in combination with TMZ. The study coordinator will associate a
      multidisciplinary approach involving translational pharmacokinetic studies, and research on
      potential predictive biomarkers of response through pharmacogenetic and pharmacogenomic
      approachs. This study will include patients with not previously treated GBM, candidates for a
      complete or partial surgical resection and who are eligible for adjuvant treatment based on a
      combination of TMZ and radiotherapy.
    

Trial Arms

NameTypeDescriptionInterventions
A PazopanibOtherOpen label study with one group
  • Pazopanib

Eligibility Criteria

        Inclusion Criteria:

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

          -  Age ≥ 18 years and < 70 years

          -  Histologically confirmed diagnosis of GBM

          -  Surgically treated other than exclusive biopsy (complete or partial resection) of the
             GBM, for which adjuvant radiotherapy and chemotherapy is indicated

          -  Eligibility criteria that will need to be checked before patient registration and - No
             TMZ interruption resulting in hematological toxicity should has occurred

          -  AND the delivery of radiation dose as defined in the Stupp protocol should be at least
             equal to 80%

          -  Eastern Cooperative Oncology Group (ECOG) performance status of Glioblastoma ≤ 2

          -  Life expectancy>3 months

          -  Measurable disease criteria : Based on the RANO criteria (Wen 2010) objective tumor
             response will be assessed by MRI and 18F-DOPA PET)

          -  Archived tumor tissue must be available for all subjects for biomarker analysis before
             and/or during treatment with investigational product.

          -  Stable doses of corticosteroid for more than 1 week.

          -  Adequate biological function

          -  Women of childbearing potential must have a negative serum pregnancy test within 14
             days of first dose of study treatment and agree to use effective contraception, as
             defined in Pregnancy Section in overall Safety Section during the study and for 6
             months following the last dose of investigational product.

        Exclusion Criteria:

          -  Prior malignancy.

          -  Surgical treatment consisting in exclusive biopsy or absence of initial surgery

          -  Pre-treated GBM

          -  Allergy to any of the tested drugs

          -  Clinically significant gastrointestinal abnormalities that may increase the risk for
             gastrointestinal bleeding including,

          -  Clinically significant gastrointestinal abnormalities that may affect absorption of
             investigational product

          -  Corrected QT interval (QTc) > 480 msecs

          -  History of any one or more of ardiovascular conditions within the past 6 months

          -  Poorly controlled hypertension

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

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

          -  Evidence of active bleeding or bleeding diathesis.

          -  Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
             increase the risk of pulmonary hemorrhage

          -  Recent hemoptysis

          -  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.

          -  Unable or unwilling to discontinue use of prohibited medications listed in Appendix C
             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 (Appendix C).

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

               -  radiation therapy, surgery or tumor embolization within 14 days prior to the
                  first dose of pazoapnib 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

          -  Administration of any non-oncologic investigational drug within 30 days or 5
             half-lives whichever is longer prior to receiving the first dose of study treatment

          -  Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
             progressing in severity, except alopecia.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended Phase 2 Dose (RP2D) of pazopanib in oral route in addition to the maintenance phase of the Stupp protocol, according the rate (33 %) of tolerate toxicities
Time Frame:phase I
Safety Issue:
Description:To evaluate the Recommended Phase 2 Dose (RP2D) of pazopanib in oral route in addition to the maintenance phase of the Stupp protocol, regarding the toxicities that should not be more than 33 %

Secondary Outcome Measures

Measure:overall tolerance of pazopanib : number of biological toxicities, blood pressure and hemorragic events
Time Frame:2 years
Safety Issue:
Description:To define the overall tolerance of pazopanib associated with TMZ during the maintenance phase of the "Stupp protocol" regarding biological toxicities, blood pressure and hemorragic events
Measure:antitumor activity of the adjunction of daily dose of pazopanib to the maintenance phase of the Stupp protocol
Time Frame:2 years
Safety Issue:
Description:To assess the antitumor activity of the adjunction of daily dose of pazopanib to the maintenance phase of the Stupp protocol according to the Revised Assessment in Neuro-Oncology (RANO) criteria (response rate) and the median duration of response.
Measure:determine the median Progression-Free-Survival
Time Frame:12 months
Safety Issue:
Description:To determine the median Progression-Free-Survival (mPFS), the PFS rate at 12 (PFS-12) months.
Measure:determine the median Overall Survival (mOS)
Time Frame:12 months
Safety Issue:
Description:To determine the median Overall Survival (mOS), the OS rate at 6 (OS-6) and 12 (OS-12) months.
Measure:pharmacokinetics profile: area under curve regarding plasma concentration /time between 0 and 8 h (AUC0-8 hours) from 0 to 24 h (AUC 0-24 hours), maximum plasma concentration (Cmax), time to the concentration maximum (Tmax) and plasma half-life (t1/2)
Time Frame:2 years
Safety Issue:
Description:To determine the pharmacokinetics (PK) profile of pazopanib when given in combination with TMZ.
Measure:determine the pharmacokinetics (PK) profile of TMZ
Time Frame:2 years
Safety Issue:
Description:To determine the pharmacokinetics (PK) profile of TMZ when given in combination with pazopanib.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Centre Antoine Lacassagne

Last Updated

July 22, 2019