Recurrent Glioblastoma (WHO-Grade IV Glioma) Clinical Trial
Official title:
Phase II Clinical Trial on the Combination of Avelumab and Axitinib for the Treatment of Patients With Recurrent Glioblastoma
Phase II clinical trial on the combination of avelumab and axitinib for the treatment of patients with recurrent glioblastoma (histologically confirmed WHO grade IV glioma), at documented recurrence/progression following prior treatment with surgery, radiation therapy and temozolomide.
High-grade gliomas of the central nervous system (CNS) are characterized by profound tumor
related neo-angiogenesis, and intracranial perilesional edema. Glioblastoma (WHO-grade IV
glioma) expresses high levels of VEGF and frequently carries an amplified gene copy numbers
of the VEGFR2, KIT and PDGFR or EGFR genes, key mediators of the process of cancer related
neo-angiogenesis. In patient diagnosed with recurrence/progression glioblastoma (recGB)
following prior therapy with surgery, radiation therapy and temozolomide, cytotoxic salvage
therapies resulted in a best overall response rate of 5 to 10%, 6-month PFS rates of 9% to
21%, and a median OS of 25 to 30 weeks. No treatment option has demonstrated to improve the
survival expectancy of recGB patients in a randomized clinical trial. Bevacizumab treatment
has been registered by FDA based on objective tumor response rates and PFS results obtained
in uncontrolled phase II trials. There is currently no treatment registered by EMA for the
indication of recGB.
Axitinib, a VEGFR-specific small molecule tyrosine kinase inhibitor (Tki) has demonstrated
anti-tumor activity when evaluated as a mono-therapy and in combination with lomustine for
the treatment of patients with recGB (EudraCT 2011-000900-16). Immunocytochemical profiling
of the peripheral blood of recurrent GBM patients treated with axitinib or axitinib plus
lomustine showed that axitinib treatment increases the number of naive CD8+ T cells and
central memory CD4+ and CD8+ T cells. There was also a reduction of TIM3 expression and an
increased cytokine production in the patients treated with axitinib. Upon progression during
axitinib treatment patients displayed an increased immune suppression with an increased
number of Treg, an increased PD-1 expression on CD4+ and CD8+ T cells, and a reduced T cell
functionality.
Avelumab (MSB00107; anti-PD-L1) is a fully human anti-PD-L1 IgG1 monoclonal antibody (mAb)
that has demonstrated anti-tumor activity in several tumor types. Expression of PD-L1 by
tumor cells has been correlated with a higher probability for respons to avelumab throughout
different tumor types. Glioblastoma has been reported to expresses the PD-L1 ligand.
In preclinical mouse models we demonstrated that axitinib reduces the immune suppressive
microenvironment through reduction of the suppressive capacity of monocytic MDSCs (both in
intra-cranial as well as subcutaneous tumors). Moreover, it also increased the number of
tumor-infiltrating T cells. When we combined axitinib with active immunotherapy in the form
of CTLA4 blockade not only a supplementary reduction of the suppressive capacity of these
monocytic MDSCs was found, but also a reduction of the intratumoral granulocytic MDSCs and an
increased antigen-presenting function of intratumoral DCs (manuscript accepted for
publication in High-grade gliomas of the central nervous system (CNS) are characterized by
profound tumor related neo-angiogenesis, and intracranial perilesional edema. Glioblastoma
(WHO-grade IV glioma) expresses high levels of VEGF and frequently carries an amplified gene
copy numbers of the VEGFR2, KIT and PDGFR or EGFR genes, key mediators of the process of
cancer related neo-angiogenesis. In patient diagnosed with recurrence/progression
glioblastoma (recGB) following prior therapy with surgery, radiation therapy and
temozolomide, cytotoxic salvage therapies resulted in a best overall response rate of 5 to
10%, 6-month PFS rates of 9% to 21%, and a median OS of 25 to 30 weeks. No treatment option
has demonstrated to improve the survival expectancy of recGB patients in a randomized
clinical trial. Bevacizumab treatment has been registered by FDA based on objective tumor
response rates and PFS results obtained in uncontrolled phase II trials. There is currently
no treatment registered by EMA for the indication of recGB.
Axitinib, a VEGFR-specific small molecule tyrosine kinase inhibitor (Tki) has demonstrated
anti-tumor activity when evaluated as a mono-therapy and in combination with lomustine for
the treatment of patients with recGB (EudraCT 2011-000900-16). Immunocytochemical profiling
of the peripheral blood of recurrent GBM patients treated with axitinib or axitinib plus
lomustine showed that axitinib treatment increases the number of naive CD8+ T cells and
central memory CD4+ and CD8+ T cells. There was also a reduction of TIM3 expression and an
increased cytokine production in the patients treated with axitinib. Upon progression during
axitinib treatment patients displayed an increased immune suppression with an increased
number of Treg, an increased PD-1 expression on CD4+ and CD8+ T cells, and a reduced T cell
functionality.
Avelumab (MSB00107; anti-PD-L1) is a fully human anti-PD-L1 IgG1 monoclonal antibody (mAb)
that has demonstrated anti-tumor activity in several tumor types. Expression of PD-L1 by
tumor cells has been correlated with a higher probability for respons to avelumab throughout
different tumor types. Glioblastoma has been reported to expresses the PD-L1 ligand.
In preclinical mouse models we demonstrated that axitinib reduces the immune suppressive
microenvironment through reduction of the suppressive capacity of monocytic MDSCs (both in
intra-cranial as well as subcutaneous tumors). Moreover, it also increased the number of
tumor-infiltrating T cells. When we combined axitinib with active immunotherapy in the form
of CTLA4 blockade not only a supplementary reduction of the suppressive capacity of these
monocytic MDSCs was found, but also a reduction of the intratumoral granulocytic MDSCs and an
increased antigen-presenting function of intratumoral DCs (manuscript accepted for
publication in American Journal of Cancer Research).
The rational for combining avelumab with for the treatment of recGB is based on the potential
of axitinib to normalize the glioblastoma associated neo-vasculature, counteracting the
immunosuppressive role of VEGF in the tumor microenvironment and controlling intracranial
edema. These features may result in a synergistic anti-tumor effect with the PD-L1 inhibitory
mAb avelumab. In addition, axitinib may reduce the inflammatory edema related to the
anti-tumor effect mediated by PD-L1 inhibition with avelumab.
Patients with recGBM often develop neurological symptoms related to perilesional edema.
Corticosteroids are considered a standard of care for controlling intracranial edema in
patients with glioblastoma. High dose corticosteroids however are known to be
immunosuppressive and are likely to counteract the therapeutic effect of anti-PD-L1 antibody
therapy. Axitinib has the capacity to control recGBM associated edema of the brain. Out of
the 32 patients who were treated with corticosteroids at baseline in the AxiG trial (EudraCT
2011-000900-16) 17 could lower and 5 could stop their steroids during treatment with
axitinib. PFS was identical for patient with or without need for steroids at baseline in the
AxiG trial but OS was numerically superior for patients not in need for steroids at baseline.
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