Recurrent Glioblastoma (WHO-Grade IV Glioma)Phase 2GliAvAxNCT03291314
Clinical Trial on the Combination of Avelumab and Axitinib for the Treatment of Patients With Recurrent Glioblastoma
A Phase 2 study testing Axitinib and Avelumab in people with Recurrent Glioblastoma (WHO-Grade IV Glioma), run by Universitair Ziekenhuis Brussel at 1 site in Belgium.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Recurrent Glioblastoma (WHO-Grade IV Glioma)
- What is being tested?
- Axitinib and Avelumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- 1 siteBelgium
- Study dates
- 3 May 2017to 1 Jan 2019
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis:
- Histologically confirmed diagnosis of World Health Organization Grade IV malignant glioma (glioblastoma or gliosarcoma);
- Documentation of recurrent (or progressive according to RNAO criteria) glioblastoma following prior treatment with surgery (resection or biopsy), radiation therapy and temozolomide chemotherapy;
- A formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or 15 unstained slides (10 minimum) obtained from an archival FFPE tumor tissue block will be required.
- Presence of a measurable tumor lesion that is characterized by gadolinium enhancement on T1-MRI of the brain (with a shortest diameter of >5 mm) and enhanced lesion to normal brain uptake on FET-PET imaging of the brain;
- If first recurrence of GBM is documented by MRI, an interval of at least 12 weeks after the end of prior radiation therapy is required unless there is either: i) histopathologic confirmation of recurrent tumor, or ii) new enhancement on MRI outside of the radiotherapy treatment field.
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- An interval of >28 days and full recovery (ie, no ongoing safety issues) from surgical resection and an interval of >4 weeks after the last administration of any other treatment for glioblastoma.
- Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative, as allowed by local guidance/practice) has been informed of all pertinent aspects of the study.
- Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
- Age ≥ 18 years.
- Estimated life expectancy of at least 3 months.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
- No evidence of pre-existing uncontrolled hypertension as documented by 2 baseline blood pressure (BP) readings taken at least 1 hour apart. The baseline systolic BP readings must be ≤ 140 mm Hg, and the baseline diastolic BP readings must be ≤ 90 mm Hg. Use of antihypertensive medications to control BP is allowed.
- Adequate bone marrow function, including:
- Absolute neutrophil count (ANC) ≥ 1,500/mm3 or ≥ 1.5 x 109/L;
- Platelets ≥ 100,000/mm3 or ≥ 100 x 109/L;
- Hemoglobin ≥ 9 g/dL (may have been transfused).
- Adequate renal function, including:
- Estimated creatinine clearance ≥ 30 mL/min as calculated using the Cockcroft-Gault (CG) equation;
- Urinary protein <2+ by urine dipstick. If dipstick is ≥ 2+, then 24-hour urinary protein <2 g per 24 hours.
- Adequate liver function, including:
- Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN);
- AST and ALT ≤ 2.5 x ULN.
- Serum pregnancy test (for females of childbearing potential) negative at screening.
- Male patients able to father children and female patients of childbearing potential and at risk for pregnancy must agree to use 2 highly effective methods of contraception throughout the study and for at least 90 days after the last dose of assigned treatment.
Who cannot join
- Any of the following prior cancer therapies:
- Prior immunotherapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways;
- Prior therapy with axitinib as well as any prior therapies with other VEGF pathway inhibitors (including bevacizumab).
- Participation in other therapeutic studies within 4 weeks prior to enrollment in the current study.
- Persisting toxicity related to prior therapy NCI CTCAE v4.03 Grade > 1; however, sensory neuropathy Grade ≤ 2 is acceptable.
- Current or prior use of immunosuppressive medication within 7 days prior to enrollment, except for steroid treatment needed to palliate glioblastoma associated neurological symptoms and intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection);
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- No treatment with enzyme inducing anti-epileptic drugs (EIAED) during and at least 14 days before the administration of axitinib;
- Known severe hypersensitivity reactions to monoclonal antibodies (Grade > 3), any history of anaphylaxis.
- Known prior or suspected hypersensitivity to study drugs or any component in their formulations.
- Diagnosis of any other malignancy within 5 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix, or low-grade (Gleason 6 or below) prostate cancer on surveillance with no plans for treatment intervention (eg, surgery, radiation or castration).
- Active autoimmune disease that might deteriorate when receiving an immunostimulatory agents. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
- Gastrointestinal abnormalities including:
- Inability to take oral medication;
- Requirement for intravenous alimentation;
- Prior surgical procedures affecting absorption including total gastric resection;
- Treatment for active peptic ulcer disease in the past 6 months;
- Active gastrointestinal bleeding, unrelated to cancer, as evidenced by clinically significant hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy;
- Malabsorption syndromes.
- Active infection requiring systemic therapy.
- Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
- Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or chronic infection.
- Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines).
- Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose anticoagulants for maintenance of patency of central venous access device or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed.
- Evidence of inadequate wound healing (including dehiscence of the craniotomy scar).
- Grade ≥ 3 hemorrhage within 4 weeks of patient enrollment.
- Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, LVEF less than LLN, clinically significant pericardial effusion, cerebrovascular accident, transient ischemic attack.
- Any of the following in the previous 6 months: deep vein thrombosis or symptomatic pulmonary embolism.
- Evidence of tumor involvement of the myocardium or pericardium or tumor thrombus extending to the heart.
- Current use or anticipated need for treatment with drugs or foods that are known strong CYP3A4/5 inhibitors, including their administration within 10 days prior to patient enrollment (eg, grapefruit juice or grapefruit/grapefruit-related citrus fruits [eg, Seville oranges, pomelos], ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, troleandomycin, mibefradil, and conivaptan). The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed.
- Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers, including their administration with 10 days prior to patient enrollment(eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, St John's wort).
- Pregnant female patients, breastfeeding female patients.
- Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, uncontrolled asthma, and pneumonitis or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the detailed description
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.
- Being tested
- Axitinib, Avelumab
- Medical subject headings
- Glioblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AxitinibDrug
Also called InlytaTM
- 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) [7].
AvelumabDrug
Also called MSB00107
- 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.
| Study group | Role | What they receive |
|---|---|---|
| Axitinib + Avelumab | Experimental | On day 1 of the treatment phase, patients recruited to this arm will initiate concomitant continuous daily treatment with axitinib (InlytaTM, 5 mg comp BID) in combination with avelumab (10 mg/kg IV Q2 weeks) Receives: Drug: Axitinib; Drug: Avelumab |
| Axitinib (+Avelumab) | Experimental | On day 1 of the treatment phase, patients recruited to this arm will initiate treatment with continuous daily axitinib (InlytaTM, 5 mg comp BID).
Patients who tolerate treatment with axitinib and are able to taper the dose of corticosteroids to a maximal daily dose of 8 mg methylprednisolone (or an equivalent dose of another oral corticosteroid) will initiate combination therapy with avelumab (10 mg/kg IV Q2 weeks) on day 43, following the the first MRI-based tumor response evaluation in week 6.
Patients who do not tolerate monotherapy with axitinib, or cannot decrease their daily dose of corticosteroids to a maximal daily dose of 8 mg methylprednisolone will not be allowed to initiate avelumab treatment. Receives: Drug: Axitinib; Drug: Avelumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
6-month PFS%
The percentage of patients who are alive and free-from confirmed tumor progression at 6-month (24 weeks).
Measured: 24 weeks
Secondary outcomes (5)
Median OS (Overall survival)
Estimate OS according to stratum and for the total study population by Kaplan-Meier estimates.
Measured: an average of 1 year
Objective Tumor Response (OR)
To assess anti-tumor activity by evaluating the OR as assessed by iRANO criteria.
Measured: up to 24 weeks
Overall Safety profile
To evaluate the overall safety profile of avelumab in combination with axitinib by evaluating the adverse events (AEs) and laboratory abnormalities as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
Measured: Overall safety will be continuously monitored throughout the duration of the treatment, until one month after last patient visit.
Evolution of neuro-cognitive function
Document neuro-cognitive function by Cogstate computer based neurocognitive assessment during study treatment.
Measured: Up to 24 weeks; on week 1, week 9 of the treatment phase and week 20 of the follow-up phase
Continuous activity
Assess the activity level in treated recGB patients by continuous activity tracking during study treatment by means of an activity tracking device.
Measured: Activity will be continuously monitored for 2 weeks, two times with an interval of 6 weeks during the treatment phase.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Sep 2017
- Study start3 May 2017
- Primary completion1 Jan 2019
- Study completion1 Jan 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Recurrent Glioblastoma (WHO-Grade IV Glioma)Studies of the same condition, open and under way.
- More trials run by Universitair Ziekenhuis BrusselThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- Open label, single-center, stratified phase II clinical trial. Patients will be stratified according to their baseline use of corticosteroids: \<Stratum A\> = no need for corticosteroids and \<Stratum B\> = baseline need for steroid treatment
- Masking
- None (open label)
- Enrolment
- 52 participants (actual)
Sponsor and investigators
- Lead sponsor
- Universitair Ziekenhuis Brussel
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Bart Neyns, Universitair Ziekenhuis Brussel
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03291314
- Sponsor's protocol ID
- 2017-BN-001
- Acronym
- GliAvAx
- Status last verified
- Jan 2019
- First submitted
- 29 Jun 2017
- Last updated
- 23 Jan 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. doi: 10.1200/JCO.2008.19.8721. Epub 2009 Aug 31.
PubMed 19720927Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009 Feb 10;27(5):740-5. doi: 10.1200/JCO.2008.16.3055. Epub 2008 Dec 29.
PubMed 19114704Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD; North American Brain Tumor Consortium. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol. 2008 Apr;10(2):162-70. doi: 10.1215/15228517-2007-062. Epub 2008 Mar 4.
PubMed 18356283Meyers CA, Scheibel RS. Early detection and diagnosis of neurobehavioral disorders associated with cancer and its treatment. Oncology (Williston Park). 1990 Jul;4(7):115-22; discussion 122, 126-7, 130.
PubMed 1697183Taphoorn MJ, Klein M. Cognitive deficits in adult patients with brain tumours. Lancet Neurol. 2004 Mar;3(3):159-68. doi: 10.1016/S1474-4422(04)00680-5.
PubMed 14980531Bosma I, Vos MJ, Heimans JJ, Taphoorn MJ, Aaronson NK, Postma TJ, van der Ploeg HM, Muller M, Vandertop WP, Slotman BJ, Klein M. The course of neurocognitive functioning in high-grade glioma patients. Neuro Oncol. 2007 Jan;9(1):53-62. doi: 10.1215/15228517-2006-012. Epub 2006 Oct 3.
PubMed 17018697Meyers CA, Hess KR, Yung WK, Levin VA. Cognitive function as a predictor of survival in patients with recurrent malignant glioma. J Clin Oncol. 2000 Feb;18(3):646-50. doi: 10.1200/JCO.2000.18.3.646.
PubMed 10653880Li J, Bentzen SM, Li J, Renschler M, Mehta MP. Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis. Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):64-70. doi: 10.1016/j.ijrobp.2007.09.059.
PubMed 18406884Brown PD, Jensen AW, Felten SJ, Ballman KV, Schaefer PL, Jaeckle KA, Cerhan JH, Buckner JC. Detrimental effects of tumor progression on cognitive function of patients with high-grade glioma. J Clin Oncol. 2006 Dec 1;24(34):5427-33. doi: 10.1200/JCO.2006.08.5605.
PubMed 17135644Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009 May;10(5):459-66. doi: 10.1016/S1470-2045(09)70025-7. Epub 2009 Mar 9.
PubMed 19269895
Study at a glance
From the registry record, last updated by the sponsor on 23 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Clinical Trial on the Combination of Avelumab and Axitinib for the Treatment of Patients With Recurrent Glioblastoma
- ClinicalTrials.gov ID
- NCT03291314
- Acronym / sponsor ID
- GliAvAx / 2017-BN-001
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 52 participants (actual)
- Lead sponsor
- Universitair Ziekenhuis BrusselUniversity, hospital or other
- Study start
- 3 May 2017 (actual)
- Primary completion
- 1 Jan 2019 (actual)
- Study completion
- 1 Jan 2019 (actual)
- First posted
- 25 Sep 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Open label, single-center, stratified phase II clinical trial. Patients will be stratified according to their baseline use of corticosteroids: <Stratum A> = no need for corticosteroids and <Stratum B> = baseline need for steroid treatment
| Arm | Type | Receives |
|---|---|---|
| Axitinib + Avelumab | Experimental | Drug: Axitinib, Drug: AvelumabOn day 1 of the treatment phase, patients recruited to this arm will initiate concomitant continuous daily treatment with axitinib (InlytaTM, 5 mg comp BID) in combination with avelumab (10 mg/kg IV Q2 weeks) |
| Axitinib (+Avelumab) | Experimental | Drug: Axitinib, Drug: AvelumabOn day 1 of the treatment phase, patients recruited to this arm will initiate treatment with continuous daily axitinib (InlytaTM, 5 mg comp BID). Patients who tolerate treatment with axitinib and are able to taper the dose of corticosteroids to a maximal daily dose of 8 mg methylprednisolone (or an equivalent dose of another oral corticosteroid) will initiate combination therapy with avelumab (10 mg/kg IV Q2 weeks) on day 43, following the the first MRI-based tumor response evaluation in week 6. Patients who do not tolerate monotherapy with axitinib, or cannot decrease their daily dose of corticosteroids to a maximal daily dose of 8 mg methylprednisolone will not be allowed to initiate avelumab treatment. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (25 listed)
- Diagnosis:
- Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative, as allowed by local guidance/practice) has been informed of all pertinent aspects of the study.
- Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
- Age ≥ 18 years.
- Estimated life expectancy of at least 3 months.
Key exclusion criteria (32 listed)
- Any of the following prior cancer therapies:
- Participation in other therapeutic studies within 4 weeks prior to enrollment in the current study.
- Persisting toxicity related to prior therapy NCI CTCAE v4.03 Grade > 1; however, sensory neuropathy Grade ≤ 2 is acceptable.
- Current or prior use of immunosuppressive medication within 7 days prior to enrollment, except for steroid treatment needed to palliate glioblastoma associated neurological symptoms and intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection);
- No treatment with enzyme inducing anti-epileptic drugs (EIAED) during and at least 14 days before the administration of axitinib;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AxitinibAlso: InlytaTM1. 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) [7]. | Drug | Axitinib (+Avelumab), Axitinib + Avelumab |
| AvelumabAlso: MSB001072. 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. | Drug | Axitinib (+Avelumab), Axitinib + Avelumab |
Primary outcome
6-month PFS%
Time frame: 24 weeks
The percentage of patients who are alive and free-from confirmed tumor progression at 6-month (24 weeks).
5 secondary outcomes
Median OS (Overall survival)
Time frame: an average of 1 year
Objective Tumor Response (OR)
Time frame: up to 24 weeks
Overall Safety profile
Time frame: Overall safety will be continuously monitored throughout the duration of the treatment, until one month after last patient visit.
Evolution of neuro-cognitive function
Time frame: Up to 24 weeks; on week 1, week 9 of the treatment phase and week 20 of the follow-up phase
Continuous activity
Time frame: Activity will be continuously monitored for 2 weeks, two times with an interval of 6 weeks during the treatment phase.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jan 2019.
- Background: PubMed 19720927Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. doi: 10.1200/JCO.2008.19.8721. Epub 2009 Aug 31.
- Background: PubMed 19114704Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009 Feb 10;27(5):740-5. doi: 10.1200/JCO.2008.16.3055. Epub 2008 Dec 29.
- Background: PubMed 18356283Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD; North American Brain Tumor Consortium. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol. 2008 Apr;10(2):162-70. doi: 10.1215/15228517-2007-062. Epub 2008 Mar 4.
- Background: PubMed 1697183Meyers CA, Scheibel RS. Early detection and diagnosis of neurobehavioral disorders associated with cancer and its treatment. Oncology (Williston Park). 1990 Jul;4(7):115-22; discussion 122, 126-7, 130.
- Background: PubMed 14980531Taphoorn MJ, Klein M. Cognitive deficits in adult patients with brain tumours. Lancet Neurol. 2004 Mar;3(3):159-68. doi: 10.1016/S1474-4422(04)00680-5.
- Background: PubMed 17018697Bosma I, Vos MJ, Heimans JJ, Taphoorn MJ, Aaronson NK, Postma TJ, van der Ploeg HM, Muller M, Vandertop WP, Slotman BJ, Klein M. The course of neurocognitive functioning in high-grade glioma patients. Neuro Oncol. 2007 Jan;9(1):53-62. doi: 10.1215/15228517-2006-012. Epub 2006 Oct 3.
- Background: PubMed 10653880Meyers CA, Hess KR, Yung WK, Levin VA. Cognitive function as a predictor of survival in patients with recurrent malignant glioma. J Clin Oncol. 2000 Feb;18(3):646-50. doi: 10.1200/JCO.2000.18.3.646.
- Background: PubMed 18406884Li J, Bentzen SM, Li J, Renschler M, Mehta MP. Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis. Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):64-70. doi: 10.1016/j.ijrobp.2007.09.059.
- Background: PubMed 17135644Brown PD, Jensen AW, Felten SJ, Ballman KV, Schaefer PL, Jaeckle KA, Cerhan JH, Buckner JC. Detrimental effects of tumor progression on cognitive function of patients with high-grade glioma. J Clin Oncol. 2006 Dec 1;24(34):5427-33. doi: 10.1200/JCO.2006.08.5605.
- Results publication: PubMed 19269895Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009 May;10(5):459-66. doi: 10.1016/S1470-2045(09)70025-7. Epub 2009 Mar 9.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Axitinib and Avelumab in people with Recurrent Glioblastoma (WHO-Grade IV Glioma), run by Universitair Ziekenhuis Brussel at 1 site in Belgium.
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 32 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 23 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Belgium. 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?
6-month PFS% (time frame: 24 weeks). 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 NCT03291314, which also lists 10 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 23 Jan 2019.