Clinical Trial on the Combination of Avelumab and Axitinib for the Treatment of Patients With Recurrent Glioblastoma

NCT03291314 | Completed Phase 2

• 1 other identifier: 2017-BN-001
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Recurrent Glioblastoma (WHO-Grade IV Glioma)

Outcome Measures

Primary Outcomes (1)

• 6-month PFS%

  The percentage of patients who are alive and free-from confirmed tumor progression at 6-month (24 weeks).

  24 weeks

Secondary Outcomes (5)

• Median OS (Overall survival)

  an average of 1 year

• Objective Tumor Response (OR)

  up to 24 weeks

• Overall Safety profile

  Overall safety will be continuously monitored throughout the duration of the treatment, until one month after last patient visit.

• Evolution of neuro-cognitive function

  Up to 24 weeks; on week 1, week 9 of the treatment phase and week 20 of the follow-up phase

• Continuous activity

  Activity will be continuously monitored for 2 weeks, two times with an interval of 6 weeks during the treatment phase.

Study Arms (2)

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)

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.

Drug: Axitinib; Drug: Avelumab

Interventions

Axitinib DRUG

1\. 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) \[7\].

Also known as: InlytaTM

Axitinib (+Avelumab); Axitinib + Avelumab

Avelumab DRUG

2\. 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.

Also known as: MSB00107

Axitinib (+Avelumab); Axitinib + Avelumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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;

You may not qualify if:

• 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);
• 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;

Sponsors & Collaborators

• Universitair Ziekenhuis Brussel: lead

Study Sites (1)

UZ Brussel

Brussels, 1090, Belgium

Location

Related Publications (10)

• 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.

  PMID: 19720927 BACKGROUND

• Kreisl 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.

  PMID: 19114704 BACKGROUND

• Lamborn 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.

  PMID: 18356283 BACKGROUND

• Meyers 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.

  PMID: 1697183 BACKGROUND

• Taphoorn 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.

  PMID: 14980531 BACKGROUND

• Bosma 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.

  PMID: 17018697 BACKGROUND

• Meyers 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.

  PMID: 10653880 BACKGROUND

• Li 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.

  PMID: 18406884 BACKGROUND

• Brown 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.

  PMID: 17135644 BACKGROUND

• Stupp 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.

  PMID: 19269895 RESULT

MeSH Terms

Conditions

Glioblastoma

Interventions

Axitinib; avelumab

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Indazoles; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Model Details: 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

Study Record Dates

• First Submitted: June 29, 2017
• First Posted: September 25, 2017
• Study Start: May 3, 2017
• Primary Completion: January 1, 2019
• Study Completion: January 1, 2019
• Last Updated: January 23, 2019

Record last verified: 2019-01

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)