AK105 With Anlotinib and Radiotherapy Adjuvant Therapy in MGMT Unmethylated Newly Diagnosed Glioblastoma: a Prospective, Open-label Single-arm, Exploratory Trial.

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School1 site in 1 country28 target enrollmentSeptember 2021

ConditionsMGMT-Unmethylated Glioblastoma

InterventionsAnlotinib AK105 Radiotherapy

DrugsAnlotinib AK105

Overview

Phase: Phase 2
Intervention: Anlotinib
Conditions: MGMT-Unmethylated Glioblastoma
Sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Enrollment: 28
Locations: 1
Primary Endpoint: PFSR-6m
Last Updated: 4 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

This is a prospective, open-label single-arm, exploratory, two-stage design trial, aiming to investigate safety and efficacy of AK105 with anlotinib and radiotherapy adjuvant therapy in MGMT unmethylated newly diagnosed glioblastoma.

Detailed Description

Glioblastoma is the most common and aggressive primary brain tumor in adults. Treatment usually involves surgery, after which chemotherapy and radiation therapy are used. The Central Brain Tumor Registry of the United States (CBTRUS) Statistical Report primary brain and other central nervous system tumors diagnosed in the United States in 2012-2016, glioblastoma accounted for 48.3% of primary malignant brain tumors. The Stupp protocol has become standard of care for the treatment of newly diagnosed GBM, however, some MGMT unmethylated glioblastomas are still resistant to temozolomide. Immunotherapy is being studied as treatment for the cancer, AK105 is a humanized monoclonal antibody that specially binds to PD-1. Anlotinib hydrochloride is a multi-target receptor tyrosine kinase inhibitor. Based on the mechanism study, tumor vascular abnormalities promote tissue hypoxia and increase lactic acid, thereby activating immunosuppression and inhibiting T cell function. Anti-angiogenic drugs enhance the infiltration of effector immune cells by inducing normalization of blood vessels and reducing immunosuppression.

Registry

clinicaltrials.gov

Start Date

September 2021

End Date

November 1, 2023

Last Updated

4 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Responsible Party

Principal Investigator

Yang Yang

Professor of medicine

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Eligibility Criteria

Inclusion Criteria

•The patient voluntarily joined the study and signed a written informed consent;
•Pathologically confirmed treatment-naïve glioblastoma with PCR tested MGMT unmethylated;
•The interval between the last biopsy or surgery is 4-6 weeks, and the surgical incision is healed well;
•According to Rano criteria, there are evaluable measurable disease;
•18-70 years of age;
•Karnofsky performance status (KPS) ≥ 60; and estimated survival of at least 3 months;
•The main organ function to meet the following criteria:
•routine blood test: HB≥90g/L(no blood transfusion in 14 days); ANC≥1.5×109/L; White blood cell counts≥3.5×109/L; PLT≥90×109/L; 2) blood biochemical test: ALT and AST ≤2.5×ULN(times the upper limit of normal) and if liver/bone metastases≤5×ULN; TBIL ≤1.5 ULN; Serum Cr≤1.5×ULN and CrCL≥60 ml/min; 3) APTT, INR and PT≤1.5×ULN;
•The woman patients of childbearing age who must agree to take contraceptive methods during the research and within another 6 months after it; who are not in the lactation period and examined as negative in blood serum test or urine pregnancy test within 7 days before the research.

Exclusion Criteria

•Prior therapy with anti-angiogenic drugs, such as anlotinib, apatinib, lenvatinib, sorafenib, sunitinib, surufatinib, regorafenib or fruquintinib ect, or with anti-PD-1(L1) or anti-CTLA-4 agents;
•Patients who get other monoclonal antibodies have severe hypersensitivity;
•Present or along with other malignancies within 5 years. Exceptions include cured basal cell carcinoma of the skin or in situ prostate cancer or in situ cervical cancer;
•Patients have any active autoimmune disease that required systemic treatment, including but not limited to autoimmune hepatitis, enteritis, vasculitis, nephritis; asthma that require bronchodilators for medical intervention. Exceptions include patients with vitiligo, psoriasis, alopecia or well-controlled type 1 diabetes but not required systemic treatment, or hypothyroidism with normal thyroid function after alternative treatment;
•In the past, there is a treatment toxicity of CTCAE5.0 ≥2 grade that has not been completely relieved (the adverse reaction grades in this article, unless otherwise specified, are defaulted to the CTCAE 5.0 standard);
•Immunodeficiency diagnosis or receiving chronic systemic steroid therapy (\>10mg/day prednisone or equivalent) or any other form of immunosuppressive therapy, and continued to be used within 2 weeks before the first dose in this study;
•Those with multiple factors affecting oral drugs (such as inability to swallow, post gastrointestinal resection, chronic diarrhea and intestinal obstruction, etc.);
•Imaging (CT or MRI) shows that the tumor has invaded or unclearly separated the large blood vessels;
•Patients with active bleeding, or unexplained persistent decline in hemoglobin should postpone their screening/enrollment until the bleeding stops and the investigator judges it to be safe;
•Within 4 weeks before the first dose in this study, patients with CTCAE5.0 grade 3+ bleeding; patients treated with anticoagulants or vitamin K antagonists such as warfarin, heparin or their analogues; on the premise that the international normalized ratio of prothrombin time (INR) ≤1.5, it is allowed to use low-dose warfarin (≤1mg/D), low-dose heparin (≤12000U /D) or low-dose aspirin (≤100mg/D) for preventive purposes;

Arms & Interventions

AK105 injection with anlotinib and radiotherapy

AK105 200mg intravenously (IV) on day 1 of each 21-day cycle until disease progression or treatment intolerance, the dose can not be adjusted. Anlotinib 12mg capsules given orally on once daily in 21-day cycle until disease progression or treatment intolerance(14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21), the dose can be adjusted to 10mg or 8mg according to the specific conditions of the patient. The conventional radiotherapy regimen delivered 2.0Gy once a day, five days a week to a total dose of 60Gy.

Intervention: Anlotinib