Hypofractionated Stereotactic Radiotherapy With Anlotinib in Patients With Recurrent High-Grade Gliomas

A Phase II Study of Hypofractionated Stereotactic Radiotherapy Combined With Anlotinib in Patients With Recurrent High-Grade Glioma

A Phase II Study of Hypofractionated Stereotactic Radiotherapy (HSRT) With Anlotinib in Patients With Recurrent High-Grade Glioma. The primary endpoint is overall survival after radiotherapy. Secondary endpoints included progress-free survival, objective response rate, cognitive function, quality of life, toxicity.

Study Overview

• Status: Active, not recruiting
• Conditions: Malignant Glioma
• Intervention / Treatment: Radiation: Hypofractionated Stereotactic Radiotherapy; Drug: Anlotinib

Detailed Description

Original histopathologically proven diagnosis World Health Organization (WHO) Grade 3/4 glioma patients who underwent surgery, chemoradiotherapy and adjuvant chemotherapy (Stupp Protocol). Recurrence based on Response Assessment in Neuro-Oncology (RANO) criteria and/or histopathology. Intervention included CyberKnife hypofractionated stereotactic radiotherapy (25Gy/5fx) with Anlotinib once daily (12mg/d) on days 1-14 of a 21-day cycle.

• Study Type: Interventional
• Enrollment (Estimated): 22
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yun Guan, MD; Phone Number: +86 15301987553; Email: yguan10@fudan.edu.cn
• Study Contact Backup: Name: Xin Wang, MD; Phone Number: +86 13120557273; Email: wangxinck@fudan.edu.cn

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • CyberKnife Center, Department of Neurosurgery, Huashan Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18-70 years of age;
2. Karnofsky performance status (KPS) ≥ 60;
3. Original histopathologically proven diagnosis World Health Organization (WHO) Grade 4 glioma;
4. Underwent surgery, chemoradiotherapy and adjuvant chemotherapy (Stupp Protocol) after initial diagnosis, recurrent based on the Response Assessment in Neuro-Oncology (RANO) criteria and/or histopathologically proven;
5. Measurable disease;
6. Estimated survival of at least 3 months;
7. Hgb > 9 gm; absolute neutrophil count (ANC) > 1500/μl; platelets > 100,000; Creatinine < 1.5 times the upper limit of laboratory normal value; Bilirubin < 2 times the upper limit of laboratory normal value; serum glutamate pyruvate transaminase (SGPT) or serum glutamate oxaloacetate transaminase (SGOT) < 3 times the upper limit of laboratory normal value;
8. Signed informed consent form;
9. Agreed to participate the follow-up.

Exclusion Criteria:

1. Prior invasive malignancy unless disease free;
2. Received re-irradiation;
3. More than 3 relapses or evidence of subtentorial recurrent disease or tumor greater than 6 cm in maximum diameter;
4. Prior therapy with an inhibitor of vascular endothelial growth factor (VEGF) or VEGFR;
5. Pregnancy or or nursing mothers;
6. Participated in other trials after diagnosis of recurrent;
7. Influence factors toward oral medications;
8. Patients with CTCAE5.0 grade 3+ bleeding;
9. Suffering from severe cardiovascular disease: myocardial ischemia or myocardial infarction above grade II, poorly controlled arrhythmias (including men with QTc interval ≥ 450 ms, women ≥ 470 ms); according to NYHA criteria, grades III to IV Insufficient function, or cardiac color Doppler ultrasound examination indicates left ventricular ejection fraction (LVEF) <50%;
10. Long-term unhealed wounds or fractures;
11. History of organ transplantation;
12. Serious diseases that endanger patients' safety or affect patients' completion of research,according to the researchers' judgment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HSRT With Anlotinib; Hypofractionated stereotactic radiotherapy using CyberKnife 25Gy/5fx, 5 days a week for 1 week.; Anlotinib once daily (12mg/d) orally administered on days 1-14 of a 21-day cycle until disease progression or treatment intolerance.	Radiation: Hypofractionated Stereotactic Radiotherapy; Hypofractionated stereotactic radiotherapy (CyberKnife, 25Gy/5fx); Other Names: Hypofractionated Stereotactic Radiosurgery; Drug: Anlotinib; Anlotinib once daily (12mg/d) on days 1-14 of a 21-day cycle.; Other Names: AL3818

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Estimated using the Kaplan-Meier method	From the start of treatment to the date of death or the last follow-up, up to approximately 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive function	Mini-Mental State Exam (MMSE, score range 0 to 30) to evaluate the cognitive function. Any score of 24 or more (out of 30) indicates a normal cognition. Below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment.	Bimonthly up to intolerance the toxicity or PD, up to approximately 24 months
Progression-free survival (PFS)	Estimated using the Kaplan-Meier method	From the start of treatment to the date of disease progression or death, up to approximately 24 months
Objective response rate (ORR)	ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Assessment in Neuro-Oncology (RANO) prior to progression or any further therapy.	Bimonthly up to intolerance the toxicity or progressive disease (PD), up to approximately 24 months
Quality of Life score (QoL): European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) version 3.0	EORTC QLQ-C30 (version 3.0) questionnaire to evaluate the quality of life. All scales range in score from 0 to 100. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.	Bimonthly up to intolerance the toxicity or PD, up to approximately 24 months
Toxicity rate	Common Terminology Criteria for Adverse Events (CTCAE) 5.0 to assess the toxicity. Estimated using an exact binomial distribution together with 95% confidence interval.	Bimonthly up to intolerance the toxicity or PD, up to approximately 24 months

Collaborators and Investigators

• Sponsor: Huashan Hospital
• Investigators: Principal Investigator: Enmin Wang, MD, Huashan Hospital

Publications and helpful links

General Publications

• Wuthrick EJ, Curran WJ Jr, Camphausen K, Lin A, Glass J, Evans J, Andrews DW, Axelrod R, Shi W, Werner-Wasik M, Haacke EM, Hillman GG, Dicker AP. A pilot study of hypofractionated stereotactic radiation therapy and sunitinib in previously irradiated patients with recurrent high-grade glioma. Int J Radiat Oncol Biol Phys. 2014 Oct 1;90(2):369-75. doi: 10.1016/j.ijrobp.2014.05.034. Epub 2014 Aug 4.
• Clarke J, Neil E, Terziev R, Gutin P, Barani I, Kaley T, Lassman AB, Chan TA, Yamada J, DeAngelis L, Ballangrud A, Young R, Panageas KS, Beal K, Omuro A. Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma. Int J Radiat Oncol Biol Phys. 2017 Nov 15;99(4):797-804. doi: 10.1016/j.ijrobp.2017.06.2466. Epub 2017 Jun 30.
• Minniti G, Scaringi C, De Sanctis V, Lanzetta G, Falco T, Di Stefano D, Esposito V, Enrici RM. Hypofractionated stereotactic radiotherapy and continuous low-dose temozolomide in patients with recurrent or progressive malignant gliomas. J Neurooncol. 2013 Jan;111(2):187-94. doi: 10.1007/s11060-012-0999-9. Epub 2012 Nov 6.
• Guan Y, Li J, Gong X, Zhu H, Li C, Mei G, Liu X, Pan L, Dai J, Wang Y, Wang E, Liu Y, Wang X. Safety and Efficacy of Hypofractionated Stereotactic Radiotherapy with Anlotinib Targeted Therapy for Glioblastoma at the First Recurrence: A Preliminary Report. Brain Sci. 2022 Apr 2;12(4):471. doi: 10.3390/brainsci12040471.

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2019
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: December 11, 2019
• First Submitted That Met QC Criteria: December 12, 2019
• First Posted (Actual): December 13, 2019

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 4, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Hypofractionated Stereotactic Radiotherapy; Anlotinib; Recurrent High-grade Glioma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma
• Other Study ID Numbers: KY2019-525; HSCK-002 (Other Identifier: CyberKinfe Center, Huashan Hospital)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes