Elemene Plus Stupp Protocol Versus Stupp Protocol Alone for Newly-diagnosed Glioblastoma

Efficacy and Safety of Elemene Plus Stupp Protocol Versus Stupp Protocol Alone for Newly-diagnosed Glioblastoma: A Multi-center Phase II Randomized Controlled Trial

The goal of this phase II randomized clinical trial is to compare the safety and efficacy of Elemene plus Stupp Protocol (the new protocol) and Stupp Protocol alone (the standard protocol) in patients with newly-diagnosed glioblastomas (ndGBMs). The main questions to answer are:

• Whether the new treatment protocol (Elemene plus Stupp Protocol) is clinically safe for ndGBM patients.
• Whether the new treatment protocol (Elemene plus Stupp Protocol) brings better survival benefits for ndGBM patients compared to the standard-of-care Stupp Protocol.

Study participants will be enrolled in 5 hospitals in China and randomly assigned to receive either the new protocol or the standard protocol. The overall survival (OS) rate in the 12th month, the progression-free survival (PFS) rate in the 6th month, OS, PFS, and adverse events assessed by the CTCAE (Common Terminology Criteria for Adverse Events) will be evaluated for all patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Glioblastoma, IDH-wildtype
• Intervention / Treatment: Drug: Placebo; Drug: Elemene

Detailed Description

Glioblastoma (GBM) is a WHO grade 4 adult-type diffuse glioma and the most common malignant, primary brain tumor with a 5-year overall survival (OS) of only ~5% in real-world studies. The Stupp Protocol, consisting of fractionated focal irradiation in daily fractions of 2 Gy given 5 days/week for 6 weeks (a total of 60 Gy), plus concomitant daily temozolomide (TMZ, 75 mg/m2/day, 7 days/week from the first to the last day of radiotherapy) after maximal safe tumor resection, followed by six cycles of adjuvant TMZ (150-200 mg/m2/day for 5 days during each 28-day cycle), has been adopted as the standard of care for patients with newly-diagnosed GBMs (ndGBMs) since 2005.

However, there have been no other treatment modalities except for tumor treating fields (TTFields) that have brought survival benefits for ndGBM patients during the past two decades. Since TTFields therapy is super expensive (about 1 million yuan/0.15 million dollars per year) and fewer than 10% of ndGBM patients can afford it around the globe, the Stupp Protocol is still being used as the first-line and the most widely-adopted treatment option for ndGBM patients around the world.

Elemene, a Chinese anti-tumor medicine extracted from the plant Curcuma Wenyujin, has been isolated as a monomeric drug and has a broad-spectrum anti-tumor effect in various cancers, such as lung cancer, breast carcinoma, leukemia, and ovarian cancer. In recent years, its application in GBMs as revealed in the preliminary retrospective studies published in Chinese Journals and a few English Journals have shown survival benefits with acceptable toxicity. Elemene can pass through the blood-brain barrier because of its small molecular weight and lipid solubility and has synergistic anti-tumor effects with TMZ and radiotherapy for GBM patients. Several in vitro studies also have shown that Elemene could inhibit GBM cell proliferation, promote cell differentiation, and induce cancer cell apoptosis.

All these findings from the above studies have indicated the potential survival benefits of Elemene in treating ndGBMs. However, so far, no clinical trials have tested the efficacy and safety of the new treatment protocol (Elemene added to the Stupp Protocol) for ndGBMs compared with the conventional Stupp protocol.

In this study, the investigators aimed to launch a multi-center, phase II, randomized, controlled clinical trial to test the safety and efficacy of Elemene plus Stupp Protocol compared with Stupp Protocol alone for ndGBM patients.

• Study Type: Interventional
• Enrollment (Anticipated): 74
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yu Wang, MD, PhD; Phone Number: 01069152530; Email: ywang@pumch.cn

Study Locations

• China
  • Beijing, China
    • Peking Union Medical College Hospital
    • Contact: Yu Wang, MD, PhD; Email: ywang@pumch.cn
    • Contact: Xiaopeng Guo, MD; Email: guoxiaopeng_pumch@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• newly-diagnosed supratentorial glioblastoma, IDH-wildtype, WHO grade 4
• male or female adult patients < 70 years old
• Karnofsky performance status (KPS) score higher or equal to 60
• a minimum life expectancy of 12 weeks
• adequate bone marrow function (white blood cell ≥ 2.0 × 10^9/L, neutrophils ≥ 1.5 × 10^9/L, hemoglobin ≥ 90 g/L, and platelets ≥ 100 × 10^9/L)
• adequate hepatic function (direct bilirubin and indirect bilirubin ≤ 1.5 mg/dL, and alanine aminotransferase [ALT] and aspartate aminotransferase [AST] < 4 times the upper limit of normal)
• adequate renal function (creatinine < 80 umol/L)
• adequate coagulation function (international normalized ratio [INR] ≤ 1.3)
• voluntary to participate in this trial, complete all pre-specified treatment regimens, and complete required follow-up

Exclusion Criteria:

• unwilling to participate or accept the pre-specified treatment regimen and required follow-up schedule
• prior treatment (surgery, radiotherapy, chemotherapy) for glioblastoma
• pregnant or lactating patients
• allergic to Elemene and its components
• severe liver and kidney dysfunction, coagulation disorders, or decreased hematopoietic ability
• serious infection
• serious hyperlipidaemia
• medical illness or psychosocial circumstance that may compromise participant safety

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Stupp Protocol; Patients receive maximal safe tumor resection, concurrent radiochemotherapy with TMZ, and adjuvant TMZ (the Stupp Protocol). Placebo that has the same appearance and flavor with Elemene is given 20ml orally, three times a day for 28 consecutive days (as one cycle) for 6 cycles, during the phase of adjuvant TMZ administration.	Drug: Placebo; Placebo (with the same appearance and flavor with Elemene) of 20ml is given orally, three times a day, for 28 consecutive days (as a cycle), for 6 cycles.
Experimental: Ele-Stupp Protocol; Patients receive maximal safe tumor resection, concurrent radiochemotherapy with TMZ, and adjuvant TMZ (the Stupp Protocol). Elemene is given 20ml:176mg orally, three times a day for 28 consecutive days (as one cycle) for 6 cycles, during the phase of adjuvant TMZ administration.	Drug: Elemene; Elemene of 20ml is given orally, three times a day, for 28 consecutive days (as a cycle), for 6 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The overall survival (OS) rate in the 12th month (12m-OS)	The rate of patients who are still alive in the 12th month after randomization	12th month after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The overall survival (OS)	The survival time from randomization to death from any cause	From randomization to death, assessed up to 24 months
The progression-free survival (PFS)	The survival time from randomization to objective tumor progression or death	From randomization to objective tumor progression or death, assessed up to 24 months
The progression-free survival (PFS) rate in the 6th month (6m-OS)	The rate of patients who have no objective tumor progression in the 6th month after randomization	6th month after randomization
Adverse events	Adverse events evaluated using the CTCAE version 4.03	From randomization to death, assessed up to 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subgroup analyses for primary and secondary outcomes	Subgroups to be divided by sex, age, molecular alterations, KPS score, and extent of resection.	From randomization to death, assessed up to 24 months

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital
• Investigators: Study Chair: Wenbin Ma, MD, Peking Union Medical College Hospital; Principal Investigator: Yu Wang, MD, PHD, Peking Union Medical College Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2023
• Primary Completion (Anticipated): December 1, 2026
• Study Completion (Anticipated): May 1, 2027

Study Registration Dates

• First Submitted: April 9, 2023
• First Submitted That Met QC Criteria: April 22, 2023
• First Posted (Estimate): May 4, 2023

Study Record Updates

• Last Update Posted (Estimate): May 4, 2023
• Last Update Submitted That Met QC Criteria: April 22, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma
• Other Study ID Numbers: K3649-I-23PJ571

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data (IPD) can be made available upon publication.
• IPD Sharing Time Frame: Upon publication.
• IPD Sharing Access Criteria: Via communication with the corresponding authors.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No