Efficacy and Tolerability of Cisplatin Plus Alternating Weekly Temozolomide in Recurrent High-grade Gliomas

Efficacy and Tolerability of Cisplatin Plus Alternating Weekly Temozolomide in Recurrent High-grade Gliomas: A Single-arm Prospective Phase II Clinical Study

Currently, the prognosis of recurrent high-grade gliomas is still dismal with no standard treatment protocol established. Cisplatin (CDDP), recommended by National Comprehensive Cancer Network (NCCN) as a chemotherapeutic agent in salvage treatment for recurrent high-grade gliomas, was shown to reduce O6-alkylguanine DNA-alkyl transferase (AGAT) activity and potentially capable of enhancing the antitumor effects of temozolomide (TMZ). Compared to the standard 5-day TMZ regimen, alternating weekly regimen that deliver more prolonged exposure of TMZ may lead to higher cumulative doses, and may deplete more O6-methylguanine DNA methyltransferase (MGMT), thus reducing the resistance of tumor cells to TMZ.

The investigators therefore initiate a single-arm Phase II study to evaluate the efficacy and tolerability of CDDP plus alternating weekly TMZ regimen in patients with recurrent high-grade gliomas.

Study Overview

• Status: Completed
• Conditions: High-grade Gliomas
• Intervention / Treatment: Drug: CDDP; Drug: Temozolomide

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Huashan Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histological diagnosis of primary tumor as high-grade gliomas (WHO III or IV)
• All patients should complete radiation therapy for primary gliomas.
• MRI showed unequivocal evidence of tumor recurrence or progression.
• The time to be enrolled should be more than 90 days after the radiation therapy.
• Written informed consent
• Eastern Cooperative Oncology Group(ECOG) score: 0-2
• The patients with recurrent gliomas were treated without dose-dense TMZ therapy before enrollment.
• Surgical interventions for recurrent gliomas are permitted and patients with no residual tumor are permitted

Exclusion Criteria:

• Abnormal function of liver or renal (value more than 1.5 fold normal upper limit)
• Blood routing: Hb < 90g/L, absolute neutrophil count≤1.5*10^9/L, platelet < 100*10^9/L
• Pregnant or lactating women
• Allergic to administered drugs
• Radiation therapy in the previous 90 days before enrollment
• The patients with recurrent gliomas were treated with dose-dense TMZ therapy before enrollment.
• Acute infection in need of antibiotics intravenously
• Participation in other clinical trials in the 90 days before enrollment

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: CDDP plus Temozolomide; Patients were treated with CDDP and TMZ. CDDP was administered iv from Day 1 to 3 with everyday dose of 30mg. TMZ was orally administered from Day 1 to 7 and Day 15 to 21, with everyday dose of 125mg/m2 (Level 2). The period of one chemotherapy cycle is 28 days. TMZ dose levels were listed in Table 1. Table 1 TMZ dose levels Dose levels Daily TMZ dose( mg/m2/d ) TMZ dose per cycle(mg/m2); 150 2100; 125 1750; 100 1400; 75 1050

Drug: CDDP; Drug: Temozolomide; If hematologic and nonhematologic toxicity assessed according to the Common Terminology Criteria for Adverse Events (CTCAE; version 4.0) from the previous cycle had been grade 0 or 1, then TMZ dose escalation to was allowed to the maximum of 150 mg/m2. If grade 4 hematologic toxicity or grade 3 nonhematologic toxicity had occurred, then TMZ dose was reduced in 25 mg/m2 steps. If grade 4 nonhematologic toxicity occurred, patient treatment was halted. If grade 4 hematologic toxicity or grade 3 nonhematologic toxicity continued when TMZ dose was in the minimum of 75 mg/m2, patient treatment was halted.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
progression free survival (PFS)	at 6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
overall survival(OS)	at 1 year and 2 years

Collaborators and Investigators

• Sponsor: Huashan Hospital
• Investigators: Study Chair: Zhiyong Qin, MD, Huashan Hospital; Principal Investigator: Ying Mao, MD, Huashan Hospital; Principal Investigator: Yu Yao, MD, Huashan Hospital; Principal Investigator: ZhenYu Zhang, Huashan Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2014
• Primary Completion (Actual): May 1, 2018
• Study Completion (Actual): June 1, 2018

Study Registration Dates

• First Submitted: September 28, 2014
• First Submitted That Met QC Criteria: October 8, 2014
• First Posted (Estimate): October 13, 2014

Study Record Updates

• Last Update Posted (Actual): July 17, 2018
• Last Update Submitted That Met QC Criteria: July 14, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: recurrent high-grade gliomas; cisplatin (CDDP); temozolomide (TMZ)
• 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; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: CAT001; Huashan H (Other Identifier: Huashan H)