Exploring the safety and efficacy of a novel drug combination for treating recurrent high-grade astrocytomas: A phase 1 clinical trial
Original author: Wu J, et al. (2021) (DOI: 10.1158/1078-0432.CCR-20-4730)
Content writer – Clinical
February 01, 2023
Astrocytoma is a type of brain tumor that originates from star-shaped glial cells in the brain called astrocytes. According to the WHO classification, they are classified into four grades based on the degree of malignancy and aggressiveness:
WHO Grade I or pilocytic astrocytoma
WHO Grade II or diffuse astrocytoma
WHO Grade III or anaplastic astrocytoma
WHO Grade IV or glioblastoma multiforme
Pilocytic astrocytoma and diffuse astrocytoma are considered low-grade astrocytomas, while anaplastic astrocytoma and glioblastoma multiforme are considered high-grade astrocytomas. High-grade astrocytomas are difficult to treat due to their aggressive nature and resistance to therapy. These tumors often recur even after initial treatment, decreasing long-term survival rates. Current treatment options are often limited and may not effectively target the underlying biology of these tumors, leading to a need for more effective and targeted therapies.
Zotiraciclib is an oral small-molecule inhibitor of cyclin-dependent kinases, specifically targeting CDK9. So far, the clinical investigations of its activity are mostly limited to hematological malignancies. Previously, the authors of the present study investigated the effects of zotiraciclib alone and in combination with temozolomide (TMZ) on glioma cell lines and animal models. They found that:
Zotiraciclib penetrates the blood-brain barrier.
It suppresses transcription by inhibiting CDK9.
It decreases ATP by suppressing glycolysis and causing mitochondrial dysfunction, which leads to the selective killing of glioma cells.
It synergistically works with TMZ on both, TMZ-sensitive and resistant cells.
It increases the survival of the orthotopic glioblastoma mouse model.
Based on these preclinical findings, they launched a phase 1 clinical trial looking into the safety and efficacy of zotiraciclib plus TMZ in recurrent glioblastoma and anaplastic astrocytoma patients (NCT02942264). Described below is a summary of the clinical trial.
The primary objective was to determine the optimal dose and schedule by assessing safety through dose-limiting toxicity (DLT). Secondary endpoints included a progression-free survival rate at 4 months and patient-reported outcomes. The trial consisted of 2 phases; dose escalation and cohort expansion. Firstly, patients were randomly assigned to two arms, receiving either a dose-dense or metronomic TMZ schedule, in combination with zotiraciclib at different dose levels (150mg, 200mg, 250mg, 300mg). A Bayesian Optimal Interval design was used to establish the maximum tolerated dose (MTD). In the second phase, the trial was expanded in both arms and the patients were randomized to receive the MTD combination regimen until 18 patients have been treated at each dose.
This clinical trial was conducted at the Center for Cancer Research of the National Cancer Institute (NCI), Bethesda, Maryland, USA. All the patients recruited were:
Over 18 years old.
Had a histologically confirmed diagnosis of either anaplastic astrocytoma (intact 1p/19q chromosome) or glioblastoma/gliosarcoma.
Two or fewer prior relapses.
Not taking any drug that affects the inducers or inhibitors of CYP1A2 or 3A4.
Patients in the dose-dense TMZ arm were given oral TMZ 125mg/m2 daily on days 1 to 7 and then 15 to 21. In the metronomic arm, it was given 50mg/m2 daily. Zotiraciclib was given 200mg per day orally on days 1, 12, 15, and 26 on a 28-day cycle, after a single initial dose given 3 days before cycle 1/day1. The BOIN design guided the dose escalation and de-escalation of zotiraciclib in each arm. After the MTD of zotiraciclib was determined, patients were randomized to receive zotiraciclib at the MTD combined with either dose-dense or metronomic TMZ.
The trial assessed patients through physical examinations, toxicity evaluations, and laboratory investigations. Magnetic resonance imaging evaluation of the patient’s brain was completed at the baseline and every 2 cycles to determine the treatment response according to Response Assessment in Neuro-Oncology (RANO) Criteria. Toxicities were graded using the Common Terminology Criteria for Adverse Events (CTCAE Version 4.0) and the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) was used to assess symptoms severity and interference in the patient's life.
During the cohort expansion phase of the trial, patients participated in pharmacokinetics (PK), pharmacogenetics (PG), and neutrophil analysis. Blood samples were collected at various time points to measure complete blood count (CBC) with differential, blood smear, neutrophil chemotaxis, reactive oxygen species (ROS) production, and neutrophil cell surface markers. PK was characterized by measuring the plasma concentration of zotiraciclib using a liquid chromatography-tandem mass spectrometry assay and analyzing parameters such as the area under the curve (AUC), maximum plasma concentration (Cmax), and half-life T1/2. A baseline blood sample per patient was analyzed for the genotype of drug-metabolizing enzymes and transporters to compare patient exposures with different genotype groups.
Results & discussion
The study enrolled 53 patients between December 2016 and December 2019, 40 in the dose-escalation phase and 13 in the cohort expansion phase. The safety results showed that the DLT rate is proportional to the dosage of zotiraciclib in both arms. The non-hematologic DLTs included fatigue, elevated liver enzymes, and diarrhea, while neutropenia was the only hematologic DLT. Zotiraciclib-induced neutropenia was of special interest because it occurred after 24 hours of taking the drug and resolved within 72 hours. The most common non-hematologic adverse effects were alanine aminotransferase and aspartate aminotransferase elevation, diarrhea, fatigue, and nausea.
In terms of primary and secondary outcomes:
250mg of zotiraciclib was established as the MTD in both arms.
PFS4 was 0.40 in Arm 1 (dose-dense TMZ) and 0.25 in Arm 2 (metronomic TMZ).
Based on this, the dose-dense TMZ combined with 250mg zotiraciclib was selected as the optimal dose and schedule for future studies.
The combination of zotiraciclib and temozolomide showed promising results in terms of safety and tolerability. The study indicated that transient neutropenia is not severe enough to stop the further development of zotiraciclib. Further investigation with a larger sample size is needed to confirm these results.
Impact of the research
This study contributes to the ongoing research on treatment options for malignant astrocytomas, specifically glioblastoma, and anaplastic astrocytoma. The combination of zotiraciclib with temozolomide, a standard chemotherapy drug, shows promising results in terms of safety and tolerability. These findings pave the way for further investigations, including larger phase 2 and 3 clinical trials, to confirm the efficacy of this combination therapy and potentially improve outcomes for patients with recurrent high-grade astrocytomas.