A pilot clinical study of apatinib plus irinotecan in patients with recurrent high-grade glioma: Clinical Trial/Experimental Study.

BACKGROUND: Malignant glioma is the most common primary malignant brain tumor that displays high vascularity, making vascular endothelial growth factor receptors become promising targets. This study was conducted to evaluate the efficacy and safety of apatinib, a new potent oral small-molecule tyrosine kinase inhibitor targeted vascular endothelial growth factor receptor 2, combined with irinotecan, in patients with recurrent malignant glioma.
METHODS: Ten patients with recurrent malignant glioma who were experiencing relapse after treatment of temozolomide were enrolled in this study. They received oral apatinib (500 mg qd) in conjunction with irinotecan (340 mg/m or 125 mg/m depending on use of enzyme-inducing antiepileptic drugs) for 6 cycles. After that the patients continued to take apatinib as maintenance. Dosage adjustment occurred in only 3 (30.0%) patients.
RESULTS: Among the 10 patients, 9 were available for the efficacy evaluation. There were 5 with partial response, 2 with stable disease and 2 with progressive disease. The objective response rate and the disease control rate (DCR) were 55% (5/9) and 78% (7/9), respectively. The median progress free survival time was 8.3 months. As for safety analysis, the most 3 common adverse events were gastrointestinal reaction (31.8%), hypertension (22.7%), and myelosuppression (18.0%).
CONCLUSION: Apatinib combined with irinotecan seems to be a promising therapeutic option for recurrent malignant glioma patients. Perspective clinical studies with adequate sample size are required to validate our results. TRIAL REGISTRATION: NCT02848794 /Ahead-BG306.

Introduction

Malignant glioma (MG) is one of the most common primary tumors in the central nervous system (CNS). Glioblastoma (GBM) accounts for 55% of glioma and is nearly always fatal. Standard treatment for newly diagnosed MG is surgery followed by radiotherapy and temozolomide (TMZ) with additional maintenance TMZ.[ The prognosis of MG is closely correlated with the pathological classification and World Health Organization (WHO) grade level. At the time of disease recurrence, tumors can progress to a more aggressive state and few treatment options are available. It was reported that survival after relapse and retreatment of MG was usually in the range of 6 to 8 months,[ and the median time to the second progression was 14 weeks.[ Treatment options for patients with recurrent GBM are limited and include repeat resection, RT, and systemic chemotherapy, such as TMZ, nitrosoureas, platinum-based regimens (carboplatin, cisplatin), cyclophosphamide, and irinotecan.[ Thus, recurrent GBM remains a largely unmet medical need, which highlights the need for novel and effective therapies.

Significant progress has been made in understanding the molecular characteristics of MG and the potential of targeted therapeutic approaches to the disease. Grade IV glioma have long been associated with pathologic hallmarks of extensive tumor necrosis; intense vascular proliferation; and increased expression of angiogenic factors, the most notable of which is vascular endothelial growth factor (VEGF). VEGF is an important regulator of angiogenesis and has been implicated in pathologic angiogenesis associated with tumor growth.[ It is highly expressed in GBM, and overexpression correlates with high-grade malignancy and poor prognosis.[ Consistent with being hypoxia driven, VEGF expression is localized to regions of GBM that border areas of necrosis.[

Bevacizumab neutralizes the biologic activity of VEGF and inhibits the binding of VEGF to its receptors on the surface of endothelial cells. It was granted accelerated approval by the US FDA in 2009 as a single agent or combined with irinotecan for patients with GBM with progressive disease (PD) following prior therapy.[ In the bevacizumab-alone and the bevacizumab-plus-irinotecan treatment, it was reported that estimated 6-month median progress free survival time (mPFS) rates were 42.6% and 50.3%, respectively; objective response rate (ORR) were 28.2% and 37.8%, respectively; and median overall survival (mOS) were 9.2 and 8.7 months, respectively.[

Apatinib (Hengrui Pharmaceutical Co, Ltd, P.R. China) is a small-molecule tyrosine kinase inhibitor (TKI) that highly selectively binds to and strongly inhibits vascular endothelial growth factor receptor 2 (VEGFR-2), which was approved for marketing in China in 2014 and admitted for the treatment of advanced gastric cancer patients who had failed after the second-line.[ Apatinib has demonstrated a substantial potential to be a new therapeutic option in a variety of tumor types.[ Given the current evidence for bevacizumab in recurrent GBM, we investigated the efficacy and safety of apatinib in combination with irinotecan in a pilot study in patients with recurrent MG who were experiencing relapse after treatment with TMZ.

Patients and methods

Study design

This multicentric single-arm, open-label, pilot phase II trial studied the efficacy and safety of apatinib plus irinotecan in high-grade recurrent MG.

The primary endpoint was PFS and secondary endpoints consisted of OS, ORR, and disease control rate (DCR). Complete response (CR), partial response (PR), stable disease (SD), and PD were measured by RECIST 1.1 criteria; PFS was defined as the time from the beginning of intervention treatment to PD or death from any cause; ORR = (CR + PR)/total number of cases × 100%; DCR = (CR + PR + SD)/total number of cases × 100%.

Eligible criteria

Eligible patients were ≥18 years old with histologically confirmed high-grade glioma (World Health Organization [WHO] Grade III or IV) for which they had received surgery and postoperative standard Stupp regimen, radiotherapy, or chemoradiotherapy. All experienced recurrence within 3 months and had measurable lesion by magnetic resonance imaging (MRI) confirmation. A minimum of 4 weeks was required from prior intracranial surgery, radiation, and other chemotherapeutic agents. Other key inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, acceptable cardiac, hematologic, hepatic and renal function (ie, hemoglobin ≥90 g/L, absolute neutrophil count ≥1.5 × 109 L−1, platelet count ≥80 × 109 L−1, bilirubin <1.5 × the upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase <2.5 × ULN or 5 × ULN if hepatic metastases exited, serum creatinine ≤1.5 × ULN or endogenous creatinine clearance rate >45 mL/min). A patient was excluded if there was evidence of ≥grade 2 pulmonary hemorrhage or ≥grade 3 hemorrhage anywhere else according to Common Terminology Criteria for Adverse Events (CTC AE) Version 3.0; the patient was a female who was pregnant or nursing; the patient with uncontrolled blood pressure with medication (>140/90 mm Hg); the patient receiving thrombolytics or anticoagulants; or the patient had any other condition that would make the treatment unsafe.

The study was approved by hospital ethics committee of the Affiliated Lianyungang Hospital of Xuzhou Medical University. All patients signed written informed consent before participating in the study.

Study treatment

Between May 2015 and November 2016, 10 patients were enrolled. Here we reported these treatment response and safety data (Table 1). The patients received irinotecan 125 mg/m2 or 340 mg/m2 depending on use of enzyme-inducing antiepileptic drugs of every 21-day cycle concurrently oral apatinib in the first 6 cycles and then apatinib maintenance therapy. The initial apatinib dose was 500 mg. If grade 3 or 4 toxicity occurred, the dose was adjusted to 250 mg. The majority of the patients had received prior surgery (90%). Half of patients had received concurrent chemoradiotherapy. After that 90% of them had received TMZ treatment.

Table 1

The clinical characteristics of 10 high-grade malignant gliomas patients treated with apatinib plus irinotecan.

Statistical methods

The method of Kaplan-Meier was used to estimate the distribution of survival. Statistical analyses were performed using SPSS version 16.0 (IBM, Armonk, NY).

Results

Efficacy

Tumor assessments were performed at baseline, and the response to therapy was determined by MRI and neurologic examination after 12 weeks until disease progression. The investigators utilized the MacDonald criteria to evaluate the MRI. Eight of 10 patients received at least 12 weeks of apatinib treatment and were eligible for the first efficacy analysis, and a patient, who had hypertension history, stopped treatment after 1 cycle of treatment due to severe hypertension. After reviewing the data of these 9 glioma patients, we found the mPFS was 8.3 months. Survival curves for PFS were estimated using the Kaplan-Meier method (Fig. 1). In total, there were 5 with PR, 2 with SD, and 2 with PD. Three patients were still alive, 1 patient was not applicable, and 1 patient was in treatment at the time of analysis. The ORR was 55% (5/9) and the DCR was 78% (7/9).

Figure 1

The efficacy evaluation of apatinib in high-grade malignant gliomas patients: PFS curve of apatinib combined with irinotecan therapy. PFS = progress free survival time.

The detailed data of 2 typical cases (1 case with GBM and another one with anaplastic astrocytoma) were shown as follows. One 40-year-old male patient was first diagnosed to have GBM at the top left temporal (WHO grade IV) in April 2014. He was treated by tumor resection, 6 weeks of concurrent chemoradiotherapy with TMZ 75 mg/m2/d, then maintenance therapy with TMZ 150 mg/m2/d. MRI examination showed disease recurrence in March 2015 (Fig. 2A). From March 2015 to June 2015 the patient was treated by combination of apatinib and irinotecan for 6 cycles (Table 1, No. 1) and maintenance with apatinib 500 mg/d until disease progress in April 2016. MRI reviews in the follow-up showed SD (Fig. 2B–D). The patient died in October 2016, and he got 13 months of PFS and 19 months of OS. The second patient is a 54-year-old female who was diagnosed to have anaplastic astrocytoma at the top right frontal (WHO grade III) in October 2012. Also, she was treated by tumor resection and postoperative standard Stupp regimen. The patient was hospitalized again because of disease recurrence in May 2016 (Fig. 3A). From May 2016 to October 2016 the combination of apatinib and irinotecan for 6 cycles was administrated (Table 1, No. 2) and then apatinib 500 mg/d as maintenance. Three MRI scans showed significant reduction of lesions and the evaluation results are PR, almost achieved CR (Fig. 3B–D).

Figure 2

MRI of the patient (no. 1) with glioblastoma: (A) pretreatment MRI scan; (B) posttreatment MRI scan after 3 mo; (C) posttreatment MRI scan after 11 mo; (D) MRI scan of second relapse in April 2016. MRI = magnetic resonance imaging.

Figure 3

MRI of the patient (no. 2) with anaplastic astrocytoma: (A) pretreatment MRI scan; (B) posttreatment MRI scan after 3 mo; (C) posttreatment MRI scan after 4 mo; (D) posttreatment MRI scan after 9 mo. MRI = magnetic resonance imaging.

Toxicity

Adverse events (AEs) encountered in the study were exhibited in Table 2. Overall, the grade 1 adverse reactions accounted for 45.4% of the total AEs. Grade 2, 3, and 4 AEs accounted for 27.3%, 22.7%, and 4.5%, respectively. Three patients experienced a reduction in the dose of the apatinib during the course of treatment for myelosuppression or hand-foot syndrome. One case of dose interruption occurred because of fecal occult blood (+). These AEs were quickly reduced and recovered after a dose reduction or interruption. So it is critical to detect the toxicity of the drug and adjust the dosage (from 500 mg to 250 mg as maintenance therapy) of the drug in time. The most frequently observed treatment-related AEs were as follows: gastrointestinal reaction (31.8%), hypertension (22.7%), and myelosuppression (18.0%) (Table 2). No drug-related AEs occurred in this study.

Table 2

Adverse events in the combination therapy of apatinib and irinotecan.

Discussion

This is the first clinical trial to investigate the safety and efficacy of apatinib combined with irinotecan in patients with recurrent MG. Our data demonstrated that apatinib in combination with irinotecan followed by single-agent apatinib maintenance was effective in PFS, ORR, and DCR, and were well tolerated in this Chinese population.

No standard treatment regimen has been proposed for recurrent MG so far. Treatment regimen was usually decided after the comprehensive assessments of general status of patients, location and size of recurrent tumor, and the efficacy of previous treatment. Single-agent irinotecan, which is a topoisomerase I inhibitor, is commonly used in the relapse setting with response rates of 15% or less, ORR is <10%, and mOS is 30 weeks or less.[ Single-agent bevacizumab and bevacizumab in combination with irinotecan had been demonstrated to have notable antitumor activity in pretreated patients with GBM in first or second relapse and the observed 6-month PFS rate far exceeded the 15% rate assumed for salvage chemotherapy and irinotecan alone.[

Both of apatinib and bevacizumab are antiangiogenic agents. However, apatinib is oral small molecular TKI, and its target is intracellular domain of VEGFR-2. It has some advantages over bevacizumab. It was reported that apatinib could promote tumor cell apoptosis via intracellular autocrine VEGF signaling, while bevacizumab could not.[ Moreover apatinib can reverse multidrug resistance (MDR) by inhibiting the function of multiple ABC transporters. P-glycoprotein (P-gp) is one type of ABC transporters, and its overexpression is common in cancer cells. It could actively efflux a wide variety of antineoplastic drugs including irinotecan. It had been demonstrated in vitro and in vivo that apatinib could reverse P-gp mediated MDR and increased efficacy of chemotherapeutic drugs.[ Based on these study results, we thought the patients with recurrent MG who have experienced chemotherapy might benefit from combination of apatinib and irinotecan.

Our preliminary results meet our expectation. The adverse effects of apatinib were tolerant and controllable. The most common AEs were reported as leukopenia, neutropenia, hypertension, proteinuria, hand-foot skin reaction, fatigue, and diarrhea. Those were similar with our study. A patient showed grade 4 hypertension and withdrew from the study because he had hypertension history before enrollment.

In conclusion, this study provides supporting evidence that apatinib exhibits objective efficacy combined with irinotecan in high-grade MG with manageable toxicity. Given the sample size was small in this study, the efficacy and safety of apatinib combined with irinotecan in patients with recurrent MG also requires further investigation in a boarder population.

Acknowledgment

We thank the patients and all investigators.