Prolonged Use of Nimotuzumab in Children with Central Nervous System Tumors: Safety and Feasibility

Abstract

Primary brain tumors constitute the most frequent solid tumor of childhood. High expression of the epidermal growth factor receptor (EGFR) protein has been associated with tumor progression and enhanced tumorigenicity in adult and children gliomas. Nimotuzumab is a humanized antibody that targets the EGFR and has proven efficacy in adult and children gliomas. To provide a new therapeutic option for patients with active, poor prognosis central nervous system (CNS) tumors and to evaluate the feasibility and safety of long-term nimotuzumab therapy in children with diverse CNS tumors, an expanded access program was launched at the Juan Manuel Marquez hospital. Patients were required to be 18 or younger and have one CNS tumor: low-grade glioma (LGG) or high-grade glioma (HGG), brainstem glioma (BSG), ependymoma or primitive neuroectodermal tumor (PNET), and a Lansky or Karnofsky performance status ≥40. Treatment consisted of weekly nimotuzumab administered at 150 mg/m² for 12 weeks, continuing every 14 days in the absence of severe condition worsening or unacceptable toxicity. Nimotuzumab was administered alone or in combination with radiotherapy, chemotherapy, or both, depending on the tumor type, stage, and previous treatment. Eighty-eight patients, 39 with BSG, 25 with HGG, 9 with progressive LGG, 9 with anaplastic ependymomas, and 6 with other tumor types, including PNET, neuroblastoma, meduloblastoma, and thalamic tumors, were treated with the antibody. The mean number of nimotuzumab doses was 36, from 1 to 108. The most frequent adverse events were mild to moderate skin rash, mucositis, vomiting, seizures, hypothermia, hyperthermia, and paleness. One patient had a grade 3 mucositis, while the other had a grade 3 bleeding on surgery. Sixteen children stopped treatment after at least 2 years with stable disease, partial or complete response. All children were able to maintain the best response achieved on treatment after a 3-year interruption. In summary, this study shows the feasibility of very prolonged administration of nimotuzumab together with the lack of rebound effect after treatment cessation.

Introduction

Primary brain tumors are a different group of diseases that together constitute the most frequent solid tumor of childhood.^1,2 They are classified according to histology, but location and extension are important factors that influence prognosis and therapy.² Tumors can be categorized as infratentorial, supratentorial, parasellar, or spinal. Common infratentorial tumors (posterior fossa) include cerebellar astrocytomas, medulloblastomas, ependymomas, and brainstem gliomas (BSG), while the most frequent supratentorial tumors include low- and high-grade cerebral hemispheric astrocytomas, primitive neuroectodermal tumors (PNET), and ependymomas.³

Recent investigations into molecular neuro-oncology have helped to clarify the biology of children's tumors, allowing the evaluation of novel agents in clinical trials.⁴ One of the molecular markers overexpressed in pediatric central nervous system (CNS) tumors is the epidermal growth factor receptor (EGFR).⁵ This receptor contributes to the growth and survival of transformed cells, in addition to maintaining the normal cellular function.⁵ Aberrant patterns of expression of the c-erbB1 proto-oncogene (that codifies for EGFR protein) have been associated with tumor progression and enhanced tumorigenicity in adult and children high-grade gliomas (HGG), although the EGFR amplification is observed at a lesser degree in children as compared with adults.⁶

Nimotuzumab (also known as h-R3) is a humanized anti-EGFR monoclonal antibody (mAb)⁷ developed at the Center of Molecular Immunology in Havana, Cuba. Since 1998, nimotuzumab has been extensively tested in clinical trials for different tumor types. It is estimated that more than 40,000 patients have been treated with the antibody worldwide.^8

–14 Currently, nimotuzumab is indicated for the treatment of patients bearing advanced head and neck and nasopharyngeal tumors, advanced esophageal cancer, adult HGG, recurrent glioma in children, and has been registered in more than 30 developing countries.¹⁵

Nimotuzumab has been evaluated in several trials in children with HGG.^8,9 A multicenter Phase II trial was conducted to evaluate the feasibility and efficacy of nimotuzumab for treating resistant HGG in children and adolescents. Pediatric patients were eligible if they had confirmed glioblastoma multiforme, anaplastic astrocytoma, or diffuse intrinsic pontine glioma (DIPG). Treatment included an induction consisting of 150 mg/m² nimotuzumab once a week for 6 weeks and a consolidation therapy of four infusions at the same dose in 3 weekly intervals in patients with nonprogressive disease. In total, 47 patients aged 4–17 years were enrolled in this study. Seventeen of the 45 patients evaluable for response showed disease control. The best response was achieved in DIPG, where 11 out of 21 children reached disease control. The median overall survival was significantly better for responders (median 10 months) than for nonresponders (median 3.2 months). No severe side effects related to the medication under study were observed.⁸

Since nimotuzumab showed a promising efficacy in heavily pretreated children with HGG, an exploratory trial was designed in 2006 to assess the safety and efficacy of nimotuzumab in newly diagnosed DIPGs in combination with standard radiotherapy. From 2006 to 2007, 41 patients aged 3–16 years were enrolled in the study. Treatment consisted of an induction therapy (weekly infusions of 150 mg/m² of nimotuzumab for 12 weeks), with concomitant radiotherapy up to a total dose of 54 Gy. In cases of nonprogressive disease, a consolidation therapy with nimotuzumab every 2 weeks was continued until disease progression. The disease control rate was 75.6%. The median overall survival was 9.6 months, with a significantly longer survival rate in radiological responders than in nonresponders (p=0.004).⁹

Nimotuzumab has been also used at the MD Anderson Cancer Center for the treatment of children with recurrent DIPG. According Wolff et al.,¹⁶ nimotuzumab was among the drugs associated with a longer event-free survival.

Since nimotuzumab has a proven efficacy in adult glioma¹⁰ and in children's recurrent glioma and has preliminary evidence of activity in children with newly diagnosed glioma, an expanded access program for pediatric patients with CNS tumors and poor prognosis was launched at the onco-hematology service of the Juan Manuel Marquez hospital. The aim of this study was to provide a new therapeutic option for children with active (residual or recurring) CNS tumors and to evaluate the feasibility and safety of long-term nimotuzumab therapy in patients with diverse CNS tumors. The study assessed the acceptability of a very durable therapy with an intravenous drug by the children and parents, the willingness of the research team to recruit and treat the children with a novel antibody for a very prolonged time, the number of eligible patients, and the treatment compliance rates.

Materials and Methods

Patients 18 years or younger were required to have one CNS tumor: a low-grade glioma (LGG) or HGG, BSG, ependymoma, or PNET (medulloblastoma); histologic verification of the malignancy at original diagnosis (excluding intrinsic brainstem tumors); measurable disease by magnetic resonance imaging (MRI) or CT scan; a Lansky or Karnofsky performance status ≥40, and an adequate bone marrow, renal, and liver function, defined as hemoglobin ≥10 g/L, total leukocytes ≥2×10⁹ cells/L, platelets ≥100×10⁹/L, functional hepatic tests within normal limits demonstrated by GPT, GOT ≤2.5 times the upper reference value, and renal function: seric creatinine ≤1.5 times the upper reference value.

Before enrollment in the study, maximal surgical resection was intended for all children, but surgery was limited in some cases due to the tumor extension or patient comorbidities.

Treatment consisted of weekly nimotuzumab administered at 150 mg/m² for 12 weeks, continuing every 14 days in the absence of severe patient condition worsening or unacceptable toxicity. Nimotuzumab was administered as monotherapy or in combination with external beam radiotherapy, chemotherapy, or both. Chemotherapy for patients with HGG consisted of four to six cycles of prednisone, procarbazine, cyclophosphamide, and cisplatin; patients with progressive or relapsing LGG received vincristine, carboplatin, and etoposide; and patients bearing ependymomas were treated with cyclophosphamide, vincristine, and etoposide for six cycles. The majority of the children with BSG received nimotuzumab in combination with radiotherapy, while 9 patients were treated with the antibody together with prednisone, procarbazine, cyclophosphamide, and cisplatin. Patients with relapsing tumors received the antibody in combination with irradiation, chemotherapy (ifosfamide, carboplatin, and etoposide), or as monotherapy.

To evaluate safety, a complete physical examination, including detailed neurological assessment and laboratory studies (hematology and biochemistry), was obtained before treatment and every 3 months, thereafter. Toxicities were graded according to the National Cancer Institutes’ Common Toxicity Criteria (version 3.0). For those patients receiving more than 40 doses of nimotuzumab, additional tests, including cardiac function (electrocardiogram/ventricular ejection fraction) and renal function (glomerular filtration), were done every 3 months.

Although evaluating the efficacy of nimotuzumab in this heterogeneous population was not the aim of this study, MRI or CT scans were obtained before therapy and at 12-week intervals to monitor the tumor size. The results of the efficacy evaluation will be reported in separate articles according to the tumor type. Survival analysis was done using the Kaplan–Meier method.

The investigation was conducted under the principles embodied in the Helsinki declaration. The Institutional Review Board of the Juan Manuel Marquez hospital approved the study. Informed consent was obtained before study entry from each patient or parent/legal guardian.

Results

Eighty-eight patients, 27 males and 61 females, received nimotuzumab at the onco-hematology service of the Juan Manuel Marquez Hospital, between 2007 and 2011. The study included 39 children with BSG, 25 patients with supratentorial HGG, 9 patients with progressive LGG, 9 patients with anaplastic ependymomas, and 6 patients with other tumor types, including PNET, neuroblastoma, meduloblastoma, and thalamic tumors. The mean age was 10 years (2–18 years). Fourteen patients above 16 provided their informed consent to participate in the expanded access program, while for 74 children under 16, the parent or legal guardian signed the informed consent form. All children had a Karnofsky or Lansky performance status of 40 or more. Forty-five children had surgery before enrollment: HGG (18), ependymomas (9), LGG (7), BSG (5), medullablastomas (3), PNET (1), tallamic tumor (1), and neuroblastoma (1). All patients had poor prognosis on account of incomplete tumor resection or inoperability. Children received nimotuzumab in combination with radiotherapy (43 children), chemotherapy (35 patients), radiochemotherapy (1 child), or as monotherapy (9 patients) (Fig. 1).

FIG. 1.

Flow diagram by disease groups in new versus recurrent patients, and treatment administered in combination with nimotuzumab. BSG, brainstem glioma; CPT, chemotherapy; HHG, high-grade glioma; LGG, low-grade glioma; PNET, primitive neuroectodermal tumors; RTP, radiotherapy.

Children were treated with nimotuzumab until severe deterioration of the performance status (Karnofsky or Lansky performance status ≤20) or until uncontrollable toxicity. Only one patient interrupted nimotuzumab after 23 doses due to an adverse event. This patient had a vasovagal event and vomiting. Duration of nimotuzumab therapy ranged from 14 days to 48 months. The mean number of nimotuzumab doses was 36 (median 21), from 1 to 108 doses. Forty-four children (50%) received more than 20 doses of nimotuzumab, 26 patients (29.5%) received more than 40 doses, while 9 patients (10.2%) had more than 90 antibody administrations.

Efficacy assessment in such heterogeneous populations was not the aim of the expanded access program. To preliminarily assess the benefit of treatment with nimotuzumab, the overall survival by tumor type was estimated. The median survival time for children with BSG and ependymomas was 17.26 months (95% CI: 0.83–39.9) and 52.20 months (95% CI: 22.8–81.5), respectively. The mean survival for children bearing supratentorial LGG and HGG was 52.9 months (95% CI: 33.1–72.6) and 38.5 months (95% CI: 26.1–51.05). Children carrying PNET, neuroblastoma, medulloblastoma, and thalamic tumors had a mean survival time of 26.17 months (95% CI: 15.2–37.1). The median survival time has not been reached for patients bearing LGG and HGG, PNET, neuroblastoma, medulloblastoma, and thalamic tumors.

Nimotuzumab was very well tolerated. Five patients developed mild to moderate skin rash (9 episodes) (Fig. 2), 3 subjects had grade 1 or 2 mucositis, and 1 patient developed grade 3 mucositis that did not end up in treatment discontinuation. This patient was receiving nimotuzumab alone and had 8 antibody doses before developing grade 3 mucositis. The mucositis initially presented as erythema of the oral mucosa that progressed to erosion and ulceration. Bacterial or viral cultures were not obtained from the ulcerated lesions. The lesions healed 2–3 weeks later and treatment with the antibody was not interrupted. This patient received 14 doses of the antibody.

FIG. 2.

Moderate skin rash developed after nimotuzumab exposure.

Other related adverse events consisted of grade 1 or 2 vomiting (4 patients), seizures (3 patients), hypothermia (3 patients), hyperthermia (3 patients), paleness (3 patients), bronchospasm (2 patients), chills (2 patients), transaminase elevation (2 patients), vasovagal event, nausea, headache, and cough (1 patient each). Toxicity did not increase with continual nimotuzumab exposure. The frequency and severity of these related adverse events is described in Table 1.

Table 1.

Nimotuzumab-Related Adverse Events

	Intensity
	Grade 1–2	Grade 3–4
Skin rash	5 (5.68%)	0 (0%)
Mucositis	3 (3.40%)	1 (1.13%)
Vomiting	4 (4.54%)	0 (0%)
Seizures	3 (3.40%)	0 (0%)
Hypothermia	3 (3.40%)	0 (0%)
Hyperthermia	3 (3.40%)	0 (0%)
Paleness	3 (3.40%)	0 (0%)
Bronchospasm	2 (2.27%)	0 (0%)
Chills	2 (2.27%)	0 (0%)
Transaminase elevation	2 (2.27%)	0 (0%)
Vasovagal event	1 (1.13%)	0 (0%)
Nausea	1 (1.13%)	0 (0%)
Headache	1 (1.13%)	0 (0%)
Cough	1 (1.13%)	0 (0%)
Bleeding (on surgery)	0 (0%)	1 (1.13%)

Number of patients and frequency.

Seven patients had a surgical procedure while receiving nimotuzumab. Only one patient had a complication in the wound healing process. This 9-year-old girl bearing an anaplasic ependymoma had a second surgery after a tumor relapse. This patient was receiving nimotuzumab for 273 days (20 doses) before surgery and had a grade 3 hemorrhage/bleeding complication requiring blood transfusion during surgery. This patient completely recovered and no further wound healing problems were detected. She was also receiving treatment with steroids at high dose, at the moment of surgery. The remaining patients did not show any wound-healing complications.

All children receiving more than 40 doses of nimotuzumab had a cardiac and renal function assessment every 3 months. No cardiac or liver function alterations were detected in these 26 children. None of the patients developed a second primary tumor.

Overall, children and parents reacted very favorably to the repeated antibody infusions. Apart from chemotherapy that causes a lot of discomfort, nimotuzumab infusions were very well tolerated and children did not need hospitalization. Patients were enrolled very fast and the treatment compliance rate was very high.

Nimotuzumab administration was interrupted after at least 2 years of treatment for all patients with stable disease, partial or complete response. In total, 16 children (6 HGG, 3 LGG, 3 ependymomas, and 4 BSG) interrupted nimotuzumab after receiving nimotuzumab for 2–4 years. Remarkably, none of the children has progressed after 3 years of treatment discontinuation: 10 patients are in complete response, while 6 patients have disease stabilization, according contrast-enhanced MRI. All children were able to maintain the best response achieved on treatment. No rebound effect has been seen.

Discussion

Children with primary brain tumors represent a major therapy challenge that requires the coordinated efforts of specialists in fields such as neurosurgery, neuropathology, radiation oncology, pediatric oncology, and neuro-oncology.¹⁷ Since EGFR expression has been found to correlate with enhanced malignant potential for pediatric brain tumors, the use of EGFR antagonists is a very appealing therapeutic strategy.⁵

Nimotuzumab is a humanized anti-EGFR antibody approved for the treatment of adults with newly diagnosed astrocytoma and children with recurrent glioma. Cancer, as a serious chronic disease may require long-term treatment or multiple treatments over a long period of time.¹⁸ Accordingly, evaluating the toxicity of long-lasting treatments is essential. The main goal of this expanded access program was to offer a potentially active drug to children carrying poor prognosis CNS tumors and to evaluate the feasibility and tolerability of prolonged therapy with nimotuzumab in children with several brain tumors. All patients had active tumors at the moment of enrollment.

To our knowledge, this study describes one of the lengthiest treatments ever administered to children with brain tumors. Globally, nimotuzumab was very well tolerated in spite of the overlong administration (median number of doses, 21). The antibody was not discontinued at the moment of radiologic progression if the patient remained with satisfactory performance status. Adverse events consisted mostly of mild or moderate infusion reactions and constituted the cause of interruption for only one patient. Remarkably, 16 children were treated for 2–4 years and received up to 106 doses of the antibody. Two grade 3 events consisting of mucositis and bleeding were reported, while the most frequent related toxicity was mild to moderate skin rash (5.6%). This finding is in agreement with the previously described safety profile of the antibody. Nimotuzumab is the safest anti-EGFR drug since it binds preferentially to those tissues with high EGFR expression, sparing normal tissues like the skin, liver, and kidneys.^19,20

Usually, short- and long-term toxicities of some treatments constitute a significant problem for children with brain tumors. Temozolomide, which is commonly administered for 6 months, is associated with prolonged thrombocytopenia, neutropenia, lymphopenia, and pneumocystis pneumonia.^21,22 Hypertension and proteinuria are characteristic adverse events associated with bevacizumab (avastin) in child therapy. Fatal adverse events such as intracranial hemorrhage and venous thromboembolism are reported in patients treated with this antibody.²³ Other adverse events associated, with avastin therapy for 24 months to children with recurrent LGGs, have been grade 3 proteinuria, primary inflammatory arthritis, and somnolence.²⁴ Gefitinib, a small tyrosine kinase inhibitor targeting EGFR, has been used in children with newly diagnosed BSG, continuing for up to 13 monthly courses. Four patients were withdrawn from the study for dose-limiting toxicity. Grade 3 adverse events consisted in lymphopenia, neutropenia, gastrointestinal toxicity, infection, and pulmonary, renal, and skin toxicity.²⁵ In spite of the long-term therapy, nimotuzumab was much better tolerated than the above referred treatments.

Long-lasting treatment with nimotuzumab yielded preliminary survival benefits for all tumor subtypes, as compared with historical control data (4). However, this result should be interpreted with caution provided the heterogeneity of patient population and treatment modalities used with nimotuzumab.

Nimotuzumab has been interrupted now for 3 years in 16 children who received the antibody for 4 years. None of the children has progressed so far. Ten of these patients have no evidence of disease, while 6 patients still have active, but nonprogressing tumors requiring MRI with spectroscopy. This result is unexpected, considering previous findings with other biologics. A rebound phenomenon such as rapid tumor regrowth is sometimes observed after the discontinuation of bevacizumab therapy. Zuniga et al. had described that after withdrawal of bevacizumab in patients with recurrent HGG, there was a rapid tumor regrowth or rebound radiographic phenomenon with accelerated clinical decline.²⁶ In a separate trial, 13/14 LGG patients progressed after stopping bevacizumab at a median of 5 months. Authors concluded that nearly all tumors progress once treatment is discontinued.²⁴

In summary, this study proves the feasibility of the very prolonged administration of nimotuzumab together with the lack of rebound effect. The efficacy of nimotuzumab and the optimal duration of therapy remain to be proven in well-designed clinical trials.

Footnotes

Disclosure Statement

There are no existing financial conflicts.

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