Neuro-Oncology

Neuro-Oncology 16(11), 1554– 1559, 2014

doi:10.1093/neuonc/nou091
Advance Access date 20 May 2014

Phase 2 study of safety and efficacy of nimotuzumab in pediatric

patients with progressive diffuse intrinsic pontine glioma
Ute Bartels, Johannes Wolff, Lia Gore, Ira Dunkel, Stephen Gilheeney, Jeffrey Allen, Stewart Goldman, Michal Yalon,
Roger J. Packer, David N. Korones, Amy Smith, Kenneth Cohen, John Kuttesch, Douglas Strother, Sylvain Baruchel,
Janet Gammon, Mark Kowalski, and Eric Bouffet

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The Hospital for Sick Children, Toronto, Ontario, Canada (U.B., S.B., J.G., E.B.); The MD Anderson Cancer Center, Houston, Texas (J.W.);
Children’s Hospital Colorado, Anschutz Medical Campus, Aurora, Colorado (L.G.); Memorial Sloan Kettering Cancer Center, New York,
New York (I.D., S.G.); NYU Langone Medical Center, New York, New York (J.A.); Ann & Robert H. Lurie Children’s Hospital of Chicago
Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Sheba Medical Center, Tel Hashomer, Israel (M.Y.); Children’s
National Medical Center, Washington, DC (R.J.P.); University of Rochester Medical Center, Rochester, New York (D.N.K.); University of Florida,
Gainesville, Florida (A.S.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.C.); Vanderbilt Children
Hospital, Nashville, Tenneessee (J.K.); Alberta Children’s Hospital, Calgary, Alberta, Canada (D.S.); YM Biosciences Inc, Mississauga, Ontario,
Canada (M.K.)

Corresponding Author: Ute Bartels, MD, The Hospital for Sick Children, Division of Haematology/Oncology, 555 University Ave, Toronto, ON M5G 1X8,
Canada (ute.bartels@sickkids.ca).

Background. The prognosis of diffuse intrinsic pontine glioma (DIPG) remains poor, with no drug proven to be effective.
Methods. Patients with clinically and radiologically confirmed, centrally reviewed DIPG, who had failed standard first-line therapy were
eligible for this multicenter phase II trial. The anti-epidermal growth factor receptor (EGFR) antibody, nimotuzumab (150 mg/m2), was
administered intravenously once weekly from weeks 1 to 7 and once every 2 weeks from weeks 8 to 18. Response evaluation was based
on clinical and MRI assessments. Patients with partial response (PR) or stable disease (SD) were allowed to continue nimotuzumab.
Results. Forty-four patients received at least one dose of nimotuzumab (male/female, 20/24; median age, 6.0 years; range, 3.0–17.0 years).
All had received prior radiotherapy. Treatment was well tolerated. Eighteen children experienced serious adverse events (SAEs). The
majority of SAEs were associated with disease progression. Nineteen patients completed 8 weeks (W8) of treatment: There were 2 PRs,
6 SDs, and 11 progressions. Five patients completed 18 weeks (W18) of treatment: 1 of 2 patients with PR at W8 remained in PR at
W18, and 3 of 6 children with SD at W8 maintained SD at W18. Time to progression following initiation of nimotuzumab for the 4
patients with SD or better at W18 was 119, 157, 182 and 335 days, respectively. Median survival time was 3.2 months. Two patients
lived 663 and 481 days from the start of nimotuzumab.
Conclusions. Modest activity of nimotuzumab in DIPG, which has been shown previously, was confirmed: A small subset of DIPG pa-
tients appeared to benefit from anti-EGFR antibody treatment.

Keywords: children, diffuse intrinsic pontine glioma, epidermal growth factor receptor, nimotuzumab, phase II trial.

The dismal prognosis for children with diffuse intrinsic pontine gli- Over the last 3 decades, numerous clinical trials have been con-
oma (DIPG) is well documented. Ninety percent or more of affect- ducted and failed to show any significant survival benefit.4 – 11
ed children will succumb to their disease within 2 years, and the Nimotuzumab is a monoclonal antibody, which is produced in
median overall survival in prospective trials is 8 – 12 months.1,2 Cuba, and is directed against the human epidermal growth factor
Focal radiation (RT) is the only proven treatment, but it does not receptor (EGFR). It was originally intended to be used for adult
prevent the inevitable tumor recurrence.3 Following RT, the ma- cancers of epithelial origin, either alone or in combination with
jority of children will show clinical benefit with improvement, or radiation and chemotherapy.12 In 2005, a phase II German
even disappearance of neurological symptoms, and general well- study of nimotuzumab described 3 partial responses at week
being. However, once DIPG children show recurrence of their 21, suggesting promising activity in children with recurrent high-
symptoms, their average life span is usually about 3 months. grade glioma and DIPG.13 The aim of our collaborative study was

Received 16 December 2013; accepted 13 April 2014

# The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.
For permissions, please e-mail: journals.permissions@oup.com.

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 Bartels et al.: Nimotuzumab in progressive DIPGs

to confirm these findings in a larger population of children with During the induction phase, participants received nimotuzumab
progressive DIPG. infusions over 30 – 60 minutes using a low protein binding 0.22
mm in-line filter once weekly for 8 weeks. During the following
consolidation phase, nimotuzumab infusions were given once
Patients and Methods every 2 weeks for 10 weeks (5 infusions). Continuation of treat-
Inclusion and Exclusion Criteria ment beyond these phases was permitted at the discretion of
the investigator and the sponsor/designee until progression of
Children aged between 3 and 18 years with progressive or recur- disease or occurrence of unacceptable toxicity.
rent DIPG following standard of care first-line therapy were eligi-
ble. Strict eligibility criteria included radiologically verified DIPG

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with pontine epicenter involving at least two-thirds the pons, Toxicity and Dose Adjustments
presence of 2 of the 3 classical clinical signs or symptoms (cranial Participants were monitored for adverse events (AEs) at each
nerve and corticospinal tract deficits and ataxia) at initial diagno- study visit. As a protocol requirement, participants were to be ob-
sis, and duration of initial symptoms ,6 months. served for any potential AE from the start of the nimotuzumab
Standard of care first-line therapy was defined as focal RT infusion until at least 1 hour after the end of the infusion. Toxici-
≥54 Gy with or without chemotherapy or biological agents. Pa- ties were graded according to the Common Terminology Criteria
tients with evidence of either clinical and/or radiological progres- for Adverse Events (CTCAE) Version 3.0 of the National Cancer In-
sion (in the case of chemotherapy) during or following first-line stitute. Grade 5 (death) toxicity includes death not otherwise
therapy (radiotherapy completed ≥12 weeks prior) were eligible. specified (NOS) and disease progression NOS.
Progression was defined by the occurrence of new symptoms
and/or worsening of existing symptoms (cranial nerve deficit,
ataxia, long tract signs) on 2 consecutive clinic visits. If such pro- Criteria for Response and Progression
gression was associated with acute neurological deterioration, All participants who received at least one dose of nimotuzumab
then its presence at one clinic visit was sufficient for study were evaluable for objective response rate. Baseline scans were
entry. Clinical progression was also sufficient, even in the absence required no later than 14 days prior to the start of treatment. Ini-
of confirmatory imaging changes. Radiological progression, how- tial response evaluation was performed at the completion of the
ever, did not qualify for enrollment if there were no accompanying induction phase after 8 weeks and at the completion of the con-
clinical signs or symptoms of progression. solidation phase after 18 weeks, as applicable. Tumor response
Further eligibility criteria included a Lansky or Karnofsky perfor- assessments were based on 3-dimensional (3D) MRI measure-
mance status .40%, radiologically measurable tumor in at least ments. Two-dimensional (2D) measurements were allowed only
2 dimensions, and adequate hematological, renal, and hepatic in the rare circumstance when the length of a lesion could not be
function. For female patients of childbearing age, a negative preg- determined. Assessments were performed by both the investiga-
nancy test was required. For both sexes, if applicable, use of effec- tor and an independent tumor assessment board (ITAB) unaware
tive contraception was required throughout participation in the of the participant’s clinical condition. Tumor response criteria
study. Patients with disseminated CNS disease, neurofibromatosis were determined by changes in size using width (W), transverse
type 1, or known contraindications to monoclonal antibodies (T), and length (L) measurements on either T2 or FLAIR-weighted
were excluded. MRIs. Complete response (CR) was defined as disappearance of all
Each participating center had to obtain institutional review measurable disease. Partial response (PR) was defined in 3D re-
board approval of the study’s protocol prior to enrolling patients. sponse criteria as ≥65% decrease, and progressive disease (PD)
Written informed consent and/or assent from patients or their was defined as ≥40% increase of the 3 perpendicular diameters.
legal representatives was obtained for all participants. When the length of the lesion was not determinable, comparison
of the product of the longest diameter and its longest perpendic-
ular diameter (TxW) was used. 2D measurement response criteria
Study Conduct defined PR as ≥50% decrease and PD as ≥25% increase in the
The baseline brain MRI included axial T1, without and with gado- products of the 2 perpendicular diameters. Objective response
linium, axial T2 or fluid-attenuated inversion recovery (FLAIR) (OR) was defined as all patients with either PR or CR. Stable dis-
weighted images, and a sagittal sequence. Follow-up brain ease (SD) was defined as the absence of CR, PR, or PD. Treatment
MRIs were repeated at weeks 9 and 19 and thereafter as clinically was discontinued in case of global deterioration in a participant’s
indicated. Spinal MRI was optional, depending upon clinical symp- physical or neurological condition, regardless of the radiological
toms. Neurological status and standard blood studies (CBC and assessment. Hence, clinical progression was considered as
comprehensive metabolic panel) were monitored at study entry tumor progression (PD).
and at the same intervals as MRI.

Trial Design and Statistical Methods

Drug Preparation, Administration, and Treatment Plan The study population was defined as the intent-to-treat popula-
Nimotuzumab was supplied by YM Biosciences as an injectable tion including all study patients who received at least one dose of
solution in single-use, 10 mL vials containing 5 mg/mL of product. nimotuzumab. Those participants were evaluated for safety, re-
It required dilution in 0.9% NaCl to a final concentration of 1 mg/mL. sponse, and progression-free survival (PFS). A safety monitoring
The dose and volume of the infused study drug were calculated committee was established and conducted regular safety
basedupon the participant’s body surface area at 150 mg/m2. reviews.

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Bartels et al.: Nimotuzumab in progressive DIPGs

The OR rate was defined as the number of participants experi- Table 1. Patient characteristics
encing an OR at week 8 plus the number of participants who were
assessed as SD at that time but demonstrated OR after the con- No. %
solidation phase, divided by the number of enrolled participants
who received at least one dose of nimotuzumab. ITT population 44 100
Based on the hypothesis of a 15% response rate with treat- Age (years)
ment (vs 0% without) and an a priori determined 1-sided signifi- .3 ≤ 12 39 88.6
cance level of.025 with a 90% power, a total of 44 participants .12 5 11.4
were needed for study recruitment, considering an expected Gender
10% dropout rate. Female 24 54.5

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Male 20 45.5
Race
Results Caucasian 25 56.8
Hispanic/Latin American 6 13.6
Study Cohort
Asian 4 9.1
Forty-four of the 46 participants enrolled into the trial from Feb- African American 3 6.8
ruary 2008 to June 2010 received at least one course of nimotu- Other 6 13.6
zimab and were considered eligible and evaluable for toxicity and Lansky/Karnofsky status
response. The median age of the study population was 6.0 years 100%–91% 6 13.6
(range, 3.0 – 17.0 years). Twenty-four participants (54.5%) were 90%– 81% 9 20.5
female, and 25 (56.8%) were of Caucasian descent. Thirty-two 80%– 61% 17 38.4
children had a Karnofsky/Lansky score . 60% at the time of 60%– 41% 12 27.3
study enrollment (Table 1). All participants had prior radiotherapy, Prior surgery
and 25 (57%) had received prior chemotherapy. The most com- Biopsy 2 4.5
monly used chemotherapy agents at the time of initial treatment Ventriculostomy 1 2.3
were temozolomide (n ¼ 17; 38.7%), etoposide (n ¼ 13; 29%), Shunt insertion 6 13.6
cisplatin (n ¼ 8; 18.2%), and vincristine (n ¼ 7; 15.9%). Four par-
ticipants (9.1%) had received bevacizumab as part of their first-
Abbreviation: ITT, intention to treat.
line treatment. Thirty-five participants (79.5%) were receiving
dexamethasone at the time of study enrollment.
SD, and 11 progressions (PDs). One of 2 participants with PR at
Toxicity and Safety week 8 remained in PR at week 18, and 3 of 6 participants
(13.6% of the original cohort) with SD at week 8 maintained
A total of 320 nimotuzumab infusions were given, and all but one stable disease at week 18. The time to progression following
participant had at least one adverse event (AE). The majority of initiation of nimotuzumab treatment for the 3 children with SD
AEs was mild to moderate (grade 1 –2) in severity and were un- and the one with PR at week 18 was 119, 157, 335, and 182
related/unlikely related to the study drug but were rather due to days, respectively. Eventually, all tumors progressed. The 2 lon-
CNS dysfunction and disease progression. A total of 24 partici- gest study survivors lived for 663 and 481 days after the start
pants (54.5%) reported 54 study drug-related AEs, all of which of nimotuzumab.
were grade 1–2 except for 4 participants. Three of those 4 partic- Of the nineteen participants who completed the induction
ipants experienced grade 3 lymphopenia, neutropenia, and hypo- phase and underwent clinical and MRI assessment at week 8, 6
kalemia. Eighteen participants experienced serious adverse events children were not on steroids at both inclusion and week 8. The
(SAEs), including 3 children who experienced 4 grade 5 SAEs. Two steroid dose for the remaining 13 children remained unchanged
SAEs occurred after the ninth injection in one participant. This par- (n ¼ 5), decreased (n ¼ 5), increased (n ¼ 2), and unknown (n ¼ 1).
ticipant’s MRI revealed both intracranial tumor hemorrhage and Mean changes in performance status (increases and decreases)
tumor necrosis, each considered as separate SAEs. This participant from baseline were noted and fluctuated over the course of the
died 12 days after the last dose of nimotuzumab. Two other par- study. No clinically meaningful changes were documented.
ticipants died due to progressive neurologic dysfunction and car-
diac arrest; both events were considered unrelated SAEs.
Survival
Median time to progression was 1.7 months (95% CI, 1.4 – 1.9
Radiological and Clinical Response months) with a range of 0.2 – 11.0 months. Median survival
Nineteen participants completed the induction phase and under- time for the entire cohort was 3.2 months (95% CI, 2.2 – 4.3
went clinical and MRI assessment at week 8. Five participants months) with a range 0.2– 21.8 months (Figs 1 and 2).
completed the consolidation phase, 3 of whom continued to The mean overall survival of participants who completed in-
receive nimotuzumab beyond the 18th week. duction therapy and showed progressive disease after completion
Independent central radiological review was conducted on all of induction therapy (n ¼ 11) was 146 days (range, 87 –268 days),
participants. 3D measurements were available for all participants which did not differ significantly compared with the overall sur-
except for 8 in whom only 2D measurements were reliably feasi- vival of 282 days (range, 85 – 663 days) in participants with SD/
ble. Radiological responses observed at week 8 included 2 PRs, 6 PR (n ¼ 8) (P ¼ .06).

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responses in pediatric patients with recurrent high-grade gliomas

and DIPG.13 In that trial, 20 children with recurrent DIPG and
high-grade glioma were treated with a weekly IV infusion of
150 mg/m2 nimotuzumab for 6 weeks. Those who did not show
evidence of progression were eligible for a consolidation phase
consisting of 4 150 mg/m2 infusions given at a 3-week interval.
Six of 17 eligible participants demonstrated partial response or
stable disease at the end of the 6-week induction phase, includ-
ing 4 with recurrent DIPG. The authors subsequently updated
these results and reported 1 partial response and 9 SD at the

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end of the 8-week induction period in a group of 21 participants
with recurrent DIPG. At week 21, they described 3 partial responses
including a sustained response in a participant who received the
drug for 14.5 months.13 Our results confirm these results: we ob-
served 2 partial responses in our study cohort. The difference in the
response rate is within the range of variations expected in such
Fig. 1. Progression-free survival distribution. clinical trials, and the fact that 2 independent studies done in 2 dif-
ferent continents showed similar results adds validity to the finding
that a small proportion of patients with progressive/recurrent DIPG
responds to the anti-EGFR antibody nimotuzumab.
Nimotuzumab was well tolerated, without severe skin toxici-
ties or adverse gastrointestinal effects. The majority of adverse
events were attributed to disease progression. One study patient
suffered intratumoral hemorrhage and tumor necrosis. While a
causal relationship to the treatment with nimotuzumab cannot
be ruled out with certainty, the occurrence of spontaneous intra-
tumoral bleeds in the disease course of DIPGs is reported in nearly
20% of patients and is most commonly located in the necrotic
areas.18
Based on promising results in recurrent tumors, an interna-
tional study of radiation plus nimotuzumab was conducted in
newly diagnosed DIPG patients. Forty-one patients were enrolled
in this study. The median progression-free survival in this trial was
5.5+0.2 months, and the median overall survival was 9.6+1
months, revealing no significant improvement over historical con-
trols. Unfortunately, the hopes that the promising results ob-
Fig. 2. Overall survival.
served in recurrent tumors could be reproduced in newly
diagnosed patients did not come true.19 This difference between
the promising results of the phase II study in the recurrent setting
Discussion
and the disappointing outcome observed in the frontline study
The epidermal growth factor receptor (EGFR) has been implicated confirms the fact that only a small subset of patients (in the
in the development of high-grade astrocytic tumors. In the adult range of 5% – 10%) seems to benefit from this antibody. There-
population, more than 40% of glioblastomas harbor EGFR ampli- fore, it is not surprising that the results of the phase II study
fication, mutation, or overexpression.14 By contrast, EGFR amplifi- did not translate into a survival benefit in the context of an
cation is uncommon in pediatric high-grade gliomas and DIPGs, upfront study in an unselected group of DIPG patients. Notwith-
although EGFR overexpression is often detected without gene standing these results, a pilot study was initiated combining
amplification.15 In a study performed on postmortem tissue, nimotuzumab with vinorelbine and radiation. At a median
Zarghooni et al described EGFR immunopositivity in 7 of 11 follow-up of 9 months, 8 of ten children were alive without pro-
(64%) DIPGs and copy number gain in one.16 The UK and French gressive disease.20
group conducted a trial of the EGFR inhibitor erlotinib in children Interpretation of these data is complex, as the main limitation
with DIPG and recurrent high-grade gliomas. In that trial, tissue of all these trials is the lack of tissue material, which precludes
collection was mandated for inclusion. Overexpression of EGFR analysis of molecular correlates of clinical response. At the time
(assessed by immunohistochemistry) was found in 8 of 20 this study was conducted, the data on safety of biopsies at initial
(40%) brainstem tumors and 6 of 8 (75%) supratentorial le- diagnosis of DIPGs had not yet matured,21,22 and the requirement
sions.17 Since EGFR overexpression or level of activity has been as- for a biopsy at the time of recurrence as an eligibility criterion was
sociated with responsiveness to EGFR inhibitors in solid tumors, in considered unethical. In our experience, as in the original phase II
particular lung cancer, the use of EGFR inhibitors has raised signif- study, it appears that some patients benefitted from the admin-
icant hope for the management of high-grade gliomas.14 istration of nimotuzumab, as demonstrated by the evidence of
The primary aim of this phase II study of nimotuzumab was to partial responders in both studies. Survival times longer than 6
confirm early data from Fleischhack et al, who reported promising months are exceptional following DIPG progression, and both

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Bartels et al.: Nimotuzumab in progressive DIPGs

Table 2. Phase I/II trials with epidermal growth factor receptor small molecules in diffuse intrinsic pontine glioma

Drug Trial No. of 1-year EFS 1-year OS Median EFS in Median OS in Number of Patients Reference
Patients Months Months alive .2 years

Gefitinib Phase I 20 16.1+7.4% 48+11% 24

Gefitinib Phase II 44 20.9+5.6% 56.4+7.6% 7.4 3 (at 3 years) 25
Erlotinib Phase I 21 8 12 NA 18
Vandetanib Phase I 21 21.4%+11% 37.5%+10.5% 3 26
Vandetanib & Phase I 25 52%+10% 2 29

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dasatinib

Abbreviations: EFS, event-free survival; NA, not applicable; OS, overall survival; SE, standard error.

studies reported patients with sustained tumor control. However, biopsies in DIPG trials. The feasibility of this approach is currently
in the absence of molecular data, it is impossible to know wheth- assessed in cooperative studies (http://clinicaltrials.gov/ct2/show/
er the responders had tumors that exhibited EGFR overexpression NCT01182350). These studies will probably confirm the large mo-
or amplification. lecular heterogeneity of DIPGs that precludes a “one drug fits all”
EGFR antibodies, such as nimotuzumab, bind to the extracellu- approach and the need to explore the feasibility and relevance of
lar domain and result in a blockade of ligand binding and receptor tailored strategies to improve the outcome of this devastating
activation. EGFR can also be targeted by inhibitors of receptor ty- condition.
rosine activity (so-called “small molecules”), which bind to ATP in
a reversible fashion, inhibit ATP, and stop subsequent down-
stream signaling.12 Several clinical trials with these small mole- Conflict of interest statement. None declared.
cule EGFR inhibitors have been conducted in patients with DIPG
(Table 2). In these studies, as in ours, there appears to be a subset
of patients who may benefit from these agents. The Pediatric Funding
Brain Tumor Consortium conducted 2 studies of gefitinib in com- YM Biosciences Inc.
bination with radiation in children with DIPG. The phase I study
reported 1-year overall and event-free survival rates of 48%
and 16%, respectively.23 The results of the phase II study report- References
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