Phase 2 study of safety and efficacy of nimotuzumab in pediatric patients with progressive diffuse intrinsic pontine glioma.
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/m(2)), 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 patients appeared to benefit from anti-EGFR antibody treatment.
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.).
Ute
U
Bartels
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.).
Johannes
J
Wolff
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.).
Lia
L
Gore
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.).
Ira
I
Dunkel
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.).
Stephen
S
Gilheeney
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.).
Jeffrey
J
Allen
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.).
Stewart
S
Goldman
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.).
Michal
M
Yalon
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.).
Roger J
RJ
Packer
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.).
David N
DN
Korones
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.).
Amy
A
Smith
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.).
Kenneth
K
Cohen
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.).
John
J
Kuttesch
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.).
Douglas
D
Strother
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.).
Sylvain
S
Baruchel
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.).
Janet
J
Gammon
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.).
Mark
M
Kowalski
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.).
Eric
E
Bouffet
D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D012449:Safety; D015996:Survival Rate
D061067:Antibodies, Monoclonal, Humanized; C501466:nimotuzumab
children; diffuse intrinsic pontine glioma; epidermal growth factor receptor; nimotuzumab; phase II trial