A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma.
OBJECTIVE
Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib.


METHODS
A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two-stage Green-Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs.


RESULTS
The six-month progression-free survival (PFS) rates in phase II (n = 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n = 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib.


CONCLUSIONS
The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma.
Dana-Farber Cancer Institute, Boston, MA 02215, USA. David_Reardon@DFCI.harvard.edu
David A
DA
Reardon
Morris D
MD
Groves
Patrick Y
PY
Wen
Louis
L
Nabors
Tom
T
Mikkelsen
Steve
S
Rosenfeld
Jeffrey
J
Raizer
Jorge
J
Barriuso
Roger E
RE
McLendon
A Benjamin
AB
Suttle
Bo
B
Ma
C Martin
CM
Curtis
Mohammed M
MM
Dar
Johann
J
de Bono
D000328:Adult; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007191:Indazoles; D000077341:Lapatinib; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D009367:Neoplasm Staging; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012008:Recurrence; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics
D020533:Angiogenesis Inhibitors; D000927:Anticonvulsants; D000970:Antineoplastic Agents; D007191:Indazoles; D011743:Pyrimidines; D011799:Quinazolines; D013449:Sulfonamides; C410723:epidermal growth factor receptor VIII; D000077341:Lapatinib; C516667:pazopanib; D066246:ErbB Receptors