A phase Ib study of pertuzumab (P), a recombinant humanized antibody to HER2, and docetaxel (D) in patients (pts) with advanced solid tumors

Abstract

3166 Background: P represents the first in a new class of targeted therapeutics known as HER dimerization inhibitors (HDIs). It blocks ligand-associated heterodimerization of HER2 with other HER-kinase family members, thereby inhibiting intracellular signaling. Study endpoints: determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLTs) of P and D, and the pharmacokinetic (PK) interaction. Methods: DLTs are assessed in cycle 1 and defined as non-hematological toxicity ≥ grade 3, grade 4 neutropenia of > 7 days, thrombocytopenia grade 4. If DLT is observed in ≥ 2/6 pts at a dose level, MTD is exceeded. Pts are treated with a fixed dose of 1050 mg of P and an escalating dose of D as an IV infusion on day 1, q 3 weeks. Three dose levels of D are explored: 60, 75, and 100 mg/ m2. Results: To date, a total of 8 pts (6 males) have received 36 cycles, median 5 (range 1–9). Mean age: 59.5 years, PS 0/1: 5/3 pts. Tumor types: prostate (4), ovarian (2), head & neck (1) and melanoma (1). At dose level D 75 mg/ m2, 2 pts developed DLTs: grade 3 diarrhea and fatigue, and febrile neutropenia, respectively. None of 6 pts treated at dose level 1 developed DLTs. Most frequent grade 1/2 toxicities per cycle included: diarrhea 36% (grade 3 6%), fatigue 31% (grade 3 6%), mucositis 17%, and nausea 8%. Neutropenia and leukopenia grade 3/4 occurred in 28% and 19% of cycles, respectively. Preliminary data from 8 pts suggest that PK parameters of D are not altered in combination with P. Mean clearance of D single agent versus D combined with P is 59 L/h ± 14 and 68 L/h ± 16, respectively. Tumor assessment: 1 PR, 5 SD and 1 progression. Conclusions: The RP2D will be 60 mg/m2 D and 1050 mg of P but further evaluation of D at 75 mg/m2 and P at 420 mg (840 mg loading dose) q 3 weeks is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche Ltd., Hoffmann-La Roche Boehringer Ingelheim, Celgene, Novartis, Oncolytics Biotech, Topotargets Hoffmann-La Roche, GlaxoSmithKline Hoffmann-La Roche, Novartis, Quintiles Oncology