[353] A phase I trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin.
Dees EC, ONeil BH, Humes EW, Carey LA, Collichio F, Johri A, Graham ML, Orlowski RZ University of North Carolina at Chapel Hill, Chapel Hill, NC
The proteasome inhibitor bortezomib (Vc; VELCADE, PS-341) is a dipeptide boronic acid derivative that has shown antitumor activity in preclinical models and Phase I clinical trials. In addition, preclinical data indicate that it blocks activation of several survival pathways, including NF- B, and may thereby act to sensitize tumor cells to chemotherapeutics such as anthracyclines. Preclinical studies in models of breast cancer have shown that the combination of Vc and pegylated liposomal doxorubicin (D; Doxil) has enhanced antitumor activity over either drug alone. This phase I trial was designed to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the VcD combination in patients (pts) with refractory solid tumors, and to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of the combination. Vc is administered as an intravenous bolus on day (d) 1, 4, 8, and 11 of a 21d cycle (c), while D is given on d 4 at 30 mg/m. To date, 27 pts have been treated, with Vc doses ranging from 0.9 to 1.5 mg/m using a standard dose escalation scheme. Pts include 21 women and 6 men, with median age 55 yrs (35-69) and a variety of tumor types including 14 breast cancer, 4 lung, 3 bladder, 2 head and neck, and others. The median number of prior therapies is 4, and 11 of the breast cancer pts had prior anthracycline. The most frequent toxicities have been grade 1-2 fatigue, nausea, thrombocytopenia, lymphopenia, and anemia. 4 pts have had grade 1-2 peripheral neuropathy/pain after multiple cycles. DLTs were nausea and vomiting in one of six pts treated with Vc at 1.2 mg/m, and diarrhea in one of six pts treated with Vc at 1.5 mg/m. Other grade 3 toxicities seen in later cycles include palmar plantar erythrodysesthesia (2), thrombocytopenia (2), anemia (2), neutropenia (4), nausea and diarrhea (1) and abdominal pain (1). One pt had an asymptomatic drop in ejection fraction to 35% after 5 c of therapy, which reversed without intervention within 2 weeks of discontinuing. Among 6 pts at 1.5 mg/m Vc and 30 mg/m D, 3 have had grade 3 GI toxicity and 3 have required first cycle delays for grade 2 neutropenia. Therefore, accrual is ongoing at 1.3 mg/m Vc and 30 mg/m D to further evaluate these as recommended doses for phase II study of the VcD combination. Doxil PK and bortezomib PD are being analyzed, but preliminary results suggest that 20S proteasome inhibition is similar to that obtained with Vc alone in prior studies. Of the 11 pts with breast cancer evaluable to date, one has near complete remission of cutaneous disease, one had resolution of a large malignant effusion and stable adenopathy for 5 c, one has near PR in liver metastases after 2 c, and one had stable disease in liver metastases for 5 months. 3 additional pts in this heavily pre-treated solid tumor population have had stable disease for >4 c.
Thursday, December 4, 2003 4:30 PM
Poster Session: Treatment: Chemotherapy -- New Drugs and Formulations (4:30 PM-7:00 PM)
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