Phase I trial of liposomal doxorubicin and ZD1839 in patients with refractory gynecological malignancies or metastatic breast cancer.
BACKGROUND
Pegylated liposomal doxorubicin has activity in both breast and ovarian cancer. Preclinical data noted that ZD1839 acts synergistically with chemotherapy. Given the lack of cross-resistance between these two agents, a phase I trial was initiated examining the safety and efficacy of the combination of liposomal doxorubicin and ZD1839 in patients with recurrent gynecologic or metastatic breast cancer.


METHODS
Dose-limiting toxicity (DLT) was defined within the first two cycles of treatment. Escalating doses of liposomal doxorubicin were administered every 4 weeks with ZD1839. Pharmacokinetic analysis and correlative studies were performed.


RESULTS
Thirty-five patients were enrolled in this study: six in each cohort. One DLT (febrile neutropenia) was observed in cohort 2. Dose level 3 was determined to be the maximum tolerated dose (MTD), and an additional ten patients were accrued. Serious adverse events (SAEs) included one patient with mental status changes believed secondary to disease progression and two central nervous system (CNS) bleeds believed to be unrelated to the combination of study agents. Toxicities were generally mild except for skin and gastrointestinal toxicity. No cardiac toxicity was observed. The best response to therapy included four partial responses and 20 patients with stable disease.


CONCLUSIONS
Liposomal doxorubicin with ZD1839 is an active regimen but is associated with increased skin toxicity in patients with advanced breast and gynecologic cancer.
Campos
Susana M
SM
Department of Gynecology Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA, USA. scampos@partners.org
Berlin
Suzanne T
ST
Parker
Leroy M
LM
Chen
Wendy Y
WY
Bunnell
Craig A
CA
Atkinson
Tina
T
Lee
Julie
J
Matulonis
Ursula
U
Hirsch
Michelle S
MS
Harris
Lyndsay
L
Krasner
Carolyn N
CN
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001900:Boston; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000556:secondary; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D000077156:Gefitinib; D005833:Genital Neoplasms, Female / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011799:Quinazolines / Q000008:administration & dosage; D016879:Salvage Therapy; D013997:Time Factors; D016896:Treatment Outcome
D011799:Quinazolines; D004317:Doxorubicin; D000077156:Gefitinib
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