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Bortezomib Plus Docetaxel in Advanced Non-Small Cell Lung Cancer and Other Solid Tumors: a Phase I California Cancer Consortium Trial

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Bortezomib Plus Docetaxel in Advanced Non-Small Cell Lung Cancer and Other Solid Tumors: a Phase I California Cancer Consortium Trial CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector ORIGINAL ARTICLE Bortezomib Plus Docetaxel in Advanced Non-small Cell Lung Cancer and Other Solid Tumors: A Phase I California Cancer Consortium Trial Primo N. Lara, Jr., MD,*† Mariana Koczywas, MD,‡ David I. Quinn, MD, PhD,§ Heinz Josef Lenz, MD,§ Angela M. Davies, MD,* Derick H.M. Lau, MD, PhD,*† Paul H. Gumerlock, PhD,* Jeff Longmate, PhD,‡ James H. Doroshow, MD,‡ David Schenkein, MD,͉͉ Oscar Kashala, MD,͉͉ and David R. Gandara, MD*† n recent years, the inhibition of the 26S proteasome has Background: This phase I study was performed to determine the emerged as a rational anti-neoplastic strategy. The 26S dose-limiting toxicity and maximum tolerated dose (MTD) of do- I proteasome is a very large proteolytic complex involved in a cetaxel in combination with bortezomib in patients with advanced non-small cell lung cancer (NSCLC) or other solid tumors. significant catabolic pathway, the ubiquitin–proteasome path- way, for many intracellular regulatory proteins, including I␬B Methods: Patients were enrolled in cohorts of three over six dose ␬ ␬ ␬ levels. Each treatment cycle was 3 weeks long and consisted of one kinase/nuclear factor- B(I B/NF- B), p53, and the cyclin- docetaxel infusion (day 1) and four bortezomib injections (days 1, 4, dependent kinase inhibitors p21 and p27, which contribute to 8, and 11). Dose escalation and MTD determination were based on the regulation of the cell cycle, apoptosis, and angiogene- 1–3 the occurrence of dose-limiting toxicities in cycle 1 only. sis. It consists of a 19S cap on both ends, which recognizes Results: A total of 36 patients were enrolled, 26 of whom had ubiquitin-tagged proteins that are marked for degradation, NSCLC. All patients received at least one dose of study drug at one and a 20S core, which contains three kinds of proteolytically of five dose levels. The MTD of the combined regimen was active sites: chymotrypsin-like, caspase-like, and trypsin- 2,4 determined to be 1.0/75 mg/m2 bortezomib/docetaxel. The combi- like. Disrupting the ubiquitin–proteasome pathway can nation was generally well tolerated. Toxicities were manageable, affect tumor growth, proliferation, and apoptosis and is there- 1,5 and no additive toxicities were observed. The most common adverse fore an attractive target for anticancer therapy. The inhibi- events were fatigue (67% of patients), nausea (50%), diarrhea tion of proteasome function may, through multiple mecha- (39%), and neutropenia (39%). Two patients with NSCLC achieved nisms, lead to arrested growth of malignant cells, impaired a partial response, and seven (19%) patients achieved stable disease tumor angiogenesis, decreased metastasis, and sensitization (including six patients with NSCLC). of cells to chemotherapeutic agents. Conclusion: The combination of bortezomib and docetaxel was Bortezomib (VELCADE, Millennium Pharmaceuticals, feasible and well tolerated in patients with advanced NSCLC or Cambridge, MA) is a proteasome inhibitor with proven clin- other solid tumors. The recommended phase II dose is bortezomib ical activity in multiple myeloma6 that is presently being 1.0 mg/m2 on days 1, 4, 8, and 11 plus docetaxel 75mg/m2 on day evaluated for activity in solid tumors, including non-small 1, cycled every 21 days. Therapeutic doses of docetaxel and bort- cell lung cancer (NSCLC).7,8 It is a boronic acid dipeptide ezomib are achievable for this combination. derivative and a selective and potent inhibitor of the 26S proteasome.9,10 In the National Cancer Institute (NCI) cell Key Words: Bortezomib, Docetaxel, Non-small cell lung cancer, line screen, bortezomib demonstrated a unique pattern of Proteasome. cytotoxic activity and growth inhibition against a broad range 9 (J Thorac Oncol. 2006;1: 126–134) of tumor types, with an average GI50 of7nM. Analysis using the COMPARE algorithm11 showed that cytotoxicity stemming from bortezomib was unique among all cancer *University of California, Davis Cancer Center, Sacramento, California; drugs in its molecular mechanism of action. †Veterans Affairs Northern California Health Care System Preliminary in vitro studies have shown that bort- (VANCHCS), Martinez, California; ‡City of Hope National Medical ezomib alone can induce growth inhibition in A549, H520, Center/City of Hope Medical Group, Duarte, California; §University of H460, H358, and H322 NSCLC tumor cell lines.12–16 We Southern California/Norris Comprehensive Cancer Center, Los Angeles, California; ͉͉Millennium Pharmaceuticals Inc., Cambridge, Massachu- have previously reported that bortezomib therapy stabilizes setts p21 and p27 in NSCLC A549 cells.17 In Bold et al.’s study Address correspondence to: Primo N. Lara, Jr., MD, Department of Internal with MIA-PaCa-2 cells, 18 bortezomib caused the accumula- Medicine, University of California, Davis Cancer Center, 4501 X Street, tion of p21 and p27 and a complete decrease in Bcl-2; Sacramento, CA 95817. Email: [email protected] Copyright © 2006 by the International Association for the Study of Lung resistance to chemotherapy-induced apoptosis mediated by Cancer Bcl-2 overexpression was bypassed. A common abnormality ISSN: 1556-0864/06/0102-0126 defined in human tumors is the loss of p27 protein as a result 126 Journal of Thoracic Oncology • Volume 1, Number 2, February 2006 Journal of Thoracic Oncology • Volume 1, Number 2, February 2006 Bortezomib Plus Docetaxel in Advanced NSCLC of increased ubiquitin activity. Loss of p27 is associated with PATIENTS AND METHODS a poor prognosis in many tumor types, including NSCLC.19,20 Conversely, overexpression of p27 triggers apoptosis in sev- Patients eral different human cancer cell lines.21 Meanwhile, abnor- Institutional review boards at each of the study centers mal overexpression of Bcl-2 is found in approximately 20 to approved the study, and all patients provided written in- 25% of NSCLC and is associated with resistance to chemo- formed consent before any study-related procedures took therapy-induced apoptosis.22 place. Patients with histologically confirmed locally ad- When bortezomib is combined with standard chemo- vanced or metastatic NSCLC as well as other solid tumors, who were treatment-naı¨ve or had previously received up to therapeutic agents, results have shown an enhanced antitumor two chemotherapy regimens, were enrolled subject to the effect in NSCLC and other solid tumor cells.14,18,23,24 Bort- following main inclusion criteria: (1): age Ն8 years; (2) ezomib may sensitize tumor cells to chemotherapy-induced measurable or evaluable disease; (3) Karnofsky Performance apoptosis through mechanisms of cell-cycle dysregula- Status (KPS) Ն60; (4) life expectancy Ն3 months; and (5) 16,24 tion. Bortezomib plus docetaxel has been shown to have adequate hematologic, renal, and hepatic end-organ function. significant additive cytotoxicity in SKOV3 human ovarian Patients were excluded if they had: (1) previously received carcinoma cells.25 This was confirmed in an in vivo study of docetaxel, cisplatin (at a cumulative dose Ͼ350 mg/m2), or athymic nude mice inoculated with SKOV3 cells, in which a radiation therapy to Ͼ25% of bone marrow; (2) grade 2 or significantly greater reduction in tumor growth was seen in higher peripheral neuropathy; (3) electrocardiographic evi- the group treated with combined bortezomib and docetaxel dence of acute ischemia or new conduction system abnormal- compared with either monotherapy group.26 Our own studies ities; or (4) uncontrolled brain metastases or central nervous in NSCLC cell lines with bortezomib as a single agent or in system disease. combination with docetaxel suggest a general model to ex- plain the varied responses seen with the sequences of do- Study Design cetaxel followed by bortezomib.17,27 We found that treatment This phase I, open-label, dose-escalation study was with docetaxel induces the accumulation and phosphorylation conducted at four centers in the United States. Each treatment of p27 and the phosphorylation of Bcl-2. The addition of cycle was 3 weeks in duration and consisted of one docetaxel bortezomib to cells maintains the p27 induction and decreases infusion (day 1) and four bortezomib injections (days 1, 4, 8, the levels of Bcl-2. These effects enhance docetaxel cytotox- and 11) followed by a 10-day rest period (days 12 to 21). icity. Cycle 2 was to commence on day 22 (cycle 2, day 1). A full The aim of this phase I trial was to establish the course of treatment was defined as eight treatment cycles dose-limiting toxicity (DLT) and maximum tolerated dose (eight docetaxel doses and 32 bortezomib doses); however, (MTD) of bortezomib and docetaxel combination therapy in patients who experienced symptomatic benefit from treatment patients with locally advanced or metastatic NSCLC or other were permitted to receive further treatment after discussion solid tumors. In this dose-escalation study, we examined between the investigator and the sponsor. bortezomib at dose levels based on previous studies in pa- On day 1 of each cycle, bortezomib was administered 1 tients with advanced solid tumors,7,28 in combination with hour after completion of the 1-hour docetaxel infusion, ac- docetaxel at escalating doses up to the standard dose of 75 cording to the planned dose escalation (Table 1), in accor- mg/m2.29 dance with the schedule considered to be optimal in preclin- TABLE 1. Planned Study Drug Doses Number of patients Dose (mg/m2) Initial Additional enrollment, Expanded enrollment, Cohort Bortezomib Docetaxel enrollment if 1 of 3 initial patients has a DLT if0of3or<1of6hasaDLTa 1 1.0 60 3 3 10 26533 37033 47533 5 1.3 75 3 3 3† 6 1.5 75 3 3 DLT, dose-limiting toxicity. aThe low maximal tolerated dose (MTD) was the highest docetaxel dose in combination with bortezomib 1.0 mg/m2 at which Յ1 of 6 patients had a DLT. The high MTD was the docetaxel dose in combination with bortezomib 1.3 mg/m2 or 1.5 mg/m2, at which Յ1 of 6 patients had a DLT.
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