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 pathway, 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. If an MTD was not established at either the low- or high-dose bortezomib, then the additional enrollment in cohorts 4 and 6 was to be referred to as the low- and high-dose expanded cohorts (DEC), respectively. Additional patients enrolled at the low-MTD/high-MTD or low-DEC/high-DEC were required to have a diagnosis of measurable NSCLC. †A maximum of six patients were to be enrolled at the 1.3/75 mg/m2 and/or the 1.5/75 mg/m2 dose combinations of bortezomib and docetaxel, respectively. Expanded enrollment at one of these dose combinations was to occur only if six patients had not already received doses at the cohort determined to be the high MTD or high-dose expanded cohorts.

ical trials.30 Before each scheduled study drug dose, patients Safety, KPS, and efficacy evaluations were performed were evaluated for possible toxicities that may have occurred during an end-of-therapy visit 10 days after administration of since the previous dose. A complete treatment cycle was the last bortezomib dose and during an end-of-study visit 3 defined as one docetaxel and four bortezomib doses, as weeks after the end-of-therapy visit. specified above. Dose escalation and determination of the MTD were Molecular Correlative Studies based on the occurrence of DLTs in cycle 1. Three patients The 20S proteasome inhibition assay provides a mea- were to be enrolled at bortezomib 1.0 mg/m2 plus docetaxel surement of percentage proteasome inhibition, the molecular at a specified dose level. If no DLTs occurred in these first target of bortezomib. This assay was used to provide a more three patients, enrollment commenced at the next dose level. relevant assessment than standard pharmacokinetic parame- However, if one of the first three patients had a DLT, three ters, which do not adequately guide dosing because bort- additional patients were to be enrolled at that dose level, and ezomib rapidly exits the intravascular compartment.31 Blood only if none of these additional patients had a DLT could samples for assay were taken immediately before and 1 hour enrollment commence at the next dose level. If at least two after bortezomib dosing on days 1 and 11 of cycles 1 and 2 patients in a cohort experienced a DLT, the previous dose to show the effect of the bortezomib dosing schedule on level was to be declared the MTD, and 10 additional patients maximal percentage proteasome inhibition. were to be enrolled at that dose level. The low MTD was the CRP and IL-6 are downstream indicators of proteasome highest docetaxel dose in combination with bortezomib 1.0 inhibition and were used to evaluate the efficacy of bort- mg/m2 at which one or none of six patients had a DLT. The ezomib. Blood samples for the measurement of CRP and IL-6 high MTD was the highest docetaxel dose in combination were collected at the screening visit; on days 1 and 11 of with bortezomib 1.3 or 1.5 mg/m2 at which one or none of six cycles 1, 2, 4, 6, and 8; and at the end-of-therapy and patients had a DLT. If an MTD was not established at either end-of-study visits. low- or high-dose bortezomib, additional enrollment in cohorts 4 and 6 (Table 1) were to be referred to as the low- and End Points high-dose expanded cohorts, respectively. A maximum of six The primary end point was to establish the DLT and patients were to be enrolled at the 1.3/75 mg/m2 and/or the MTD of bortezomib and docetaxel combination therapy. 1.5/75 mg/m2 dose combinations of bortezomib and do- Secondary end points included the overall disease response; cetaxel, respectively. change from baseline in measurable tumors; time to con- Toxicities were graded according to the NCI Common firmed disease response (complete response and partial re- Toxicity Criteria (NCI CTC, Version 2.0). The DLT was sponse [PR]); time to disease progression; duration of re- based on observed adverse events after each study drug sponse (time from start of response to start of progression); administration in cycle 1 (days 1–21). The occurrence of any change from baseline in KPS, CRP level, and IL-6 level; and the pharmacodynamic analysis based on the 20S proteasome of the following toxicities was considered a DLT if it was, in inhibition assay. the investigator’s opinion, related to the study drug: platelet count Յ25,000 cells/mm3; febrile neutropenia (absolute neu- trophil count [ANC] Ͻ1000 cells/mm3 with temperature Statistical Analysis Ն38.5°C); grade 4 neutropenia (ANC Ͻ500 cells/mm3 from Statistical analyses were primarily descriptive because days1to7orANCϽ200 cells/mm3 without fever of Ն7 the objective of the study was to determine the MTD after days’ duration starting on or after day 8); grade 4 anemia escalating bortezomib and docetaxel doses. The MTD was (hemoglobin Ͻ6.5 g/dL); grade 2 or greater peripheral neu- determined in the MTD-evaluable population, which was ropathy; or any other grade 3 or greater toxicity, with the defined as all patients who received bortezomib and docetaxel and whose data were interpretable in the context of study exception of inadequately managed nausea, vomiting, and drug-specific toxicity (i.e., patients were to have had suffi- diarrhea. cient safety assessments performed to determine whether a During each treatment cycle, KPS and body weight DLT had occurred and were not to have received alternate were measured on days 1 and 11, and vital signs were anti-neoplastic therapies through day 21 of cycle 1). Patients assessed on days 1, 4, 8, and 11. Laboratory samples were in the expanded cohorts were excluded from the MTD- collected for hematology, clinical chemistry, and urinalysis evaluable population, as defined in the protocol. Patients who on days 1, 4, 8, and 11 and for C-reactive protein (CRP) and were discontinued from the study for reasons other than DLT interleukin-6 (IL-6) on days 1 and 11. Blood samples for before completing cycle 1 were not included in the analysis of pharmacodynamic assessment, performed using the 20S pro- the MTD and were replaced. Overall response to therapy was teasome inhibition assay,31 were obtained from all patients analyzed using a SAS algorithm based on the RECIST before and 1 hour after bortezomib administration on days 1 guidelines. Changes in the sum of tumor measurements for and 11 of cycles 1 and 2 only. measurable lesions were calculated using radiographic mea- Target and non-target lesions were measured by using surements provided by the investigators. All safety, efficacy, conventional methods, and the overall disease response was and pharmacodynamic end point analyses were performed assessed according to the Response Evaluation Criteria in using the intent-to-treat population, which was defined as all Solid Tumors (RECIST) guidelines.32 patients who received at least one dose of study treatment.

RESULTS MTD-evaluable population. One patient at the 1.0/70 mg/m2 dose level was excluded from the MTD-evaluable population Patient Demographics because of an incorrect dose calculation and was replaced. At A total of 36 patients were enrolled in the study. All the 1.0/75 mg/m2 dose level, two patients did not complete patients received at least one dose of study drug at one of five cycle 1, one because of a serious AE of bacteremia and one bortezomib/docetaxel dose levels: 1.0/60 (n ϭ 4), 1.0/65 (n ϭ because of patient request, and were replaced. One of these 2 5), 1.0/70 (n ϭ 4), 1.0/75 (n ϭ 16), and 1.3/75 mg/m (n ϭ replacement patients had a dose delayed in error and was 7) (Table 2). Most patients were male (22 of 36; 61%) and consequently replaced, resulting in an MTD-evaluable pop- white (27 of 36; 75%). Median age of the patients was 59.5 ulation of three patients. years (range, 42–79 years). Patient baseline demographics Three patients were enrolled and treated at the 1.3/75 and laboratory data were generally well balanced among dose mg/m2 dose level. One of these three patients experienced a cohorts. DLT (grade 3 fatigue) at this dose level; therefore, three The most common primary diagnosis was lung cancer further patients were enrolled. One of the original three (27 of 36 patients; 75%), and all but one of these 27 patients patients did not complete cycle 1, receiving fewer than four had NSCLC. One (3%) patient each had a diagnosis of bortezomib doses, and so was not included in the MTD- pancreatic or prostate cancer; five (14%) patients had a evaluable population. This patient was not replaced because diagnosis of “other,” which included pleural mesothelioma or three additional patients had already been enrolled at this gastric, small bowel, thyroid, or urinary bladder cancers; and dose level. However, one of the three further patients to be two (6%) patients had cancer of unknown primary site. A enrolled requested to be withdrawn from the study and so did total of 27 patients had received prior chemotherapy, whereas not complete cycle 1. A replacement patient was enrolled and 13 patients had received prior radiation therapy. later experienced a DLT (grade 3 fatigue). Because two of DLT and MTD of Bortezomib in Combination five MTD-evaluable patients experienced DLTs at this dose level, the MTD for this study was declared to be 1.0/75 with Docetaxel mg/m2 bortezomib and docetaxel, respectively, and the No patients in the first four dose cohorts experienced 2 2 1.0/75 mg/m bortezomib/docetaxel cohort was expanded DLTs during cycle 1. One patient at the 1.0/60 mg/m dose with 10 additional patients (Table 3). level and two patients at the 1.0/65 mg/m2 dose level did not complete cycle 1, receiving fewer than four bortezomib doses. This was because of an unacceptable adverse event KPS, CRP, and IL-6 (AE) (gastrointestinal hemorrhage) not related to study drug At baseline, overall mean KPS values were 77.50, in the patient at the lower dose level and to a bortezomib dose 84.00, 87.50, 81.33, and 81.67 in patients enrolled at the five being missed in error by two patients at the higher dose level. dose levels (lowest to highest, respectively). An overall mean All these patients were replaced and were excluded from the change from baseline in KPS of between 0 and 10 was

TABLE 2. Demographic and Baseline Characteristics Bortezomib/docetaxel dose cohorts (mg/m2)

1.0/60 1.0/65 1.0/70 1.0/75 1.3/75 Total n 45416736 Age, years Mean (SD) 62.5 (7.94) 65.6 (7.50) 52.0 (5.35) 58.4 (10.34) 59.1 (11.70) 59.3 (9.84) Median 60.0 62.0 51.5 59.0 61.0 59.5 Range 56–74 59–76 46–59 42–74 45–79 42–79 Gender, n (%) Male 2 (50) 3 (60) 1 (25) 12 (75) 4 (57) 22 (61) Female 2 (50) 2 (40) 3 (75) 4 (25) 3 (43) 14 (39) Race, n (%) White 4 (100) 4 (80) 2 (50) 10 (63) 7 (100) 27 (75) Asian 0 0 1 (25) 4 (25) 0 5 (14) Black 0 1 (20) 1 (25) 0 0 2 (6) Hispanic 0 0 0 2 (13) 0 2 (6) KPS, n (%) 70 1 (25) 1 (20) 0 4 (27) 3 (50) 9 (26) 80 3 (75) 2 (40) 1 (25) 5 (33) 0 11 (32) 90–100 0 2 (40) 3 (75) 6 (40) 3 (50) 14 (41) Missing 0 0 0 1 1 2

KPS, Karnofsky Performance Status.

TABLE 3. Patient Disposition Bortezomib/docetaxel doses (mg/m2)

1.0/60 1.0/65 1.0/70 1.0/75 1.3/75 Total

Enrolled n % 45416736 ITT populationa 4 (100) 5 (100) 4 (100) 16 (100) 7 (100) 36 (100) MTD populationb 3 (75) 3 (60) 3 (75) 3 (19) 5 (71) 17 (47) Completed the studyc 0 1 (20) 1 (25) 2 (13) 1 (14) 5 (14) Terminated from the study early 4 (100) 4 (80) 3 (75) 14 (88) 6 (86) 31 (86) Primary reason for early termination Progressive disease 1 (25) 1 (20) 3 (75) 10 (63) 3 (43) 18 (50) Patient request 0 2 (40) 0 2 (13) 1 (14) 5 (14) Investigator judgmentd 1 (25) 1 (20) 0 1 (6) 1 (14) 4 (11) Unacceptable AE 1 (25) 0 0 1 (6) 1 (14) 3 (8) Noncompliance 1 (25) 0 0 0 0 1 (3)

ITT, intent to treat; MTD, maximal tolerated dose; AE, adverse event. Values are presented as n (%). aPatients who received at least one dose of bortezomib or docetaxel. bPatients who received bortezomib and docetaxel and completed cycle 1, and whose data were interpretable in the context of study drug-speciﬁc toxicity. Patients in the expansion of cohort 4 were not included. cPatients who completed eight treatment cycles were considered to have completed the study. dThe investigator considered changes in the patient’s condition unacceptable for further treatment.

observed for patients assessed at each time point up to cycle 1.0 mg/m2 and 1.3 mg/m2 bortezomib, respectively. The 8, the last cycle analyzed; these changes were generally mean total dose of bortezomib administered during all treat- increases in KPS. At the end-of-therapy and end-of-study ment cycles was 34.5 mg (range, 2.24–307.6 mg) during the visits, small mean decreases in KPS from baseline were median treatment duration of 37.5 days (range, 1–718 days), observed overall and at most dose levels. Overall median and the mean total dose of docetaxel administered during all baseline CRP level was 11.9 mg/L (range, 1.4–103.0 mg/L). treatment cycles was 602.7 mg (range, 85.0–5508.7 mg) Generalized increases from baseline were observed in CRP during the median treatment duration of 37.5 days (range, levels; however, there was no apparent trend among levels. 1–718 days). The overall median baseline IL-6 level was 5.0 pg/mL (range, As would be expected with this patient population, all 2.0–59.9 pg/mL). There was little or no change from baseline 36 treated patients experienced at least one treatment-emer- in median IL-6 levels, and no apparent trend was observed gent AE: 24 (67%) had fatigue, 18 (50%) experienced nausea, among dose levels. 14 (39%) had diarrhea not otherwise specified (NOS), and 14 (39%) had neutropenia. Other AEs occurring in 20% or more Inhibition of 20S Proteasome Activity of patients were: alopecia, myalgia, and peripheral neuropa- Maximal inhibition of 20S proteasome activity was thy NOS (10 patients each, 28%); anemia NOS, arthralgia, observed 1 hour after dosing in all dosing cohorts in cycle 1 and insomnia (nine patients each, 25%); and lower limb and cycle 2. There was a pattern of 20S proteasome activity edema and pyrexia (eight patients each, 22%). These AEs inhibition 1 hour after bortezomib administration, with a were mostly of grade 1 or 2 intensity. All patients also return to baseline activity before the next scheduled dose experienced at least one AE considered by the investigator to (Figure 1). Although the mean maximal percent inhibition be at least possibly related to bortezomib and/or docetaxel. was similar between both bortezomib dose levels (1.0 and 1.3 The most commonly reported treatment-related AEs were mg/m2)—approximately 60% 1 hour after dosing on day 1, fatigue (20 patients, 56%), neutropenia (14 patients, 39%), cycle 1, and 69 to 82% 1 hour after dosing on day 11, cycle and nausea (13 patients, 36%). Peripheral neuropathy (eight 1—there was a suggestion of increased inhibition with in- patients, 22%), paraesthesia (four patients, 11%), dizziness creased dose. No apparent differences were observed with excluding vertigo (three patients, 8%), and headache NOS increasing docetaxel dose levels (60–75 mg/m2). Most pa- (three patients, 8%), all of grade 1 or 2 intensity, were the tients had Ͻ50% proteasome inhibition relative to baseline most commonly reported treatment-related AEs of the ner- before the next scheduled dose. vous system. Approximately two thirds of patients (22, 61%) expe- Safety rienced at least one AE of grade 3 or 4 intensity, 17 patients A total of 36 patients received at least one dose of the (59%) who received bortezomib 1.0 mg/m2, and five patients study drug at one of five bortezomib/docetaxel dose levels. (71%) who received bortezomib 1.3 mg/m2 (Table 4). These Thirty-two (89%) patients completed at least one cycle of AEs were considered to be at least possibly related to bort- treatment. An average of 4.4 (range, 0–33) and 3.3 (range, ezomib and/or docetaxel in 17 patients (47%): 12 (41%) who 0–11) treatment cycles were completed at the dose levels of received bortezomib 1.0 mg/m2 and five (71%) who received

FIGURE 1. Percent inhibition of 20S proteasome activity relative to baseline (cycle 1, day 1 pre-dose).

TABLE 4. Most Commonly Reported (Ͼ5%) Treatment-Emergent Adverse Effects of Grade 3 or 4 Intensitya Cohort: Study drug dose of bortezomib/docetaxel (mg/m2)

MedDRA preferred term 1: 1.0/60 2: 1.0/65 3: 1.0/70 4: 1.0/75 Subtotal for cohorts 1–4 5: 1.3/75 Total

(n ϭ 4) (n ϭ 5) (n ϭ 4) (n ϭ 16) (n ϭ 29) (n ϭ 7) (n ϭ 36)

Patients with at least one 2 (50) 3 (60) 1 (25) 11 (69) 17 (59) 5 (71) 22 (61) treatment-emergent AE of grade 3 or 4 intensity Neutropenia 1 (25) 2 (40) 1 (25) 6 (38) 10 (34) 3 (43) 13 (36) Fatigue 0 0 0 2 (13) 2 (7) 3 (43) 5 (14) Hyponatremia 0 0 0 2 (13) 2 (7) 1 (14) 3 (8) Anxiety NEC 0 1 (20) 0 1 (6) 2 (7) 0 2 (6) Dehydration 0 0 0 2 (13) 2 (7) 0 2 (6) Device blockage 0 1 (20) 0 1 (6) 2 (7) 0 2 (6) Disease progression NOS 0 0 1 (25) 0 1 (3) 1 (14) 2 (6) Dyspnea exacerbated 0 1 (20) 0 1 (6) 2 (7) 0 2 (6) Mental status changes 0 1 (20) 0 0 1 (3) 1 (14) 2 (6)

Values are expressed as n (%). MedDRA, Medical Dictionary for Regulatory Activities; NEC, not elsewhere classiﬁed; NOS, not otherwise speciﬁed; AE, adverse event. aA patient was counted only once within a preferred term. bortezomib 1.3 mg/m2. The most commonly reported treat- m2. Eleven patients (31%) experienced at least one AE of ment-related grade 3 or 4 toxicity was neutropenia (13 pa- grade 4 intensity. Grade 4 neutropenia (nine patients, 25%) tients, 36%), which was reported for 10 patients (34%) who and hyponatremia (one patient, 3%) were generally consid- received bortezomib 1.0 mg/m2 and three patients (43%) who ered by the investigator to be at least possibly related to received bortezomib 1.3 mg/m2. Fatigue was the only other bortezomib and/or docetaxel, whereas all other grade 4 events study drug-related grade 3 or 4 toxicity reported for more were considered unlikely or not related to bortezomib and/or than 10% of patients; it was reported in four patients (11%) docetaxel. overall: one patient (3%) who received bortezomib 1.0 mg/m2 No patients needed to discontinue the study drugs and three patients (43%) who received bortezomib 1.3 mg/ because of a treatment-related AE. Six patients (17%) and

Copyright © 2006 by the International Association for the Study of Lung Cancer 131 Lara et al. Journal of Thoracic Oncology • Volume 1, Number 2, February 2006 one patient (3%) required dose reductions after cycles 2 and times to disease response for the two patients with a con- 4, respectively. Most patients (18; 50%) who were terminated firmed PR were 75 and 122 days, and the respective durations from the study early did so because of progressive disease, of response were 68 and 84 days. The median time to disease and three patients (8%) were terminated because of a non– progression for all patients was 77 days. study drug-related unacceptable AE (Table 3). These were grade 4 gastrointestinal hemorrhage, grade 3 bacteremia, and grade 4 disease progression NOS (generalized muscle atro- DISCUSSION phy likely related to hypothyroidism in a patient with med- This dose-escalation study of bortezomib and docetaxel ullary carcinoma of the thyroid), in patients in the 1.0/60, represents the initial clinical experiment using this combina- 1.0/75, and 1.3/75 mg/m2 dose levels, respectively. The tion to treat patients with locally advanced or metastatic patient withdrawn from the study for noncompliance had a NSCLC and other solid tumors. We determined the MTD of 2 Ͼ2-week non–safety-related delay between the last dose of the combined regimen to be 1.0/75 mg/m bortezomib/do- cycle 4 and the first dose of cycle 5. Two patient deaths cetaxel. The study drugs were administered over a 3-week occurred during the study, one from an AE (gastrointestinal treatment cycle consisting of one docetaxel infusion on day 1 hemorrhage) that began 12 days after the last study drug dose and four bortezomib injections on days 1, 4, 8, and 11, and was not considered to be related to the study drugs, and followed by a 10-day rest period (days 11–21). one from clinical deterioration 17 days after the last dose of The combination of bortezomib and docetaxel at the study drug; that patient was considered to have developed MTD was generally well tolerated: no additive toxicities were progressive disease 14 days after the last dose of study drug observed, and the reported toxicities were manageable in and had been withdrawn from the study before death. most patients in this clinical study. No patient discontinued a study drug because of a treatment-related AE. The overall Tumor Measurement and Assessment of AEs were not unexpected in this population of patients with Disease Response locally advanced or metastatic NSCLC or among patients Of 36 patients, two achieved a PR as best overall receiving treatment with bortezomib and docetaxel. The char- response, both occurring at the MTD (1.0/75 mg/m2 bort- acteristics of the study population were consistent with those ezomib/docetaxel). Seven patients (19%) achieved stable dis- seen in other phase I studies of NSCLC, with one half of ease, including three at 1.0/60 mg/m2 bortezomib/docetaxel, patients having relapsed or refractory cancer that had been one at 1.0/70 mg/m2 bortezomib/docetaxel, and three at pretreated with multiple lines of prior chemotherapy. 1.0/75 mg/m2 bortezomib/docetaxel dose levels (Table 5). The mean degree of inhibition of 20S proteasome The two patients who achieved a PR had a diagnosis of stage activity 1-hour after dosing observed in this study was com- IV metastatic NSCLC, one classified as large cell carcinoma parable with that seen at similar doses in phase I studies of and one as carcinoma. The former had received gemcitabine bortezomib monotherapy.7,28,33–35 In addition, the suggestion plus carboplatin therapy, followed 3 months later by gefitinib, of increased inhibition with increased dose in this study is after which he progressed. The latter patient had previously supported by results from other studies indicating dose- received carboplatin plus paclitaxel, achieving a response of dependent inhibition.7,28,33–35 No association between inhibi- stable disease. Of the nine patients showing response or tion of 20S proteasome activity and clinical response or stable disease, eight (89%) had a primary diagnosis of toxicity was observed in this study. Results from other clin- NSCLC. ical studies indicate that the degree of 20S proteasome inhi- The median percent change in tumor lesion size from bition observed in this study is sufficient to produce clinical baseline through to cycle 8 was similar at each assessment, effects. Clinically relevant efficacy was observed at 65 to and no difference was apparent with increasing dose. The 80% inhibition in a phase I study in advanced solid tumors7

TABLE 5. Summary of Best Response to Treatment, Overall and by Dose Level (ITT Population) Cohort: Study drug doses, bortezomib/docetaxel (mg/m2)

1: 1.0/60 2: 1.0/65 3: 1.0/70 4: 1.0/75 5: 1.3/75 Total a(36 ؍ n) (7 ؍ n) (16 ؍ n) (4 ؍ n) (5 ؍ n) (4 ؍ n)

Best response during study per RECIST criteriab PR 0 0 0 2 (13) 0 2 (6) Stable disease 3 (75) 0 1 (25) 3 (19) 0 7 (19) Progressive disease 0 2 (40) 3 (75) 7 (44) 3 (43) 15 (42)

ITT, intent to treat; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors. aThe remaining 12 (33%) of the total of 36 patients were not assessable for disease response either because they had withdrawn from the study before the first disease assessment or because they had insufficient data. bOverall best response to therapy (including confirmed and unconfirmed responses) was computed by the sponsor based on the RECIST guidelines and includes data from day 1 of cycle 1 to the end-of-study visit. Patient 004-008 (1.3/75 mg/m2 dose level) had a PR according to the RECIST guidelines; however, this patient had clinical deterioration on the same day and was withdrawn from the study and is therefore considered to have progressive disease.

132 Copyright © 2006 by the International Association for the Study of Lung Cancer Journal of Thoracic Oncology • Volume 1, Number 2, February 2006 Bortezomib Plus Docetaxel in Advanced NSCLC and at dose levels producing Ն60% inhibition in a phase I dosing may better separate acute and cumulative bortezomib- study in refractory hematologic malignancies.35 Degree of related toxicities.33 Meanwhile, a recent study has shown that 20S proteasome inhibition up to 65% was a significant weekly docetaxel 40 mg/m2 results in a lower incidence of predictive factor for toxicity in the phase I study by Papan- grade 3 or 4 neutropenia compared with docetaxel 75 mg/m2 dreou et al.;7 however, most AEs were seen at 65 to 75% 20S every 3 weeks. However, efficacy seemed to be slightly proteasome inhibition, and their severity did not correlate lower.29 with degree of inhibition. Nevertheless, the availability of a Determining antitumor activity was not the main goal 20S proteasome assay31 has enabled the use of this parameter of the study. However, results from disease response assess- as a guide in dose escalation studies.7,10,33 In animals, toxic- ments show the combination of bortezomib and docetaxel to ities become significantly more pronounced above 80% 20S be active in solid tumors, with a PR achieved in two patients proteasome inhibition36; the dose estimated to produce this (both with NSCLC). Although preliminary, these results degree of inhibition in humans, the maximal safe dose, has suggest that bortezomib in combination with docetaxel is been calculated as 1.96 mg/m2.36 active in the treatment of NSCLC. Indeed, this early prospec- To date, a number of phase II and phase III clinical tive study is part of a larger program to evaluate the safety trials have shown that bortezomib alone and in combination and efficacy of bortezomib in NSCLC, as both monotherapy is well tolerated and active in multiple myeloma and non- and in combined regimens. Our group is conducting a NCI- Hodgkin’s lymphoma,6,37–40 and activity has been seen in sponsored randomized phase II trial of two different sched- prostate cancer and lung cancers in phase I trials.7,41–43 By ules of bortezomib plus docetaxel (concurrent versus sequen- inhibiting protein degradation by the proteasome, bortezomib tial) as second-line treatment for patients with advanced targets multiple pathways significant to tumor progression NSCLC. and can help to overcome multiple cellular drug resistance In conclusion, toxicities were manageable when do- associated with chemotherapeutic monotherapy.44 In cetaxel and bortezomib were administered in combination, NSCLC, bortezomib monotherapy28,45 or bortezomib com- and the confirmed MTD indicates that the standard docetaxel bined with standard chemotherapy agents41–43,46 has shown regimen should not need to be altered when administered encouraging results. along with a clinically active dose of bortezomib for future The combination of bortezomib with docetaxel has clinical efficacy studies. been evaluated in several other studies, and the MTD seems to be highly dependent on the treatment schedule. In a phase ACKNOWLEDGMENTS Supported in part by Millennium Pharmaceuticals and I study of patients with breast cancer, the bortezomib/do- the American Cancer Society CRTG 001701CCE (to PNL). cetaxel combination was well tolerated, and all toxicities We thank the CRAs and research nursing staff at the were manageable. DLTs were not observed in patients with California Cancer Consortium institutions for their hard breast cancer treated with 1.3/75 mg/m2 bortezomib/do- work on this trial. We also thank Ms Tracey Baratta, Con- cetaxel administered on the same schedule used in this sortium Manager, for her administrative support. study.47 When docetaxel was given weekly for 2 weeks and bortezomib twice weekly for 2 weeks of a 21-day cycle in REFERENCES patients with refractory solid tumors, the MTD was only 25 1. Adams J. The proteasome: A suitable antineoplastic target. Nat Rev 2 2 mg/m and 0.8 mg/m , respectively.43 However, in a phase Cancer 2004;4:349–360. I/II study in patients with hormone-refractory prostate cancer, 2. Kisselev AF, Goldberg AL. Proteasome inhibitors: From research tools the MTD was not reached, and docetaxel 40 mg/m2 on days to drug candidates. Chem Biol 2001;8:739–758. 2 3. Myung J, Kim KB, Crews CM. The ubiquitin-proteasome pathway and 1 and 8 combined with bortezomib 1.6 mg/m on days 2 and proteasome inhibitors. Med Res Rev 2001;21:245–273. 9 of a 21-day cycle was well tolerated.48 4. DeMartino GN, Slaughter CA. The proteasome, a novel protease regu- A number of practical issues should be considered lated by multiple mechanisms. J Biol Chem 1999;274:22123–22126. when integrating bortezomib chemosensitization into lung 5. Adams J, Palombella VJ, Elliott PJ. Proteasome inhibition: A new strategy in cancer treatment. Invest New Drugs 2000;18:109–121. cancer chemotherapy regimens. The optimal dosing schedule 6. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or needs to address the potential for DLTs (e.g., fatigue), the high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med optimal sequencing with various chemotherapeutic regimens, 2005;352:2487–2498. and the duration of bortezomib treatment, including the 7. Papandreou CN, Daliani DD, Nix D, et al. Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with obser- potential for cumulative toxicity with long-term administra- vations in androgen-independent prostate cancer. J Clin Oncol 2004;22: tion.30 Comparative phase II studies are required to determine 2108–2121. the efficacy and toxicity advantages and disadvantages of 8. Cusack JC. Rationale for the treatment of solid tumors with the protea- different bortezomib/docetaxel treatment schedules. The some inhibitor bortezomib. Cancer Treat Rev 2003;29(Suppl 1):21–31. 9. Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: A schedule used in the present study delivers a higher dose novel class of potent and effective antitumor agents. Cancer Res 1999; intensity of bortezomib and a similar dose intensity of do- 59:2615–2622. cetaxel over the 3-week cycle, in comparison with the weekly 10. Adams J, Kauffman M. Development of the proteasome inhibitor Vel- schedule.48 Various administration schedules of bortezomib cade (Bortezomib). Cancer Invest 2004;22:304–311. monotherapy in phase I trials have produced comparable dose 11. Weinstein JN, Myers TG, O’Connor PM, et al. An information-intensive 7,28,33-35,49 approach to the molecular pharmacology of cancer. Science 1997;275: intensities. However, a weekly schedule seems to 343–349. enable a greater dose per administration, and intermittent 12. Ling YH, Liebes L, Ng B, et al. PS-341, a novel proteasome inhibitor,

induces Bcl-2 phosphorylation and cleavage in association with G2-M 32. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to phase arrest and apoptosis. Mol Cancer Ther 2002;1:841–849. evaluate the response to treatment in solid tumors: European Organiza- 13. Ling YH, Liebes L, Zou Y, Perez-Soler R. Reactive oxygen species tion for Research and Treatment of Cancer, National Cancer Institute of generation and mitochondrial dysfunction in the apoptotic response to the United States, National Cancer Institute of Canada. J Natl Cancer Bortezomib, a novel proteasome inhibitor, in human H460 non-small Inst 2000;92:205–216. cell lung cancer cells. J Biol Chem 2003;278:33714–33723. 33. Hamilton AL, Eder JP, Pavlick AC, et al. Proteasome inhibition with 14. Mortenson MM, Schlieman MG, Virudachalam S, Bold RJ. Effects of bortezomib (PS-341): A phase I study with pharmacodynamic end points the proteasome inhibitor bortezomib alone and in combination with using a day 1 and day 4 schedule in a 14-day cycle. J Clin Oncol chemotherapy in the A549 non-small-cell lung cancer cell line. Cancer 2005;23:6107–6116. Chemother Pharmacol 2004;54:343–353. 34. Blaney SM, Bernstein M, Neville K, et al. Phase I study of the 15. Yang Y, Ikezoe T, Saito T, Kobayashi M, Koefﬂer HP, Taguchi H. proteasome inhibitor bortezomib in pediatric patients with refractory Proteasome inhibitor PS-341 induces growth arrest and apoptosis of solid tumors: A Children’s Oncology Group study (ADVL0015). J Clin non-small cell lung cancer cells via the JNK/c-Jun/AP-1 signaling. Oncol 2004;22:4804–4809. Cancer Sci 2004;95:176–180. 35. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the 16. Ling YH, Liebes L, Jiang JD, et al. Mechanisms of proteasome inhibitor proteasome inhibitor PS-341 in patients with refractory hematologic PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small malignancies. J Clin Oncol 2002;20:4420–4427. cell lung cancer cell lines. Clin Cancer Res 2003;9:1145–1154. 36. Adams J. Development of the proteasome inhibitor PS-341. Oncologist 17. Lara PN Jr, Davies AM, Mack PC, et al. Proteasome inhibition with 2002;7:9–16. PS-341 (bortezomib) in lung cancer therapy. Semin Oncol 2004;31:40– 37. Goy A, Younes A, McLaughlin P, et al. Phase II study of proteasome 46. inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s 18. Bold RJ, Virudachalam S, McConkey DJ. Chemosensitization of pan- lymphoma. J Clin Oncol 2005;23:667–675. creatic cancer by inhibition of the 26S proteasome. J Surg Res 2001; 38. O’Connor OA, Wright J, Moskowitz C, et al. Phase II clinical experi- 100:11–17. ence with the novel proteasome inhibitor bortezomib in patients with 19. Esposito V, Baldi A, De Luca A, et al. Prognostic role of the cyclin- indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Oncol 2005;23:676–684. Res 1997;57:3381–3385. 39. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of 20. Gandara DR, Lara PN, Lau DH, Mack P, Gumerlock PH. Molecular- bortezomib in relapsed, refractory myeloma. N Engl J Med 2003;348: clinical correlative studies in non-small cell lung cancer: Application of 2609–2617. a three-tiered approach. Lung Cancer 2001;34(Suppl 3):S75–S80. 40. Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses 21. Katayose Y, Kim M, Rakkar AN, Li Z, Cowan KH, Seth P. Promoting of bortezomib in relapsed or refractory myeloma. Br J Haematol apoptosis: A novel activity associated with the cyclin-dependent kinase 2004;127:165–172. inhibitor p27. Cancer Res 1997;57:5441–5445. 41. Appleman L, Ryan D, Clark J, et al. Phase I dose escalation study of 22. Kim YC, Park KO, Kern JA, et al. The interactive effect of Ras, HER2, bortezomib and gemcitabine safety and tolerability in patients with P53 and Bcl-2 expression in predicting the survival of non-small cell advanced solid tumors (Abstract). J Clin Oncol 2003;22(Suppl):209. lung cancer patients. Lung Cancer 1998;22:181–190. 42. Davies A, Lara P, Lau D, et al. The proteasome inhibitor, bortezomib, in 23. Nawrocki ST, Sweeney-Gotsch B, Takamori R, McConkey DJ. The proteasome inhibitor bortezomib enhances the activity of docetaxel in combination with gemcitabine (Gem) and carboplatin (Carbo) in ad- orthotopic human pancreatic tumor xenografts. Mol Cancer Ther 2004; vanced non-small cell lung cancer (NSCLC): Final results of a phase I 3:59–70. California Cancer Consortium study (Abstract). J Clin Oncol 2004;22: 24. Denlinger CE, Rundall BK, Keller MD, Jones DR. Proteasome inhibi- 7106. tion sensitizes non-small-cell lung cancer to gemcitabine-induced apo- 43. Messersmith W, Baker S, Dinh K, et al. Phase I trial of bortezomib ptosis (Discussion). Ann Thorac Surg 2004;78:1207–1214. (PS-341) in combination with docetaxel in patients with advanced solid 25. Millennium Pharmaceuticals, Inc. VELCADE and Taxotere in SKOV-3 tumors (Abstract). J Clin Oncol 2004;22:3052 human ovarian carcinoma cells (Data on ﬁle). 2001. Cambridge, MA 44. Frankel A, Man S, Elliott P, Adams J, Kerbel RS. Lack of multicellular 26. Pink M, Pien C, Ona V, Worland P, Adams J, Kauffman M. PS-341 drug resistance observed in human ovarian and prostate carcinoma enhances chemotherapeutic effect in human xenograft models (Ab- treated with the proteasome inhibitor PS-341. Clin Cancer Res 2000;6: stract). Proc AACR 2002;43:158. 3719–3728. 27. Gumerlock PH, Kimura T, Holland WS, Shih CD, Lara PN Jr, Gandara 45. Stevenson J, Nho C, Johnson S, et al. Effects of bortezomib (PS-341) on DR. Differential in vivo activity of docetaxel plus PS-341 combination NF-B activation in peripheral blood mononuclear cells (PBMCs) of therapy in non-small cell lung carcinoma (NSCLC) xenografts (Ab- advanced non-small lung cancer (NSCLC) patients: A phase II/pharma- stract). J Clin Oncol 2004;22:649. codynamic trial (Abstract). J Clin Oncol 2004;22: 7145. 28. Aghajanian C, Soignet S, Dizon DS, et al. A phase I trial of the novel 46. Fanucchi M, Fossella F, Fidias P, et al. Bortezomib Ϯ docetaxel in proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin previously treated patients with advanced non-small cell lung cancer Cancer Res 2002;8:2505–2511. (NSCLC): A phase 2 study (Abstract). J Clin Oncol 2005;23: 7034. 29. Gervais R, Ducolone A, Breton JL, et al. Phase II randomised trial 47. Albanell J, Baselga J, Guix M, et al. Phase I study of bortezomib in comparing docetaxel given every 3 weeks with weekly schedule as combination with docetaxel in anthracycline-pretreated advanced breast second-line therapy in patients with advanced non-small-cell lung cancer cancer (Abstract). J Clin Oncol 2003;21(Suppl):16. (NSCLC). Ann Oncol 2005;16:90–96. 48. Dreicer R, Roth B, Petrylak D, et al. Phase I/II trial of bortezomib plus 30. Mack PC, Davies AM, Lara PN, Gumerlock PH, Gandara DR. Integra- docetaxel in patients with advanced androgen-independent prostate can- tion of the proteasome inhibitor PS-341 (Velcade) into the therapeutic cer (Abstract). J Clin Oncol 2004;22: 4654. approach to lung cancer. Lung Cancer 2003;41(Suppl 1):S89–S96. 49. Dy GK, Thomas JP, Wilding G, et al. A phase I and pharmacologic trial 31. Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ. of two schedules of the proteasome inhibitor, PS-341 (bortezomib, Proteasome inhibition measurements: Clinical application. Clin Chem velcade), in patients with advanced cancer. Clin Cancer Res 2006;11: 2000;46:673–683. 3410–3416.