Phase II trial of karenitecin in patients with relapsed or refractory non-small cell lung cancer (CALGB 30004)

Lung Cancer (2005) 48, 399—407

Phase II trial of karenitecin in patients with relapsed or refractory non-small cell lung cancer (CALGB 30004)夽 Antonius A. Millera,∗, James E. Herndon IIb, Lin Gub, Mark R. Greenc

The Cancer and Leukemia Group B a

Comprehensive Cancer Center of Wake Forest University, Medical Center Blvd., Winston-Salem, NC 27157, USA b CALGB Statistical Center, Durham, NC, USA c Medical University of South Carolina, Charleston, SC, USA Received 30 August 2004 ; received in revised form 22 November 2004; accepted 23 November 2004 KEYWORDS

Summary

Karenitecin; Non-small cell lung cancer

Purpose: This Phase II trial was designed to determine the response rate, survival, failure-free survival, and toxicity of second-line therapy with karenitecin in patients with relapsed or refractory non-small cell lung cancer (NSCLC). Methods: Eligibility criteria included: only one prior chemotherapy program, measurable disease, performance status 0—1, adequate hematologic, renal, and hepatic function. Cases were stratified as relapsed or refractory. Results: Fifty-five patients were accrued and 52 were eligible of whom 28 had relapsed and 24 had refractory disease. Overall patient characteristics were: median age 63 years (range, 45—79 years), 52% males, 63% performance status 1, 50% adenocarcinoma, 21% squamous, 15% large cell, and 12% undifferentiated NSCLC. In both strata, one patient each (4%) had a partial response and 12 patients each (43% for relapsed, 50% for refractory) had stable disease. Median survival was 10.4 months (95% CI, 8.5—17.0) for relapsed NSCLC and 6.0 months (95% CI, 3.7—9.7) for refractory NSCLC. One-year survival was 36% (95% CI, 14—58%) and 21% (95% CI, 5—37%) for relapsed and refractory NSCLC, respectively. Frequent toxicities were neutropenia (grade 3/4 in 15/15%) and thrombocytopenia (grade 3/4 in 17/8%). No patient had lethal toxicity. Conclusion: Second-line treatment with karenitecin was tolerable with reversible bone marrow suppression as the major toxicity. The partial response rates, median

夽 Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 2003. * Corresponding author. Tel.: +1 336 713 4392; fax: +1 336 713 4798.

E-mail address: [email protected] (A.A. Miller).

0169-5002/$ — see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2004.11.019

400

A.A. Miller et al. survival times, and 1-year survival rates in the relapsed and refractory subgroups are comparable to overall second-line outcomes for other agents considered active in this clinical setting. © 2004 Elsevier Ireland Ltd. All rights reserved.

1. Introduction In the treatment of metastatic non-small cell lung cancer, response rates to the best available chemotherapy regimens remain below 50%. While survival is improved by chemotherapy compared to best supportive care, the survival benefit is modest, and response durations are 6 months or less. Many patients who relapse after a response to initial chemotherapy, or who have disease which is refractory to first-line therapy, continue to have a performance status of 0—1, and normal organ function. These patients are candidates for second-line chemotherapy. During the past decade, camptothecin analogues have emerged as an important new class of anti-tumor drugs. The semisynthetic 7-[(2trimethylsilyl)ethyl]-20(S)-camptothecin named karenitecin is a novel, lipophilic camptothecin derivative that is chemically distinct from other camptothecin analogues, such as the water-soluble irinotecan and topotecan [1,2]. The lipophilicity may improve tissue diffusion. Camptothecins contain a lactone ring and the intact lactone (rather than the carboxylate form) is the active moiety. The lactone species of irinotecan and topotecan represent 20% or less of the total drug concentration in human plasma at physiologic pH. Karenitecin has greater lactone stability (85—100%) in human plasma, which may result in enhanced anti-tumor activity. Unlike irinotecan, karenitecin is neither a prodrug nor does it undergo glucuronidation and should lack gastrointestinal toxicity. Karenitecin is not a P-glycoprotein substrate. In the preclinical development, karenitecin demonstrated activity in vitro and in vivo against various human xenograft tumor models when administered intravenously or orally for various tumor types including human prostate, colon, lung, breast, ovarian carcinoma, melanoma, glioblastoma multiforme, and multiple myeloma [1,2]. Karenitecin’s anti-tumor activity in preclinical models was similar or superior to other camptothecins. Preclinical toxicology studies of karenitecin predicted reversible myelosuppression (neutropenia and thrombocytopenia) as the major toxicity in humans. In a Phase I study of adult patients with solid tumors and adequate renal and hepatic function

[3], karenitecin was administered using an accelerated dose titration design at doses of 0.15, 0.3, 0.6, 1.2, 2.4, and 1.0 mg/m2 . The dose-limiting toxicity (DLT) consisted of reversible grade 4 neutropenia and thrombocytopenia in patients treated at 1.2 and 2.4 mg/m2 . No cumulative myelosuppression was observed. Gastrointestinal toxicity was infrequent and mild (grade 1—2 diarrhea). The recommended Phase II dose of karenitecin was 1 mg/m2 daily for 5 consecutive days [3]. The pharmacokinetic results in nine patients treated at this dose included: a plasma half-life of 15 h; an area under concentration × time curve (AUC) of 171 ␮g h/L; a clearance of 6 (L m2 )/h; and a lactone percentage of the total AUC of 89%. The half-life was longer for karenitecin than for other camptothecins, such as irinotecan and topotecan. This Phase II study of karenitecin as second-line therapy stratified patients into two groups, namely relapsed versus refractory NSCLC, because a difference in response rates and survival between these two groups was anticipated. The objectives were to determine the response rates, the survival and failure-free survival times, and the toxicity profile of karenitecin as salvage therapy in patients with NSCLC.

2. Patients and methods 2.1. Patient eligibility Either histologic or cytologic documentation of NSCLC was required. Only one prior chemotherapy program, including adjuvant or neoadjuvant therapy, was allowed. A chemotherapy ‘‘program’’ was defined as therapy prescribed by a single front-line protocol (for instance, a sequential first-line protocol of chemotherapy combination A followed by combination B was considered a single program). Prior treatment with irinotecan or other camptothecin drug was not allowed. The interval had to be at least 4 weeks from prior radiation or prior chemotherapy (except at least 6 weeks from prior mitomycin-C). CNS metastases were allowed if they were under control and if the patient was neurologically stable and off steroids. All patients had to have measurable disease, an Eastern Coopera-

Phase II trial of karenitecin in patients with NSCLC

401

tive Oncology Group (ECOG) performance status of 0 or 1, and an age of 18 or older. Pregnant and nursing women were excluded. Required laboratory values for entry included: absolute neutrophil count ≥1500 ␮L−1 , platelet count ≥100,000 ␮L−1 , serum creatinine ≤ upper limit of normal, and bilirubin ≤1.5 mg/dL. The patient had to be aware of the neoplastic nature of his/her disease and willingly consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, sideeffects, risks, and discomforts. Institutional review board or human protection committee approval of the protocol and consent form at all institutions was required. Initial evaluation of all patients included a complete history and physical examination, complete blood counts and comprehensive chemistry panel, chest X-ray, computer tomogram (CT) or magnetic resonance imaging (MRI) of chest and abdomen, CT or MRI of the brain, and bone scan.

cally advanced disease with concurrent radiation (response to chemotherapy not assessable), recurrent or progressive disease within 6.0 months after completion of the neoadjuvant chemotherapy; and (e) adjuvant chemotherapy after surgical resection with recurrence within 6.0 months after completion of chemotherapy. The study chairman reviewed all cases for their correct assignment to relapsed versus refractory disease.

2.2. Stratification Patients were stratified as having relapsed or refractory NSCLC based on the results achieved with the last chemotherapeutic program they had received. ‘‘Relapsed’’ was defined by one of the following scenarios: (a) one prior chemotherapy program for recurrent or metastatic disease with initial objective response to chemotherapy, but then progressive disease off chemotherapy; (b) chemotherapy prior to surgery (neoadjuvant) for locally advanced disease without concurrent radiation, initial objective response to chemotherapy but then recurrent or progressive disease; (c) neoadjuvant chemotherapy for locally advanced disease with concurrent radiation (response to chemotherapy not assessable), recurrent or progressed disease more than 6.0 months after completion of the neoadjuvant chemotherapy; and (d) adjuvant chemotherapy after surgical resection with recurrence more than 6.0 months after completion of chemotherapy. ‘‘Refractory’’ was defined by one of the following scenarios: (a) one prior chemotherapy program for recurrent or metastatic disease without an objective response and then progressive disease; (b) one prior chemotherapy program for recurrent or metastatic disease with an objective response, but subsequently progression during the same chemotherapy producing the response; (c) neoadjuvant chemotherapy for locally advanced disease without concurrent radiation, no objective response to chemotherapy and progressive disease; (d) neoadjuvant chemotherapy for lo-

2.3. Treatment Karenitecin (IND #57250) was manufactured and supplied by BioNumerik Pharmaceuticals Inc. (San Antonio, TX; Frederick H. Hausheer, chairman). Karenitecin was diluted with D5W before administration (using non-PVC plastic or glass and nonPVC administration sets). Karenitecin 1 mg/m2 was administered as a single 60 min intravenous infusion daily for 5 consecutive days every 21 days (21 days = 1 cycle). Karenitecin was known to be mildly emetogenic and premedication with a 5—HT3 receptor antagonist was at the discretion of the treating physician. Patients with responding or stable disease were treated for six cycles unless there was unacceptable toxicity. Patients with further reduction in tumor size after six cycles were allowed to continue until two cycles beyond best response unless there was unacceptable toxicity. If febrile neutropenia (temperature ≥38.5 ◦ C (101 ◦ F) sustained for more than 1 h concomitant with an ANC <500 mm−3 ) developed, the dose of karenitecin was decreased to 0.75 mg/m2 for the next and all subsequent cycles. If febrile neutropenia developed again despite this dose reduction, then 0.50 mg/m2 was given in the next and all subsequent cycles. If febrile neutropenia occurred on a subsequent cycle despite this second-dose reduction, protocol therapy was discontinued. Filgrastim (G-CSF) or sargramostim (GM-CSF) use for patients on this protocol was discouraged, but G-CSF could be instituted for the treatment of febrile neutropenia if adverse prognostic factors existed. If thrombocytopenia (platelets <25,000 ␮L−1 ) developed, the dose of karenitecin was decreased to 0.75 mg/m2 for the next and all subsequent cycles. If thrombocytopenia developed again despite this dose reduction, then 0.50 mg/m2 was given in the next and all subsequent cycles. If thrombocytopenia occurred on a subsequent cycle despite this second-dose reduction, protocol therapy was discontinued. Patients with disease progression were removed from protocol treatment and followed for secondary malignancies and survival. Patients requir-

402 ing radiation therapy during protocol treatment were considered to have disease progression.

2.4. Evaluations Before each cycle of chemotherapy, a history and physical examination, toxicity assessment, complete blood counts, and serum chemistry were performed. This study utilized the Common Toxicity Criteria Version 2.0 of the National Cancer Institute (NCI). On day 1 of a cycle, treatment was only initiated if the neutrophil count was ≥1500 ␮L−1 and the platelet count was ≥100,000 ␮L−1 . Complete blood counts were obtained weekly while on treatment. If treatment was delayed for more than 3 weeks, the patient was removed from protocol therapy. Tumor response was determined after every two cycles. The response evaluation criteria in solid tumors (RECIST) of the NCI were applied [4].

2.5. Statistics A single-stage Phase II design was used to assess the activity of karenitecin within each stratification subgroup. We planned to accrue at least 25 patients to the relapsed subgroup in order to differentiate between a response rate of 10 and 30% with ˛ = ˇ = 0.1. We also planned to enter at least 20 patients to the refractory subgroup in order to differentiate between a response rate of 5 and 25% with ˛ = ˇ = 0.1. Patients were followed for response and survival. Kaplan—Meier curves were used to describe overall survival and failure-free survival. Survival time was defined as the time between registration and death. Failure-free survival was the time from initiation of treatment until disease progression, relapse, or death, whichever came first. The frequency of toxicity occurrence was tabulated by type and grade.

A.A. Miller et al. marizes the characteristics of the 52 eligible patients. A nearly equal number of male and female patients were entered.

3.2. Treatment At least two cycles were administered in 96% of the patients in the relapsed subgroup and 79% of the patients in the refractory subgroup. Nine patients (32%) in the relapsed subgroup received six cycles and seven patients (29%) in the refractory subgroup received six cycles.

3.3. Response Table 2 summarizes the response to treatment. Four percent of the patients achieved a partial response. The early death in one patient in the relapsed subgroup was due to disease related complications and not due to protocol treatment. One patient in the refractory subgroup received one cycle of treatment after which she developed grade 3 neutropenia with fever and grade 3 thrombocytopenia; she was removed from protocol by her physician due to this toxicity and a decline in performance status and was deemed unevaluable. Another patient in the refractory subgroup was unevaluable because he withdrew consent during cycle 2 of treatment. Besides completing at least six cycles of chemotherapy, the predominant reason for patients coming off treatment was treatment failure (46% in each subgroup).

3.4. Survival Table 3 provides survival statistics. The median patient follow-up is 10.5 months. Overall, the median survival and failure-free survival times were estimated to be 8.6 months and 2.5 months, respectively. The estimated overall 1-year survival rate was 29%.

3. Results

3.5. Toxicity

3.1. Accrual

Table 4 summarizes the adverse events experienced by patients on protocol. The most common toxicities were reversible neutropenia and thrombocytopenia. Grade 4 toxicities were limited to the bone marrow. Grade 4 neutropenia was observed in 7% of the patients in the relapsed subgroup and 25% of the patients in the refractory subgroup. Grade 4 thrombocytopenia (17%) was only recorded in the refractory subgroup. Overall, the toxicities were more pronounced in the refractory subgroup than

This trial (CALGB 30004) was activated on April of 2001 and closed in April of 2003, and 55 patients were accrued. Three patients were not eligible due to a performance status of 2; two were in the relapsed subgroup and one in the refractory subgroup. Fifty-two patients were included in the efficacy analyses and all patients with adverse event data were included in the toxicity analysis. Table 1 sum-

Phase II trial of karenitecin in patients with NSCLC

Table 1

403

Patient characteristics Relapsed (N = 28)

Sex Male Female

Refractory (N = 24)

Overall (N = 52)

14 (50%) 14 (50%)

13 (54%) 11 (46%)

27 (52%) 25 (48%)

5 (18%) 6 (21%) 9 (32%) 8 (29%) 64 (46, 79)

2 (8%) 8 (33%) 12 (50%) 2 (8%) 62 (45, 74)

7 (13%) 14 (27%) 21 (40%) 10 (19%) 63 (45, 79)

Race White Black Asian

24 (86%) 4 (14%) 0 (0%)

22 (92%) 1 (4%) 1 (4%)

46 (88%) 5 (10%) 1 (2%)

Performance status 0 1

9 (32%) 19 (68%)

10 (42%) 14 (58%)

19 (37%) 33 (63%)

Weight loss <5% 5—9% 10—20%

26 (93%) 2 (7%) 0 (0%)

16 (67%) 5 (21%) 3 (13%)

42 (81%) 7 (13%) 3 (6%)

Diagnosis Adenocarcinoma Squamous Undifferentiated large Undifferentiated NSCLC

14 8 3 3

12 3 4 5

(50%) (13%) (17%) (21%)

26 11 7 8

(50%) (21%) (13%) (15%)

Prior chemotherapy Adjuvant Neoadjuvant with radiation Neoadjuvant alone Metastatic/recurrent disease

4 (14%) 9 (32%) 2 (7%) 13 (46%)

2 (8%) 3 (13%) 4 (17%) 15 (63%)

6 12 6 28

(12%) (23%) (12%) (54%)

Age 40—49 50—59 60—69 70+ Median (minimum, maximum)

(50%) (29%) (11%) (11%)

the relapsed subgroup. No grade 5 toxicity was encountered.

4. Discussion The recommendations for second-line palliative chemotherapy in NSCLC have recently changed as Table 2

exemplified in the guidelines of the American Society of Clinical Oncology (ASCO). The 1997 guidelines stated that there was no evidence that either confirmed or refuted that second-line chemotherapy improved survival in non-responding or progressing patients with advanced NSCLC [5]. In the 2003, ASCO update, docetaxel is recommended as second-line therapy for patients with locally advanced or metastatic NSCLC with adequate per-

Response to therapy

Best response

Relapsed (N = 28)

Refractory (N = 24)

Overall (N = 52)

Partial response Stable disease Progressive disease Unevaluable Early death Response rate (95% CI)

1 (4%) 12 (43%) 14 (50%) 0 (0%) 1 (4%)b 3.6% (0.1%, 18%)

1 (4%) 12 (50%) 9 (38%) 2 (8%)a 0 (0%) 4.2% (0.1%, 21%)

2 (4%) 24 (46%) 23 (44%) 2 (4%) 1 (2%) 3.8% (0.5%, 13%)

a b

Patients had no follow-up assessment of disease status. Patient died within 60 days of registration and prior to any disease re-assessment.

404

Table 3

A.A. Miller et al.

Survival and failure-free survival #Patients

#Deaths/#failures

Median (95% CI) (months)

28 24 52

16 21 37

10.4 (8.5, 17.0) 6.0 (3.7, 9.7) 8.6 (6.4, 11.2)

Failure-free survival Relapsed 28 Refractory 24 Overall 52

26 24 50

1.8 (1.4, 3.9) 2.9 (1.5, 4.3) 2.5 (1.5, 3.8)

Survival Relapsed Refractory Overall

formance status who have progressed on first line platinum-based therapy [6]. Two Phase III trials established docetaxel as the first chemotherapeutic agent with proven benefit for patients with recurrent or refractory disease following initial chemotherapy. In one of these Phase III trials, docetaxel was compared to best supportive care alone [7], and in the other, docetaxel was compared with an alternative chemotherapy regimen consisting of either vinorelbine or ifosfamide [8]. In both of these trials, patients with a performance status of 0—2

Table 4

One-year (95% CI) 36%(14%, 58%) 21%(5%, 37%) 29%(15%, 43%) N/A N/A N/A

and one or more prior platinum-based chemotherapy regimens were eligible. The results are summarized in Table 5. One of the trials [7] did not allow prior treatment with taxanes (i.e. paclitaxel) whereas the other one [8] did allow such prior therapy. In the trial of docetaxel versus best supportive care, a higher death rate from toxicity was seen among the patients randomized to docetaxel 100 mg/m2 , and therefore the dose of docetaxel was reduced to 75 mg/m2 [7]. The survival time for patients who received docetaxel was signifi-

Adverse events of grade 3 and 4 severity with an incidence ≥5% Stratification

Grade of toxicity, N (%)

Total, N

3

4

Relapsed Refractory

6 (21%) 2 (8%)

2 (7%) 6 (25%)

28 24

Leukocytes

Relapsed Refractory

1 (4%) 2 (8%)

1 (4%) 0 (0%)

28 24

Hemoglobin

Relapsed

2 (7%)

0 (0%)

28

Platelets

Relapsed Refractory

2 (7%) 7 (29%)

0 (0%) 4 (17%)

28 24

Transfusion: packed red blood cells

Relapsed Refractory

2 (7%) 4 (17%)

0 (0%) 0 (0%)

28 24

Relapsed Refractory

2 (7%) 2 (8%)

0 (0%) 0 (0%)

28 24

Gastrointestinal Nausea Diarrhea (without colostomy)

Refractory Refractory

2 (8%) 2 (8%)

0 (0%) 0 (0%)

24 24

Hemorrhage Bleeding with grade 3/4 thrombocytopenia

Refractory

2 (8%)

0 (0%)

24

Infection/febrile neutropenia Febrile neutropenia

Refractory

2 (8%)

0 (0%)

24

Blood/bone marrow Neutrophils

Constitutional symptoms Fatigue (lethargy/malaise/asthenia)

Phase II trial of karenitecin in patients with NSCLC

Table 5

405

Selected trials of second-line therapy in NSCLC No. of patients (N)

Phase III (TAX 317) Best supportive care Docetaxel 100 mg/m2 Docetaxel 75 mg/m2

Response rate (%)

Median survival (months)

One-year survival (%)

Reference

100 48 55

— 6.3 5.5

4.6 5.9 7.5

19 19 37

[8]

Phase III (TAX 320) Vinorelbine/ifosfamide Docetaxel 100 mg/m2 Docetaxel 75 mg/m2

89/34 125 125

0.8 10.8 6.7

5.6 5.5 5.7

19 21 32

[9]

Phase II Gemcitabine + placebo Gemcitabine + CI-994

89 91

3.8 3.5

6.2 6.3

NA NA

[10]

Phase II Pemetrexed

79

8.9

5.7

23

[11]

Phase III Pemetrexed Docetaxel

283 288

9.1 8.8

8.3 7.9

30 30

[12]

Phase II Karenitecin

52

3.8

8.6

29

NA, not available.

cantly better (p = 0.047) than that of those who received best supportive care alone [7]. In the trial of docetaxel versus vinorelbine/ifosfamide, a trend toward improved overall survival in the docetaxel 75 mg/m2 group was noted, although this was not statistically significant [8]. However, the 1-year survival rate was significantly (p = 0.025) better in patients receiving docetaxel 75 mg/m2 [8]. In a randomized Phase II study of gemcitabine + the oral histone deacetylase inhibitor CI994 versus gemcitabine + placebo in second-line NSCLC, patients with a Karnofsky performance status ≥80 and prior platinum-based therapy were eligible [9]. The addition of CI-994 did not increase the activity of gemcitabine and the response rates are low, but the survival times are comparable to the docetaxel experience (Table 5) [9]. Another Phase II study reported the results of pemetrexed disodium as a second-line therapy of NSCLC in patients with a performance status of 0—1 [10]. In this trial, patients with NSCLC were eligible if they had progressive disease within 3.0 months after first line chemotherapy or progression while being treated with first line chemotherapy [10]. In this refractory patient population, pemetrexed was considered an active agent based on the results summarized in Table 5. A randomized Phase III trial of pemetrexed versus docetaxel as second-line chemotherapy for NSCLC accrued 571 patients [11]. The majority had a performance status of 0—1 (88%) and stage IV

disease (75%). The treatment with pemetrexed resulted in efficacy results similar to those achieved with docetaxel (Table 5). In the context of these Phases II and III trials (Table 5), our Phase II study of karenitecin is small and the confidence intervals are wide (Table 3). In addition, the eligibility criteria across these trials were not the same. The Phase III trials of docetaxel included patients with performance status 2. In the trial of docetaxel versus best supportive care, 24% of the patients had a performance status of 2 [7], and in the trial of docetaxel versus vinorelbine/ifosfamide, 17% of patients had a performance status of 2 [8]. Our trial was conducted in patients with a performance status of 0 and 1. On the other hand, the study of pemetrexed also limited eligibility of patients to a performance status of 0 and 1 [9], and the Phase III study of pemetrexed accrued only 13% of patients with a performance status of 2 [11]. Similar to our refractory sub-group, the pemetrexed Phase II study was for patients with disease that was refractory to chemotherapy. Interestingly, the response rate for pemetrexed was 8.9%, and thus superior to the response rate for karenitecin in the refractory sub-group (4.2%); nevertheless, our median survival time of 6.0 months and 1-year survival rate of 21% (Table 3) compare favorably with the 5.7-month median survival and 1-year survival of 23% in the pemetrexed Phase II study (Table 5). Another factor that has to be considered is the pro-

406 portion of females in the study because women with NSCLC have a better prognosis [6]: In our study, 48% of patients were female while the study of docetaxel versus best supportive care [7] and the study of docetaxel versus vinorelbine/ifosfamide [8] included 31 and 35% of females, respectively. The Phase II study of pemetrexed does not provide a percentage of females [10]. In the Phase III study of pemetrexed, only 28% of the patients were female [11]. The statistical design of the study made inferences about the response rate to karenitecin as second-line treatment within the framework of a hypothesis test. Based upon that test, the response rate of 4% is at a level that was not regarded as clinically meaningful when the study was initiated. However, the median survival times and 1-year survival rates (Table 3) for karenitecin suggest that this drug has clinical activity in second-line therapy for NSCLC. Disease stabilization (Table 2, 43 and 50%, respectively) may have contributed to the survival results. As noted by Kelly, the benefits of achieving stable disease include control of metastasis, greater time to progression, and prolongation of survival [12]. Karenitecin has modest and reversible hematologic toxicity and is overall well tolerated (Table 4). To establish the role of karenitecin in comparison to other active agents in second-line therapy for NSCLC (Table 5), further clinical trials appear warranted.

Acknowledgment The research for CALGB 30004 was supported, in part, by grants from the National Cancer Institute (CA31946, CA03927, CA33601, and CA03927). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. The following institutions participated in this study: CALGB Statistical Center, Durham, NC—–Stephen George, supported by CA33601. Christiana Care Health Services Inc. CCOP, Wilmington, DE—–Stephen Grubbs, supported by CA45418. Duke University Medical Center, Durham, NC—– Jeffrey Crawford, supported by CA47577. Missouri Baptist Medical Center, St. Louis, MO—– Alan P. Lyss. Northern Indiana Cancer Research Consortium CCOP, South Bend, IN—–Rafat Ansari, supported by CA86726.

A.A. Miller et al. Rhode Island Hospital, Providence, RI—–William Sikov, supported by CA08025. Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, NC—–James N. Atkins, supported by CA45808. Southern Nevada Cancer Research Foundation CCOP, Las Vegas, NV—–John Ellerton, supported by CA35421. Syracuse Hematology-Oncology Association CCOP, Syracuse, NY—–Jeffrey Kirshner, supported by CA45389. University of California at San Diego, San Diego, CA—–Stephen L. Seagren, supported by CA11789. University of Chicago Medical Center, Chicago, IL— –Gini Fleming, supported by CA41287. University of Iowa, Iowa City, IA—–Gerald Clamon, supported by CA47642. University of Missouri/Ellis Fischel Cancer Center, Columbia, MO—–Michael C. Perry, supported by CA12046. University of Nebraska Medical Center, Omaha, NE—–Anne Kessinger, supported by CA77298. University of Texas Southwestern Medical Center, Dallas, TX—–Debasish Tripathy. Wake Forest University School of Medicine, Winston-Salem, NC—–David D. Hurd, supported by CA03927. Washington University School of Medicine, St. Louis, MO—–Nancy Bartlett, supported by CA77440.

References [1] Hausheer FH, Haridas K, Zhao M, et al. Karenitecins: a novel class of orally active highly lipophilic topoisomerase I inhibitors. Proc Am Assoc Cancer Res 1997;39:420. [2] Hausheer FH, Haridas K, Zhao M, et al. Karenitecins. Part II. A novel class of orally active highly lipophilic topoisomerase I inhibitors. Proc Am Assoc Cancer Res 1998;39:420. [3] Schilsky RL, Hausheer FH, Bertucci D, et al. Phase I trial of karenitecin (KT) administered intravenously daily for five consecutive days in patients with advanced solid tumors using accelerated dose titration. Proc Am Soc Clin Oncol 2000;19:195a. [4] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205—16. [5] American Society of Clinical Oncology. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. J Clin Oncol 1997;15:2996—3018. [6] Pfister DG, Johnson DH, Azzoli CH, et al. American Society of Clinical Oncology treatment of unresectable nonsmall cell lung cancer guideline: update 2003. J Clin Oncol 2004;22:330—53. [7] Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095—103.

Phase II trial of karenitecin in patients with NSCLC

407

[8] Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum — containing chemotherapy regimens. J Clin Oncol 2000;18:2354—62. [9] Von Pawel J, Shepherd F, Gatzmeier U, et al. Randomized phase II study of the oral histone deacetylase inhibitor CI994 plus gemcitabine (Gem) vs. placebo (PBO) plus Gem in second-line non-small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2002;21:310a.

[10] Smit EF, Mattson K, Von Pawel J, et al. ALIMTA (pemetrexed disodium) as second-line treatment of non-smallcell lung cancer: a phase II study. Ann Oncol 2003;14:455— 60. [11] Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589—97. [12] Kelly K. The benefits of achieving stable disease in advanced lung cancer. Oncology 2003;17:957—63.