Cancer Therapy Vol 3, 237-242, 2005

Phase II trial of celecoxib plus carboplatin and gemcitabine for first-line therapy in stage IIIB/IV non-small cell lung cancer-a negative study

Research Article

Frank E. Mott*, Christian T. Cable, Jon Herrington, Joel Marcus, Rebecca Griggs, Melissa Ainslie

Lung Cancer Clinic, Scott & White Clinic, Texas A&M University HSC, 2401 South 31^st Street, Temple, TX, USA

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*Correspondence: Frank E. Mott, MD FACP, Assistant Professor of Medicine, Director Lung Cancer Clinic, Scott & White Clinic, Texas A&M University HSC, 2401 South 31^st Street, Temple, TX 76508; Tel: 254-724-7048; fax: 254-724-4904; e-mail: fmott@swmail.sw.org

Key words: celecoxib, carboplatin, gemcitabine, non-small cell lung cancer

Abbreviations: absolute neutrophil count, (ANC); bone scan, (BS); complete blood count, (CBC); computerized tomographic, (CT); creatinine clearance, (CrCl); Cyclo-oxygenase 1, (COX-1); cyclo-oxygenase 2, (COX-2); Eastern Cooperative Oncology Group, (ECOG); Functional Assessment of Cancer Therapy – Lung,, (FACT-L); Magnetic resonance imaging, (MRI); non-small cell lung cancer, (NSCLC); non-steroidal anti-inflammatory drugs, (NSAID); partial response, (PR); partial response, (PR); performance status, (PS); prostaglandin E2, (PGE2); Quality of Life, (QOL); Response Evaluation Criteria in Solid Tumors, (RECIST); time to progression, (TTP); upper limit of normal, (ULN); white blood cell, (WBC)

This study was supported by a grant from Bristol-Myers-Squibb Pharmaceutical Company

Received: 2 March 2005; Revised: 31 March 2005

Accepted: 8 April 2005; electronically published: April 2005

Summary

The cyclo-oxygenase 2, (COX-2), inhibitor celecoxib has been described as having pro-apoptotic activity both in-vitro and in-vivo. To assess its clinical merit, we conducted a phase II trial of celecoxib in combination with a carboplatin-gemcitabine chemotherapy regimen in good performance status patients with untreated, advanced non-small cell lung cancer (NSCLC). Treatment consisted of gemcitabine 1100 mg/m2 days 1,8; carboplatin area under the curve (AUC) of 5 day 8; repeated every 28 days for four cycles and given concurrently with celecoxib 400 mg orally twice daily. Thirteen patients were enrolled and twelve were evaluable. The study was stopped early due to sub-optimal response and due to emerging evidence from external sources of potential cardiovascular risks with COX-2 inhibitors. Two patients demonstrated a partial response (PR), three were stable, and seven had progression. Time to progression ranged from one to eight months with a median of two months. Survival ranged from one to 21 months, with a median of six months; only two patients were still alive at the time of study closure. Grade 3 or 4 toxicities included myelosuppression and one myocardial infarction. Quality of Life (QOL) analysis was included in the assessment.

I. Introduction

The combination of carboplatin and gemcitabine as a treatment regimen for advanced non-small cell lung cancer has been well described (Carmichael et al, 1996; Edelman et al, 1998; Carrato et al, 1999; Iaffaioli et al, 1999; Jovtis et al, 1999; Ng et al, 1999; Sederholm, 1999; Mott et al, 2003). Only two published trials have given carboplatin on day eight of the treatment cycle (Iaffaioli et al, 1999; Mott et al, 2003). While most regimens employed a 21-day cycle, the trial by Iaffaioli, et al not only gave carboplatin on day eight, but also used a 28-day cycle (Iaffaioli et al, 1999). Our previous trial8 utilized this same regimen and schedule but in a more homogeneous population of advanced NSCLC. We studied thirty patients with advanced NSCLC treated with gemcitabine 1100 mg/m2 on days one and eight and carboplatin at an AUC of five on day eight, given every 28 days up to six cycles (Mott et al, 2003). Ten percent of the patients had a partial response and 45% had stable disease. Median time to progression (TTP) was 5.8 months. Median, one-, and two-year survivals were 8.3 months, 27%, and 16% respectively.

Based on the results of our trial, we decided to investigate the same chemotherapy regimen in combination with the COX-2 inhibitor, celecoxib. The enzyme cyclo-oxygenase converts arachidonic acid to prostaglandins. Cyclo-oxygenase 1 (COX-1) is constitutively present in the body with predominance in gastric mucosa, vascular endothelium, platelets, and the kidney; while COX-2 is inducible and is present mainly in smooth muscle, neurons, monocytes, and macrophages (Fosslien, 2000). A number of tumors have been shown to over-express COX-2, including mammary, gastric, colorectal, and lung carcinomas (Hida et al, 1998; Ochiai et al, 1999; Fosslien, 2000; Hosomi et al, 2000; Soslow et al, 2000; Dempke et al, 2001). The mechanism by which COX-2 mediates cancer growth is complex and still not fully defined; however, it has been established that it can increase prostaglandin E2 (PGE2), bcl-2, and IL-6, thus inhibiting apoptosis and enhancing angiogenesis and metastasis (Fosslien, 2000). Inhibitors of COX-2 have reduced polyp formation in familial adenomatous polyposis and demonstrated anti-angiogenic and anti-tumor activity both in-vitro and in-vivo (Masferrer et al, 2000; Reddy et al, 2000; Steinbach et al, 2000). The specific COX-2 inhibitor, celecoxib, has been the most tested agent in its class. In NSCLC, it has been used alone in resectable disease, in combination with chemotherapy for recurrent or relapsed disease, and in combination with chemotherapy and radiation for locally advanced disease (Carbone et al, 2002; Csiki et al, 2002; Gadgeel et al, 2003; Johnson et al, 2003; Shehadeh et al, 2003; Choy 2004). These studies have suggested that the appropriate “pro-apoptotic” dose be 400 mg twice daily, which is double the recommend arthritis dosing.

Quality of life, (QOL), is important in patients with ultimately incurable cancers. Therefore, any treatment that is recommended for palliation of the disease should not produce a negative impact on QOL. Even though this was a phase II trial, we determined to measure QOL at baseline and then throughout chemotherapy to see if there was any measurable effect, positive or negative.

II. Patients and methods

A. Patient eligibility

Patients had to have histologically confirmed NSCLC and advanced stage. This included anyone with stage IV disease, except with brain metastases, and stage IIIB disease with a malignant pleural effusion. All patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at the time of enrollment. Evaluation included a computerized tomographic (CT) scan of the chest and abdomen to the level of the adrenal glands, complete blood count (CBC), comprehensive metabolic profile (CMP), and creatinine clearance (CrCl). At a minimum, patients were required to have a white blood cell (WBC) count > 3000/mm³ with absolute neutrophil count > 1500/mm³, hemoglobin ³ 8 g/dl, platelets ³ 100,000/mm³, total bilirubin < 1.4 mg/dl, AST < 3 times the upper limit of normal (ULN), serum creatinine < 1.6 mg/dL, and a creatinine clearance > 39 ml/min. A whole body bone scan (BS) was required only if the patient had bone pains and/or an elevated alkaline phosphatase and/or calcium level. Magnetic resonance imaging (MRI) of the brain was also required only if the patient exhibited neurological signs or symptoms, mental status changes, or frequent headaches. Patients were excluded if they had received any prior chemotherapy for the diagnosis of NSCLC. Prior radiotherapy to focal lesions was allowed but must not have been to any sites of measurable disease and at least three weeks must have elapsed before enrolling on the protocol. Patients with an allergy to sulfa compounds were ineligible to take celecoxib at the study doses and were excluded from the study. Patients were not allowed to use any other COX-2 inhibitors or non-steroidal anti-inflammatory drugs (NSAID). Corticosteroids were allowed only as part of the antiemetic regimen. The Institutional Review Committee approved the study design and all patients gave informed, written consent to participate. The study was initially designed to accrue 40 patients. Endpoints were primarily response and time to disease progression. Survival was a secondary endpoint.

B. Treatment

Celecoxib was provided at a dose of 400 mg by mouth twice daily, beginning on the first day of chemotherapy and taken indefinitely, until either disease progression, unacceptable toxicity related to the drug, or patient preference to discontinue. If the baseline creatinine increased by two-fold or greater, celecoxib was held for up to two weeks until the creatinine returned to within 20% above the baseline value, then celecoxib was resumed at a 50% dose reduction. If another hold was required, celecoxib was discontinued. If any patient developed hypertension on celecoxib, then anti-hypertensive agents were allowed; however, if the hypertension could not be adequately controlled, celecoxib was discontinued.

Chemotherapy consisted of gemcitabine administered intravenously at a dose of 1100 mg/m² on day one and eight and carboplatin administered intravenously at an AUC of 5 on day eight of each treatment cycle. Cycles were repeated at 28-day intervals. The antiemetic regimen consisted of prochlorperazine 10 mg by mouth on day one prior to administration of gemcitabine and ondansetron 24 mg plus dexamethasone 16 mg orally on day eight prior to the combination of gemcitabine and carboplatin administration.

Doses of both gemcitabine and carboplatin were reduced by 25% if the absolute neutrophil count (ANC) was less than 1000/mm³ or the platelet count was less than 100,000/mm³ and they were held if the ANC was less than 500/mm³or the platelet count was less than 50,000/mm³. Any non-hematologic toxicity, (except alopecia and nausea), that was grade 3 required a 50% dose reduction and any grade 4 toxicities required holding doses until resolution. Held doses were not made up.

The protocol was initially written with the plan to administer up to six cycles of chemotherapy, similar to our initial trial. However, a number of studies indicated that four cycles of treatment was comparable in efficacy with less toxicity and, therefore, the protocol was revised (Socinski et al, 2003).

C. Assessment

Sites of measurable and evaluable disease were imaged midway through chemotherapy and at the end of chemotherapy, then at three-month intervals thereafter until disease progression or patient withdrawal. Laboratory monitoring was performed weekly during therapy, then at three-month intervals or as clinically necessary. Additional evaluations were allowed as deemed clinically necessary by the patient’s doctor. Patients were also allowed to receive additional therapy if deemed appropriate.

Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST) (Therasse et al, 2000). A complete response was defined as disappearance of disease at all known sites. A partial response (PR) was defined as a 30% reduction in the sum of maximal diameters of all measurable lesions. Progression was defined as the development of one or more new lesions or a 20% increase in the sum of maximal diameters of any one lesion. Stable disease did not meet the criteria for either progression or response. Adverse events were assessed using the Common Toxicity Criteria of the National Cancer Institute of the United States.26

Survival and time to progression (TTP) were calculated from the date of enrollment.

Quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy – Lung, (FACT-L), questionnaire administered at enrollment, midway through, and at the end of chemotherapy. (Cella, 1995; Chang et al, 2002).

III. Results

From January 2003 until study closure in October 2004, 13 patients were enrolled in the trial and 12 were ultimately evaluable. One patient died due to respiratory failure less than a week after enrolling on the trial and before starting any therapy and was therefore excluded from analysis. All but one of the patients had stage IV disease. The first three patients were enrolled in the trial under the original plan of six cycles of therapy, while the remaining patients were treated under the revised protocol of four cycles. Treatment and toxicities are shown in Table 1. The “% dose” was based on the actual total dosage of chemotherapy, (not celecoxib), given divided by the intended dose if full doses for four complete cycles, (six cycles for the first three patients), were administered. Myelosuppression during chemotherapy administration was significant and led to treatment delays and/or dosage modifications in several patients. There were no dosage adjustments necessary for celecoxib administration. Disease progression and myelosuppression were the most common reasons why patients did not complete the full four cycles of chemotherapy.

Table 2 shows response and survival results for each patient. Survival was measured by actual event times. Due to the small size of this study, the original intention to calculate median survival by the Kaplan-Meier method could not be done. Only one patient, (number 2), had a durable response to therapy that has lasted for nearly 21 months. All other patients had progression, including seven who progressed during chemotherapy treatment. The median time to progression was two months, median survival six months, and only two of the patients were still alive at the time the study was closed. One patient, (number 3), died at six months before follow-up imaging studies to document disease progression could be performed. All causes of death were due to disease progression. Additional therapy is also shown in Table 2.

Accrual to the trial was suspended in September 2004 when information was released regarding adverse cardiovascular effects of rofecoxib, another COX-2 inhibitor.29, 30 By December 2004, questions were emerging regarding the safety of celecoxib at higher “cancer doses”, such as used in this trial.31 Therefore, the safety monitoring committee and principal investigator opted to close the trial, especially in the face of poor response and survival data. As noted in Table 1, one of the patients, (number 2), did have a myocardial infarction and developed hypertension requiring treatment, after having been on celecoxib for 16 months. Interestingly, this is the only patient who showed a durable survival.

Table 1.

Patient	Age/Sex	Stage	PS	Cycles	% dose	Grade 3/4 toxicity**
1	57F	IV	0	3*	46%	NP
2	66M	IV	0	6*	100%	NP, htn, MI***
3	61M	IV	1	3*	50%	NP, A
4	66F	IV	1	1	25%	NP, A, T, inc. ALT
5	59F	IV	0	4	88%	NP, T
6	SOM	IV	1	2	32%	NP
7	79M	IV	0	4	100%	Staph bacteremia
8	74M	IV	0	2	50%	None
9	65M	IV	0	4	88%	None
10	71F	IV	0	4	100%	None
11	6SF	IV	0	1	12.50%	None
12	73F	IIIB	0	3	83%	NP, A, T

*Patients 1,2,3 enrolled on protocol for 6 cycles, all others 4 cycles.

**NP= neutropenia; A= anemia; T= thrombocytopenia; MI= nyocardial infarction; htn= hypertensbn; ALT=alanine aminotransferase

***MI occurred 16 months after chemotherapy but while still on celecoxib

Table 2.

Patient	Response	TTP	Survival	Additional, Treatment
1	Progression	3 mos	19 mos	Carbopletin-paclitaxel, vinorebine, topotecan, iressa
2	Partial	**	Alive (21 mos)	No
3	Stable*	?	6 nos	No
4	Progression	1 mon	I non	No
5	Stable	6 mos	9 mos	Iressa
6	Progression	2 mos	12 mos	Iressa
7	Progression	3 mos	5 nos	No
8	Progression	2 mos	3 mos	No
9	Stable	8 mos	Alive (9 mos)	Docetaxel
10	Partial	6 mos	7mos	No
11	Progression	1 mon	2 nos	No
12	Progression	2mos	3mos	No

Using the FACT-L questionnaire, administered at entry, midway, and the end of treatment; there was no significant impact, positive or negative, on quality of life with the study regimen. However, only six patients completed all of the questionnaires.

IV. Discussion

Our initial study (Mott et al, 2003) of gemcitabine and carboplatin in which the carboplatin dose was administered on day eight demonstrated a combined partial response and stable disease rate of approximately 50%, with survival comparable to other regimens. With acceptable toxicity, it seemed like an ideal regimen to investigate in combination with a COX-2 inhibitor. Unfortunately, the majority of the patients treated on this trial progressed while on therapy and demonstrated a median survival that was not much better than expected with supportive care alone. However, due to the small study size, these endpoints need to be viewed cautiously.

It is unknown why poor responses were seen in this trial. Some patients will have aggressive disease and do poorly, regardless of what type of therapy is given. It may be possible that a negative interaction exists between celecoxib and the carboplatin-gemcitabine combination; however, the number of patients in this study was too small to make any conclusions.

Quality of life assessment, due to the number of patients surveyed, was not helpful and no conclusions regarding the impact of this regimen on QOL can be made. Toxicity was primarily myelosuppression, with anemia and neutropenia especially. This was a dose-limiting factor for several patients. Seven of twelve patients, (58%), experienced grade 3 or 4 neutropenia, compared with only 27% in our original trial (Mott et al, 2003). It is unclear whether this was due to the addition of celecoxib. Lastly, the COX-2 inhibitors, in general, came under scrutiny for adverse cardiovascular and cerebrovascular events in 2004, thus bringing their role in cancer therapy into question. Given this fact along with the poor response in our patient population, we were forced to close the study. Due to the small study size, we cannot recommend or refute the combination of carboplatin-gemcitabine with celecoxib as administered in this study protocol.

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Frank E. Mott