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Clinical Trials |
Vanderbilt University, Nashville, Tennessee 37232 [M. H. J., D. H. J., Y. S., D. P. C., R. F. D.]; Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [C. J. L.]; Methodist- LeBonheur Health Care, Memphis, Tennessee 38105 [F. Y.]; West Virginia University, Morgantown, West Virginia 26506 [J. S. R.]; Erlanger Medical Center, Chattanooga, Tennessee 37403 [L. L. S.]; and Saint Thomas Hospital, Nashville, Tennessee 37205 [A. G. C.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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CPT-11 is a water-soluble prodrug that is metabolized in vivo to an active metabolite, SN-38. SN-38 interacts with topoisomerase I, an enzyme that relieves torsional strain in DNA during DNA replication and transcription and stabilizes the DNA cleavage reaction of the enzyme (4, 5, 6) . During cell division, DNA replication forks collide with these enzyme-DNA cleavage complexes, resulting in double-stranded DNA breaks and subsequent programmed cell death (7 , 8) .
Because cisplatin represents one of the most active chemotherapeutic agents for NSCLC, the combination of CPT-11 with cisplatin in the therapy of this disease is a logical area of investigation. Therapeutic synergy for these agents has been demonstrated in human lung cancer xenograft models (9 , 10) . The exact mechanism for the synergy observed between platinum and topoisomerase targeting agents is not well understood; however, simultaneous exposure or sequencing of the platinum compound just prior to the topoisomerase agent appears optimal (11) . To date, most clinical trials combining cisplatin with CPT-11 in NSCLC have involved monthly administration of cisplatin (12, 13, 14, 15) . In most of these studies, CPT-11 has been given prior to cisplatin on day 1 only and thereafter as a single agent on days 8 and 15 of a 28-day cycle. Given the laboratory data suggesting a therapeutic advantage to delivering both agents on the same day and sequencing cisplatin prior to CPT-11 (11) , Saltz et al. (16) recently developed a Phase I trial of such a regimen and found it to be quite well tolerated. For chemotherapy-naïve patients, the recommended starting doses were 30 mg/m2 cisplatin, followed immediately by 65 mg/m2 CPT-11 on a weekly schedule for 4 of 6 weeks for each treatment cycle (16) . The current trial was undertaken to evaluate the efficacy and safety of this weekly regimen in an open-label, nonrandomized, multicenter, academic- and community-based Phase II trial in patients with advanced NSCLC.
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PATIENTS AND METHODS |
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9 g/dl, serum creatinine 
1.5 mg/dl,
total bilirubin 2.0 mg/dl, and serum glutamic oxaloacetate
transaminase 3 times the institutional upper limit of normal.
Patients with adequately controlled brain metastases were included. Patients were not eligible for study enrollment if they had any of the following: (a) active or uncontrolled infection; (b) significant cardiovascular disease (uncontrolled hypertension, unstable angina, active congestive heart failure, myocardial infarction within the previous 6 months, or uncontrolled serious arrhythmia); (c) pregnancy, lactation, or refusal to use effective contraception; (d) any other severe, concurrent illness which in the judgment of the investigator would make the patient inappropriate for entry into this study; (e) Gilbert’s disease was excluded given recent evidence of excessive CPT-11-induced neutropenia in patients with this disease; or (f) uncontrolled diabetes mellitus.
All study candidates were required to provide written informed consent as approved by local institutional review boards before initiation of any study procedures. Patients were enrolled both at academic institutions (Vanderbilt-Ingram Cancer Center, Fox Chase Cancer Center, and West Virginia University Medical Center) and at community hospitals via the Vanderbilt-Ingram Cancer Center Affiliate Network.
Treatment and Evaluation Plan.
The pretreatment evaluation included medical history and physical
examination, laboratory evaluation (complete blood count, serum
chemistries, and pregnancy test for women of childbearing potential),
and baseline tumor measurement. Medical history, complete blood counts,
and serum creatinine were obtained prior to each chemotherapy
treatment. Physical examination, performance status, weight, complete
blood counts, liver function tests, and full serum chemistries were
repeated prior to each 6-week cycle.
The weekly cisplatin/CPT-11 regimen used the starting doses and treatment schedule recommended by Saltz et al. (16) after their Phase I study of this regimen. Therapy was given in repeated 6-week cycles comprising weekly treatment with both drugs for 4 weeks, followed by a 2-week rest. Cisplatin was given as a 30-min i.v. infusion at a starting dose of 30 mg/m2 ; immediately following the completion of cisplatin administration, CPT-11 was given as a 30-min i.v. infusion at a starting dose of 65 mg/m2 .
Patients received standard i.v. hydration with 5% dextrose in normal saline or normal saline for 2 h to assure adequate hydration before cisplatin administration. Cholinergic symptoms occurring during or within 1 h after receiving CPT-11 could be treated with atropine (1 mg or as needed; Ref. 17 ). Dexamethasone (10 mg) was administered as part of the pretreatment antiemetic regimen unless a contraindication to corticosteroid use was identified. Ondansetron or granisteron (per physician preference) was given prior to each cisplatin dose. Loperamide was provided as therapy for delayed diarrhea (18) . Patients were instructed to begin taking loperamide at the first sign of diarrhea (i.e., first poorly formed or loose stool or first episode of one to two more bowel movements than usual in 1 day) that occurred >12 h after CPT-11 administration. Loperamide was to be taken in the following manner: 4 mg at the first onset of diarrhea, then 2 mg every 2 h around the clock until diarrhea free for at least 12 h. During the night, patients were allowed to take 4 mg every 4 h.
All toxicities were graded according to the National Cancer Institute
Common Toxicity Criteria. For subsequent treatment cycles, the CPT-11
dose was increased to a maximum of 95 mg/m2
in
stepwise increments of 10 mg/m2
in patients
experiencing grade 1 hematological and nonhematological
toxicity. CPT-11 was reduced to 55, 45, or 35
mg/m2
in stepwise decrements in patients
experiencing grade 2 toxicity. Cisplatin dose escalation was
not permitted. Cisplatin dose was reduced by 50% (to 15
mg/m2
) for serum creatinine of 1.5–2 mg/dl and
omitted for a serum creatinine >2 mg/dl.
During a course of treatment, CPT-11 doses were decreased by 10 or 20 mg/m2 for grade 2 or 3 hematological toxicities or diarrhea, respectively. Cisplatin doses was decreased by 25% for any grade 2 toxicity, except diarrhea. Grade 3 hematological toxicity required reduction of cisplatin dose by 50%. Cisplatin was not dose adjusted for grade 2 or 3 diarrhea. Both agents were held for grade 3 nonhematological toxicity, any grade 4 toxicity, grade 4 diarrhea, or neutropenic fever. A total of six cycles of treatment were planned. Patients were to be discontinued from study participation if they withdrew consent, had disease progression, experienced unacceptable drug toxicity not responding to dosage modification, or developed an intercurrent, noncancer-related illness that prevented therapy continuation or regular follow-up.
Tumor response was assessed according to WHO criteria (i.e., measurable disease, evaluable disease, nonevaluable disease, complete response, partial response, stable disease, and progressive disease). Tumor reassessment by the same imaging method used to establish baseline tumor measurement was generally performed after every two cycles of therapy. Confirmation of response required a repeat imaging study 4 weeks after the initial study demonstrating continued tumor response. Previously irradiated lesions were excluded from evaluation for tumor response. In addition, time to response (time from start of therapy to first observation of objective response), duration of response (time from first observation of objective response to first observation of progressive disease), time to tumor progression (time from start of therapy to first observation of progressive disease), and survival (time from start of therapy to death) were measured.
Statistical Considerations.
A two-staged Simon accrual design was used (19)
. An
overall response rate of 20% was assumed for standard therapy, and a
target response rate of 40% was established. Assuming a dropout rate
of 10%, a sample size of 50 patients provided at least 83% power and
a type 1 error of <5%. If 17 responses occurred in 43 patients, a
95% CI of 25–56% would be achieved. Given that this was a Phase II
trial, a sample size of 50 was expected to yield meaningful results
with acceptable power. Time-to-event end points were calculated using
Kaplan-Meir methods with appropriate censoring.
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RESULTS |
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. The median age was 59 years (range, 44–79 years). Seven patients
(14%) had stage IIIB disease, and 43 patients (86%) had stage IV
disease. All stage IIIB patients had malignant pleural effusions. Among
patients with stage IV disease, 27 patients had one metastatic site, 13
had two sites of involvement, 1 had three sites, and 2 had four
different sites involved. Brain, bone, and liver involvement was
observed in 10, 22, and 8% of patients, respectively. The majority of
patients (56%) had symptoms related to their NSCLC, as evidenced by
baseline performance status of 1 or 2. None of the patients had
undergone prior chemotherapy. Five patients (10%) had undergone an
attempt at primary surgical resection, and 4 (8%) had received prior
radiotherapy to tumor sites, whereas 10 (20%) had received both
radiation and surgery.
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The mean doses of CPT-11 (expressed as percentage of dose planned) at the start of cycles 1, 3, and 6 were 100, 96, and 92%. CPT-11 was dose escalated to 75, 85, or 95 mg/m2 in 8.8, 1.8, and 1.2% of the 160 total treatment cycles. CPT-11 doses were reduced by one, two, or three levels in 31, 9.9, and 9.2% of cycles, respectively. Myelosuppression (43%; 31 of 72) and diarrhea (48%; 35 of 72) were the major reasons for dose reduction. Mean cisplatin doses (expressed as a percentage of dose planned) at the start of cycles 1, 3, and 6 were 100, 96, and 70%, respectively. Cisplatin dose escalation above the starting dose of 30 mg/m2 was not permitted. Cisplatin was reduced to 22.5 mg/m2 (25% dose reduction) and to 15 mg/m2 (50% dose reduction) in 36 and 8.5% of the 160 total treatment cycles, respectively. Myelosuppression (54%; 35 of 64), vomiting (29%; 19 of 64), and elevated creatinine (11%; 7 of 64) accounted for the dose reductions.
The intended dose intensities for CPT-11 and cisplatin were 43.3 and 20 mg/m2 /week, respectively. When considering both dose omissions and modifications, the mean delivered dose intensities for CPT-11 and cisplatin were 38.7 mg/m2 (89% relative dose intensity) and 12.7 mg/m2 (62% relative dose intensity), respectively.
Efficacy.
The cutoff date for analysis was December 1999. An intent to treat
efficacy analysis was performed, with all 50 patients included.
Objective tumor responses were observed in 18 patients (36%; 95% CI,
24–54%). All 18 responses were partial. Stable disease was observed
in 38% (19 of 50) of patients. The remaining patients had progressive
disease (16%; 8 of 50) or went off study prior to initial tumor
reevaluation (10%; 5 of 50).
The median follow-up for patients still alive was 15.6 months (range,
12.5–21.9 months). Median time to response was 3.3 months (range,
1.2–8.9 months), and median duration of response from the time of
first evidence of objective response was 4.2 months (range, 0.4–14.1
months). Estimated median time to tumor progression was 6.9 months
(range, 0.6–15.2 months; Fig. 1
). Median survival was 11.6 months (95% CI, 8.06–15.6), and the 1-year
survival rate was 46% (Fig. 2)
. Objective response, time to disease progression, and median survival
for patients with stage IIIB disease (7 patients) were 28%, 10.6
months, and 15.6 months, respectively. For stage IV patients, the
results were 37.2%, 6.7 months, and 10.9 months, respectively. The
objective response rate, time to tumor progression, and median survival
for PS 2 patients (9 patients) were 33%, 3 months, and 3.86 months,
respectively. For PS 0, 1 patients, the results were 36.5%, 7 months
(P = 0.0012), and 14.7 months (P =
0.0015), respectively.
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). There was one grade 3 and one grade 4 case of cisplatin-induced
peripheral neuropathy. Grade 3 or 4 renal toxicity was not observed.
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. Three patients
(6%) had neutropenic fever, defined as grade 4 neutropenia with
simultaneous fever grade 2. There was one treatment-related
death secondary to neutropenic sepsis. Grade 3 or 4 anemia was observed
in 14% of patients in 5% of cycles. Twenty-eight patients (56%)
received erythropoietin. Three patients required a total of five units
of packed red cell transfusions. Grade 4 thrombocytopenia was seen in
14% of patients and 6% of cycles. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Single-agent CPT-11 is active in patients with advanced NSCLC, and there is evidence for synergy with cisplatin in preclinical models (9, 10) . Phase I studies of monthly cisplatin with weekly CPT-11 were carried out by Japanese investigators, and therapeutic outcomes were encouraging (12, 13, 14 , 30) . We recently reported the results of the first United States Phase II trial using the monthly cisplatin with weekly CPT-11 regimen in patients with advanced NSCLC (15) . Therapeutic outcomes were comparable with those seen with other newer regimens including an objective response rate of 28.8%, median survival of 9.9 months, and 1-year survival rate of 37%. The latter trial was conducted at four academic centers and included patients with ECOG performance status 0–2.
The current trial was undertaken because same-day administration of cisplatin followed by CPT-11 is a potentially more effective method of combining these agents. Furthermore, Phase I trials suggested that tolerability might be superior, in part because of the lower dose and more frequent administration of cisplatin (16) . Indeed, typical cisplatin toxicities were less than or equal to those observed in our previous Phase II trial using the monthly cisplatin regimen. Grade III/IV nausea, vomiting, neuropathy, and elevated creatinine were 12% versus 33%; 12% versus 14%; 4% versus 4%; and 0 versus 4% in the weekly versus monthly regimens. Grade III/IV diarrhea was higher with the weekly regimen (26% versus 17.3%, respectively), but dose adjustments largely alleviated this problem in subsequent cycles. As further evidence for the weekly regimen’s tolerability, the median number of treatment cycles was three, and dose intensity was well maintained for both agents. Because treatment cycles with this regimen are of 6 weeks duration, the three cycles of therapy are equivalent to six cycles of a conventional 3-week/cycle regimen. A majority of the dose omissions for both cisplatin and CPT-11 occurred in weeks 3 or 4. In future studies using weekly irinotecan and cisplatin, rather than modifying the doses of CPT-11 and/or cisplatin, it may be more prudent to alter the schedule slightly. For example, changing to a 21-day schedule with weekly drug administration in weeks 1 and 2, followed by a 1-week rest, may help preserve dose intensity.
The current trial was undertaken with patients treated in both the academic and community practices settings that included the Vanderbilt-Ingram Cancer Center, Fox Chase Cancer Center, West Virginia University and the Vanderbilt-Ingram Cancer Center Affiliate Network. Two previous Phase II trials carried out in these centers investigated 24-h paclitaxel and 1-h paclitaxel plus carboplatin regimens (31 , 32) . Respective response rates (21 and 25%), median survivals (8.8 and 7.4 months), and 1-year survival rates (32 and 31%) observed in these two studies were virtually identical when these regimens were subsequently evaluated in multicenter Phase III trials (20 , 26) . Therefore, relative to our own historical controls, we are encouraged that the weekly cisplatin plus CPT-11 regimen may offer superior efficacy to that of currently used regimens. This can only be addressed in a Phase III trial.
In conclusion, this multicenter academic- and community-based Phase II trial demonstrated superior efficacy for a weekly cisplatin and CPT-11 regimen when contrasted with results observed in historical controls. Tolerability was remarkably good, thus allowing for maintenance of dose intensity and prolonged treatment duration. A Phase III comparison to an approved regimen is currently in development.
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Vanderbilt University Medical Center, 1956 TVC,
Nashville, TN 37232-5536. 
2 The abbreviations used are: NSCLC, non-small
cell lung cancer; ECOG, Eastern Cooperative Oncology Group; CPT-11,
irinotecan; CI, confidence interval; PS, performance status.
Received 6/20/00; revised 10/18/00; accepted 10/23/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  Y. Xu and M. A. Villalona-Calero Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity Ann. Onc., December 1, 2002; 13(12): 1841 - 1851. [Abstract] [Full Text] [PDF]
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