A Phase II Pilot Trial of Concurrent Biochemotherapy with Cisplatin, Vinblastine, Temozolomide, Interleukin 2, and IFN- 2B in Patients with Metastatic Melanoma

Purpose: In an effort to reduce the frequency of central nervous system (CNS) progression in patients with metastatic melanoma with ongoing systemic response to biochemotherapy, we modified our standard concurrent biochemotherapy regimen by replacing dacarbazine (DTIC) with oral temozolomide. Experimental Design: Patients received cisplatin, vinblastine, and temozolomide (20 mg/m cisplatin and 1.2 mg/m vinblastine i.v., days 1–4; 150 mg/m p.o. temozolomide, days 1–4) concurrent with interleukin 2 (9 MIU/m/ day) by continuous i.v. infusion on days 1–4 and IFN(5 MU/m/day) on days 1–5, 8, 10, and 12. Prophylactic antibiotics and a maximum of four cycles were administered. Routine granulocyte-colony stimulating factor and aggressive antiemetics were also provided. Tumor staging included torso computed tomography scans and brain magnetic resonance imaging pretreatment, after cycle 4 and then every 3 months for 2 years. Torso computed tomography scans were also performed after cycle 2. Results: A total of 147 treatment cycles were administered to 48 patients. No patients had received prior chemotherapy or interleukin 2; however, 19 (40%) had received prior adjuvant IFN. Significant toxicities included 2 deaths from cardiac events (pericarditis al tamponade and posttreatment myocardial infarction with associated ventricular arrhythmia) and 3 gastrointestinal serious adverse events (pancreatitis, appendicitis, and upper GI bleed). No other nonhematological grade 4 toxicities were observed. Tumor responses were seen in 22 of 47 evaluable patients (relative risk, 47%) with 7 complete responses (15%). Response durations ranged from 1 to 29 months with 1 currently ongoing. Median survival was 7.5 months. The CNS was the initial site of progression in 2 responding patients. An additional 6 responding patients developed CNS progression within 3 months of systemic progression. Initial CNS progression was significantly less frequent what was seen with the prior DTIC-based biochemotherapy regimen (2 of 22 versus 12 of 19; P 0.001). Conclusion: This regimen appears to be active and reasonably well tolerated in patients with metastatic melanoma. Although the substitution of temozolomide for DTIC reduced the incidence of initial CNS progression, this effect did not appear to result in an improved overall outcome. INTRODUCTION Many investigators have studied combinations of IL-2based immunotherapy and cisplatin and DTIC-based chemotherapy (so called biochemotherapy) in patients with metastatic melanoma (1–3). Composite results from a variety of inpatient regimens show a response rate of near 50% with 10–20% complete response and a median survival of 11–12 months (3). Two meta-analyses suggested that biochemotherapy produces a higher response rate than either chemotherapy or IL-2-based immunotherapy alone and a potentially longer median survival (4, 5). Furthermore, a single institution Phase III trial comparing CVD chemotherapy to sequentially administered CVD and IL-2 IFN2b showed that the biochemotherapy combination produced a doubling of the response rate and time to progression and a 3-month prolongation in median survival (6). Although both a National Cancer Institute Surgery Branch Trial comparing cisplatin, DTIC, and tamoxifen high-dose IL-2 and IFNand an European Organization for Research and Treatment of Cancer trial comparing IL-2 and IFNcisplatin also produced higher response rates for the biochemotherapy arms, no overall survival benefit was observed in either study (7, 8). The determination of the overall value of biochemotherapy must await the completion of the Intergroup Phase III trial comparing Received 11/21/01; revised 6/3/02; accepted 6/5/02. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This study was supported by grants from Amgen, Chiron, and Schering Plough. 2 To whom requests for reprints should be addressed, at Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, East Campus, Kirstein 158, Boston, MA 02215. E-mail: [email protected]. 3 The abbreviations used are: IL, interleukin; DTIC, dacarbazine; CVD, cisplatin, vinblastine, and DTIC; CVT, cisplatin, vinblastine, and oral temozolomide; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; MRI, magnetic resonance imaging; SBP, systolic blood pressure; CR, complete response; PR, partial response; AJCC, American Joint Committee on Cancer; GI, gastrointestinal; PS, performance status. 3075 Vol. 8, 3075–3081, October 2002 Clinical Cancer Research Research. on October 24, 2017. © 2002 American Association for Cancer clincancerres.aacrjournals.org Downloaded from concurrently administered CVD and IL-2 and IFN to CVD alone (9). Despite high response rates with biochemotherapy, the response durations have been disappointing, perhaps explaining the equivocal impact of biochemotherapy therapy on overall survival in the three Phase III studies reported to date. Although 10–20% of responses to biochemotherapy may last 2 years, the median duration of response in most studies has been 6 months (2, 10, 11). Furthermore, there appears to be a high rate of initial CNS progression in responding patients (10, 12). For example, in a pilot trial of concurrent biochemotherapy, we reported that 11 of 19 major responders had the CNS as their initial site of relapse (13). Subsequent to this report, an additional patient exhibited an isolated CNS relapse 44 months after achieving a durable systemic response. Although occasionally such patients can be salvaged with local therapy to the CNS, the median survival after CNS relapse is only about 3–4 months (14). Successful approaches to preventing CNS relapse in patients exhibiting a major response to biochemotherapy might significantly enhance the duration of tumor responses and prolong overall survival. Temozolomide is an analogue of DTIC that has the potential advantages of being p.o. absorbed and crossing relatively well into the CNS (15). This ability to penetrate the CNS prompted the investigation of temozolomide therapy for primary brain tumors eventually leading to Food and Drug Administration approval of temozolomide for the treatment of patients with refractory anaplastic astrocytomas (16). Temozolomide has also been shown to be active in patients with melanoma with responses observed in both systemic and CNS disease (17, 18). A Phase III European trial comparing temozolomide to DTIC in patients with metastatic melanoma showed the two agents to have equivalent antitumor activity (19). Although most of these patients did not have routine CNS assessment after systemic progression, an analysis of a subset of patients so followed suggested that the incidence of CNS metastasis was less for the group of patients who had received temozolomide (20). Therefore, in an effort to prevent initial CNS relapse and thereby enhance the quality and durabililty of responses to biochemotherapy, we performed a Phase II trial of a standard concurrent biochemotherapy regimen in which temozolomide had been substituted for DTIC. PATIENTS AND METHODS Patient Selection. Eligibility criteria for this trial were similar to our previous Phase II pilot trial of concurrent biochemotherapy involving CVD together with IL-2 and IFN (13). All patients who were entered onto this study had histologically confirmed, bidimensionally measurable, and clearly progressive metastatic melanoma, an ECOG performance status of 0 or 1, and adequate organ function as defined by WBC count 4,000/ l, platelet count 100,000/ l, serum bilirubin 1.5 mg/dl, serum creatinine 1.5 mg/dl, or calculated creatinine clearance 75 ml/min. Patients were required to have an FEV1 of 2.0 liters or 75% of that predicted for height and age. Patients who were 50 years of age or with a history of cardiac disease (congestive heart failure, symptoms of coronary artery disease, serious cardiac arrhythmias, or prior myocardial infarction on electrocardiogram) were required to have a normal cardiac stress test. Screening tests for HIV antibody were required to be negative. Patients with active brain metastases were excluded. Patients with a history of brain metastasis had to be at least 2 months removed from definitive therapy, have been off corticosteroids, and have no evidence of disease progression or residual edema on pretreatment brain MRI. In addition, patients with other medical conditions requiring systemic corticosteroids, organ allografts, contraindications to the use of vasopressor agents, active infections requiring antibiotic therapy, a history of second malignancy other than nonmelanoma skin cancer, or carcinoma in situ or stage I carcinoma of the cervix were also excluded. Patients who received prior cytotoxic chemotherapy or IL-2 therapy were also excluded. Prior immunotherapy with agents other than IL-2 in the adjuvant or metastatic setting was allowed, but this had to be completed 4 weeks before entry in this protocol. The protocol was approved by the Human Investigational Review Boards at both the Beth Israel Deaconess 4 M. B. Atkins, unpublished information. Table 1 Treatment regimen Treatment Dose Length of treatment Temozolomide 150 mg/m/day Days 1–4 Cisplatin 20 mg/m/day Days 1–4 Vinblastine 1.2 mg/m/day Days 1–4 IFN2b (Schering) 5 10 units/m s.c. Days 1–5, 8, 10, 12 IL-2 (Chiron) 9 10 IU/m/day by continuous i.v. infusion 4 days G-CSF 5 g/kg s.c. daily Days 6–15 Ondansetron or granisetron 32 mg 1–2 mg i.v. Days 1–6 Abbreviation: G-CSF, granulocyte-colony stimulating factor. a Cycle every 21 days; assess response day 42; maximum of 4 cycles. Table 2 Patient characteristics