A phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin in adult patients with refractory or metastatic solid malignancies.

PURPOSE: 7-t-Butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a novel third generation camptothecin selected for development based on the blood stability of its pharmacologically active lactone form and its high potency in preclinical models. Here, we report the initial phase I experience with i.v. AR-67 in adults with refractory solid tumors. EXPERIMENTAL DESIGN AND METHODS: AR-67 was infused over 1 hour daily five times, every 21 days, using an accelerated titration trial design. Plasma was collected on the 1st and 4th day of cycle 1 to determine pharmacokinetic parameters. RESULTS: Twenty-six patients were treated at nine dosage levels (1.2-12.4 mg/m(2)/d). Dose-limiting toxicities were observed in five patients and consisted of grade 4 febrile neutropenia, grade 3 fatigue, and grade 4 thrombocytopenia. Common toxicities included leukopenia (23%), thrombocytopenia (15.4%), fatigue (15.4%), neutropenia (11.5%), and anemia (11.5%). No diarrhea was observed. The maximum tolerated dosage was 7.5 mg/m(2)/d. The lactone form was the predominant species in plasma (>87% of area under the plasma concentration-time curve) at all dosages. No drug accumulation was observed on day 4. Clearance was constant with increasing dosage and hematologic toxicities correlated with exposure (P < 0.001). A prolonged partial response was observed in one subject with non-small cell lung cancer. Stable disease was noted in patients with small cell lung cancer, non-small cell lung cancer, and duodenal cancer. CONCLUSIONS: AR-67 is a novel, blood-stable camptothecin with a predictable toxicity profile and linear pharmacokinetics. The recommended phase II dosage is 7.5 mg/m(2)/d five times every 21 days.

Phase II study of picoplatin as second-line therapy for patients with small-cell lung cancer.

PURPOSE: This study was designed to confirm the efficacy and safety of picoplatin, a cisplatin analog designed to overcome platinum resistance, in patients with small-cell lung cancer (SCLC) with platinum-refractory/-resistant disease. PATIENTS AND METHODS: All patients received intravenous picoplatin 150 mg/m(2) every 3 weeks. Tumor response, progression-free survival, and overall survival were evaluated. Adverse events were assessed for frequency, severity, and relationship to treatment. Quality of life was assessed with the Lung Cancer Symptom Scale instrument. RESULTS: Seventy-seven patients were treated with picoplatin (median number of cycles, two; range one to 10). Three patients (4%) had a partial response, 33 (43%) had stable disease (four of these were unconfirmed partial responses), 36 (47%) had progressive disease, and five were not assessable for response. Median progression-free survival was 9.1 weeks (95% CI, 7.0 to 12.1 weeks). Median overall survival was 26.9 weeks (95% CI, 21.1 to 33.4). The most common grade 3 and 4 toxicities were thrombocytopenia (48%), neutropenia (25%), and anemia (20%). The most commonly reported adverse events of any severity included thrombocytopenia (64%), anemia (49%), neutropenia (39%), nausea (27%), fatigue (16%), and dyspnea (16%). No severe neurotoxicity or nephrotoxicity were observed. There were no treatment-related deaths. CONCLUSION: Picoplatin demonstrated clinical efficacy in platinum-refractory SCLC. The major toxicity was hematologic. These results warrant further evaluation in this patient population.

Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer.

PURPOSE: Single-agent intravenous (IV) topotecan is an effective treatment for small-cell lung cancer (SCLC) after failure of first-line chemotherapy. This open-label, randomized, phase III study compared oral and IV topotecan in patients with SCLC sensitive to initial chemotherapy. PATIENTS AND METHODS: Patients with limited- or extensive-disease SCLC, documented complete or partial response to first-line therapy, Eastern Cooperative Oncology Group performance status < or = 2, and measurable recurrent disease (WHO criteria) with a treatment-free interval of > or = 90 days were assigned to treatment with either oral topotecan 2.3 mg/m2/d on days 1 through 5 or IV topotecan 1.5 mg/m2/d on days 1 through 5 every 21 days. Primary end point was response rate as confirmed by an external reviewer blinded to treatment. RESULTS: A total of 309 patients were randomly assigned. In intent-to-treat analysis, response rates were 18.3% with oral topotecan (n = 153) and 21.9% with IV topotecan (n = 151), with a difference (oral -IV) of -3.6% (95% CI, -12.6% to 5.5%). Median survival time was 33.0 weeks for oral and 35.0 weeks for IV topotecan; 1- and 2-year survival rates were 32.6% and 12.4% for oral topotecan, respectively, and 29.2% and 7.1% for IV topotecan, respectively. Third-line chemotherapy was similar for both groups (33% for oral; 35% for IV). Incidence of grade 4 toxicity in patients who received oral and IV topotecan was as follows: neutropenia in 47% and 64%, thrombocytopenia in 29% and 18%, grade 3 or 4 anemia in 23% and 31%, and sepsis in 3% and 3%, respectively. The most frequent nonhematologic adverse events (all grades) included nausea (43% oral; 42% IV), alopecia (26% oral; 30% IV), fatigue (31% oral; 36% IV), and diarrhea (36% oral; 20% IV). CONCLUSION: Oral topotecan demonstrates activity and tolerability similar to IV topotecan in chemotherapy-sensitive SCLC patients and offers patients a convenient alternative to IV therapy.

Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer.

PURPOSE: This open-label, randomized, multicenter phase III study compared oral topotecan/intravenous cisplatin (TC) with intravenous (IV) etoposide/cisplatin (PE) in patients with untreated extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: A total of 784 patients were randomly assigned to either oral topotecan 1.7 mg/m2/d x 5 with IV cisplatin 60 mg/m2 on day 5 (n = 389) or IV etoposide 100 mg/m2/d x 3 with IV cisplatin 80 mg/m2 on day 1 (n = 395) every 21 days. RESULTS: Overall survival (primary end point) was similar between groups (P = .48; median: TC, 39.3 weeks v PE, 40.3 weeks). One-year survival was 31% (95% CI, 27% to 36%) in both groups and the difference of -0.03 (95% CI, -6.53 to 6.47) met the predefined criteria of < or = 10% absolute difference for noninferiority of TC relative to PE. Response rates were similar between groups (TC, 63% v PE, 69%). Time to progression was slightly but statistically longer with PE (log-rank P = .02; median: TC, 24.1 weeks v PE, 25.1 weeks). The regimens were similarly tolerable. Grade 3/4 neutropenia occurred more frequently with PE (84% v 59%), whereas grade 3/4 anemia and thrombocytopenia occurred more frequently with TC (38% v 21% and 38% v 23%, respectively). Lung Cancer Symptom Scale scores were statistically better with PE, but the differences were small and of debatable clinical significance. CONCLUSION: Oral topotecan with cisplatin provides similar efficacy and tolerability to the standard (etoposide with cisplatin) in untreated ED-SCLC and may provide greater patient convenience compared with intravenous etoposide and cisplatin.

Emerging role of weekly topotecan in recurrent small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive tumor that often metastasizes before the primary cancer is diagnosed. Patients with SCLC are typically elderly and often have comorbidities that may predispose them to adverse events during therapy. Although topotecan (Hycamtin; GlaxoSmithKline; Philadelphia, PA), 1.5 mg/m(2)/day via a 30-minute i.v. infusion on days 1-5 of a 21-day cycle, is a standard therapy for relapsed SCLC, this regimen can result in significant neutropenia, especially in previously treated patients. This hematologic toxicity is noncumulative and reversible, but its management can be challenging in this poor-prognosis population. Therefore, alternate treatment regimens have been investigated. Weekly topotecan (4.0 mg/m(2)) is currently investigational and has shown promising activity and favorable tolerability in patients with relapsed ovarian cancer, another aggressive malignancy with a poor prognosis. Preliminary results from a phase II trial of weekly bolus topotecan (4.0 mg/m(2)) in patients with recurrent SCLC were recently reported, and this regimen was generally well tolerated. Furthermore, weekly topotecan has been successfully included in several combination therapy regimens in patients with a variety of solid tumors. In untreated SCLC patients, a combination regimen of weekly topotecan, paclitaxel (Taxol; Bristol-Myers Squibb; Princeton, NJ), and cisplatin (Platinol; Bristol-Myers Squibb) was explored and found to be well tolerated and active in patients with extensive and limited-stage disease. Further clinical trials of weekly topotecan and regimens that include weekly topotecan in the SCLC setting are warranted.

A randomized phase I and pharmacological trial of sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide in patients with advanced solid neoplasms.

PURPOSE: O(6)-alkylguanine-DNA alkyltransferase (AGAT) is modulated by methylating agents, which, in turn, abrogates nitrosourea resistance in preclinical studies. The feasibility of administering various sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TEM) in patients with advanced solid neoplasms was evaluated in this Phase I and pharmacological study to assess this premise in the clinical setting. The study also sought to determine the maximum tolerated dose (MTD) levels of BCNU and TEM as a function of Seq, to characterize the pharmacokinetic (PK) behavior of TEM administered both before and after BCNU, assess AGAT fluctuations in peripheral blood mononuclear cells (PBMCs), and seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Sixty-three patients were randomized to receive treatment with oral TEM daily on days 1-5 and BCNU administered i.v., either on day 1 before TEM [Sequence (Seq) B-->T] or day 5 after TEM (Seq T-->B). Treatment was repeated every 6 weeks. Blood sampling for PK studies was performed on both days 1 and 5 of course one. PBMCs were sampled to evaluate major sequence-dependent effects on AGAT levels. RESULTS: Neutropenia and thrombocytopenia were the principal dose-limiting toxicities of the BCNU/TEM regimen. These effects were more prominent in patients receiving Seq T-->B, resulting in a much lower MTD of 80/100 mg/m(2)/day compared with 150/110 mg/m(2)/day for Seq B-->T. Notable antitumor activity was observed in patients with glioblastoma multiforme, sarcoma, and ovarian carcinoma. No sequence-dependent PK effects were noted to account for sequence-dependent toxicological effects. At the MTD level, AGAT activity in PBMCs decreased 3-fold, on average, and AGAT fluctuations did not appear to be sequence-dependent. CONCLUSIONS: The principal toxicities of the BCNU/TEM regimen were neutropenia and thrombocytopenia, which were consistent and predictable, albeit sequence-dependent. Seq T-->B was substantially more myelosuppressive, resulting in disparate MTDs and dose levels recommended for subsequent disease-directed evaluations (150/110 and 80/100 mg/m(2)/day for Seq B-->T and T-->B, respectively). Sequence-dependent differences in TEM PK do not account for this clinically relevant magnitude of sequence-dependent toxicity. The characteristics of the myelosuppressive effects of BCNU/TEM, the paucity of severe nonhematological toxicities, and antitumor activity at tolerable doses warrant disease-directed evaluations on this schedule.

Second-line treatment of small-cell lung cancer. The case for systemic chemotherapy.

Small-cell lung cancer is an aggressive tumor associated with high rates of regional or distant metastases at diagnosis. Although highly chemosensitive to agents given in the first-line setting (e.g., etoposide and cisplatin), most patients relapse and have a poor prognosis. Treatment options for relapsed patients include radiotherapy for limited-stage disease and chemotherapy or combined modalities for advanced-stage disease. In clinical practice, however, some oncologists maintain that chemotherapy provides an insufficient survival benefit to justify the sometimes debilitating toxicity associated with the more active regimens in particular. Other potential barriers to further treatment include patient comorbidities, performance status, site(s) of progression, progression-free interval, and previous treatments. However, numerous clinical trials demonstrate that some patients benefit from treatment, achieving prolonged survival, symptom palliation, improved quality of life, and the opportunity, albeit rare, for durable remission. Additionally, several novel chemotherapeutics are available that alone or in combination help patients lead an improved quality of life. Finally, alternative routes and schedules--oral formulations, weekly administration, and prolonged treatment vacations--have been developed to deliver chemotherapy to patients with poor performance status or multiple comorbidities. This article reviews the advantages and disadvantages of treating recurrent small-cell lung cancer and summarizes the utility of several active agents.