Carboplatin and Paclitaxel Plus ASA404 as First- Line Chemotherapy for Extensive-Stage Small- Cell Lung Cancer: A Multicenter Single Arm Phase II Trial (SAKK 15/08)

Martin Früh,1 Richard Cathomas,2 Marco Siano,1 Gregor Tscherry,3 Alfred Zippelius,4 Christoph Mamot,5 Andreas Erdmann,6 Fatima Krasniqi,4 Daniel Rauch,7 Mathew Simcock,8 Erika Küttel,8 Pierre Fustier,9 Miklos Pless,10 on Behalf of the Swiss Group for Clinical Cancer Research

Abstract

We explored the tumor-vascular disrupting agent ASA404 plus carboplatin and paclitaxel in extensive-stage small-cell lung cancer. The trial was prematurely closed after 17 patients. Progression-free survival (PFS) at 24 weeks, median PFS, overall response rate, and 1-year survival were 41%, 7 months, 94%, and 57%, respectively.
Introduction: Small-cell lung cancer (SCLC) is a highly vascularized tumor. ASA404 is a tumor vascular disrupting agent. This is the first trial to report the effects of combining chemotherapy with ASA404 in SCLC. Methods: Patients with untreated metastatic SCLC were treated with carboplatin (area under curve, 6) plus paclitaxel (175 mg/m2) plus ASA404 (1800 mg/m2) on day 1 every 21 days for up to 6 cycles. The primary endpoint was the progression-free survival (PFS) rate at 24 weeks. Results: Median age was 61 years; 53% were women, 41% had weight loss; and 96% had a performance status of 0-1. Twelve patients completed all 6 cycles, and most adverse events were related to chemotherapy. Median PFS and time to progression were 7.0 months (95% CI, 5.7-9.4 months) and 7.5 months (95% CI, 5.7-9.4 months), respectively. The progression-free survival (PFS) rate at 24 weeks was 41% (95% CI, 18%-65%). The overall response rate was 94%. The median overall survival time was 14.2 months (95% CI, 8.2-16.0 months) and 1-year survival was 57%. The median follow-up time was 17.7 months. Due to negative results with ASA404 in non–small-cell lung cancer trials, the trial was stopped prematurely after 17 of 56 planned patients were being accrued. Conclusions: This is the first report of a clinical trial with a vascular disrupting agent in SCLC. No unexpected toxicity was observed. PFS was not prolonged with carboplatin and paclitaxel plus ASA404.

Keywords: Extensive stage small cell lung cancer, Phase II trial, Serotonin, Small cell, Vascular disrupting, Vascular disruptive agent

Introduction

The incidence of small-cell lung cancer (SCLC) is decreasing in the Western world, and the proportion of patients with small-cell histology is now down to 13%.1 The clinical outcome in extensivestage (ES) SCLC is poor, and palliative chemotherapy results in an overall response rate (ORR) of 60%-80%, a median overall survival (OS) of 7-11 months, and 2-year survival rates of 1%-5%.2,3 Therefore, it is essential that treatments are improved.
Tumor vasculature provides a promising target in SCLC because this tumor is highly vascularized, with a higher microvessel density compared with other solid malignancies, including non-SCLC (NSCLC).4 Key features that distinguish tumor vasculature from normal vessels are its instability, disorganized architecture, increased vascular permeability, inefficient blood flow, and areas of angiogenesis. Given these distinct properties, there is significant therapeutic potential in vascular disruptive agents (VDA).5 ASA404 is a flavonoid that has been shown to induce apoptosis of tumor vascular endothelial cells and cytokine production, which leads to irreversible vasculature collapse of existing tumor blood vessels and necrosis.6-8
Upon administration of ASA404, serotonin is released from platelets into plasma and is involved in the antitumor and host effects of ASA404, and mediates the effects of tumor necrosis factor-alpha and nitric oxide.9 Interestingly, a correlation has been described between the degree of tumor necrosis and the plasma concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin.10 VDAs are particularly effective against poorly perfused regions at the tumor core, thus complementing the effects of chemotherapy. One can assume that ASA404 may have improved efficacy in areas of larger tumor bulks frequently encountered in aggressive SCLC that have generated a significant independent blood supply. ASA404 was primarily developed in NSCLC, where it was recently showntobeverywelltoleratedbutnotsufficientlyactivein2placebo controlled phase III trials.11
Over the past decades, different chemotherapy combinations that involve (CAV) (cyclophosphamide, doxorubicin, and vincristine); CDE (cyclophosphamide, doxorubicin, and etoposide); cyclophosphamide, etoposide, and vincristine; and, finally, etoposide with cisplatin or carboplatin have led to comparable survival outcomes.12-19 Although, no study has directly assessed, carboplatin and paclitaxel (C/P) vs. the current standard etoposide or irinotecan plus a platinum, 2 phase III trials showed parity or superiority of C/P compared with either CDE or CAV.20,21 In these 2 studies, 3 weekly doses of carboplatin (area under the curve [AUC] 7 and AUC 6, respectively) and paclitaxel (175 mg/m2 and 200 mg/m2, respectively) were used.20,21 Of note, the CAV vs. C/P study was performed in ES and limited-stage poor-risk patients, and has not been published to date; results, therefore, should be interpreted with caution.21 Preclinical studies on ASA404 have shown enhanced antitumor activity with taxane-containing chemotherapy,22-24 thus providing the rationale for the current trial.
Given the high tumor vessel density of SCLC and the preclinical synergistic activity of taxanes with ASA404, we tested the combination of C/P plus ASA404 in the first-line setting of patients with ES-SCLC. We hypothesized that the addition of ASA404 to chemotherapy would improve progression-free survival (PFS).

Patients and Methods

Patient Eligibility

Patients with a World Health Organization performance status (PS) of 0-2, aged 18 years, and with histologically or cytologically confirmed stage IV SCLC according to the 7th edition of the Union for International Cancer Control staging system were considered eligible. The patients had to have adequate hematologic, hepatic and renal function, and coagulation parameters. Previously treated brain metastases were allowed if brain imaging at study entrance showed complete remission. Patients with prior systemic anticancer therapy, radiotherapy 2 weeks, and/or major surgery 4 weeks before registration, concomitant use of drugs that could potentially cause torsades de pointes, cerebral metastases in initial tumor assessment (mandatory), significant hemoptysis, neuropathy, or significant cardiovascular disorder were excluded. Pathology was reviewed by an independent pathologist who confirmed diagnosis of SCLC in all patients. The trial was planned and conducted in accordance with the Declaration of Helsinki, the Guidelines for Good Clinical Practice issued by International Conference on Harmonistation (ICH) guideline E6 principles, and the requirements of national regulatory authorities. The trial was approved by the local ethics review boards as well as Swissmedic and was registered at the National Institutes of Health (www.clinicaltrial.gov; identifier number: NCT01057342). All of the patients gave informed consent before any trial procedure.

Trial Design

In this multicenter, single-arm, phase II trial, the patients were registered and treated with a 3-hour infusion of paclitaxel 175 mg/m2 intravenous (I.V.), carboplatin AUC of 6 over 30 minutes I.V., and ASA404 1800 mg/m2 I.V. for 20 minutes, all administered onday1ofeach3-weekcycle,uptoatotalof6cycles.Treatmentwas delayed in case of abnormal electrolytes or any grade 3 or 4 adverse events (AE) according to the National Cancer Institute (NCI) CommonTerminologyCriteriaforAdverseEvents(CTCAE)version3.0. In case of severe neutropenia, granulocyte colony-stimulating factors were allowed. If chemotherapy or ASA404 had to be delayed, then both treatments were postponed for a maximum of 3 weeks. A reduction of the chemotherapy dosage was permitted in the case of first or second occurrence of grade 3 and 4 hematologic AEs, respectively, or in case of first occurrence of grade 3 nonhematologic AEs. A reduction of the ASA404 dosage was not allowed. Prophylactic cranial irradiation in responding patients was left at the discretion of the investigators. After progression, lifelong assessment of systemic antitumor treatment and survival was performed every 6 months.

Trial Parameters

Carboplatin and Paclitaxel Plus ASA404 in Extensive-Stage Small-Cell Lung Cancer Baseline imaging included computed tomography (CT) or magneticresonanceimagingofthebrain;CTofthethoraxandabdomen; bone scintigraphy; medical history; and a physical examination, including assessment of World Health Organization PS, electrocardiography, hematologic values, hepatic function, biochemistry (magnesium, potassium, calcium corrected for albumin, sodium, lactate dehydrogenase), renal function, and coagulation tests. Women younger than 50 years old were required to undergo a pregnancy test. Evaluations on day 1 of each cycle included electrocardiography and laboratory values. CTs of the chest and abdomen were repeated every 6 weeks. If no progression had occurred after 6 months of follow-up, then imaging was performed every 12 weeks until progression.

Statistical Considerations

The primary endpoint of this trial was the proportion of patients with a tumor assessment at 24 weeks (2 weeks) that showed an absence of progression (PFS24). Patients without tumor assessment at 24 weeks but with a later assessment that showed an absence of progression without subsequent treatment were counted as successes. PFS was defined as the time from registration until progression or death due to any cause. Our aim was to show improvement in the median PFS compared with an historical control of 2 months.25 Median PFS in first-line treatment of SCLC has been consistently reported to be 6-9 months. In an ideal situation in which all patients have known progression status at 24 weeks, PFS24 can be converted to a PFS median. The trial therapy was to be considered promising if PFS24 reached 59% (ie, median PFS, 7.75 months) and uninteresting if lower than or equal to 42% (ie, median PFS, 4.75 months). The lower boundary was chosen according to the results of another single-arm phase II trial with virtually identical inclusion criteria testing cisplatin, etoposide, and bevacizumab, and showing a median PFS of 4.7 months.26 With a significance level of 5% and an 80% power, a total sample size of 57 patients eligible for assessment was required for the primary endpoint. Secondary endpoints included AEs according to the NCI CTCAE v3.0, the response rate (response according to RECIST 1.1 [Response Evaluation Criteria In Solid Tumors]), PFS, time to progression, and OS. All analyses were conducted by using the intention-to-treat principle. Time-to-event endpoints were analyzed by using the Kaplan-Meier method and all data analyses were conducted by using Statistical Analysis Systems version 9.2 (SAS Institute Inc, Cary, NC).

Results

Eight Swiss centers accrued patients between April 2010 and February 2011. After accruing 17 patients, the trial was stopped prematurely, due to the results of other studies that showed the lack of efficacy of ASA404 in patients with NSCLC.11 Patient characteristics are listed in Table 1. The median age was 61 years. The malefemale ratio was near balanced, at 53% vs. 47%; the ratio of patients with weight loss, defined as 5% during the previous 6 months vs. otherwise, came to 47% vs. 53%. The majority of patients (96%) were in a good PS, of 0-1. The most common sites of metastases included lymph nodes (76%), lung (59%), bones (53%), and liver (41%). An initial absence of brain metastases on imaging was an inclusion criterion; only 1 patient with a history of brain metastases and a complete remission after brain surgery and whole-brain irradiation was included. The median number of cycles administered per patient was 6 (range, 1-6), with 12 (71%) patients completing all 6 cycles. A total of 85 chemotherapy cycles were administered. AEinduced therapy delays of 1-14 days were necessary in 12 cycles. A dosage reduction of paclitaxel and carboplatin due to neutropenia or neutropenic fever was necessary in 4 patients (24%) on a total of 7 occasions. Other reasons for dosage reductions of paclitaxel included neuropathy (2 patients) and pain and grade 3 anemia in 1 patient each. For carboplatin, the reasons for dosage reduction were grade 3 thrombocytopenia (3 patients), neuropathy (2 patients), and elevated creatinine and grade 3 anemia in 1 patient each. Four (24%) patients had treatment stopped due to unacceptable toxicity after 1-4 cycles, which included 1 severe allergic reaction to paclitaxel; worsening peripheral neuropathy; thrombosis of an aortic aneurysm, which mandated anticoagulation; and development of a serotonin syndrome. Another patient was taken off the trial due to refractory hypomagnesemia after 3 cycles, which precluded the administration of ASA404. Eight (47%) patients went on to receive second-line therapy.

Efficacy Results

All 17 registered patients were eligible for analysis. The median follow-up was 17.7 months (range, 6.5-19.4 months). With regard to the primary endpoint, PFS24, a total of 7 (41%) patients were progression free (Clopper Pearson 95% CI, 18-65). All but 1 patient responded to trial treatment, which resulted in an ORR of 94% and a disease control rate of 100%. The median PFS was 7.0 months (95% CI, 5.7-9.4 months) (Figure 1). Of the 10 remaining patients who were not progression free at 24 weeks, 5 experienced disease progression before 6 months, and 5 had an unknown status due to no tumor assessment being conducted during the right time period. The median time to progression and the median OS were 7.5 months (95% CI, 5.7-9.4 months) and 14.2 months (95% CI, 8.2-16.0 months) (Figure 1), respectively. Ten patients died of disease progression, 1 of pneumonia, and 1 of an infection of unknown origin. All12deathsoccurredatleast6monthsaftertrialtherapyterminated and were not considered to be drug related.

Safety and Toxicity

The number of grade 3 and 4 AEs are shown in Table 2. Overall, 6 (35%) patients had a grade 2, 9 (53%) had a grade 3, and 2 (12%) had a grade 4 event. No toxic death occurred. Seven patients experienced a total of 10 serious AEs. Four have been associated with C/P plus ASA404 and included infection in 2 patients and fatigue plus pain in 1 patient. One patient experienced serotonin syndrome, which occurred several hours after the third cycle and peaked after 30 hours, with profound agitation, restlessness, myoclonia, and mydriasis.HighdosesofI.V.midazolamandsubsequentobservationinthe solved completely. This was the only serious AE associated with ASA404. Importantly, the trial showed no occurrences of relevant QTc time prolongations that might have interfered with the administration of the medication.

Discussion

To our knowledge, this is the first trial. We tested the efficacy and tolerability of the combination of C/P plus ASA404 as a first-line treatment. The trial was closed prematurely after accruing 17 of 57 planned patients due to a lack of ASA404 efficacy being observed in 2 phase III trials in NSCLC. The primary endpoint of this trial was to achieve a PFS24 rate of 59% for the drug combination to be considered promising for further exploration in this disease. Despite anORRof94%,only41%ofthepatientswereprogressionfreeat24 weeks. These findings are similar to the results of a recently published pooled analysis of 870 patients with ES-SCLC in clinical trials who demonstrated a median PFS of 5.5 months compared with 6.8 months in the current trial.25 However, the very high radiographic ORR of 94% appears to be a strong signal that the tested drug combination is active in ES-SCLC. Of note, despite this high response rate in these typically centrally located tumors, no major bleeding event was observed. Certainly, due to the small number of patients as a result of the early trial termination, no definite conclusions can be drawn from this trial. The long median OS of 14.2 months observed in this trial may be a result of patient selection because the majority of patients were women in a good PS, with minimal weight loss. An interesting observation was made in 1 patient with PS 2, the only patient with a PS 2, who developed serotonin syndrome and who had a dramatic response, with rapid shrinking of a large tumor mass. Serotonin syndrome has thus far only been reported in 3 patients in the phase I trials.27 Elevated serotonin plasma concentrations have been observed in response to ASA404-associated damage of vascular endothelium in preclinical models.28 Its primary metabolite is 5-HIAA.29 Phase I trials demonstrated a dose-dependent increase of 5-HIAA plasma concentrations.30,31 potentially leading to higher antitumor activity via increased synthesis of tumor necrosis factor-alpha and nitric oxide.32 The 5-HIAA level may be a useful marker for activity of ASA404. The biomarker studies of the phase III NSCLC trials, which included the assessment of 5-HIAA serum levels, will perhaps yield more information on this question.

Carboplatin and Paclitaxel Plus ASA404 in Extensive-Stage Small-Cell Lung Cancer

Most AEs were attributed to chemotherapy, whereas the administration of ASA404 was generally well tolerated. The majority (71%) of patients were able to receive the scheduled number of 6 cycles without the occurrence of a toxic death. Again, these findings mirror the experience reported in patients with NSCLC in which only grade 4 neutropenia (27% vs. 19%) and infusion site pain (10% vs. 0.5%) were slightly increased when ASA404 was added to C/P.11 The latter was not observed in our trial, possibly as a result of diluting the drug in 100 mL rather than 50 mL glucose 5%. Limitations of this trial include the absence of biomarker studies; the use of a nonstandard chemotherapy combination, which was chosen based on preclinical synergism between taxanes and ASA404; and the small number of patients due to its early termination. The data presented here are not the results of a planned interim analysis but rather represent outcomes of patients accrued at the time of the unforeseen stopping of the trial. Hence, interpretations of the results have to be considered preliminary and primarily serve to generate hypotheses. Our findings are interesting regardless, because they represent the first report of a VDA tested in SCLC. Naturally, there are many clinical and pathologic differences between SCLC and NSCLC, and none of the newer drugs that were successful in the treatment of NSCLC showed clinically useful activity in SCLC.33-36 Thus, lessons learned in NSCLC cannot simply be applied to SCLC, and the premature termination of the trial, therefore, does not seem justified from purely scientific reasons. One hallmark of SCLC is its higher microvessel density in SCLC compared with NSCLC.4 For this reason, there continues to be a strong rationale for testing vasculature targeting agents in this disease. Current strategies in clinical trials primarily focus on anti-angiogenesis and include agents such as sorafenib, sunitinib, aflibercept, endostar, and bevacizumab, among others.Earlytrialshaveshowndifferentialoutcomes.37-43 Onemajor issue of all these trials continues to be the failure to identify biomarkers for vascular targeting agents. Bevacizumab in combination with EP has currently entered phase III testing, and the results are awaited with interest. In conclusion, this is the first report of the use of the VDA ASA404 in patients with SCLC. Although a high response rate was observed, the addition of ASA404 to C/P did not result in an increased PFS. No unexpected toxicities were seen.

Clinical Practice Points

● Small cell lung cancer is a highly vascularized tumor. ASA404 is a tumor-vascular disrupting agent that has not been evaluated in small cell lung cancer to date. Paclitaxel/carboplatin is an active drug combination in small cell lung cancer. Preclinical studies demonstrated synergistic activity between taxanes and ASA404. In this single arm trial we studied ASA404 plus paclitaxel/carboplatin in untreated patients with metastatic small cell lung cancer. Therapy was administered every 3 weeks up to 6 cycles. We report on 17 of 56 planned patients after the trial was stopped prematurely due to negative results with ASA404 in non-small cell lung cancer trials.
● The progression free survival rate at 24 weeks was 41%, the median progression free survival was 7 months and the one year survival probability was 57%. These findings are comparable to historical controls with various platinum doublets. The overall response rate was 94% and thus higher than expected which suggests activity of the tested drug combination. No unexpected toxicities were observed.
● Despite the limited patient number enrolled onto this trial, our findings are important, because, to our knowledge, it is the first clinical report on a vascular disruptive agent in SCLC. ASA404 plus paclitaxel/carboplatin demonstrated activity and good tolerability.Wesuggestfurtherresearchtoexplorethisclassofagentsin small cell lung cancer in future trials.

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