The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open-label, single-arm trial was evaluated.
The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open-label, single-arm trial was evaluated.
Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m2 for patients on CYP3A enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m2 for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression-free survival at 6 months (PFS-6), and secondary end points included safety and median overall survival (OS).
All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0-7.0 months) and PFS-6 rate was 16% (95% CI, 5.0%-32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment-related deaths.
Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously. Cancer 2011;. © 2011 American Cancer Society.
Outcome for glioblastoma (GBM), the most common malignant primary brain tumor, remains poor with median overall survival (OS) of only 14.6 months after current standard therapy that includes maximum safe resection followed by involved-field radiation with temozolomide and adjuvant temozolomide.1 Salvage therapies after recurrence have had limited activity.2-4 Initial clinical trials with bevacizumab, a humanized monoclonal antibody (MAb) against vascular endothelial growth factor (VEGF), were conducted among recurrent GBM patients because GBM tumors are highly angiogenic5, 6 and secrete high levels of VEGF.7-9 In addition, VEGF targeting MAbs inhibit growth in in vivo orthotopic GBM xenograft models10, 11 and can enhance the antitumor activity of cytotoxic therapy.12-14 Furthermore, significant clinical benefit associated with bevacizumab plus chemotherapy had been noted in other aggressive solid tumors.15-20 Encouraging rates of radiographic response and improved survival reported by initial studies in recurrent GBM21, 22 triggered follow-up studies, which ultimately led to accelerated approval by the US Food and Drug Administration (FDA) of single-agent bevacizumab based on durable radiographic responses.23-25
However, the survival benefit after bevacizumab with or without other systemic agents is modest with most patients developing progressive disease within 8 to 10 months and dying from refractory tumor soon thereafter.22-24, 26-30 Thus, effective therapy for GBM patients after progression on bevacizumab-based therapy represents a major unmet need.
Carboplatin and irinotecan exhibit modest antitumor activity when administered separately among recurrent malignant glioma patients.31-38 In addition, both agents impair DNA replication via potentially complementary mechanisms and are associated with primarily nonoverlapping toxicities. We therefore hypothesized that a regimen combining carboplatin and irinotecan may be adequately tolerated and associated with greater antitumor benefit than either agent alone. Studies evaluating this regimen in other cancer populations were the basis for the dosing schedule utilized in the current study. The rationale for continuing bevacizumab was to avoid rebound, fulminant progressive tumor after bevacizumab discontinuation39 and to potentially normalize tumor vasculature to allow enhanced chemotherapy delivery.40
Our primary objective was to evaluate the activity, defined by progression-free survival at 6 months (PFS-6) of carboplatin and irinotecan combined with bevacizumab among adults with recurrent GBM who progressed on prior bevacizumab therapy. In addition, we sought to evaluate the safety of this regimen in this patient population.
Patients were required to have histologic confirmation of World Health Organization (WHO) grade 4 malignant glioma (GBM or gliosarcoma) that progressed after prior bevacizumab-based therapy. Patients with prior low-grade glioma were eligible if histologic transformation to grade 4 malignant glioma was confirmed. Eligible patients were also at least 18 years of age; had a Karnofsky performance status (KPS) ≥70; and were on a stable corticosteroid dose for at least 1 week. Additional enrollment criteria included hematocrit >29%; absolute neutrophil count >1000 cells/μl; platelet count >100,000 cells/μl; and serum creatinine, aspartate aminotransferase, and bilirubin within 1.5 times the institutional upper limit of normal. At least 4 weeks between surgical resection or chemotherapy, and at least 12 weeks between radiotherapy and enrollment were required. All patients provided informed consent. There were no limits based on either the number of prior episodes of progression or therapeutic regimens received.
Patients were excluded for grade ≥3 toxicity on prior bevacizumab; progressive disease or grade ≥3 toxicity on prior carboplatin or irinotecan; uncontrolled hypertension; acute hemorrhage on baseline magnetic resonance imaging (MRI); urine protein:creatinine ratio >1; homozygosity for the *28UGT1A1 allele; pregnancy or nursing; active infection requiring intravenous antibiotics; therapeutic anticoagulation with warfarin; and prior stereotactic radiosurgery, radiation implants, or radiolabeled monoclonal antibody therapy unless there was unequivocal disease progression (such as a new lesion or biopsy-proven recurrence).
Eligible patients for this open-label phase 2 study received bevacizumab at 10 mg/kg intravenously every 14 days. Carboplatin was administered at an area under the plasma curve (AUC) of 4 on day 1 of each 28-day cycle. Irinotecan was administered on days 1 and 14 at 340 mg/m2 for patients receiving cytochrome P450 CYP3A enzyme-inducing anti-epileptics (EIAEDs; phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and primidone) and at 125 mg/m2 for those not on EIAEDs. Study therapy continued until progressive disease, unacceptable toxicity, noncompliance with study protocol guidelines, or withdrawal of consent.
Study investigators determined response by neurologic examination and contrast-enhanced MRI after the first 2 treatment cycles and then prior to every other cycle based on the recently published Response Assessment in Neuro-Oncology criteria.41 A complete response (CR) required disappearance of all enhancing and nonenhancing tumor on consecutive MRIs at least 4 weeks apart, with corticosteroid discontinuation and neurologic stability or improvement. A partial response (PR) required ≥50% reduction in size (product of largest perpendicular diameters) of enhancing tumor with stability or improvement of neurologic status and corticosteroids. Progressive disease (PD) included ≥25% increase of enhancing tumor, a new enhancing lesion, significant worsening of nonenhancing tumor including that detected by fluid-attenuated inversion recovery (FLAIR) or T2 sequences, or clinical decline. Stable disease (SD) was defined as any assessment not meeting CR, PR, or PD criteria. Partial responses and stable disease also required stable or improved signal abnormality on FLAIR sequences.
Chemotherapy doses were held for grade 3 or 4, related, nonhematologic toxicity, grade 3 thrombocytopenia, grade 4 neutropenia, and fever and neutropenia (any grade) until the event resolved to grade 1 or pretreatment baseline. Thereafter, chemotherapy doses were reduced by 25%. Chemotherapy doses were also reduced by 25% for any related event that required >2 weeks to satisfy retreatment criteria. Patients who required more than 3 chemotherapy dose reductions were allowed to remain in the study and receive bevacizumab alone. Bevacizumab was discontinued for uncontrollable hypertension, grade 2 or greater hemorrhage, arterial thrombosis, wound dehiscence requiring surgical intervention, intestinal perforation or grade 4 venous thrombosis, proteinuria, or congestive heart failure. Bevacizumab was held until other related grade 3 events resolved to grade ≤1.
Initiation of each cycle required an absolute neutrophil count (ANC) ≥1000/mm3; a platelet count ≥100,000/mm3; creatinine ≤1.5 times the upper limit of normal (× ULN), bilirubin ≤2 × ULN and aspartate aminotransferase ≤2.5 × ULN; proteinuria <3+ on urinalysis or urine protein: creatinine ratio ≤1.0; and resolution of any related grade ≥3 event to grade ≤1.
Our primary goal was to evaluate the PFS-6 rate of carboplatin, irinotecan, and bevacizumab among recurrent GBM patients who had progressed on prior bevacizumab therapy. At the time this study was designed, benchmarks for outcome among recurrent GBM patients who had progressed on prior bevacizumab therapy had not been established; therefore, we chose to use the historical benchmark established with temozolomide at first recurrence. Hence, given a PFS-6 rate of 21% among recurrent GBM patients treated with temozolomide at first recurrence,42 a sample size goal of 24 recurrent GBM patients was chosen to allow 88% power to differentiate between PFS-6 rates of 5% and 25% with a type 1 error rate of 0.03.
An interim efficacy analysis after 16 patients were accrued to each arm was planned a priori. If 12 or more of these 16 patients progressed or died within 2 months of study initiation, further accrual would be suspended. The interim efficacy threshold was met, and therefore the study completed accrual as specified.
For this study among heavily pretreated patients with an extremely poor prognosis, rates of unacceptable toxicity, defined as grade ≥2 central nervous system (CNS) hemorrhage or grade 4 or 5 nonhematologic toxicity, of 15% or less were considered desirable, whereas rates of 40% or greater were considered undesirable. Stopping rules for unacceptable toxicity based upon boundaries proposed by Pocock were used to monitor this study after each group of 4 patients.43 Accrual was not suspended to formally assess the toxicity profile unless the following thresholds of unacceptable toxicity were satisfied: ≥3/4; ≥4/8; ≥5/12; ≥6/16; ≥7/20; ≥7/24. The type 1 and type 2 errors associated with this monitoring were 0.05 and 0.07, respectively. These guidelines did not adjust for differential length of follow-up of accrued patients.
PFS was defined as the time between the cycle 1 start date and the date of disease progression or death. PFS was censored at the time of last follow-up if the patient remained alive without disease progression, or at the start of nonstudy treatment if initiated before disease progression. OS was calculated from the start of therapy until death or last contact if censored. PFS and OS were summarized using Kaplan-Meier estimator including 95% confidence intervals (CIs).
Characteristics of the 25 patients who enrolled on this study between September 2009 and July 2010 are summarized in Table 1. Patients were relatively young (median age, 52 years), more than half had a KPS of at least 90, and 10 (40%) were on corticosteroids at enrollment. Patients were moderately pretreated with 14 (56%) having 2 to 3 episodes of prior progression. All patients had progressed after standard therapy with radiation and temozolomide chemotherapy as well as prior bevacizumab. Most patients (96%) had progressed on 1 prior bevacizumab regimen, whereas 1 patient enrolled after progression on 2 prior bevacizumab regimens. Thirteen patients (52%) enrolled after having progressed on bevacizumab used at recurrence, whereas 12 patients (48%) enrolled after progressing on bevacizumab incorporated into adjuvant therapy for newly diagnosed GBM patients. Sixty percent of patients progressed previously on bevacizumab in combination with chemotherapy, whereas 36% progressed on bevacizumab monotherapy and 1 patient progressed on bevacizumab with a targeted agent (sorafenib). Nearly all patients (92%) enrolled while progressing on bevacizumab therapy; however, 2 (8%) progressed on bevacizumab and then received either single-agent temozolomide or XL-184, a dual VEGFR-2/met tyrosine kinase inhibitor, for 2 to 4 months prior to study enrollment. Median duration of initial bevacizumab therapy was 9 months with a range of 2 to 34 months.
|Time from diagnosis (wk)|
|Average dose (mg/day)||2.8|
|Surgery prior to enrollment|
|No. prior PD|
|Progression on BV at enrollment|
|BV partner at prior progression|
|No. prior BV PD|
|No. of mo on prior BV|
As of January 1, 2011, 1 patient continues to receive study therapy in cycle 6, whereas all other patients have discontinued study therapy. Two patients remain free of progression including 1 patient who completed 12 cycles of therapy and remains off study and 1 patient who discontinued study therapy due to recurrent hematologic toxicity after 4 cycles and is currently receiving her fifth cycle of nonstudy irinotecan and bevacizumab with stable disease. Eight patients (32%) remain alive, including the 2 described above and 6 who are progressed on study therapy and are currently receiving additional salvage therapy. Seventeen patients (68%) have died.
Study drug administration and compliance with treatment for the intent-to-treat study population were excellent. A total of 80 cycles of therapy were administered including a median of 3 cycles (range, 1-12) per patient. Twenty-one patients (84%) discontinued study therapy due to progressive disease. Single patients discontinued study therapy due to completion of 1 year of therapy with no evidence of active disease, recurrent grade 3-4 hematologic toxicity, noncompliance, and voluntary withdrawal, respectively.
All patients were assessable for toxicity. Table 2 summarizes the frequency of grade ≥2 adverse events that were at least possibly related to the study regimen as a percentage of the total number of cycles administered during the study. Most adverse events were grade 2, whereas the most common grade 3 or 4 events were hematologic. Grade 3 or 4 neutropenia occurred in 6 (24%) and 2 (8%) patients, whereas grade 3 or 4 thrombocytopenia occurred in 3 patients (13%), and grade 3 anemia occurred in 2 patients (8%). Among nonhematologic events, grade 3 events were limited to fatigue in 3 patients (13%) and hypertension in 2 patients (8%). Nine patients (36%) required 1 dose reduction of carboplatin and irinotecan, whereas 2 patients (8%) required 2 dose reductions. There were no study-related deaths or episodes of intracranial hemorrhage.
|Anemia||7 (9%)||2 (3%)||—|
|Fatigue||4 (5%)||3 (4%)||—|
|Hypertension||2 (3%)||2 (3%)||—|
|Nausea/emesis||4 (5%)||1 (1%)||—|
|Neutropenia||14 (18%)||10 (13%)||3 (4%)|
|Thrombocytopenia||13 (16%)||7 (9%)||3 (4%)|
|Transaminase elevation||2 (3%)||1 (1%)||—|
|Weight loss||2 (3%)||—||—|
The median follow-up for all patients was 7.99 months (95% CI, 6.25-11.02). Outcome analysis was based on the intent-to-treat population and includes 1 patient who discontinued study therapy on day 2 of cycle 1 due to voluntary withdrawal. Median OS, PFS, and PFS-6 rate are summarized in Table 3 and Figure 1. Best radiographic response was stable disease in 20 patients (80%) and progressive disease in 4 (16%), whereas 1 patient was not evaluable. None of the patients met criteria for radiographic response. Among 10 patients who were on dexamethasone at study initiation, 5 were able to taper by an average of 4.6 mg per day, including 2 patients who were able to completely discontinue dexamethasone. There was no difference in either PFS or OS among patients who received adjuvant bevacizumab compared with those who received bevacizumab at recurrence, nor was there a difference in OS for patients who progressed on bevacizumab monotherapy compared with bevacizumab in combination with chemotherapy. However, PFS was improved for patients who progressed on bevacizumab monotherapy compared with those who progressed on bevacizumab plus chemotherapy (P = .0356). Specifically, 44.4% of patients who were treated after bevacizumab monotherapy remained progression-free after 6 months compared with 0% of patients who were treated after progression on bevacizumab plus chemotherapy.
|Study Design||Regimen||No. of Patients||Median PFS, mo (95% CI)||PFS-6, % (95% Cl)||Median OS, mo (95% Cl)||Citation|
|Prospective||BV+carboplatin+CPT-11||25||2.3 (1.8-3.6)||16 (5.0-32.5)||5.8 (4.0-7.0)||Current study|
|Prospective||BV+daily TMZ or VP-16||23||1.8 (1.0-2.1)||4.4 (3.1-18.2)||4.1 (2.8-5.8)||Reardon46|
|Retrospective||BV+miscellaneous agents||54 (35 GBM)||1.3 (1.2-1.5)||2 (NR)||2.9 (NR)||Quant27|
|Retrospective||BV+miscellaneous agents||19||2 (1.2-3.3)||0||5.2 (3.3-8.4)||Iwamoto48|
|Retrospective||BV+miscellaneous agents||23||1.8 (NR)||NR||NR||Norden26|
|Retrospective||BV+SRS+chemotherapy||23||2.6 (NR)||NR||7.2 (NR)||Torcuator47|
|Retrospective||BV+chemotherapy||23||1.7 (NR)||NR||3.3 (NR)||Torcuator47|
Bevacizumab is indicated for the treatment of recurrent GBM patients in the United States, Canada, and a growing number of countries worldwide.25 In addition, bevacizumab is currently being evaluated for newly diagnosed GBM patients in 2 multinational, blinded placebo-controlled randomized phase 3 studies as well as additional phase 2 studies.44, 45 Thus, a high percentage of GBM patients are currently receiving bevacizumab either at recurrence or after initial diagnosis. Although bevacizumab substantially improves rates of radiographic response and PFS, all patients ultimately progress. Furthermore, survival after bevacizumab progression is poor.
To date, effective treatment after bevacizumab progression has not been identified (Table 3). Two prospective studies have been reported. Among 19 patients with recurrent GBM who progressed on single-agent bevacizumab, median PFS after initiation of bevacizumab plus irinotecan was only 1.1 months. Overall survival was not reported for these patients.24 Similarly, among 23 recurrent GBM patients treated with bevacizumab plus protracted daily (metronomic) chemotherapy using either temozolomide or etoposide after bevacizumab failure, the median OS was 4.1 months (95% CI, 2.8-5.8) and PFS-6 was 4.4% (95% CI, 3.1-18.2).46 Several relatively small retrospective series (range of evaluated patients, 19-35) report median OS and PFS-6 probability of 2.2 to 4.1 months and 0% to 4.4%, respectively.26, 27, 48 Of note, a retrospective review reported that patients who received stereotactic radiosurgery with bevacizumab and chemotherapy achieved a median PFS of 2.6 months and a median OS of 7.2 months after prior bevacizumab failure; in comparison, patients who received bevacizumab and chemotherapy alone, without a radiosurgical boost, had a median PFS of 1.7 months and a median OS of 3.3 months. These results suggest that stereotactic radiosurgery may improve outcome for some patients after progression on bevacizumab; however, these findings require prospective evaluation.
Our phase 2 study demonstrates that continuation of bevacizumab with carboplatin and irinotecan is associated with a modest improvement in outcome compared with historical data for recurrent GBM patients who have progressed on bevacizumab therapy. Although prospective, this small series enrolled patients with relatively favorable prognostic factors including younger age and good performance status, thus further evaluation of this regimen should be considered in a randomized, controlled trial. Another concern is that our study design precludes determination of whether therapeutic benefit required combination of all 3 study agents or if a subset of the study regimen may have been sufficient to render therapeutic benefit. Specifically, we did not evaluate whether either carboplatin alone or carboplatin and irinotecan without bevacizumab may have improved outcome in our study. However, it is unlikely that irinotecan alone, irinotecan plus bevacizumab, or carboplatin plus bevacizumab were responsible for therapeutic benefit in our study based on the lack of benefit observed with these regimens in previously reported series.24, 26, 27, 48
The rationale for this study regimen was based on several considerations. Bevacizumab was included to avoid fulminant “rebound” tumor regrowth that has been reported upon abrupt bevacizumab discontinuation39 and because anti-VEGF therapy can normalize tumor vasculature and improve chemotherapy delivery.49 Furthermore, a retrospective registry series reported that bevacizumab continuation after progression on a bevacizumab regimen improves survival in patients with metastatic colorectal cancer.50 The combination of carboplatin and irinotecan was considered attractive for several reasons. First, each of these agents has modest antitumor activity when administered separately among recurrent malignant glioma patients.31-36, 38, 51 Second, the mechanisms of cytotoxicity of each agent are potentially complementary. Specifically, irinotecan inhibits DNA replication by blocking topoisomerase 1, whereas carboplatin induces DNA cross-links and adducts. Third, the primary toxicities of each agent, gastrointestinal for irinotecan and hematologic for carboplatin, are nonoverlapping; thus, combining the 2 agents is expected to be associated with acceptable toxicity. Fourth, pharmacologic metabolism paths of each agent differ, suggesting that detrimental pharmacologic interactions associated with a combined regimen are not expected. Finally, studies using carboplatin plus irinotecan for patients with other aggressive solid tumors have generated encouraging evidence of antitumor activity and overall adequate tolerance.52-54
Our study demonstrates that the combination of carboplatin, irinotecan, and bevacizumab is associated with adequate safety, despite enrolling patients who were moderately pretreated. The type, frequency, and severity of encountered toxicity was similar to that which has been reported for each agent when administered separately,31-36, 38, 51 thus the combination did not cause unexpected events. One factor that may have contributed to the acceptable safety profile we observed was the exclusion of patients homozygous for the *28 UGT1A1 allele because such patients are predicted to be at increased risk of irinotecan toxicity.55, 56
Treatment of GBM patients who progress on bevacizumab therapy is currently a dire unmet need in neuro-oncology. We demonstrate that carboplatin, irinotecan, and bevacizumab is associated with modest antitumor benefit and adequate safety in moderately pretreated GBM patients who have progressed on bevacizumab. Further evaluation of this regimen is warranted, and the identification of effective therapies for GBM patients who progress on bevacizumab should be highly prioritized.
This study was supported by National Institutes of Health grants 5P50-NS-20023 and 5 R37 CA11898, and a grant from Genentech Pharmaceuticals. D.A.R., J.J.V., and H.S.F. reported receiving speaker, advisory, and consultant honoraria from Roche/Genentech. The rest of the authors made no disclosures.