Phase 2 trial of a novel capecitabine dosing schedule in combination with bevacizumab for patients with metastatic breast cancer

Abstract

BACKGROUND:

Capecitabine has antitumor activity in metastatic breast cancer (MBC); however, its optimal dose and schedule remain unclear. Mathematical modeling predicts that a capecitabine schedule 7 days of treatment followed by 7 days of rest (7—7) will improve efficacy and minimize toxicity. Bevacizumab has demonstrated the ability to improve outcomes when it is added to chemotherapy, including capecitabine, in the first-line and second-line settings.

METHODS:

Patients with measurable MBC received oral capecitabine (2000 mg twice daily; 7—7), and intravenous bevacizumab (10 mg/kg every 2 weeks). The primary endpoint was the response rate. Secondary endpoints included toxicity, the clinical benefit rate, and progression-free survival (PFS).

RESULTS:

Forty-one patients were treated. After a median of 7 cycles (range, 1-32 cycles), partial responses were observed in 20% of patients, and stable disease for ≥6 months was noted in 35% patients. The median PFS was 8 months. The most common treatment-related toxicities were hand-foot syndrome (49% grade 2, 20% grade 3/4) hypertension (12% grade 2, 10% grade 3/4), and fatigue (12% grade 2, 2% grade 3/4). Diarrhea (5% grade 2, 0% grade 3/4), nausea (0% grade 2-4), and vomiting (0% grade 2-4) were rare.

CONCLUSIONS:

Capecitabine administered for 7 days followed by a 7-day rest in combination with bevacizumab had modest efficacy and an acceptable toxicity profile in patients with MBC. Gastrointestinal toxicity with this schedule was minimal. Cancer 2011;. © 2011 American Cancer Society.

Improvements in early detection and advances in the therapy of early stage breast cancer have led to a decline in breast cancer-related mortality over the past 2 decades.1 However, the goals of treatment for metastatic disease remain largely palliative even as prolongation of survival is increasingly possible. In this context, the limiting of treatment-related side effects is a concurrent objective.

Capecitabine (Xeloda; Genentech, South San Francisco, Calif) is an orally administered fluoropyrimidine with established activity against metastatic breast cancer (MBC).2 It is approved by the US Food and Drug Administration (FDA) as monotherapy at a dose of 2500 mg/m² (divided twice daily) for 14 days using a 21-day treatment cycle for anthracycline-resistant and taxane-resistant MBC and in combination with docetaxel for anthracycline-pretreated disease.3-8 Several trials also have demonstrated efficacy for capecitabine combined with chemotherapy (ixabepilone) and newer targeted agents, such as bevacizumab, trastuzumab, and lapatinib.9-12

At the standard single-agent dose (1250 mg/m² twice daily) and schedule, typical capecitabine-related adverse events include hand-foot syndrome, diarrhea, nausea, vomiting, and stomatitis, which often result in dose reductions and truncated treatment cycles.7, 8, 13-15 Dose interruptions or reductions have been reported in as many as 65% of patients receiving capecitabine at the FDA-recommended dose level and schedule in clinical trials, and as many as 16% of patients in studies have discontinued the drug because of toxicity rather than disease progression.12, 14

Several studies have explored alternative capecitabine doses and schedules as monotherapy and in capecitabine-based combinations for both breast and colorectal cancers.16-20 However, these dose modifications were derived empirically with unclear impact on patient outcome.

Our group developed a mathematical method to optimize therapeutic dosing based on the Norton-Simon model of tumor growth, in which schedules are determined based on efficacy rather than toxicity.21 When this model was applied to capecitabine, a 7-day-on/7-day-off (7—7) schedule was predicted as optimal. This was confirmed in animal models. We then determined that the maximal tolerated dose of capecitabine 7—7 was 2000 mg as a flat dose given twice daily in a phase 1 trial to patients with MBC.22 In that study, the 7—7 schedule suggested an improved therapeutic index and justified exploration in phase 2 studies.

We now report the results from a phase 2 trial of capecitabine 7—7 in combination with bevacizumab for the treatment of patients with MBC. At the time of trial design, the antivascular endothelial growth factor antibody bevacizumab had just demonstrated improvement in progression-free survival (PFS) when added to paclitaxel in the first-line setting.23 These and other data suggested that capecitabine 7—7 and bevacizumab may be an effective combination.24

MATERIALS AND METHODS

Patient Eligibility

Patients with histologically confirmed breast cancer were eligible if they had metastatic disease measurable by Response Evaluation Criteria in Solid Tumors (RECIST). Any number of prior chemotherapy regimens was permitted; however, prior treatment with bevacizumab or a fluoropyrimidine for MBC was not allowed. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (a 3+ score on immunohistochemistry or a fluorescent in situ hybridization score >2) could no longer be candidates for HER2-targeted therapy. Forty-one patients were enrolled at Memorial Sloan-Kettering Cancer Center (MSKCC) from March 2007 to December 2008.

Additional eligibility criteria included an Eastern Cooperative Oncology Group performance status ≤2 and adequate hepatic, renal, and hematologic function. Exclusion criteria included chemotherapy, radiotherapy, or investigational therapy ≤3 weeks before initiating study treatment. All patients had baseline computed tomography or magnetic resonance imaging studies of the brain, and those with brain metastases were ineligible. Major surgery ≤28 days before treatment, nonhealing wounds, known gastrointestinal malabsorption syndrome, and baseline proteinuria (urine protein:creatinine [UPC] ratio >1.0) were additional exclusion criteria. Patients with clinically significant cardiovascular disease (eg, uncontrolled hypertension, myocardial infarction, and unstable angina), a history of arterial thrombotic events ≤6 months, or current use of warfarin were excluded. The MSKCC institutional review board approved this protocol. All patients provided written informed consent.

Study Design and Treatment

This was a nonrandomized, open-label, phase 2 trial conducted at MSKCC. The primary objective was to estimate the overall response rate (RR) (ie, complete response [CR] + partial response [PR]) to capecitabine 7—7 in combination with bevacizumab for the treatment of MBC. Secondary endpoints included toxicity, the clinical benefit rate (RR + stable disease [SD] ≥24 weeks), and PFS.

Capecitabine 2000 mg was administered orally twice daily for 7 days followed by a 7-day rest, and this schedule was repeated to complete a 4-week cycle. Bevacizumab 10 mg/kg was administered intravenously every 2 weeks with a treatment window of ±2 days.

Patients were treated until they developed disease progression or had unacceptable adverse events. There were no dose modifications of bevacizumab during this study. For grade 3 or 4 bevacizumab-related toxicities, bevacizumab was held until symptoms resolved to grade ≤1. Capecitabine could be continued if bevacizumab was held. Capecitabine treatment delays were required for grade ≥2 toxicities. If a dose was delayed for >2 weeks because of toxicity, then the patient was withdrawn from the study. A maximum of 2 dose reductions were permitted per patient, stipulated according to grade and number of appearances. Bevacizumab was held if capecitabine required a dose delay. The use of erythropoietin-stimulating agents was permitted on study; however, granulocyte-colony–stimulating factor was not permitted.

Patient Evaluation

Patients were evaluated for toxicity weekly during the first cycle and every 2 weeks during subsequent cycles according to the National Cancer Institute Common Toxicity Criteria version 3.0 (NCI CTC v3.0). Proteinuria was monitored by UPC ratio once per cycle. Radiographic response was evaluated every 3 cycles with radiographic scans reviewed by a designated study radiologist according to RECIST. When responses occurred, scans were repeated a minimum of 4 weeks later for confirmation according to RECIST.

Statistical Considerations

The primary endpoint of this trial was the response rate, which we defined as the proportion of patients that achieved a CR or a PR. A Simon mini-max 2-stage design was used to test the null hypothesis of a 10% response rate against the alternative of a 25% response rate for the combination of capecitabine 7—7 and bevacizumab. The probabilities of type I and type II errors were set at 0.1. Twenty-seven patients were accrued to the first stage of the study. If ≥3 responses were observed, then an additional 13 patients would accrue to the second stage of the study. If >6 of 40 patients had an objective response, then the capecitabine 7—7 schedule in combination with bevacizumab would be worthy of further study. An early termination rule was included for toxicity: If ≥12 patients in the first stage experienced treatment-related grade 3 or 4 nonhematologic toxicity, then the trial would be stopped.

There were several secondary endpoints. Toxicities were summarized using NCI CTC v3.0, and the maximum grade per patient was used as a summary measure. The clinical benefit rate was calculated with exact 95% confidence intervals (CIs). PFS was defined from start of therapy to progression of disease or the last date of follow-up and was analyzed using the Kaplan-Meier method.

RESULTS

Forty-one patients were enrolled between March 2007 and December 2008. Patient characteristics are listed in Table 1. One patient withdrew consent 3 days after beginning study treatment, which left 40 patients evaluable for response; however, all 41 patients were evaluable for toxicity.

Table 1. Patient Characteristics (N=41)

Characteristic	No. of Patients (%)
ECOG PS indicates Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer.
Age: Median [range], y	54 [29-70]
ECOG PS: Median [range]	0 [0-2]
Tumor characteristics
ER or PR positive	31 (76)
HER2-positive	0 (0)
Triple negative	10 (24)
No. of metastatic sites
1	3 (7)
2	18 (44)
≥3	20 (49)
No. with visceral metastases	30 (73)
Prior therapy
Adjuvant/neoadjuvant
Total	31 (76)
Anthracyclines	26 (63)
Taxanes	22 (54)
Fluoropyrimidine-based	6 (15)
Endocrine therapy	21 (51)
Metastatic
Presented with MBC	10 (27)
No. prior chemotherapy
0	36 (88)
1	5 (12)
No. of prior endocrine therapies
1	7 (17)
2	7 (17)
3	4 (10)
≥4	4 (10)

Efficacy

Efficacy, as measured by the overall response rate (CR + PR), was the primary endpoint of this study (Table 2). After a median of 7 cycles (range 1-32 cycles), 8 of 40 patients (20%; 95% CI, 9%-36%) had a PR confirmed according to RECIST as their best response. There were no CRs. Fourteen patients (35%) had SD for ≥6 months. Of the 8 patients who attained a PR, the median response duration was 7.1 months (range, 2.8-25.2 months); for the 14 patients who had SD for ≥6 months, the median response duration was 9.9 months (range, 6.0-30.8 months). The clinical benefit rate (RR + SD >6 months) was 55%. Eleven patients had SD for <6 months. Seven patients had progressive disease. One patient remained on study therapy at >32 months. The median PFS was 8 months (95% CI, 6-14 months) (Fig. 1), and the median time to treatment failure was 7 months (95% CI, 5-8 months).

Figure 1. This Kaplan-Meier curve illustrates the progression-free survival (PFS) of patients who received capecitabine administered for 7 days followed by a 7-day rest plus bevacizumab. Events include progression. Patients who left the study because of toxicity or who were lost to follow-up were censored. Note that 1 patient withdrew consent 3 days after beginning study treatment, which left 40 patients evaluable for the analysis of response. CI indicates confidence interval.

Table 2. Efficacy of Capecitabine (7 Days of Treatment Followed by 7 Days of Rest) and Bevacizumab^a

Best Overall Response	No. of Patients (%)	95% Exact CI
Clinical benefit rate: CR+PR+SD >6 mo 22 (55) 38-71 CI indicates confidence interval; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
No. of evaluable patients	40 (100)	—
CR	0 (0)	—
PR	8 (20)	9-36
SD ≥6 mo	14 (35)	21-52
SD <6 mo	11 (28)	15-44
PD	7 (18)	7-33

Adverse Events

All 41 patients were evaluable for toxicity. There were no grade 5 events. Table 3 summarizes the most frequent, potentially treatment-related, grade 2 through 4 toxicities using NCI CTC v3.0. The most common grade ≥2 drug-related events included hand-foot syndrome (69% grade 3/4; 20%/0%), hypertension (22% grade 3/4; 10%/0%), fatigue (14% grade 3/4; 2%/0%), and neutropenia (12% grade 3/4; 7%/0%). Grade 2 diarrhea occurred in 5% of patients, and there were no grade 3 or 4 diarrhea events. Nausea and vomiting were limited to grade 1. Two patients (5%) developed grade 2 proteinuria, and there were no grade 3 or 4 episodes. Hemorrhage was rare and was limited to grade 2 epistaxis.

Table 3. Treatment-Related Toxicity With Capecitabine (7 Days of Treatment Followed by 7 Days of Rest) and Bevacizumaba

	No. of Patients (%)
Toxicity	Grade 2	Grade 3%)	Grade 4
ALT indicates alanine aminotransferase; AST, aspartate aminotransferase. a Forty-one patients were evaluable for toxicity using the National Cancer Institute Common Toxicity Criteria for Adverse Events (version 3.0).
Nonhematologic
Rash: Hand-foot syndrome	20 (49)	8 (20)	—
Mucositis	1 (2)	—	—
Vomiting	—	—	—
Nausea	—	—	—
Diarrhea	2 (5)	—	—
Thrombosis	—	1 (2)	1 (2)
Hypertension	5 (12)	4 (10)	—
Hemorrhage: Nose	1 (2)	—	—
Proteinuria	2 (5)	—	—
Fatigue	5 (12)	1 (2)	—
Neuropathy: Sensory	3 (7)	—	—
ALT or AST	4 (10)	1(2)	—
Bilirubin	4 (10)	—	—
Hematologic
Neutropenia	2 (5)	3 (7)	—
Anemia	2 (5)	—	—
Thrombocytopenia	1 (2)	—	—

Thirty-two patients required a dose delay or reduction of capecitabine for possible drug-related toxicity. Those events included hand-foot syndrome (n = 25), diarrhea (n = 2), neutropenia (n = 3), and abnormal aspartate or alanine transferase levels (n = 2). Seven patients required delays of bevacizumab because of hypertension.

There were 3 potentially serious treatment-related adverse events. One patient was hospitalized for new-onset grade 3 atrial fibrillation; in that patient, study drugs were discontinued because of inability to receive warfarin while on capecitabine according to the protocol. One patient experienced epigastric/chest pain during bevacizumab infusion and was hospitalized; cardiac in that patient, evaluation for ischemia was negative, but grade 3 portal vein thrombosis was identified incidentally. Another patient developed grade 4 thrombosis with pulmonary embolism requiring anticoagulation, and she was taken off study according to the protocol.

Nine patients discontinued therapy because of drug-related toxicities, which included hand-foot syndrome (grade 3, n = 2; grade 2, n = 3), thrombosis (pulmonary embolism: grade 4, n = 1), neutropenia (grade 3, n = 2), and headache (grade 2, n = 1). Five patients withdrew from protocol therapy for other reasons, including 1 patient who developed an unrelated gynecologic malignancy, 2 patients who required treatment with medications that have known interactions while taking capecitabine, and 2 patients who withdrew informed consent.

DISCUSSION

Capecitabine has proven palliative benefit as a treatment for MBC. This palliation may be compromised by the well documented toxicities patients experience when using the FDA-approved dose and schedule.25 The resulting empiric adjustments in dose size and treatment duration largely have an unknown impact on treatment efficacy. Retrospective studies and even some randomized, prospective trials in metastatic disease have suggested that reduced-dose capecitabine delivered on a 14—7 schedule may achieve results comparable to those achieved with the conventional dose, but those results were not definitive and often were confounded.16-18 Prospective randomized studies often have explored reduced-dose capecitabine in doublets with other cytotoxic agents, making these data difficult to interpret for the impact of the modified capecitabine dose alone.19, 26-28 An additional complication arises from data indicating that body surface area-based dosing may not be ideal.29

We developed a method to predict the optimal dosing of chemotherapy and applied it specifically to capecitabine. In xenograft models of breast cancer, we explored the optimal dosing predicted with this model by identifying the schedule of treatment that led to maximal effect.21, 22 Then, we confirmed the predictions of the model in animal experiments and in a single-agent phase 1 trial that formed the foundation for our current study in which we added bevacizumab for the treatment of HER-2 normal MBC. Our decision to add bevacizumab to capecitabine in this study was based on data, which were emerging at the time of trial design and subsequently were confirmed, indicating that the antibody improves response rate and PFS when added to chemotherapy.23, 24, 30, 31 The improvement in efficacy conferred by bevacizumab does not generally potentiate chemotherapy-associated toxicity and may be chemotherapy agent-independent.

This phase 2 trial met its primary endpoint, demonstrating a response rate worthy of further study for the combination of capecitabine 2000 mg twice daily on a 7—7 schedule with bevacizumab. With all the caveats associated with cross-trial comparisons, the response rate of 20% and the clinical benefit rate of 55% demonstrated here may be weighed against the reported results from first-line studies of conventionally dosed capecitabine with bevacizumab.12, 24, 32 Although only 88% of the patients in our study received treatment as first-line therapy, the median PFS of 8 months was consistent with the published literature for this combination given to entirely first-line populations. For example, in the first Regimens in Bevacizumab for Breast Oncology trial (RIBBON-1), the addition of bevacizumab to capecitabine in the first-line setting achieved a median PFS of 8.6 months.32 Although our response rate of 20% was lower than that reported in RIBBON-1 (35%), more of our patient population had received previous therapy for metastatic disease and had exposure to adjuvant taxanes (54% vs approximately 40%).

Capecitabine 7—7 was associated with fewer gastrointestinal adverse events than expected. Grade 2 diarrhea occurred in only 5% of patients compared with 16% of patients who received conventional dosing.12 There were no reports of grade 3/4 diarrhea or grade ≥2 nausea or vomiting. These findings support optimization of the therapeutic index, because diarrhea can be a significant and potentially life-threatening adverse event. In the current study, the incidence of hand-foot syndrome with the 7—7 schedule (20% grade 3/4) was similar to that in previous reports with conventional-schedule capecitabine, which ranged from 13% to 22%. It is significant that the only treatment-related grade 4 adverse event was attributed to bevacizumab, supporting the improved tolerability predicted by the mathematical model on which this schedule was derived. The rate of common capecitabine-related toxicities agreed with our phase 1 data for capecitabine 7—7 monotherapy with grade 3 hand-foot syndrome and diarrhea rates of 17% and 6%, respectively.22 The addition of bevacizumab therapy did not appear to potentiate capecitabine-related toxicities.

Bevacizumab-related adverse events of hypertension, proteinuria, and thrombosis were uncommon and were similar to the rates recently reported in randomized controlled bevacizumab trials.32, 33 There were no unexpected serious adverse events.

In the current study, the majority of study participants (78%) required a dose modification for capecitabine while on study. However, the protocol required dose adjustments for treatment-related grade 2 adverse events and did not permit the use of granulocyte-colony–stimulating factor. Anticoagulation use initially was restricted while were receiving bevacizumab; therefore, patients who experienced thrombosis were required to discontinue study therapy. We recognize that these parameters were more stringent than those that are acceptable currently in clinical practice and typically incorporated into clinical trials. Outside of a research study, many of the protocol-stipulated dose modifications possibly may be avoided with the use of growth factors and liberal supportive measures.

In summary, we successfully used a mathematical model and xenograft experiments to predict a less toxic and possibly equally effective dose and schedule of capecitabine for palliation of MBC. On the basis of our work, we believe that capecitabine administered for 7 days followed by a 7-day rest has demonstrated efficacy worthy of further study and that it may offer a favorable toxicity profile with respect to gastrointestinal side effects. Additional phase 2 trials currently are testing the capecitabine 7—7 dosing schedule in combination with other targeted therapies.34 The definitive test of this schedule will be a comparative, randomized phase 3 trial of capecitabine 7—7 versus conventionally scheduled capecitabine that currently is planned for the treatment of patients with MBC.

CONFLICT OF INTEREST DISCLOSURES

Supported in part by Roche Laboratories, Inc., and Genentech.