In 2008, the FDA approved bendamustine hydrochloride (TREANDA, Cephalon, Inc., North Wales, PA), an intravenously administered alkylating agent, for the treatment of patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.
Bendamustine is a cytotoxic alkylating agent that contains a purine and an amino acid antagonist; it is a bifunctional mechlorethamine derivative that also contains a purine-like benzimidazole ring.1 The effects of bendamustine are caused by the cross-linking of double- and single-stranded DNA, which disrupts DNA synthesis and induces apoptosis. The exact mechanism of action of bendamustine remains unknown.1,2
In solid tumors, bendamustine has been used alone or in combination with other chemotherapy agents and has had promising results in patients with various tumor types, including head and neck cancer, germ cell tumors, small cell lung cancer, and breast cancer.2-9 In a study comparing bendamustine, methotrexate, and fluorouracil (n=25) with cyclophosphamide, methotrexate, and fluorouracil (n=24)10 in patients with metastatic breast cancer, the bendamustine combination regimen was associated with an overall response rate of 52% and a median duration of remission of 15.2 months, compared with 46% and 6.2 months in the cyclophosphamide group.10 In another study, bendamustine was used as salvage therapy in 36 patients with advanced breast cancer; the overall response rate was 27%.11 In a study combining bendamustine with radiation therapy in 13 patients with recurrent squamous cell carcinoma of the head and neck, 62% of patients had a partial response.3 In patients with small cell lung cancer treated with single-agent bendamustine5 or bendamustine combined with carboplatin,4 the overall response rates were 29% and 73%, respectively.
Bevacizumab is a recombinant humanized antibody directed against vascular endothelial growth factor (VEGF). It is approved for the treatment of patients with colon, lung, kidney, breast (outside the United States), and brain (glioblastoma multiforme, only in the United States) tumors.
Based on the promising results of the studies of bendamustine in solid tumors, an investigator-initiated study of the combination of bendamustine and bevacizumab was conducted in patients with advanced cancer. The rationale for this first-ever clinical trial combining bevacizumab and bendamustine was that adding an anti-VEGF agent to bendamustine would result in a combination of 2 drugs with different mechanisms of antitumor activity and non-cross-toxicity, which would improve the antitumor activity of either drug alone in patients with advanced cancer. The primary objectives were to assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and tolerability of bendamustine and bevacizumab in patients with advanced cancers, and the secondary objective was to assess the antitumor efficacy of this regimen.
Patients and Methods
Study participants were patients seen in the Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program) at The University of Texas MD Anderson Cancer Center with a histologically confirmed diagnosis of cancer that was refractory to or had relapsed after standard therapy, or for which no standard therapy was available that increased survival by at least 3 months. Other criteria were ECOG performance status of 2 or less; adequate renal function (serum creatinine ≤2.0 mg/dL, or calculated glomerular filtration rate ≥40 mL/min if creatinine >2.0 mg/dL); adequate bone marrow function (absolute neutrophil count ≥1000 cells/mcL; platelet count ≥75,000 cells/mcL), unless these abnormalities are caused by bone marrow involvement; adequate hepatic function (total bilirubin ≤1.0 mg/dL [≤3.0 mg/dL if patient had Gilbert syndrome]); and alanine aminotransferase levels equal to or less than 3 times the upper limit of normal. If patients had liver metastases, a total bilirubin level of 5 mg/dL or less and alanine aminotransferase level equal to or less than 5 times the upper limit of normal were allowed. Patients were at least 3 weeks from previous cytotoxic chemotherapy, and 5 half-lives or 3 weeks from targeted or biologic therapy, whichever was shorter. All female patients of childbearing age had to have a negative human chorionic gonadotropin urine test.
Exclusion criteria were pregnancy; active bleeding; active gastric or duodenal ulcer; serious or non-healing wound, ulcer, or bone fracture; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days; history of bleeding; central nervous system metastasis; inability to complete the informed consent process and adhere to the protocol treatment plan and follow-up requirements; major surgery within 28 days before entering the study; uncontrolled systemic vascular hypertension (systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mm Hg); uncontrolled intercurrent illness, including ongoing or active infection requiring parenteral antibiotics; and psychiatric illness/social situations that would limit compliance with study requirements.
All patients signed informed consent forms fully disclosing the investigational nature of the trial before enrollment. The study protocol was approved by The University of Texas MD Anderson Cancer Center Institutional Review Board (ClinicalTrials.gov identifier: NCT01152203).
Treatment
All patients were treated at MD Anderson Cancer Center. Treatments consisted of intravenous bendamustine in escalating doses from 70 to 100 mg/m2 (days 1 and 2) and intravenous bevacizumab (10 mg/kg; days 1 and 15) (Table 1). Each treatment cycle was 28 days. Patients remained on treatment until unacceptable toxicity, disease progression, or patient consent withdrawal.
DLT was assessed during the first treatment cycle and was defined as (1) any grade 3 or 4 nonhematologic toxicity, as defined in the most current version of the NCI’s Common Terminology Criteria for Adverse Events (NCI CTCAE 4.0),12 even if expected and believed to be related to the study medications (except nausea and vomiting, electrolyte imbalances responsive to appropriate regimens, and alopecia); (2) any grade 4 hematologic toxicity lasting 3 weeks or longer despite supportive care or associated with bleeding and/or sepsis; (3) any grade 4 nausea or vomiting lasting longer than 5 days despite maximum antinausea regimens; (4) any other grade 3 nonhematologic toxicity, including symptoms/signs of vascular leak or cytokine release syndrome but excluding alopecia; (5) grade 4 thrombocytopenia; (6) any grade 4 neutropenia lasting more than 7 days (as defined by the NCI CTCAE) despite supportive care or associated with bleeding and/or sepsis; or (7) any severe or life-threatening complication or abnormality not covered in the NCI CTCAE. If more than 33% of patients at any particular dose level developed DLT, the treatment was to continue at the previous dose level.
Dose-Escalation Schedule and Distribution of Patients, Treatment Cycles, and DLTs
Patient Monitoring
Patients were monitored before starting the first dose and then every 4 weeks through medical history, physical examination, hematology and chemistry laboratory studies, urine analysis, urine pregnancy test (if applicable), vital signs, and radiologic imaging scans (within 30 days of first dose; at the end of cycle 2; and then every 2 cycles thereafter).
Dose Modification
If a grade 3 bendamustine-related toxicity occurred, patients were treated with regular medical support and their therapy continued once the severity corrected to grade 2 or less. A weekly assessment was performed and therapy was held for a maximum of 3 weeks. If grade 3 toxicity occurred (DLT), the bendamustine dose was decreased by 25% to 50%. If grade 3 or 4 toxicity occurred again, the treatment was discontinued. No dose adjustment for bevacizumab was to be made.
End Points and Statistical Considerations
The study was designed using a conventional “3 + 3” study design, followed by an expansion phase. Evaluation of toxicity at baseline and during the study was performed following the Cancer Therapy Evaluation Program’s active version of the NCI CTCAE.13 The use of growth factors was accepted during the clinical study.
Tumor response was assessed every 2 cycles (1 cycle = 4 weeks) by an MD Anderson radiologist and verified by a measurement team within the Department of Investigational Cancer Therapeutics using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1).13 These criteria defined a partial response as a 30% decrease in the sum of the longest diameters of target lesions, excluding complete disappearance of disease (complete response). Progressive disease was defined as a 20% increase in the sum of the longest diameters of target lesions. Stable disease was defined as neither sufficient shrinkage to qualify as a partial response nor a sufficient increase to qualify as progressive disease. Waterfall plot analysis was used to illustrate antitumor activity.14 Survival was measured from the first day of treatment until death from any cause or last follow-up. Time to progression was measured from the first day of treatment until patients came off study because of disease progression or death (excludes toxicity and withdrawal of consent). Patients alive and without treatment failure until the date of last follow-up were censored on that date. The patient characteristics were analyzed using descriptive statistics. Survival functions were estimated using the Kaplan-Meier method.
Results
Demographics
From July 2010 to December 2012, 43 patients with advanced cancer were registered on protocol. One patient became ineligible before initiation of therapy because of gastrointestinal bleeding. Forty-two patients have been treated. Their median age was 60 years (range, 17-80). The cohort consisted of 23 women and 19 men. The most common tumor types were colorectal cancer (n=9), head and neck cancer (n=8), non-small cell lung cancer (NSCLC; n=6), and breast cancer (n=5) (Table 2). The median number of prior therapies was 4 (range, 1-10). Prior therapies are listed in Supplemental Table 1 (available online, in this article, at JNCCN.org).
Dose Escalation and Dose-Limiting Toxicity
Dose escalation and DLTs are summarized in Table 1. No DLTs were reported during the escalation phase; therefore, the highest dose in the escalation phase was designated as the MTD: intravenous bendamustine, 100 mg/m2 (days 1 and 2) and intravenous bevacizumab, 10 mg/kg (days 1 and 15).
Patient Pretreatment Characteristics
Toxicity
A total of 117 cycles were administered. The median number of cycles administered per patient was 2 (range, 1-8). Among 41 patients who completed cycle 1, 24 (59%) had no toxicity greater than grade 1. The most common toxicities of any grade were fatigue (n=22), nausea (n=14), anorexia (n=9), and thrombocytopenia (n=7) (Table 3). Grade 3 toxicities were fatigue (n=3), thrombocytopenia (n=1), neutropenia (n=3), hypertension (n=1), and decreased white blood cell count (n=1). Two patients experienced grade 4 neutropenia (n=2).
Toxicity Profile at the Recommended Dose
Of 42 treated patients, 32 (dose escalation phase, 6; expansion phase, 26) were treated at the maximum dose for a total of 91 cycles (median, 2.5 cycles; range, 1-8). Grade 3 toxicities at the maximum dose level were fatigue (n=3), neutropenia (n=3), thrombocytopenia (n=1), and hypertension (n=1); the only grade 4 adverse event was neutropenia (n=2).
Response
Of 42 patients, 38 were evaluable for response. The remaining 4 were not evaluable for the following reasons: consent withdrawal before restaging (n=1), loss of follow-up (n=1), toxicity (n=1), and still awaiting restaging (n=1). Of the 38 evaluable patients, 23 (61%) had stable disease, including 2 (5%) who had stable disease for 6 months or more (Figure 1).
Of the 32 patients treated at the MTD, 29 were evaluated for response (1 patient was lost to follow-up, 1 had toxicity, 1 did not reach restaging). Of these 29 patients, 18 (62%) had stable disease, including 2 (7%) who had stable disease for 6 months or more (5 of these 18 patients with stable disease are still receiving treatment on study).
Response by tumor type is summarized in Table 4. Of 9 patients with colorectal cancer, 6 (75%) had stable disease. Of 7 patients with head and neck tumors, 5 (71%) had stable disease, including 1 (14%) who had stable disease for 6 months or more. Of 5 evaluable patients with NSCLC, 3 (60%) had stable disease, including 1 (20%) who had stable disease for 6 months or more.
Among the 2 patients who had stable disease for 6 months or more, the first was a 65-year-old woman with adenoid cystic carcinoma of the head and neck who was diagnosed with this disease in August of 2000. Prior therapies were left neck dissection, T2 vertebrectomy, radiation therapy to T2, right hepatectomy for liver metastases, left neck dissection (level 2-5), T1-T2 laminectomy, T2 radiation therapy, lenalidomide and valproic acid (10 cycles), and erlotinib (3 cycles). This patient remained on therapy for 9 months (8 cycles). She was taken off study because of disease progression. The second patient was a 71-year-old man who was diagnosed with non-small cell lung adenocarcinoma in December of 2008. Prior therapies were right middle lobectomy; pemetrexed, carboplatin, and bevacizumab; erlotinib and c-Met inhibitor; and docetaxel and gemcitabine. He was treated on protocol for 7.1 months (5 cycles). He discontinued the treatment because of disease progression.
Adverse Events
Time to Progression
Of the 42 patients treated, 29 had disease progression. The median time to progression was 2.4 months (95% CI, 2.1-5.2) (Figure 2). Thirteen patients were censored at the time of this analysis, but they did not have evidence of progression (6 were still on study, 2 withdrew consent, 3 came off study because of toxicity, and 2 were lost to follow-up).
Survival
At the time of this analysis (January 2013), 17 of 42 patients had died. All deaths were because of progressive disease. The median overall survival duration was 9.7 months (95% CI, 5.2-not reached) (Figure 2).
Response by RECIST (Response Evaluation Criteria in Solid Tumors) of 38 evaluable patients treated with bendamustine and bevacizumab: changes from baseline in tumor measurements. Patients with new lesions and/or clinical progression were illustrated as 21% progression (asterisks).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0020
Response by RECIST (Response Evaluation Criteria in Solid Tumors) of 38 evaluable patients treated with bendamustine and bevacizumab: changes from baseline in tumor measurements. Patients with new lesions and/or clinical progression were illustrated as 21% progression (asterisks).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0020
Response by RECIST (Response Evaluation Criteria in Solid Tumors) of 38 evaluable patients treated with bendamustine and bevacizumab: changes from baseline in tumor measurements. Patients with new lesions and/or clinical progression were illustrated as 21% progression (asterisks).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0020
Discussion
This is the first clinical trial to investigate the combination of bendamustine and bevacizumab in patients with advanced solid tumors. Overall, this regimen was well tolerated. The most common toxicities were fatigue, nausea, thrombocytopenia, anorexia, rash, and constipation. Nine (21%) of 42 patients had grade 3 toxicities, which included fatigue, hypertension, neutropenia, and thrombocytopenia. Grade 4 neutropenia was noted in 2 patients, but none experienced any DLT. The toxicity profile of this regimen was consistent with that in a previous study, which reported that the most common toxicities were myelosuppression and gastrointestinal adverse effects.15
Clinical Outcomes by Tumor Type
Taking into consideration that patients had a median of 4 prior therapies, and that 6 patients are still receiving treatment on protocol, this combination regimen yielded disease stabilization in selected patients with various tumor types (Table 5). Overall, 2 patients, 1 with NSCLC and 1 with adenoid cystic carcinoma of the head and neck, had stable disease for 6 or more months. The latter patient was the 65-year-old woman whose disease had progressed after 10 cycles of lenalidomide and valproic acid, and subsequently after 3 cycles of erlotinib. Her disease stabilization with bendamustine and bevacizumab for 9 months indicated that this regimen may have antitumor activity in this disease.
Previous studies have demonstrated the activity of bendamustine in advanced breast cancer. In a phase II trial, bendamustine was given once weekly to patients with advanced breast cancer for 3 weeks; 13 (48%) of 27 evaluable patients experienced a response (5 having a partial response and 8 experiencing stable disease for >6 months). In another phase II study using bendamustine on days 1 and 2 of a 4-week treatment course, 27% of patients had complete or partial tumor responses.11 In the current study, only 5 patients with breast cancer were treated, and no objective response was noted, probably because they were heavily pretreated (median number of therapies, 6) (Supplemental Table 1, patients 15, 17, 28, 31, and 41; available online, in this article, at JNCCN.org). In previous studies of bendamustine in breast cancer, patients had received 0 to 2 prior lines of therapy.6,8
Overall and progression-free survivals (n=42).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0020
Overall and progression-free survivals (n=42).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0020
Overall and progression-free survivals (n=42).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0020
Characteristics of Treated Patients With Stable Disease
Interestingly, 3 of 4 evaluable patients with squamous cell carcinoma of the head and neck had stable disease, but no objective response was noted.16 In a phase I trial of radiochemotherapy with bendamustine in patients with recurrent squamous cell carcinoma of the head and neck, bendamustine was given at 80 to 120 mg/m2 on day 1, followed by radiotherapy. Of 13 patients, 8 (62%) achieved a partial response according to WHO criteria.3
In the present study, 1 of 4 evaluable patients with NSCLC had stable disease for 6 months or more (and 2 additional patients had stable disease). Single-agent bendamustine was previously reported to have antitumor activity in lung cancer. In a phase II study in patients with lung cancer, bendamustine given at 70 mg/m2 from day 1 to 4 resulted in a partial response (WHO criteria) in 9 (41%) of 22 patients with small cell lung cancer, but no responses were found in 21 patients with NSCLC treated on the same regimen.17
In addition, disease stabilization was noted in the present study in a variety of gastrointestinal tumors: esophageal cancer (n=1), pancreatic cancer (n=1), colorectal cancer (n=6), and small intestine adenocarcinoma (n=1). However, none of these patients had stable disease for 6 months or more (1 patient with colorectal cancer is still on study).
Conclusions
Results of the current trial demonstrate that the combination of bendamustine and bevacizumab is well tolerated. No DLT was noted in patients treated with intravenous bendamustine at 100 mg/m2 (days 1 and 2) and at 10 mg/kg (days 1 and 15), the maximum dose tested. Although the study is still ongoing, prolonged disease stabilization with bendamustine and bevacizumab was seen in patients with adenoid cystic carcinoma of the head and neck and NSCLC. The finding of disease stabilization in this heavily pretreated patient population suggests that this combination may have antitumor activity if used earlier in the disease course in selected tumor types.
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