In December, , the commissioners of Seneca County established Clinton Township within the boundaries of the original surveyed Township 2 north, Range 15 east. Sine that time the sections east of the river have been governed "variously," sometimes by Hopewell and sometimes by Clinton; but, as related in the organic history, such mutations were stopped, and the township is now Clinton throughout its length and breadth. The Sandusky River enters the township in Section 30, just at the southwest corner of what is known as Springdale addition to Tiffin, flows northeast, and thence northwest to the great bend where it turns east, and thence flows north by east through the city and township, leaving Clinton in the northwest quarter of Section 5. The terrace is high above the water level, generally lying some distance back on each side, giving a large strip of valley or bottom lands and presenting a hundred beautiful scenes well worth the labor of a painter. Honey Creek, that old stream, sweetened by the name of pioneer memories, looks into the township in its extreme southwestern corner, while Rock Creek and its tributaries, the ancient mill-drivers, water the central southern sections, and, flowing in a tortuous course northwest, enters the Sandusky just east of Washington Street bridge.
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Improved therapies are needed for this aggressive malignancy.
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Improved therapies are needed for this aggressive malignancy. Dose-limiting toxicity DLT was determined by toxicities related to study therapy observed during cycle 1.
Eleven patients were treated, 5 on dose level 1 and 6 on dose level 2. One patient had DLT on dose level 2. Combination therapy with bendamustine and erlotinib causes excessive toxicity with severe, prolonged lymphopenia, depressed CD4 counts, and opportunistic infections and should not be pursued further. Future trials of bendamustine combinations in TNBC patients should account for potential cumulative lymphocyte toxicity necessitating patient monitoring during and after treatment.
In addition, treatment options for TNBC are limited compared with other breast cancer subtypes with no identified effective targeted therapies. In the United States, it is principally used for hematologic malignancies, while in Europe, it has also been used to treat solid tumors; several studies have revealed breast cancer treatment efficacy [ 5 — 8 ].
EGFR expression in breast cancer has been shown to be an independent poor prognostic factor [ 11 ]. Given that TNBCs are sensitive to DNA-damaging agents and have high EGFR expression and amplification, we performed a phase I clinical trial to assess the toxicity and tolerability of combination therapy with bendamustine and erlotinib. It was hypothesized that a sequential schedule would also limit the toxicity of the therapy.
Pharmacokinetic analyses were performed in multiple studies of erlotinib combined with chemotherapy revealing no significant interactions, supporting the hypothesis that the study drug combination would be safe and tolerable [ 17 , 21 ].
While significant lymphopenia and low CD4 counts have been observed with bendamustine, serious or opportunistic infections are uncommon [ 5 , 22 ]. Although lymphopenia was an expected toxicity, severe secondary infections were not anticipated in this study. However, a high degree of cumulative toxicity was observed after 11 patients were enrolled and treated on the Phase I section of the study. Therefore, the study was terminated, and the Phase II study was not performed. All patients gave informed consent prior to study treatment in accordance with the Declaration of Helsinki.
The study was registered at www. All patients had measurable or evaluable disease. No concurrent anti-neoplastic treatments were administered; bisphosphonate therapy was permitted. Patients could not have symptomatic or progressive central nervous system CNS metastases or leptomeningeal disease.
Patients were able to take oral medications and without medical problems or prior surgeries that may interfere with the absorption of oral medications. Patients with prior treatment with bendamustine or EGFR-directed therapy, known hypersensitivity to bendamustine, mannitol, or erlotinib, uncontrolled intercurrent illness that may interfere with administration of study therapy, active infection requiring systemic therapy, or HIV infection requiring anti-retroviral therapy were excluded from the study.
Pregnant and nursing women were ineligible due to the increased risk of fetal harm, including fetal death, from study therapy.
All patients of reproductive potential agreed to use an effective barrier contraceptive method or abstinence. All patients were informed of the investigational nature of this study and signed written informed consent prior to enrollment. Bendamustine was administered intravenously over 30 min on days 1 and 2 of each cycle. Erlotinib was taken by mouth once per day on days 5—21 17 days. Each treatment cycle was 28 days. Study drug doses were determined by the dose escalation scheme shown in Table 1.
No intra-patient dose escalations or re-escalations were permitted. Maintenance therapy consisted of mg of continuous daily erlotinib.
Patients were administered pro-phylactic anti-emetics prior to bendamustine administration and prescribed rescue anti-emetics. Pre-medications for prevention of hypersensitivity reactions were only administered to patients who experienced hypersensitivity to bendamustine.
For facilitation and monitoring of treatment compliance, patients were provided with a treatment calendar and log on day 1 of each cycle. Patients were required to bring their treatment logs and erlotinib pill bottles from the prior cycle to the follow-up appointment on day 1 of each cycle.
The study coordinator reviewed the log and performed pill counts. Patients were assessed for treatment response by imaging studies and physical examination every 2 cycles. The primary endpoint of the Phase I study was to determine the appropriate Phase II dose of bendamustine and erlotinib through assessment of treatment toxicity during the first cycle of treatment.
The dose escalation scheme is shown in Table 1. All patients in each cohort were observed for the first cycle of treatment 28 days prior to dose escalation or expansion of a dose level. The Phase II dose was defined as the highest dose tested in which fewer than 2 of 6 patients experienced DLT attributable to the study drug s. The primary endpoint of the planned Phase II section of the study was to determine the study therapy efficacy in patients with metastatic TNBC using progression-free survival PFS defined as the time from first treatment date until the documented time of disease progression or death.
For the time-to-event endpoints, estimates were obtained by the method of Kaplan—Meier. The median age was 53 years 38— Patient characteristics are summarized in Table 2. No patient treated on dose level 1 experienced DLT. One of the 6 patients treated on dose level 2 had DLT with grade 3 fatigue and grade 3 dyspnea during her 1st treatment cycle with no further therapy given.
She was hospitalized for progression of her breast mass with superimposed infection in the setting of grade 4 lymphopenia and was transitioned to hospice care. However, the degree of cumulative toxicities observed prompted early closure of the study and is described below. Common toxicities included fatigue, constitutional symptoms, and gastrointestinal symptoms Table 3.
Grade 3 thrombocytopenia occurred in 1 patient. CD4 counts were obtained in 7 of the 11 study patients. Lymphocyte counts over time. Individual profiles light gray lines with average trend line solid black of lymphocyte counts. Reference lines dotted black are at 1. Created using Microsoft PowerPoint. CD4 counts over time. Individual profiles light gray lines with average trend line solid black of CD4 counts. Three of these patients died as a result of infection.
Serious adverse events SAEs are summarized in Table 4. Efficacy data are summarized in Table 2. Patients received a median of 2 cycles of study therapy range 1—6. Two patients received all six cycles of treatment, one on dose level 1 and one on dose level 2. No patient attained complete response. All 11 study patients progressed within 7 months of beginning treatment, with a median time to progression of 3.
Nine patients have expired with an estimated median overall survival of Two patients who were treated on dose level 2 are currently alive at Although only 1 DLT was observed during the first cycle of therapy, high rates of severe, prolonged lymphopenia resulting in serious opportunistic infections occurred with additional cycles and persisted even long after treatment discontinuation.
It is likely that severely depressed CD4 counts contributed to the high rate of serious infections. While it is widely accepted that chemotherapy is associated with myelosuppression, lymphopenia, and infectious complications, the high incidence and severity observed on this study was unexpected. In the United States, bendamustine is primarily used for treatment of hematologic malignancies. Phase II studies in previously treated patients with hematologic malignancies have revealed higher rates of infections [ 24 , 25 ].
However, unexpectedly higher rates of lymphopenia and serious infections were observed in patients with breast cancer with our study therapy.
Lymphopenia and opportunistic infections have also been reported in patients with solid tumors treated with bendamustine, but without the high infectious complication rates that we observed. However, cases of opportunistic infections, including PCP, associated with bendamustine treatment in metastatic breast cancer have been reported [ 27 ].
We hypothesize that unexpectedly high rates of lymphopenia and opportunistic infections observed in our study were related to treatment with erlotinib that intensified expected bendamustine toxicity.
Pharmacokinetic PK analyses have been performed in multiple studies with erlotinib combined with chemotherapy revealing no significant PK interaction between erlotinib and chemotherapeutic agents [ 17 , 21 , 29 ]. Since PK analysis was not performed in our study, while unlikely, it is possible that PK interaction contributed to toxicity. The lymphopenia observed in our study is especially concerning because of the prolonged duration resulting in late serious adverse events.
Capture of late toxicity is a weakness of classical Phase I study designs, which typically base DLT on the first 1 or 2 cycles of therapy. The decision to terminate the trial was based on delayed SAEs and the prolonged duration of lymphopenia placing patients at high risk of infection over time.
Many study patients were treated with subsequent chemotherapy following study treatment despite persistent lymphopenia. We continued to follow lymphocyte and CD4 counts, and it is possible that these therapies contributed to lack of lymphocyte recovery. While infectious prophylaxis is commonly administered in hematologic malignancies, it is less frequent in solid tumors.
Prophylaxis in solid tumor patients should also be considered when severe, prolonged lymphopenia is encountered. The efficacy of the study therapy was disappointing with only 1 patient attaining a partial response. TNBC has historically been difficult to treat, likely because of its inherent genetic instability leading to rapid development of resistance [ 10 ]. The cancers treated on this trial may have had low rates of EGFR expression.
Correlative studies, including assessment of EGFR expression and gene amplification, were planned, but not performed because of early trial termination. In conclusion, the combination of bendamustine and erlotinib in TNBC patients is not feasible as it is associated with an unacceptable rate of significant lymphopenia leading to life-threatening infections.
The greater severity and duration of lymphopenia than previously observed may relate to potentiation of bendamustine-related lymphopenia by erlotinib. Future trials of bendamustine combinations in TNBC patients should account for potential cumulative toxicity to lymphocytes requiring patient monitoring during and following treatment. Study supply of bendamustine was supplied by Cephalon, Inc.
Conflict of interest The authors declare that they have no conflict of interest. Ethical standards The clinical trial described in this manuscript complies with the current laws of the country in which it was performed USA.
Rachel M. Amy S. Maryam B.