| General information |
| Database: | DB01065 |
| Objective: | Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer |
| Authors: | Rachel M. Layman |
| Title: | Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer. |
| Journal: | Cancer Chemother Pharmacol. |
| Year: | 2013 |
| PMID: | 23430121 |
| Trial Design |
| Clinical Trial Id: | NCT00834678 |
| Agent: | erlotinib
|
| Target: | Epidermal growth factor receptor
|
| Cancer Type: | breast cancer |
| Cancer Subtype: | breast cancer |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | bendamustine and erlotinib |
| Study Type: | The study was a plannedphase I/II trial evaluating the combination of bendamustine and erlotinib for treatment of metastatic TNBC. however, a high degree of cumulative toxicity was observed after II 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. |
| Key Patients Feature: | more than and equal to 18 years with histologically confirmed metastatic TNBC, defined as ER and PR<10 % by immunohistochemistry (IHC), and Her2 nonamplified on fluorescence in situ hybridization (FISH), or 0-1+ by IHC, or +2 on IHC and nonamplified by FISH. No more than one prior chemotherapy regimen for metastatic breast cancer was permitted. All patients had measurable or evaluable disease. No concurrent antineoplastic treatments were administered; bisphosphonate therapy was permitted. Patients could not have symptomatic or progressive central nervous system (CNS) metastases or leptomeningeal disease. Patients with previously treated brain or CNS metastases were permitted provided that radiation was completed more than and equal to 8 weeks prior to study registration and they were not receiving steroids. |
| Biomarker: | triple negative(human epidermal growth factor receptor 2, ER, PR) |
| Biomark Analysis: | NA |
| Control Group Info: | 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. Level1: B 100mg/m2 IV; E 100mg po. Level 1: B 120mg/m2 IV; E 100mg po. Level 2: B 120mg/m2 IV; E 150mg po. |
| Treatment Info: | 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. Level1: B 100mg/m2 IV; E 100mg po. Level 1: B 120mg/m2 IV; E 100mg po. Level 2: B 120mg/m2 IV; E 150mg po. |
| Primary End Point: | 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 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. |
| Secondary End Point: | the objective response rate [ORR = complete response (CR) + partial response (PR)] and overall survival rate (OS). |
| Patients Number: | 11 |
| Trial Results |
| DLT_MTD: | NA |
| Objective Response Rate: | Two patients received all 6 cycles of treatment, 1 on dose level 1 and 1 on dose level 2. No patient attained complete response. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | All 11 study patients progressed within 7 months of beginning treatment, with a median time to progression of 3.7 months (95 % CI 1.7-5.5). |
| Median OS A vs. C: | Nine patients have expired with an estimated median overall survival of 10.8 months (95 % CI 3.6-13.1). Level 1: 7.6 months (95 % CI 3.6-10.8). Level 2: 12.8 months (95 % CI 2.4-NR) |
| Adverse Event(agent arm): | Common toxicities included fatigue, constitutional symptoms, and gastrointestinal symptoms. One patient (9 %) was hospitalized for grade 3 diarrhea and hypotension, and another patient developed grade 3 nausea; since these toxicities occurred after completion of cycle 1, they were not considered DLTs. Two patients (18 %) developed grade 1/2 hypersensitivity reactions with bendamustine administration, and 4 patients (36 %) had grade 1/2 erlotinibrelated rash. Hematologic toxicity was frequently observed during study therapy and included grade 3/4 leukopenia, neutropenia, lymphopenia, and anemia. Grade 3 thrombocytopenia occurred in 1 patient. Prolonged lymphopenia was observed and persisted after discontinuation of study therapy, for some patients more than 300 days (Fig. 1). Two patients (18 %) had grade 3 lymphopenia, and 8 (73 %) had grade 4 lymphopenia. CD4 counts were obtained in 7 of the 11 study patients. Of these, 1 (14 %) had grade 3 suppression of CD4 counts and 6 (86 %) had grade 4 depressed CD4 counts. Serious infections, including opportunistic infections with PCP, occurred in 4 (36 %) study patients and were deemed to be related to study therapyassociated lymphopenia. Three of these patients died as a result of infection. |
| Conclusions: | 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. |