Abstract

Abstract 1739

Background:

Triple negative breast cancers (TNBC) are sensitive to agents that cause DNA crosslinking and strand breaks and have high epidermal growth factor receptor (EGFR) expression and amplification. Therefore, we sought to determine the safety and efficacy of sequential combination therapy with bendamustine (B) and erlotinib (E). While lymphopenia was an expected toxicity, ≥ grade (gr) 3 infections were not anticipated and overall hematologic toxicity and infection rates were expected to be lower than that observed in treatment of hematologic malignancies.

Methods:

A phase I/II trial of B and E was performed in patients (pts) with metastatic TNBC with ECOG performance status ≤ 2 and ≤ 1 prior chemotherapy (CTX) for metastasis. Pts were required to have adequate bone marrow function and could not have active infection or history of HIV on anti-retroviral therapy. Pts received B on days 1, 2 and E on days 5 – 21 of a 28 day cycle. Phase I consisted of dose escalation of 2 sequential 3 patient cohorts: dose level 1, B 120 mg/m2 intravenous (IV) and E 100 mg oral (po), and dose level 2, B 120 mg/m2 IV and E 150 mg po. Dose limiting toxicity (DLT) was defined on toxicities related to the study therapy observed during cycle 1, including: absolute neutrophil count < 1 × 109/L for > 7 days despite use of white blood cell growth factor support, platelet count < 25 × 109/L for > 7 days, associated with bleeding, or < 10 × 109/L at any time, gr 4 rash, gr 3 diarrhea uncontrolled medically, gr 4 diarrhea, or other non-hematologic toxicity ≥ gr 3. Response was assessed every 2 cycles.

Results:

11 pts were treated, 5 on dose level 1 and 6 on dose level 2. One pt had DLT on dose level 2. However, infection-related serious adverse events (SAE) were observed in 4/11 (36%) pts during or after treatment was completed and possibly associated with prolonged lymphopenia (see Table). Within 1 month (mo) of completing 6 cycles Pt 1 was hospitalized for Pneumocystis carinii (PCP) pneumonia (PNA). Pt 5 completed 4 cycles, but received no further CTX; 2 mo later, she developed brain metastases treated with whole brain radiation and dexamethasone. At 3 mos after treatment she was hospitalized for dyspnea, hypoxia and PNA and received empiric PCP treatment, broad spectrum antibiotics and anti-fungal therapy. No diagnostic procedure was done. Within 1 mo of completion of 6 cycles, Pt 6 was hospitalized with PNA concerning for opportunistic pathogen. Pt 8 received 1 cycle, stopped study therapy for DLT (gr 3 fatigue, gr 3 dyspnea), and was hospitalized for progressive disease. She had persistent gr 4 lymphopenia when transitioned to hospice.

Conclusion:

Combination therapy with B and E causes excessive toxicity with severe and prolonged lymphopenia resulting in clinically significant depressed CD4 counts and opportunistic infections. The extent of lymphopenia is more severe than that observed in prior published clinical trials of B. We hypothesize that E may potentiate B-related lymphopenia. Since toxicity observed is potentially life threatening this combination should not be pursued further. Pts treated on the trial with persistent lymphopenia will have serial lymphocyte and CD4 counts performed and will be placed on prophylaxis for opportunistic infections. We suggest that future trials of B combinations in TNBC patients should take into account the potential for cumulative toxicity to lymphocytes and the need for monitoring patients during and after treatment. Updated results will be presented. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Cephalon, Inc.

PtDose LevelCyclesLymphopenia GradeCD4 Count (Time off Tx)Infections and OutcomeBest ResponseDuration of Follow-up After Tx (mo)
   During Tx After Tx     
14 (0.4 mo) PCP, herpes zoster, death - sepsis SD 4.7 
-1, 1 n/a n/a Death - PD PD none 
n/a Alive SD 5.3 
n/a Death - PD PD 3.3 
23 (4.2 mo) Disseminated zoster, PCP, PNA SD 3.6 
26 (0.7 mo) Herpes zoster, PNA – suspicious for opportunistic pathogen SD 0.9 
n/a 46 (Cycle 5) Alive PR none 
n/a DLT – gr 3 fatigue/dyspnea, death – progressive breast mass vs. infection PD 1.5 
n/a n/a Alive PD none 
10 n/a 64 (Cycle 2) Admission for gr 3 diarrhea during cycle 2 SD none 
11 n/a 7 (Cycle 2) Alive PD none 
PtDose LevelCyclesLymphopenia GradeCD4 Count (Time off Tx)Infections and OutcomeBest ResponseDuration of Follow-up After Tx (mo)
   During Tx After Tx     
14 (0.4 mo) PCP, herpes zoster, death - sepsis SD 4.7 
-1, 1 n/a n/a Death - PD PD none 
n/a Alive SD 5.3 
n/a Death - PD PD 3.3 
23 (4.2 mo) Disseminated zoster, PCP, PNA SD 3.6 
26 (0.7 mo) Herpes zoster, PNA – suspicious for opportunistic pathogen SD 0.9 
n/a 46 (Cycle 5) Alive PR none 
n/a DLT – gr 3 fatigue/dyspnea, death – progressive breast mass vs. infection PD 1.5 
n/a n/a Alive PD none 
10 n/a 64 (Cycle 2) Admission for gr 3 diarrhea during cycle 2 SD none 
11 n/a 7 (Cycle 2) Alive PD none 

SD (stable disease), PD (progressive disease), PR (partial response), Tx (study therapy)

Disclosures:

No relevant conflicts of interest to declare.

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Author notes

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Asterisk with author names denotes non-ASH members.