bortezomib and capecitabine in MBC
Abstract No: 755
Author(s): K. Possinger, W. Schippinger, P. Kiewe, W. Lange, J. Preiss, N. Niederle, P. Brossart, J. Papke, W. Freier, H. van de Velde, P. Schmid
Abstract:
Background: The ubiquitin-proteasome pathway plays an essential role in intracellular degradation of key regulatory proteins that can affect cell cycle, angiogenesis, adhesion and apoptosis. Bortezomib (VELCADE, PS-341) is a first-in class selective inhibitor of the 26S proteasome. The oral fluoropyrimidine capecitabine (Xeloda) has shown substantial activity in taxane and/or anthracycline pretreated patients with metastatic breast cancer. This phase I trial was initiated to determine the maximum tolerated doses (MTD), efficacy and tolerability of combined treatment with capecitabine and bortezomib in patients with metastatic breast cancer previously treated with taxanes and/or anthracyclines.
Methods: Patients were treated with bortezomib (1.0-1.3 mg/m2; days 1, 4, 8 & 11) and capecitabine (1500-2500 mg/m2, days 1-14) in 3-weeks intervals. Dose limiting toxicity (DLT) was defined as grade (G) 4 platelets, any G platelets with bleeding, G4 ANC >4 days, febrile neutropenia, any >G2 non-hematologic toxicity except alopecia, nausea or emesis, or any = G2 toxicity persisting over day 35.
Results: To date, 13 patients (median age 58 years; median number of metastatic sites 3; visceral metastases 85%; prior anthracycline therapy 100%; prior taxane therapy 85%) have been enrolled at 3 different dose levels (1.0 & 1500 (n=3), 1.0 & 2000 (n=6), 1.3 & 2000 (n=4)). Dose-limiting mucositis occurred in 1 patient at dose level 2. No further DLT has been reported so far, and the MTD has not been reached. Hematologic and non-hematological toxicities were generally mild to moderate. No grade 4 toxicity has occurred so far. To date, grade 3 toxicity has only been reported with mucositis in 1 patient. Most common side effects were myelosuppression, nausea, mucositis and asthenia. Preliminary data indicate efficacy in anthracycline and taxane pretreated patients
Conclusions: Combination of 1 mg/m2 bortezomib in combination with 1500 mg/m2 and 2000 mg/m2 has been well tolerated. Enrollment is ongoing at the 1.3 & 2000 dose level. Updated data will presented at the meeting. Preliminary data suggest good tolerability of the combination.
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Docetaxel/bortezomib in HRPC
Abstract No: 4735
Author(s): A. A. Meluch, D. S. Spigel, F. A. Greco, J. H. Barton, G. Messina, B. Gould, M. A. Rovito, J. D. Hainsworth
Abstract:
Background: Docetaxel (75mg/m2 every 3 weeks) is now standard first-line treatment for patients (pts) with HRPC. Bortezomib, a novel proteosome inhibitor, has shown single-agent activity in pts with refractory HRPC. In an effort to improve efficacy of treatment, we evaluated the combination of docetaxel and bortezomib in this multicenter, community-based phase II trial.
Methods: Eligibility criteria: metastatic HRPC; no previous chemotherapy; ECOG PS 0-2; measurable metastatic disease or rising PSA levels with osseous metastasis; serum creatinine < 2mg/dl; adequate hepatic and bone marrow function; informed consent. All patients received docetaxel 30mg/m2 IV and bortezomib 1.6mg/m2 IV both given on days 1, 8, 15 of each 28-day cycle. Bortezomib was administered 60 minutes after infusion of docetaxel. Pts were evaluated for response after 8 weeks of treatment; treatment continued in responding patients for 6 cycles.
Results: 30 of a planned 50 pts enrolled between 7/03 and 10/04: median age, 70 years; > 1 hormonal therapy, 70%; ECOG 0/1/2, 37%/60%/3%; osseous metastases only, 57%; osseous/soft tissue, 37%; soft tissue only, 7%; prior prostatectomy, 53%; prior localized XRT, 43%. At present, 22 pts have been evaluated for PSA response: PR 5 (23%), stable 12 (54%), progression 5 (23%). 2 of 11 pts with measurable disease (18%) had PR. With median followup of 4 months, 73% of pts remain progression-free. Grade 3/4 toxicities included: fatigue 1 (3%); nausea 1 (3%). 2 pts had grade 2 neuropathy. There were no treatment-related hospitalizations.
Conclusions: The regimen of docetaxel followed by bortezomib administered on a weekly basis has activity and acceptable toxicity in patients with metastatic HRPC. Updated efficacy results will be presented.
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NF-kB, ER and bortezomib in breast
Abstract No: 3169
Author(s): M. Tapia, J. Codony-Servat, J. Domingo-Domenech, B. Ferrer, P. Fernandez, J. Ross, M. Rolfe, P. Gascon, A. Rovira, J. Albanell
Abstract:
Background: We reported that bortezomib (Velcade), a proteasome inhibitor, suppressed cell growth and induced apoptosis to varying extents (IC50 range, 4nM to 1000 nM) in a panel of breast cancer cells (Codony et al, Proc AACR 2004). Notably, bortezomib effects were unrelated to EGFR/HER2 expression. Here we addressed whether estrogen receptor (ER) and I?B kinase (IKK)/nuclear factor (NF)-?B expression were related to bortezomib effects and also studied the relation between these two systems in breast cancer.
Methods: Proteasome activity was measured by fluorogenic proteasome assay. Expression of ER, IKKs (a, ß and NEMO), NF-?B (p65, p50, p52, RelB and c-Rel) and I?B (a, ß and e) subunits were assayed by WB. Ductal breast carcinoma in situ (DCIS) and infiltrating carcinoma specimens were assayed by IHC for ER and p65 expression. p65NF-?B nuclear staining was interpreted as an activated form of NF-?B.
Results: ER-positive cell lines were relatively bortezomib resistant (MCF7, IC50 100 nM; BT474, IC50 1000 nM) while ER-negative cells were generally more sensitive (SKBR3, IC50 4 nM; MDA-MB-468, IC50 4 nM; MDA-MB-231, IC50 6 nM; MDA-MB-453, IC50 100 nM). ER-positive cell lines expressed all the assayed proteins of the IKK/NF-?B system while ER-negative cell lines lacked one or more elements of IKK/NF-?B. ER-negative SK-BR-3 cells were 200-fold more sensitive than ER-positive BT-474 cells; however bortezomib inhibited proteasome activity similarly in both cells. SKBR3 cells overexpressed c-Rel and RelB while had low levels of IKK-a, I?B-a and I?B-ß. In clinical specimens, normal breast showed mainly weak p65NF-?B cytoplasmic staining and occasional faint nuclear staining. DCIS had strong and diffuse cytoplasmic p65NF-?B staining. Twelve out of 14 (86%) ER-negative infiltrating breast cancers exhibited p65NF-?B activation (i.e. nuclear staining), whereas only 2 out of 6 (33%) ER-positive specimens had p65NF-?B activation (p=0.037).
Conclusions: An ER-negative status, coupled with a dysregulated IKK/NF-?B system, were linked to a greater antitumor effect of bortezomib. In vivo data further establishs that ER-negative breast cancers have commonly activated NF-?B.
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Bortezomib/Gem/Cis Phase 1B
Abstract No: 2103
Author(s): J. Voortman, E. Smit, B. Kuenen, H. Pinedo, C. van Groeningen, A. van den Eertwegh, D. Brouwer, H. van de Velde, G. Giaccone
Abstract:
Background: Bortezomib (VELCADE) is a reversible and specific inhibitor of the 26S proteasome. Gem/Cis is an accepted first-line treatment for several advanced solid tumors. This trial aims to determine MTD and investigate tolerability of a weekly and biweekly schedule of bortezomib in combination with Gem/Cis.
Methods: Chemotherapy-naïve patients (KPS = 70 %) with advanced solid tumors for whom first-line Gem/Cis was considered an acceptable therapeutic option received Gem 1000 mg/m2 on days 1 and 8 and Cis 70 mg/m2 on day 1 of a 21-day cycle. In the weekly schedule, bortezomib was administered on days 1 and 8 at 1.0, 1.3, or 1.6 mg/m2. In the biweekly schedule, bortezomib was administered on days 1, 4, 8, and 11 at 0.70, 1.0, or 1.3 mg/m2.
Results: 13 pts have been treated for at least 1 cycle: 7 on the weekly schedule (3 pts at 1.0 mg/m2 and 4 pts at 1.3 mg/m2) and 6 on the biweekly schedule (3 pts at 0.7 mg/m2 and 3 pts at 1.0 mg/m2). Median age: 53 y (range, 35-71); male/female = 9/4; KPS < 80%/> 80% = 1/12; tumor types = 9 NSCLC, 2 bladder ca, 1 pancreas ca, 1 HCC. One first-cycle DLT (gr 4 neutropenia and thrombocytopenia, asymptomatic) was observed in 1 pt on the weekly schedule (1.3 mg/m2). The most common gr 3/4 toxicities were asymptomatic and reversible thrombocytopenia (gr 3: 5 pts; gr 4: 2 pts) and granulocytopenia (gr 3: 2 pts; gr 4: 2 pts).Treatment was generally well tolerated. No drug-induced sensory neuropathies have been observed. The addition of bortezomib did not appear to lead to additional nausea, vomiting, or diarrhea compared with Gem/Cis alone. One gr 2 ototoxicity was observed in a pt with prior cranial radiotherapy. One gr 4 left ventricular dysfunction was observed post-cycle 4 in a pt with no prior cardiologic history. In the first 10 pts evaluated, there were 4 partial responses (2 bladder, 2 NSCLC: 1 squamous, 1 large cell).
Conclusion: Dose escalation is ongoing. The combination has been well tolerated. Bortezomib may increase myelosuppression of Gem/Cis chemotherapy. Updated information will be presented at the meeting. |
