Phase II clinical trial of ixabepilone in metastatic breast cancer (MBC) patients previously untreated with taxanes

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 651-651 ◽  
Author(s):  
N. Denduluri ◽  
J. J. Lee ◽  
J. M. Walshe ◽  
S. X. Yang ◽  
U. Vatas ◽  
...  
Keyword(s):  
Imaging System ◽  
Metastatic Breast ◽  
Sensory Neuropathy ◽  
Hematologic Toxicity ◽  
Motor Neuropathy ◽  
P53 Expression ◽  
P53 Antibodies ◽  
Best Response ◽  
Duration Of Response ◽  
Grade 3

651 Background: Ixabepilone, an epothilone B analog, stabilizes microtubules by binding to tubulin. The response rate (RR) in taxane-pretreated patients at our institution was 22%. Methods: Patients (pts) were eligible if they had MBC previously untreated with taxanes and measurable disease by RECIST criteria. Ixabepilone was given at 6mg/m2/d intravenously days 1–5 every 3 weeks until unacceptable toxicity or disease progression. Primary objectives included RR and toxicity. Pts underwent pre and/or post treatment tumor biopsies for correlative studies. Acetylated α-tubulin, Tau-1, and p53 were stained with anti-acetylated α-tubulin, anti-Tau-1, and anti-p53 antibodies in samples from 13 pts. Staining was scored quantitatively using the Automated Cellular Imaging System. Results: Twenty-three pts received 197 cycles (C). Median of 7C (range 2–22) per pt were administered. Median age was 55 (range 22–79). Seven pts received 1 prior metastatic chemotherapy regimen. Ten of 23 or 43% (exact 95% confidence interval: 23.2% to 65.5%) pts had partial responses (PR), 9 (39%) stable disease (SD) (2 unconfirmed PRs), and 4 (17%) progressive disease (PD). Median time to progression was 5.3 months; median duration of response was 5.4 months from date of best response. Four pts required dose reductions for neutropenia, neuropathy or fatigue. Grade 3/4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), infection without neutropenia (9%), motor neuropathy (4%), and muscle weakness (4%). No grade 3/4 sensory neuropathy was seen, but 35% and 13% of pts had grades 1 and 2 neuropathy respectively. Median acetylated α-tubulin at baseline was 0.2 in responders and 17.6 in non-responders (p=0.069). There were no differences in response according to Tau-1 or p53 expression at baseline. Conclusion: Ixabepilone is an effective treatment for MBC with a 43% RR in 23 pts previously untreated with taxanes. There was minimal hematologic toxicity and no grade 3 sensory neuropathy. The use of baseline level of acetylated α-tubulin to predict response may warrant further study. No significant financial relationships to disclose.

Phase II Trial of Ixabepilone, an Epothilone B Analog, in Patients With Metastatic Breast Cancer Previously Untreated With Taxanes

2007 ◽  
Vol 25 (23) ◽  
pp. 3421-3427 ◽  
Author(s):  
Neelima Denduluri ◽  
Jennifer A. Low ◽  
James J. Lee ◽  
Arlene W. Berman ◽  
Janice M. Walshe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Metastatic Breast ◽  
Sensory Neuropathy ◽  
Motor Neuropathy ◽  
P53 Expression ◽  
Epothilone B ◽  
Grade 3 ◽  
Experienced Grade

Purpose Ixabepilone is an epothilone B analog that binds to microtubules and results in microtubule stabilization and mitotic arrest. Ixabepilone was evaluated for efficacy and safety in a phase II clinical trial for women with metastatic breast cancer. Patients and Methods Patients were eligible if they had not previously received treatment with a taxane and had measurable metastatic breast cancer. Ixabepilone was administered at 6 mg/m2/d intravenously days 1 through 5 every 3 weeks until unacceptable toxicity or disease progression. Patients underwent pretreatment and post-treatment tumor biopsies, and tissues were analyzed for acetylated α-tubulin, tau-1, and p53 expression when possible. Results Twenty-three patients received 210 cycles with a median of eight cycles (range, two to 22 cycles) per patient. Thirteen patients (57%; exact 95% CI, 34.5% to 76.8%) had partial responses, six patients (26%) had stable disease, and four patients (17%) had progressive disease. Median time to progression and duration of response were 5.5 and 5.6 months, respectively. Four patients required dose reductions for neutropenia, neuropathy, or fatigue. Grade 3 or 4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), and motor neuropathy (4%). Thirty-nine percent of patients experienced grade 1, 13% experienced grade 2, and none experienced grade 3/4 sensory neuropathy. The six patients with paired biopsies all had increases in tumor α-tubulin acetylation after treatment. Baseline or cycle 2 acetylated α-tubulin, tau-1, or p53 expression did not correlate with clinical response. Conclusion Women with metastatic breast cancer previously untreated with taxanes have a meaningful durable response to single-agent ixabepilone therapy. Minimal hematologic toxicity and no grade 3 sensory neuropathy were noted.

Bortezomib Plus Thalidomide Treatment of Newly Diagnosed Patients with Multiple Myeloma - Efficacy and Neurotoxicity: Results of a Multicenter Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3600-3600 ◽  
Author(s):  
Shilun Chen ◽  
Bin Jiang ◽  
Lugui Qiu ◽  
Li Yu ◽  
Yuping Zhong ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Peripheral Neuropathy ◽  
Tumor Lysis Syndrome ◽  
Sensory Neuropathy ◽  
Staging System ◽  
Motor Neuropathy ◽  
Newly Diagnosed ◽  
Best Response ◽  
Grade 3

Abstract Introduction: The standard first-line treatment for patients with multiple myeloma (MM) has been melphalan plus prednisone (MP). However, complete responses (CRs) are rare. As single agents, bortezomib (V) and thalidomide (T) achieved responses in <50% of newly diagnosed MM patients, whereas combinations of V or T with dexamethasone (D), designated VD and TD, demonstrated response rates of 85% and 63%, respectively. We examined the anti-MM activity and neurotoxicity of VT, a steroid-free regimen. Methods: In this phase II study in 30 untreated MM patients, bortezomib 1.3mg/m2 was administered intravenously on days 1, 4, 8, and 11 of a 21-day cycle for up to 8 cycles. Thalidomide 100mg was administered orally at bedtime on days 1 through 21 for up to 8 cycles. Response was assessed with European Group for Blood and Marrow Transplantation (EBMT) criteria. Newly diagnosed MM patients (including Phase IB, II and III according to the International Myeloma Working Group [IMWG] criteria) were eligible if they were 18–80 years of age, had anticipated life expectancy >6 months, and had an age-adjusted creatinine clearance of ≥15 mL/min within 14 days before enrollment. Results: Median age was 56.6 years (range, 30–77), albumin was <3.5g/dL in 18 patients (60%), b2-microglobulin was ≥3.5mg/L in 20 patients (66%), and hemoglobin was ≥100g/L only in 9 patients (30%). International Staging System I/II/III were 3%/50%/47% respectively; all patients had stage III MM according to the IMWG criteria. There were 26 patients (87%) who completed at least two cycles of therapy and were evaluable for response; 18 (60%) completed the planned 8 cycles. Treatment was discontinued in 4 patients due to renal failure. Rates of overall response (ORR), CR, near CR (nCR), partial response (PR), and stable disease (SD) are summarized in Table 1. Median time to response was 35.6 days (range, 7–60). The best response occurred within the first 4 cycles in 96% of patients. Side effects were predictable and manageable. The main toxicities were hematologic (53%), fever (47%), gastrointestinal (40%), fatigue (37%), and peripheral neuropathy (36%). Grade 3 nonhematologic adverse events included 4 patients (15%) with renal failure associated with tumor lysis syndrome, 1 patient (4%) with peripheral sensory neuropathy and motor neuropathy that improved with VT dose reductions, and 1 patient (4%) with hypotension. One patient (4%) experienced Grade 4 thrombocytopenia. One patient (4%) died due to acute renal failure. No deep vein thromboses occurred in this study, compared with a reported incidence of thromboembolic events between 15–20% with TD-containing regimens. Conclusions: VT produced very high ORR and CR in the treatment of newly diagnosed MM patients. No DVTs occurred with this steroid-free combination without any use of anticoagulant drugs. The rate of peripheral neuropathy was lower than expected. This is a very effective regimen with manageable toxicity. Table 1. Response of Newly Diagnosed MM to Bortezomib 1.3mg/m2 and Thalidomide 100mg completed cycles N ORR n (%) CR n (%) nCR n (%) PR n (%) SD n (%) 2 cycles 26 25 (96) 12 (46) 4 (15) 9 (35) 1 (4) 4 cycles 21 20 (95) 6 (29) 7 (33) 7 (33) 0 (0) 8 cycles 18 16 (89) 5 (28) 4 (22) 7 (39) 2 (11)

Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers.

1998 ◽  
Vol 16 (8) ◽  
pp. 2739-2744 ◽  
Author(s):  
Y Bécouarn ◽  
M Ychou ◽  
M Ducreux ◽  
C Borel ◽  
F Bertheault-Cvitkovic ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Sensory Neuropathy ◽  
Progression Free Survival ◽  
Free Survival ◽  
Duration Of Response ◽  
Grade 3 ◽  
Colorectal Cancer Patients ◽  
Peripheral Sensory

PURPOSE To evaluate the objective tumor response rate and safety profile of oxaliplatin when administered to patients with previously untreated metastatic colorectal adenocarcinoma. PATIENTS AND METHODS A total of 39 patients were entered onto this phase II trial. One patient was excluded for having had a second cancer, so the study was based on 38 patients. Patients were treated with oxaliplatin 130 mg/m2 as a 2-hour infusion on day 1, every 21 days. Patients were assessed for response every three courses. All clinical and radiologic data were reviewed by an external panel of experts, with their assessment being considered definitive. RESULTS Nine partial responses (PRs) were observed (response rate, 24.3%; 95% confidence interval, 11.8% to 41.2%). The median duration of response was 216+ days. Fifteen patients (40.5%) had stable disease and 13 (35.2%) had progressive disease. The median progression-free survival time for all patients was 126+ days (range, 21 to 447+). The main toxicity was peripheral sensory neuropathy. Grade 3 neurotoxicity (National Cancer Institute common toxicity criteria [NCI-CTC]) was reported in 13%. Hematologic and gastrointestinal toxicities were mild. The incidence of grade 3 neutropenia was 5.2%, while that of grade 3 or 4 thrombopenia was 7.9%. Vomiting (grade 3 or 4) occurred in 7.9% of patients and grade 3 diarrhea in 2.6%. CONCLUSION This phase II study provides clear evidence of the safety and efficacy of oxaliplatin monotherapy at this dose and schedule in patients with previously untreated metastatic colorectal carcinoma.

Safety, Tolerability, and Pharmacology of Bortezomib in Cancer Patients with Renal Failure Requiring Dialysis: Results from a Prospective Phase 1 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3477-3477 ◽  
Author(s):  
Daniel Mulkerin ◽  
Scot Remick ◽  
Chris Takimoto ◽  
Percy Ivy ◽  
Michael Karol ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Dose Escalation ◽  
Severe Renal Impairment ◽  
Phase 1 ◽  
Case Series ◽  
Sensory Neuropathy ◽  
Red Blood Cell Transfusion ◽  
Hematologic Toxicity ◽  
Severe Impairment ◽  
Grade 3

Abstract Background: Bortezomib (btz; VELCADE®) is a specific, reversible proteasome inhibitor approved for the treatment of patients (pts) with multiple myeloma (MM) and mantle cell lymphoma following at least one prior therapy. Retrospective analyses of phase 2/3 studies and case series have shown btz alone or in combination is active and tolerable in MM pts with various degrees of renal impairment, including pts on dialysis. We previously reported clinical and pharmacologic data from the first prospective, dose-escalating study of btz in adult cancer pts with various degrees of renal impairment (ASCO 2006, abstract 2032). Here we present updated safety and tolerability data for dialysis-dependent patients. Methods: Pts with advanced cancer were stratified by renal function into controls and four groups ranging from mild impairment to dialysis dependence. Pts received btz on d 1, 4, 8, and 11 of a 21-day cycle; dose escalation (0.7, 1.0, 1.3 mg/m2) proceeded in cohorts of 3 pts based on dose limiting toxicities (DLTs) observed in cycle 1. Blood samples were taken on d 1 and 8 of cycle 1 for pharmacokinetic (PK) and pharmacodynamic (PD) analysis. Adverse events (AEs) were evaluated using NCI CTC v2.0. DLTs were grade 4 neutropenia for ≥7 d or neutropenic fever, grade 4 thrombocytopenia for ≥7 d, grade 4 hemoglobin for ≥7 d, and grade ≥3 non-hematologic toxicity. Results: To date, 59 pts have been treated, including 16 controls, 34 pts with mild-to-severe impairment, and 9 dialysis pts. Among dialysis pts: 3 were treated at 0.7, 2 at 1.0, and 4 at 1.3 mg/m2; median age was 62 y (range: 42–74); tumor types were MM (n=4), follicular lymphoma (n=1), and solid tumors (n=4). Median number of treatment cycles received was 2 in controls and across renal impairment groups. Dialysis pts received a median of 2 treatment cycles (range: 1–4); 1 pt remains on therapy. Dose escalation was well tolerated, with no DLTs, in pts with mild-to-severe renal impairment. There were no DLTs in cycle 1 in dialysis pts. Toxicities were generally mild in all groups. Among dialysis pts, no unexpected toxicities were seen. One grade 4 treatment-related AE (elevated creatinine) has been reported; grade 3 treatment-related AEs include platelets/thrombocytopenia (3 pts), diarrhea, hemoglobin, leukopenia, lymphopenia, packed red blood cell transfusion, sensory neuropathy, and vomiting (1 pt each). The overall AE profile in dialysis pts was similar to that in controls and in pts with mild-to-severe impairment, although renal and metabolic AEs appeared more common in dialysis pts. Conclusions: Btz at doses up to 1.3 mg/m2 on this schedule was well tolerated in pts with advanced malignancies with mild-to-severe renal impairment and dialysis dependence. PK and PD analyses for dialysis pts treated at 1.3 mg/m2 will be reported. Btz is a viable treatment option for pts requiring dialysis.

Preliminary Results of a Phase II Trial of Panobinostat (LBH589) In Refractory Myelodysplastic Syndromes (MDS) Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4015-4015 ◽  
Author(s):  
Ian W. Flinn ◽  
Evan Lang ◽  
Eric Raefsky ◽  
Ralph Boccia ◽  
Inés M. Macias-Pérez ◽  
...  
Keyword(s):  
Phase Ii ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Primary Objective ◽  
Hematologic Toxicity ◽  
Combination Regimen ◽  
White Males ◽  
Duration Of Response ◽  
Grade 3 ◽  
Ecog Ps

Abstract Abstract 4015 Background: MDS represents a heterogeneous group of clonal myeloid stem cell disorders with a propensity for clonal evolution with resultant progressive bone marrow failure and transformation to acute myeloid leukemia. These disorders are incurable with conventional therapy and are usually treated with hypomethylating agents and supportive care. Panobinostat (PAN, LBH589) is a pan deacetylase (DAC) inhibitor that targets a variety of tumor types, including acute and chronic leukemia, by inhibiting differentiation and inducing apoptosis. Method: This single-arm multicenter Phase II study was designed with the primary objective of assessing the overall response rate (CR, marrow CR + PR) of PAN in patients (pts) with relapsed or refractory MDS. Secondary endpoints include time-to-progression, hematologic improvement, duration of response, time-to-treatment failure, and survival. Eligible pts had histologically documented MDS, previous failure on hypomethylating (azacitidine or decitabine) therapy, no prior treatment with DAC inhibitors, no active CNS disease, and adequate organ function. Pts with up to and including 30% blasts were eligible to enroll; pts with 5q- abnormalities must have failed lenalidomide. PAN (30mg PO) was administered three times a week on Monday, Wednesday and Friday. Pts were treated for the first 21 days of a 28 day cycle. If no grade 3/4 toxicity occurred in the first 2 cycles, dose escalation (40mg PO M/W/F) would proceed. Results: The original protocol for this trial specified a dose of 20mg PAN M/W/F, which was generally well-tolerated. Accumulating data from other studies suggested that higher doses of PAN were more efficacious without a significant increase in toxicity. The dose of PAN was thus increased to 30mg M/W/F in the amended protocol. To date, 16 pts have been enrolled at 30mg; this analysis is based on 10 pts enrolled from October 2008 through December 2009; all pts in this group are ECOG PS 0 white males (median age 77years [range 62–86]). The most common non hematologic adverse events were: anorexia (5 G1/2) fatigue (8 G1/2 and 1 G3) and nausea (3 G1/2). Hematologic toxicity was assessed on an ongoing basis: 5 pts experienced G3/4 anemia; 8 G3/4 thrombocytopenia; 6 G3/4 leukopenia, and 7 G3/4 neutropenia. Response was assessed after 2 cycles. Seven of 10 pts had stable disease; 2 pts had progressive disease; 1 pt was unevaluable due to coming off study prior to evaluation. 2 of the 10pts were escalated to the 40mg dose level. There were 6 SAEs (among 3 pts) for: G3 febrile neutropenia (2), G3 neutropenia (1), G3 pain (1), G4 pneumonia (1) and G4 thrombocytopenia (1). Nine pts are currently alive with a median follow-up of 69 weeks (range 28–90). Conclusions: Collectively, these data suggest that PAN is generally well-tolerated in pts with refractory MDS. Continued investigation of this novel agent is warranted, and future studies should evaluate its safety and efficacy when used as part of a combination regimen. Disclosures: Flinn: Novartis: Research Funding.

Phase II Trial Of Bortezomib In Combination With Fractionated Cyclophosphamide and Rituximab (BCR) For Relapsed/Refractory Mantle Cell Lymphoma (MCL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5122-5122
Author(s):  
Jorge E Romaguera ◽  
Michelle A. Fanale ◽  
Felipe Samaniego ◽  
Luis E Fayad ◽  
Fredrick B Hagemeister ◽  
...  
Keyword(s):  
Research Funding ◽  
Single Agent ◽  
Sensory Neuropathy ◽  
Mental Condition ◽  
Published Data ◽  
Hematologic Toxicity ◽  
Synergistic Activity ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Grade 3

Abstract Background MCL is incurable. Bortezomib has shown single agent activity of 33% in relapsed MCL. Pre-clinical published data shows additive/synergistic activity of BCR. Materials and methods   MCL pts  ages 18 through 85, with adequate organ function unless due to lymphoma, and without HIV-1 infection or any significant medical/mental condition, were treated under an IRB-approved study, consisting of Bortezomib  1.3 mg/m2 IV given on days 1, 4, 8, and 11 (dose on day 11 omitted early on study); fractionated cyclophosphamide 300 mg/m2 q 12 hrs days 1, 2, and 3, and rituximab 375 mg/m2 day 1. Cycles were repeated every 21 days for a total of 6 or less if a response was achieved and patient qualified for SCT. Results From  9/2009 to 8/2012, twenty-one patients were entered in the study. Their clinical characteristics are as follows: Overall response (OR)/CR rates:  71%/53%. One patient had stable disease and 4 patients progressed. With a Median follow-up of 31 months, the median TTP was 15.8 months and the median OS was 36.4 months. Toxicity was mainly hematologic. With 77 cycles given, grade 3 anemia was 5%, grade 3 / 4 neutropenia was 16%/9%, and grade 3 / 4 thrombocytopenia was 19%/8%. Early in the study, day 11 dose of bortezomib was omitted because of low counts by day 11 of cycle. Non-hematologic toxicity included grade 3 neutropenic fever (1%), and grade 3 fatigue (3%). No patient developed sensory neuropathy grade ¾. Conclusion Bortezomib can be safely combined with cyclophosphamide and rituximab and results in high rates of overall/complete responses in patients with relapsed/refractory MCL. Disclosures: Off Label Use: Gemcitabine, fludarabine and melphalan for transplant conditioning. Younes:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel expenses Other.

Combination of paclitaxel and two schedules of gefitinib in patients with metastatic breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10599-10599 ◽  
Author(s):  
S. Cresta ◽  
A. Perotti ◽  
L. Merlini ◽  
M. Mansutti ◽  
A. Marchianã ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Antitumor Activity ◽  
Metastatic Breast ◽  
Sensory Neuropathy ◽  
Response Duration ◽  
Skin Toxicity ◽  
Median Response ◽  
Grade 3

10599 Background: The epidermal growth factor receptor (EGFR) may be overexpressed in breast cancer. Inhibition of EGFR signaling by gefitinib (Iressa) enhances the in vitro antitumor activity of many cytotoxic drugs including paclitaxel. Methods: In this phase II study patients (pts) with measurable metastatic breast cancer and maximum prior exposure to two chemotherapies were randomized to paclitaxel (100 mg/m2 on days 1, 8 q21) and continuous gefitinib, 250 mg daily for 21 days (arm A); or paclitaxel (100 mg/m2 on days 8, 15 q21) with gefitinib 250 mg daily from day 1 to 15 (arm B). Therapy continued for at least 4 cycles after best response. After 6 cycles, responding pts continued with gefitinib monotherapy until progression or unacceptable toxicity. Results: 16 pts in arm A and 17 in arm B were enrolled; 25 had visceral disease (12 in arm A and 13 in arm B). Median age was 53 years (range 29–70). All but one pt received prior anthracyclines and 9 also prior taxanes. Overall 17 pts responded to therapy (intent to treat analysis; arm A: 62.5%, 95% CI: 35.4–84.8%; arm B: 41.2%, 95% CI: 18.4–67.1%). Disease control (CR+PR+SD) was achieved in 81.3% of pts in arm A and 76.5% in arm B, with 10 and 6 pts who continued with gefitinib monotherapy after completing the combination schedule. Median time to progression was 250 (arm A) and 204 days (arm B), while median response duration was 212 (arm A) and 285 days (arm B). Tolerability was good with either schedule of gefitinib. Diarrhea was frequent (68.8% and 64.7%) and of grade 3–4 severity in 6% of pts in arm A and in arm B. Grade 3–4 neutropenia affected 6% and 12% of pts respectively, and 6% of pts in both arms had a grade 3–4 increase of AST and ALT. Other grade 1–2 adverse events included acneiform rash (100% in arm A and 58.8% in arm B), sensory neuropathy (68.8% and 58.8%), anemia (50.0% and 52.9%), neutropenia (25.0% and 17.6%) and myalgia (37.5% and 41.2%). Conclusions: The combination of paclitaxel with gefitinib given continuously or for 2 out of every 3 weeks is feasible and well tolerated. The discontinuous schedule caused less skin toxicity. The good antitumor activity deserves further studies to identify sensitive subgroups and mechanisms of sensitivity. IRESSA is a trademark of the AstraZeneca group of companies. [Table: see text]

Multicenter study of weekly trastuzumab, paclitaxel and carboplatin followed by a week of rest every 28 days in patients with HER2+ metastatic breast cancer (MBC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1083-1083
Author(s):  
M. Ruiz ◽  
J. Salvador ◽  
J. Bayo ◽  
M. Lomas ◽  
A. Moreno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Objective Response ◽  
Neoadjuvant Treatment ◽  
Growth Control ◽  
Metastatic Breast ◽  
Tolerability Profile ◽  
Combination Methods ◽  
Duration Of Response ◽  
Grade 3

1083 Background: The addition of Carboplatin to Trastuzumab and Paclitaxel improves the efficacy in HER2+ metastatic breast cancer (MBC). We have conducted a multicenter Phase II study to investigate the efficacy and safety of this combination given weekly × 3 followed by 1 week of rest. Primary endpoint was objective response rate and secondary endpoints were time to progression, overall survival and to study the toxicity profile of the combination. Methods: Between August 2003 and April 2006, 40 patients with HER2+ MBC (IHC 3+ or FISH+) have been included in the study. Pats received Trastuzumab (loading dose of 4 mg/kg/wk and 2 mg/kg/d following wks), Paclitaxel (80 mg/m2) and Carboplatin (AUC 2) all given weekly × 3 followed by 1 week of rest. Treatment was given until disease progression or unacceptable toxicity. Results: 40 pats had baseline data available. Median age was 54 yrs (range 29–75). 38 (95%) pats received prior adjuvant or neoadjuvant treatment. 11 (27,5%) pats have received one prior CT line for metastatic disease. 87,5% pats had PS 0 or 1 at study entry. Disease sites were liver 16 (40%), bone 12 (30%), lymph nodes 13 (32,5%) and lung 8 (20%). 19 (47,5%) had = 2 lesions. 97,5% had measurable disease. 36 pats have been evaluated for response: 11 CR (31%, 95% CI: 15–46%), 11 PR (31%, 15- 36%), 9 SD (25%, 9–36%), 5 PD (14%, 2–26%) and 4 NE resulting in an ORR of 61% (95% CI: 45–77%) and tumor growth control rate (RR+SD) of 86% of patients (95% CI: 75–97%). Median TTP was 12.1 mo (95% CI: 8.8–19.9 mo) and median duration of response and OS have not been reached yet. For a time of observation of 35 mo, the OS is 80,6%. 37 patients have received 194 cycles with a median of 5 cycles. Grade 3–4 toxicities/pats were: 3(7.5%) anaemia, 2 (5%) leucopenia, 8(20%) neutropenia, 1 (2,5%) febrile neutropenia, 1 (2,5%) trombopenia, 2(5%) asthenia, 2(5%) diarrhea, 3(7.5%) nausea, 2(5%) vomiting, 3(7.5%) mucositis Conclusions: This interim analysis shows an interesting activity with this regimen. One week of rest may be of better convenience for the patient and hospital but also may improve the tolerability profile and efficacy of the combination. Further results would be available for presentation. No significant financial relationships to disclose.

Gemcitabine plus docetaxel versus docetaxel in patients (pts) with HER2-negative locally advanced or metastatic breast cancer (MBC): A randomized phase III study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1015-1015
Author(s):  
D. L. Nielsen ◽  
S. T. Langkjer ◽  
K. Bjerre ◽  
S. Cold ◽  
L. Stenbygaard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Agent ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Rank Test ◽  
Hematologic Toxicity ◽  
Phase Iii Study ◽  
Her 2 ◽  
Grade 3

1015 Background: Gemcitabine (G), either as a single agent or in combination with taxanes, has demonstrated efficacy in MBC in phase II and III studies. We conducted a phase III study to compare time to progression (TTP) of G plus docetaxel (T) versus (vs.) T alone. The secondary endpoints included overall survival (OS), overall response rate (ORR), and toxicity. Methods: Females with HER-2-negative locally advanced or MBC and a WHO performance status ≤ 2 were randomized to GT (G 1,000mg/m2 day 1 + 8; T 75mg/m2 day 1) or T (100mg/m2 day 1) every 21 days. Pts were previously untreated, had prior anthracycline-based (neo)adjuvant chemotherapy or had received a single prior anthracycline-bsed chemotherapy regimen for MBC. Time-to-event endpoints were estimated using the Kaplan-Meier method, and the log-rank test was applied for comparisons between regimens. The planned sample size was 254 evaluable pts with α I and β of 0.05 and 0.90, respectively. Results: A total of 336 pts were randomized (170 GT; 166 T), data from one centre are yet missing and the present evaluation is based on data from 306 pts (155 GT; 151 T). The pts had a median age of 58 years in both regimens; range 36–73 years and 30–74 years, respectively. The median TTP was 7.5 months for the GT regimen vs. 6.5 months for the T regimen. The GT arm demonstrated an ORR of 44% vs. 38% in the T arm with 4 and 3 % complete responses, respectively. The OS was 13.4 vs. 13.2 months in the GT and T arm, respectively. Hematologic toxicity was common, especially grade 3–4 neutropenia (GT = 69%; T = 61%); infection was reported in 22 and 20% of the pts, respectively (none of the pts received G-CSF). The most commonly reported non-hematologic toxicities of grade 3–4 included mucositis (GT = 2%; T = 5%), diarrhea (GT = 4%; T = 7 %), fatigue (GT = 6%; T = 11%), oedema (GT = 10%; T = 3%), and peripheral neuropathy (GT = 9%; T = 28%). Conclusions: Preliminary data of GT as first- or second-line chemotherapy demonstrates a TTP advantage among HER-2-negative pts with advanced breast cancer. Updated results and proper statistical analyses will be presented. No significant financial relationships to disclose.

Phase Ib trial of combining aldoxorubicin plus doxorubicin.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2550-2550
Author(s):  
Kamalesh Kumar Sankhala ◽  
Sant P. Chawla ◽  
Victoria S Chua ◽  
Doris Quon ◽  
Allison Bonk ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Safety Data ◽  
Tumor Xenograft ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Best Response ◽  
Grade 3

2550 Background: Aldoxorubicin is a novel drug that covalently binds to albumin in the circulation with release in low pH environments. Preclinical studies in pancreatic and ovarian tumor xenograft models demonstrated that aldoxorubicin plus doxorubicin administered at 50% of their MTD provided complete and prolonged tumor remission in these models with less toxicity than each drug administered at their MTD. We evaluated the toxicity profile of a fixed dose of doxorubicin and escalating doses of aldoxorubicin in subjects with advanced solid tumors. Methods: Phase 1b open label, dose-escalation study of aldoxorubicin administered at either 175, 240 or 320 mg/m2 (130, 180, or 240 mg/m2 doxorubicin equivalents) iv + 35 mg/m2doxorubicin iv, both on Day 1 of 21 day cycles, for up to 8 cycles. The MTD is the dose level immediately below where 2/6 subjects experience a dose limiting toxicity (DLT) , or the maximum dose of 320 mg/m2aldoxorubicin. Additional subjects may be enrolled at the MTD to provide more safety data. Results: 10 subjects have been treated as of January 21, 2013. No DLT was observed and the MTD was defined as 320 mg/m2 aldoxorubicin and 35 mg/m2 doxorubicin iv administered on Day 1 of 21 day cycles. A median of 4.5 cycles have been received. 3/10 subjects were terminated due to either progressive disease (2) or death (1). No subject was terminated due to an adverse event. Grade 3 or 4 neutropenia was seen at all dose levels (8/10 subjects). 4/10 subjects exhibited grade 3 or 4 thrombocytopenia and 3/10 subjects had grade 3 or 4 anemia. Neutropenic fever occurred in 3/10 subjects. Other grade 3/4 adverse events seen in 2 or fewer subjects included fatigue, increased liver enzymes and dehydration. No significant mucositis or cardiotoxicity was observed. At this time the best response has been stable disease in 6/10 subjects and a partial response in 1 subject (malignant fibrous histiocytoma). Conclusions: The combination of aldoxorubicin (320 mg/m2)) + doxorubicin (35 mg/m2) can be safely administered to subjects with solid tumors. Hematologic toxicity is common and can be controlled with growth factors. The dose of aldoxorubicin is 90% of the MTD of aldoxorubicin administered as a single agent. Thus, doxorubicin does not appear to add to the toxicity of this combination. Clinical trial information: NCT01673438.

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