Phase I study of a novel capecitabine schedule based on Norton-Simon mathematical modeling

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1045-1045 ◽  
Author(s):  
M. Theodoulou ◽  
T. A. Traina ◽  
U. Dugan ◽  
D. Lake ◽  
M. Fornier ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Metastatic Breast ◽  
Maximum Tolerated Dose ◽  
Ecog Performance Status ◽  
Safe Delivery ◽  
Optimal Dosing ◽  
Ecog Ps

1045 Background: We have previously described a mathematical method to optimize chemotherapy dose and schedule (Norton et al, AACR 2005). Capecitabine (C) has activity in breast cancer when conventionally dosed for 14 days (d) q3 weeks (14/7). However, the predicted optimal dosing schedule for C using our model is 7d followed by a 7d rest (biweekly, 7/7). We tested this hypothesis in a Phase I/II study described below. Methods: Eligible patients (pts) have measurable, metastatic breast cancer (MBC), ECOG performance status (PS) =2 and normal organ function. There is no limit to number of prior chemotherapy (CRx) regimens. Pts with prior fluoropyrimidine for MBC are excluded. HER2+ pts must not be candidates for trastuzumab. C is given in divided daily doses for 7d followed by a 7d rest. A standard “3+3” dose escalation scheme employs flat dosing which begins at 1,500mg BID and increases by 500mg/dose level. Primary endpoint is the maximum tolerated dose (MTD), defined as the highest dose for which the incidence of dose-limiting toxicity (DLT) is <33%. Results: 19 pts are now accrued; 17 pts have been treated, 2 withdrew prior to receiving C. Medians: age 47 y (range 34–62 y) and ECOG PS 0 (range 0–2). Sites of MBC: bone 8, viscera 16, soft tissue 11. ER/PR+ 11. HER2+ or unknown 2. Prior adjuvant tx: CRx 17, hormone tx 10. Six pts had adjuvant fluoropyrimidine-based tx. Three pts had 1 prior CRx for MBC; 12 pts received first-line hormone tx for MBC. Fifteen pts had prior anthracycline and taxane. Treatment-related toxicities after a median of 4 cycles (range 1–10) are shown in the table . The MTD has not been reached. Pts continue accrual to the 2500mg/2500mg dose level. Conclusions: Capecitabine 7/7 is well tolerated and allows for safe delivery of higher daily doses than routinely used in practice, as predicted by the mathematical model. Capecitabine 7/7 will be tested in a Phase II program at MSKCC in combination with targeted agents. [Table: see text] No significant financial relationships to disclose.

Phase I trial of metronomic cyclophosphamide (CTX) and lenalidomide (LEN) in patients with castration-resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 164-164
Author(s):  
Jue Wang ◽  
Timothy R. McGuire ◽  
James K. Schwarz ◽  
Jane L Meza ◽  
James E E Talmadge
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Patient Characteristics ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Level 1 ◽  
Grade 3

164 Background: Angiogenesis and suboptimal antitumor immune response are important in the progression of CRPC. Both LEN and metronomic CTX have known anti-angiogenic and immunomodulatory activities. A phase I study of a novel combination of metronomic CTX with LEN in patients with CRPC who have failed prior docetaxel therapy was initiated to assess safety and effects on potential biomarkers. Methods: CTX was given 50 mg PO QD(day 1-28) and LEN 10-25 mg PO QD(day 1-21) on a 28 day cycle. Dose limiting toxicity was defined as any treatment-related grade 4 hematologic event or grade 3 / 4 non-hematologic event during cycles one. Quantification of circulating tumor cells (CTC), plasma cytokines, analgesic consumption and quality of life assessments were performed. Measurement of Treg and MDSCs were performed in some patients. Results: 17 patients with CRPC have been enrolled in L0-4; all patients are evaluable for toxicity. Patient characteristics include: ECOG performance status 0/1= 4/13; median age=77 (range 50–86); median PSA=36.7 (range 1.36–2287). Dose level 1 (CTX 50 mg/d, LEN 10 mg/d) was expanded to 6 patients after one out of three initial patients was removed from the study for Gr 3 gastrointestinal bleeding (in cycle 1). Dose level 1 (CTX 25 mg/d, LEN 10 mg/d) had no DLT’s. The maximum tolerated dose has not yet been reached. Other Grade 3/4 toxicities observed after cycle 1 included grade 3 pain (N=1), grade 3 neutropenia (N=4), grade 3 thrombocytopenia (N=2), grade 4 neutropenia (N=2). Most frequent grade 1 and 2 toxicities included anemia, fatigue, neutropenia, and hypocalcemia. Overall, 9 of 14 patients (64%) have experienced a reduction in PSA. One patient had partial response after one cycle. Stable disease was documented in 5 of 14 (36%) evaluable patients. Two inflammatory cytokines, IL-6 (N = 19; r = 0.64; p = 0.0035) and IL-8 (N = 9; r = 0.86; p = 0.0028), were found to significantly correlated with PSA. Conclusions: The combination of metronomic CTX and LEN can be safely administered. Preliminary clinical activity was observed in this heavily-pretreated patient population. Enrollment to this study continues and clinical and biomarker studies are ongoing.

Safety of a novel capecitabine dosing schedule when combined with lapatinib in patients with HER2-positive metastatic breast cancer refractory to trastuzumab

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1131-1131
Author(s):  
T. A. Traina ◽  
M. Theodoulou ◽  
K. Feigin ◽  
S. Patil ◽  
S. Geneus ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Performance Status ◽  
Optimal Schedule ◽  
Metastatic Breast ◽  
Her2 Positive ◽  
Ecog Performance Status ◽  
Study Results ◽  
Her 2 ◽  
Ecog Ps

1131 Background: Capecitabine (C) is active in breast cancer and is usually dosed for 14 days (d) followed by a 7d rest (14 - 7). We described a mathematical method which predicts the optimal schedule for C to be 7d followed by a 7d rest (7 - 7) (Norton et al, Amer Assn Can Res. 2005). The MTD of C(7 - 7) is 2,000mg BID (Traina et al, J Clin Oncol. April 2008). Lapatinib (L) improves time to progression when added to C(14 - 7) in patients (pts) with HER-2-positive (+) metastatic breast cancer (MBC) that progressed after trastuzumab (T). To optimize this effective combination, we are testing C(7 - 7) + L in a phase II trial. Methods: Eligible pts have measurable, HER-2(+) MBC that has progressed after T. HER-2(+)=IHC 3+ or FISH>2. Pts have normal LVEF by MUGA, ECOG performance status (PS) <2 and normal organ function. <3 prior chemotherapy (CRx) regimens are permitted. Prior fluoropyrimidine is excluded. Therapy (tx) consists of C (2,000 mg BID, 7 - 7) and L (1,250 mg, daily). Cycle length = 4 wk. Pts are evaluated for toxicity q4 weeks (wk), for response q12wk; LVEF by MUGA q12wk. Primary endpoint: response rate (RR). Secondary endpoints: toxicity, stable disease >6 months, PFS. Using a Simon optimal 2-stage design, with alpha = 10%, power = 90% to discriminate between RR 10% and 25%, 21 pts will be accrued to the first stage. If >2 pts respond, 29 additional pts will be enrolled. If >7/ 40 pts respond, then C(7 - 7) + L will be considered worthy of further study. Results: As of January 5, 2008, 6 pts are enrolled and evaluable. Median (med) age 64 yrs (42–71), med ECOG PS 1 (0–1), ER/PR(+) 3, HER-2(+) 6, sites of MBC: bone (2), viscera (4), soft tissue (5). Med baseline LVEF 62% (51–68%). Prior tx: Adjuvant: CRx (5), hormone tx (3), T (3); MBC: CRx (2), hormone tx (1), T (3). After a med of 3 cycles (1–4), there were no grade 3, 4, or 5 events. Tx-related toxicity is: Gr 2 fatigue (1); Gr 1 AST (4), diarrhea (3), ALT (2), vomiting (1), hand-foot (1), fatigue (1). No withdrawls due to reduced LVEF. Two pts evaluable for response: PR = 1, SD<6 mo = 1. Conclusions: Capecitabine (7 - 7) + lapatinib appears well tolerated compared to C(14 - 7)+L (Geyer et al). Additional safety and efficacy data is anticipated prior to this meeting. [Table: see text]

Vorinostat in combination with gemcitabine and cisplatinum in patients with advanced non-small cell lung cancer (NSCLC): A Phase I dose-escalation study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8049-8049 ◽  
Author(s):  
J. Trédaniel ◽  
R. Descourt ◽  
D. Moro-Sibilot ◽  
J. Misset ◽  
E. Gachard ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Ecog Performance Status ◽  
Dose Escalation Study ◽  
Platinum Agent ◽  
Elevated Creatinine ◽  
Expansion Cohort ◽  
Dose Levels

8049 Background: Preclinical data indicate that vorinostat, a histone deacetylase inhibitor, enhances the efficacy of gemcitabine and platinum chemotherapy agents. This study investigated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of vorinostat plus gemcitabine and a platinum agent in patients (pts) with advanced NSCLC. Methods: Eligible pts (aged ≥18 years; stage IIIB/IV NSCLC, ECOG performance status ≤1, no prior systemic chemotherapy [except adjuvant]) were sequentially enrolled on escalating doses of vorinostat plus gemcitabine and a platinum agent (standard 3+3 design) for ≤6 cycles ( Table ). Carboplatin regimens were to be investigated if dose levels 1 or 2 exceeded the MTD. Results: 28 pts enrolled to date (M/F: 22/6; median age: [range] 55 [34–70] years; 20 chemonaïve) at 5 dose levels ( Table ). Two pts had DLTs: elevated creatinine leading to cisplatin dose reduction (dose level 2) and febrile neutropenia (dose level 5) ( Table ). Dose level 5 was achieved without reaching the MTD; however, based on clinical tolerability, dose level 4 was chosen as the recommended dose (RD). 24 pts had adverse events (AEs): 86% mild/moderate, 53% not considered treatment-related. The most common drug-related Grade 3/4 AEs were thrombocytopenia (19 events) and neutropenia (14 events). Serious AEs occurred in 15 pts, and 5 deaths occurred (1 ‘probably‘ and 4 ‘definitely not‘ treatment-related). Of 19 evaluable pts at 5 dose levels, 9 (47%) had a partial response, 8 stable disease, and 2 disease progression ( Table ). Updated results of pts treated at the RD in an expansion cohort will be presented. Conclusions: These phase I data suggest that vorinostat can be administered with standard doses of gemcitabine and cisplatin and the combination is active in the initial treatment of metastatic NSCLC: randomized trials are needed to determine whether addition of vorinostat improves outcomes in such pts. [Table: see text] [Table: see text]

Clinical outcomes of patients with breast cancer in a phase I clinic: The M. D. Anderson Cancer Center experience

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1054-1054
Author(s):  
J. J. Wheler ◽  
A. Tsimberidou ◽  
S. Moulder ◽  
M. Cristofanill ◽  
D. Hong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Clinical Outcomes ◽  
Median Duration ◽  
Phase I Trial ◽  
Performance Status ◽  
Metastatic Breast ◽  
Ecog Performance Status

1054 Background: Patients with metastatic breast cancer refractory to standard therapy are eligible for phase I trials. We assessed prognostic factors and clinical outcomes for patients with breast cancer in a phase I clinic focused on targeted agents. Methods: We reviewed the medical records of sequential patients with metastatic breast cancer who presented to our phase I clinic from September 2004 to May 2008. We assessed the relationship between overall survival and patients’ demographic and clinical characteristics using both univariate and multivariate (Cox proportional hazard model) analyses. Results: Ninety-two patients were identified with median age of 53 years (range 28 to 83 years). The median number of prior therapies was 5 (range 1 to 16). The median follow-up of surviving patients is 7.4 months. The median overall survival is 6.7 (95% CI: 5.2, 9.7) months. In univariate analysis, factors predicting shorter survival were elevated Ca-125 (p = 0.001) (Ca27.29 was not significant), albumin < 3.5 g/dL (p = 0.002), worsening ECOG performance status (p = 0.004), absolute neutrophil count < 7.3 x 109/L (p = 0.004), ≥ 10 prior treatment regimens (p = 0.008), ≥ 5 prior chemotherapy-only regimens (p = 0.008), body mass index (BMI) < 25 (p = 0.018), and elevated platelet counts (p = 0.007). In multivariate analysis, independent factors predicting shorter survival were ≥10 prior treatments (vs. <10 prior treatments) (HR = 3.27; 95% CI 1.37, 7.81; p = 0.0077), ECOG performance status 2–3 (vs. 0–1) (HR = 2.92; 95% CI 1.28, 6.66; p = 0.01), and albumin < 3.5 g/dL (vs. > 3.5g/dL) (hazard ratio [HR] = 2.88; 95% CI; 1.41, 5.89; p = 0.004). Of 78 patients treated on a first phase I trial, 14 (18%) demonstrated stable disease (SD), with a median duration of 18 weeks (range 10–25). Of those 19 patients treated on a second phase I trial, 6 (32%) had SD with a median duration of 12 weeks (range 8–17). Two of 4 (50%) patients treated on a third phase I trial had SD with a median duration of 20 weeks (range 16–24). Conclusions: Patients with metastatic breast cancer referred for our phase I studies had a median survival of 6.6 months. In this preliminary analysis, independent factors predicting shorter survival were ≥ 10 prior treatments, worsening ECOG performance status and low albumin levels. No significant financial relationships to disclose.

A Phase I Study of OMN54 (Aneustat™) in Patients with Advanced Malignancies

2020 ◽  
Vol 7 (2) ◽  
pp. 125-132
Author(s):  
Karen A. Gelmon ◽  
Christian Kollmannsberger ◽  
Stephen Chia ◽  
Anna V. Tinker ◽  
Teresa Mitchell ◽  
...  
Keyword(s):  
Phase I ◽  
Salvia Miltiorrhiza ◽  
Performance Status ◽  
Parent Drug ◽  
Maximum Tolerated Dose ◽  
Ecog Performance Status ◽  
Advanced Malignancies ◽  
Gi Toxicity ◽  
Adequate Organ Function ◽  
Recommended Phase Ii Dose

Background/Objective: With the increasing interest in natural products, a phase I openlabel study of OMN54 (Aneustat™) in patients with advanced malignancies was initiated to determine toxicity, maximum tolerated dose (MTD), dose limiting toxicities (DLT), and pharmacokinetics (PK). OMN54 is a multitargeted agent, combining three Chinese botanicals; Ganoderma lucidium, Salvia miltiorrhiza and Scutellaria barbata. Methods: Eligible patients (pts) were >18 years of age with advanced solid tumors, able to swallow oral capsules, ECOG performance status < 2, measurable disease as defined by RECIST 1.1 and adequate organ function. Results: Twenty-two patients were enrolled in 6 dose levels, 2 with daily dosing and 4 with twicedaily dosing ranging from 1 to 5 grams daily. All were evaluated for toxicity and 20 for response. No treatment-related dose-limiting toxicities (DLTs) were reported and the recommended phase II dose (RP2D) was determined to be 2.5 g twice daily. Seven adverse events in 5 patients were reported as possibly drug-related; 6 were GI toxicity and 1 was a skin disorder. All were grade 1 except one grade 2 vomiting. No RECIST responses were seen. Six pts were treated with > 2 cycles; one for 8 cycles. Four patients had reductions in TGF –β and EGF, exploratory biomarkers possibly suggestive of a drug effect. Plasma half-lives of 1 -2 hours were noted for all parent drug chemical markers with no accumulation over time. Conclusion: OMN54 was well tolerated, with no DLTs observed. Further studies at the RP2D will assess the biological activity.

Phase I dose and schedule finding study of pegylated liposomal doxorubicin (D) and weekly docetaxel (T)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12012-12012 ◽  
Author(s):  
O. S. Shaye ◽  
A. B. El-Khoueiry ◽  
A. Garcia ◽  
D. Wei ◽  
S. Groshen ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Metastatic Breast ◽  
Pegylated Liposomal Doxorubicin ◽  
Dose Intensity ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Salivary Gland Carcinomas ◽  
Common Grade ◽  
Grade 3

12012 Background: The combination of D and T has many potential applications, particularly in breast and ovarian cancers. A phase 3 trial is examining D + T versus T in first-line metastatic breast cancer ( NCT00091442 ). D has better tumor localization and penetration in solid tumors than conventional doxorubicin. In previous studies, the maximum tolerated dose (MTD) of the combination was identified as D 30 mg/m2 and T 75 mg/m2 q4 weeks (wks), with a recommended dose and schedule of D 30 mg/m2 and T 60 mg/m2 q3wks without G-CSF. We conducted a phase I study to determine the MTD of D with weekly T. Our hypothesis was that the lower incidence of myelosuppression with weekly T would allow for higher doses of both drugs. Methods: There were 2 schedules. Arm A: D q4wks starting at 25 mg/m2 with weekly T for 3 wks starting at 30 mg/m2. Arm B: D q2wks starting at 15 mg/m2 with weekly T for 3 wks starting at 30 mg/m2. One cycle was 28 days. Standard 3+3 design was used with MTD defined as the highest dose level causing dose limiting toxicity (DLT) in ≥ 2/6 patients (pts). Results: 32 pts were treated; 13 females, 19 males, median age of 60 years. Median number of cycles administered was 2 (1–13) with a median follow-up of 11.5 months. Tumor types included lung (16%), thyroid (9%), esophagus (9%), nasopharynx, breast, colorectal, stomach and kidney (6% each). Arm A (13 pts) was closed after 2/7 evaluable pts at dose level 2 (D 33mg/m2; T 30 mg/m2) experienced DLT in the form of grade 3 stomatitis. The most common grade 3/4 toxicities were neutropenia (3/13), stomatitis (3/13) and fatigue (3/13). Arm B accrued 19 pts. The trial was closed at the highest planned dose in Arm B (D 20mg/m2 q2wks and T 35 mg/m2 weekly) with only 1/6 evaluable pts experiencing DLT in the form of grade 4 fatigue and weakness. The most common grade 3/4 toxicities in Arm B included neutropenia (5/19 pts), fatigue (5/19 pts) and stomatitis (2/19 pts). There was no grade 3/4 hand-foot syndrome or cardiotoxicity. 2 partial responses were observed in nasopharyngeal and salivary gland carcinomas, with 13 pts achieving stable disease. Conclusions: The combination of D q2 wks and T weekly for 3/4 wks is well tolerated and results in a higher dose intensity of both drugs than in previously evaluated regimens. [Table: see text]

A phase I-II and pharmacodynamic (PD) study of the combination of the proteasome inhibitor bortezomib (B) and paclitaxel (P) in patients with taxane-sensitive solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13029-13029
Author(s):  
E. Gallerani ◽  
S. Cresta ◽  
D. Tosi ◽  
C. Sessa ◽  
G. Capri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Phase I ◽  
Anticancer Agents ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Peripheral Blood Mononuclear

13029 Background: Proteasome inhibition blocks the chemotherapy-induced activation of NF-кB increasing chemosensitivity to anticancer agents due to increased apoptosis. NF-кB is frequently aberrantly activated in primary human carcinomas and over-expressed in aggressive breast cancer lines1 supporting the rationale for combining B with P. We designed a phase I-II and PD trial to determine the recommended dose (RD) of the B&P combination, to screen for antitumor activity in patients with potentially taxane-sensitive tumors, to search for drug-induced changes and to identify potential surrogate markers of drug activity and toxicity in peripheral blood mononuclear cells (PBMC). Methods: Eligibility included ECOG performance status < 2, neurotoxicity < 2 and adequate organ functions. Treatment was given Q21 days: B on days 1,4, 8 and 11 and P on days 1 and 8. PBMC for gene expression profiling have been collected on day 1 and 4 before and after therapy. RECIST for response was applied. Results: Twenty-nine patients (20 female, median age 60 yrs) were accrued and 25 are evaluable (breast cancer: 13, ovarian cancer: 7, prostate cancer 1, other 4) ; 16 pts were treated in 4 escalation levels and the RD defined respectively at 1.3 mg/m2/dose & 100 mg/m2/dose for B&P. Neurotoxicity was the main toxicity (G1 36%, G2 20% and 1 case G3) requiring treatment discontinuation in 2 pts at cy 6 & 7. Other toxicities (all grades) were nausea and vomiting (68%), diarrhea (56%, G3 12%), alopecia (52%), asthenia (36%, G2 4%), and myalgia (32%, G2 8%). Antitumor activity consisted of 3 PR in pts with ovarian cancer lasting respectively 14, 8+ and 16 wks; 2 PRs in pts with breast cancer (12+ wks,14+ wks) and 1 PR in a pt with prostate cancer. Conclusions: Thus far the regimen has acceptable toxicity with evidence of antitumor activity. The trial will continue until accrual of four additional patients as planned. Footnotes 1 Adams J Current Opin Oncol 2002, 14:628–634. [Table: see text]

Randomized phase II study of biweekly gemcitabine (gem)-paclitaxel (pac), gem-carboplatin (carb) and gem-cisplatin (cis) as first-line treatments in metastatic breast cancer (MBC) after anthracycline failure

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1099-1099 ◽  
Author(s):  
B. Xu ◽  
Z. Jiang ◽  
S. Kim ◽  
S. Yu ◽  
J. Feng ◽  
...  
Keyword(s):  
Performance Status ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Ecog Performance Status ◽  
Eligibility Criteria ◽  
Dominant Type ◽  
Tumor Involvement ◽  
Number Of Cycles ◽  
Ecog Ps ◽  
Tumor Types

1099 Background: Biweekly gem-pac and gem-cis regimens have shown promising activity and safety in different tumor types. In MBC biweekly gem-pac is active and well tolerated. The aim of this multi-country study is to evaluate the efficacy and safety of gem in combination with pac, carb or cis on a biweekly schedule in patients (pts) with MBC. Methods: Major eligibility criteria included: tissue diagnosis of stage IV breast carcinoma; prior anthracycline therapy; ECOG performance status (PS) of 0 or 1; and written informed consent. Pts were randomized to receive gem 2500 mg/m2 in combination with pac 150 mg/m2 (Arm A), carb AUC 2.5 (Arm B) or cis 50 mg/m2 (Arm C) on day 1 of 2-week cycles. The primary endpoint was response rate, with safety a secondary endpoint. Results: This interim analysis was planned to occur when patient enrollment had reached 50% (75/150 pts), at which point there were 26 pts in Arm A, 25 in Arm B and 24 in Arm C, with 12 pts still on treatment. The baseline characteristics were similar in the three arms, including mean age (Arm A 50.2 yr, Arm B 46.1, Arm C 47.3); ECOG PS (PS 0: 50.0%, 64.0%, 54.2%); mean number of sites of tumor involvement (2.9, 2.6, 2.7); dominant type of metastasis (visceral: 73.1%, 80.0%, 79.2%); and disease-free interval (<24 mo: 53.8%, 60.0%, 41.7%). The mean number of cycles was 6.4, 6.0 and 5.8. There was a partial response in 5/26 efficacy qualified pts (19.2%), 5/25 pts (20.0%) and 2/23 pts (8.7%) in Arms A, B and C, respectively, stable disease in 10 pts (38.5%), 9 pts (36.0%) and 9 pts (39.1%), and progressive disease in 5 pts (19.2%), 6 pts (24.0%) and 6 pts (26.1%). There were no treatment-related deaths. Conclusions: The three regimens appear to show activity and have manageable toxicity when given on a biweekly schedule. [Table: see text] No significant financial relationships to disclose.

Phase II evaluation of liposomal doxorubicin combined with docetaxel in patients with metastatic breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1112-1112
Author(s):  
J. Fasano ◽  
D. Hershman ◽  
Y. Novik ◽  
K. Blozie ◽  
A. Tiersten
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Liposomal Doxorubicin ◽  
Performance Status ◽  
Metastatic Breast ◽  
Time To Progression ◽  
Ecog Performance Status ◽  
Weekly Docetaxel ◽  
Mixed Response ◽  
Response To Chemotherapy

1112 Background: The combination of anthracyclines and taxanes are effective in the treatment of metastatic breast cancer. Liposomal doxorubicin has been shown to be as effective as doxorubicin with less toxicity and it can be combined safely with docetaxel. Methods: Monthly liposomal doxorubicin (30 mg/m2) in combination with weekly docetaxel (30 mg/m2) was evaluated in women with metastatic breast cancer. Cycles were continued until disease progression or unacceptable toxicity. Radiologic assessment was performed every two months. The primary outcome was time to progression. Secondary endpoints included overall response rate, median survival and toxicity. Results: Between 12/2002 and 9/2005, 12 women were enrolled and received this combination as front- line chemotherapy for metastatic breast cancer. The mean age was 46.5 (31–60) years. Nine (75%) patients had tumors that were ER+ or PR+. Five (41.7%) women had tumors that over-expressed her-2/neu. Ten women had an EGOG performance status of 1. Two women had an ECOG performance status of 2. The median number of cycles received was 4 (1–12). Four (25%) women were taken off study due to intolerable toxicity and 7 (58.3%) due to progressive disease. One (8.3%) woman remains progression free. Ten (83.3%) women had a partial response, one (8.3%) woman had a mixed response and one (8.3%) was not evaluable for response to chemotherapy. The median time to progression was 21 (6–52) weeks. Three women remain alive with disease. One woman remains alive and progression-free. Ten (83%) patients experienced Grade 3/4 toxicities, including: stomatits 6 (50%), nausea/vomiting 1 (8.3%), neutropenia 3 (25%), infection 3 (25%), dyspnea 2 (16.7%), and PPE 1 (8.3). Conclusions: Monthly liposomal doxorubicin plus weekly docetaxel in women with metastatic breast cancer resulted in an encouraging response, but was difficult to tolerate. Further evaluation of this combination with improved supportive care may be warranted. [Table: see text]

Phase I trial of escalating doses of weekly everolimus (RAD001) in combination with docetaxel for the treatment of metastatic breast cancer (MBC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1066-1066
Author(s):  
S. L. Moulder ◽  
E. Rivera ◽  
J. Ensor ◽  
A. Gonzalez-Angulo ◽  
M. Christofanilli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Single Agent ◽  
Metastatic Breast ◽  
Maximum Tolerated Dose ◽  
Entire Group ◽  
Interpatient Variability ◽  
Grade 3

1066 Background: Inhibition of mTOR with everolimus (E) may improve efficacy in combination with docetaxel (D), but both drugs are metabolized by CYP3A4, thus a pharmacokinetic (PK) interaction may also exist. Methods: 15 patients (pts) with MBC were treated with docetaxel and everolimus using the continuous reassessment method (CRM) to determine maximum tolerated dose (MTD). Docetaxel doses were 40–75 mg/m2 IV on day 1 of a 21 day cycle. Everolimus doses were 20–50 mg PO on days 1 and 8 of a 21 day cycle (except cycle 2, where only day 8 was given to allow single agent PK analyses of both drugs). Response was measured every 2 cycles using RECIST. Results: Median age= 58 years and 77% of pts had >2 prior chemotherapies for MBC. Initially 2 of 2 pts treated (D= 75 mg/m2, E= 30 mg) developed DLT (neutropenic fever/infection), prompting a mandatory PK evaluation for all pts enrolled in subsequent cohorts. A second cohort of 3 patients (D=60 mg/m2, E=20mg) had no DLT, but no pts received day 8 of E due to grade 3–4 neutropenia. PK analyses demonstrated a 42% lowered (-42%) D clearance at the 60 mg/m2 in the presence of E (n=1). Subsequent cohorts were accrued at D=40 mg/m2 with escalating doses of E (Table). For the entire group, an 18% decrease (-18%) in D clearance was observed when D was administered concomitantly with E. High interpatient variability of D clearance was observed (range +16% to -135%). No pts had CR/PR, but 6 had SD>4 cycles and 2 had SD=8 cycles. Conclusions: Weekly everolimus appears to cause widely variable and unpredictable changes in docetaxel clearance making this combination unfeasible. [Table: see text] No significant financial relationships to disclose.

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