Neoadjuvant weekly nab-paclitaxel (wA), carboplatin (Cb) plus bevacizumab (B) with or without dose-dense doxorubicin-cyclophosphamide (ddAC) plus B in ER+/HER2-negative (HR+) and triple-negative (TN) breast cancer (BrCa): A BrUOG study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1045-1045 ◽  
Author(s):  
Natalie Faye Sinclair ◽  
Maysa M. Abu-Khalaf ◽  
Tina Rizack ◽  
Kayla Rosati ◽  
Gina Chung ◽  
...  
Keyword(s):  
Clinical Stage ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Residual Cancer ◽  
Serious Adverse Events ◽  
Residual Cancer Burden ◽  
Grade 3 ◽  
Gi Bleed ◽  
Dose Dense ◽  
Dose Reductions

1045 Background: High risk BrCa patients (pts) often receive weekly paclitaxel (wP) as well as ddAC. Switching to wA(Abraxane) or adding B or Cb may enhance its efficacy, especially in TN pts. Methods: Pts with clinical stage IIA-IIIC BrCa received wA 100 mg/m2, Cb AUC 6 + B 15 mg/kg q3wks x 12 wks only (cohort 1/Yale) or followed by ddAC + B x 4 (cohort 2/Brown). Endpoints: pathologic complete response (pCR) - absence of invasive BrCa in breast + axillary nodes, residual cancer burden (RCB), clinical CR/partial response (cCR/cPR), and toxicity. Correlative studies are being performed on biopsies obtained at baseline and after run-in doses of wA or B only. Post-op pts resume B for 34 wks; other systemic therapy, including ddAC in cohort 1, is at MD discretion. Results: 55 of 60 pts (median age 47, range 25-68; 31 HR+/29 TN) are evaluable for response (see table below). Median # doses wA 11,Cb 4, ddAC 4. Dose reductions: wA 25% for neutropenia (ANC), Cb 15% for thrombocytopenia (tcp). B 7% held for hypertension. Grade 3-4 toxicities (>5%): ANC 85%, tcp 35%, anemia 25%. Serious adverse events during wA: 3 nausea/dehydration (N/D), 3 infection w/o neutropenic fever (FN), 2 GI bleed; during ddAC: 6 (21%) FN despite G-CSF, 3 N/D. Conclusions: The combination of wA, q3wk Cb + B was well tolerated, with cCR+cPR 84%. However, overall pCR was only 11% (27% in TN) after 12 wks of this regimen (cohort 1). Subsequent preop ddAC raised overall pCR to 54%, and 81% in TN, demonstrating that longer treatment duration or inclusion of anthracycline-based therapy improves responses. Results for cohort 2 compare favorably with those from I-SPY, GeparQuinto and NSABP B-40; the addition of Cb and/or B in TN is being evaluated in CALGB 40603. [Table: see text]

scholarly journals Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance)

2015 ◽  
Vol 33 (1) ◽  
pp. 13-21 ◽  
Author(s):  
William M. Sikov ◽  
Donald A. Berry ◽  
Charles M. Perou ◽  
Baljit Singh ◽  
Constance T. Cirrincione ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Stage Ii ◽  
Open Label ◽  
Grade 3 ◽  
Dose Dense ◽  
The Impact

Purpose One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab. Patients and Methods Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m2 once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed. Results Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated. Conclusion In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent.

Safety and effectiveness of dose dense neoadjuvant chemotherapy in patients with stage II/III breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10622-10622
Author(s):  
S. A. McDaniel ◽  
H. Krontiras ◽  
J. T. Carpenter ◽  
L. M. Nabell ◽  
K. I. Bland ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Dose Dense ◽  
To Receive

10622 Background: NSABP B-18 randomized women with operable breast cancer to receive chemotherapy either pre- or postoperatively; OS and DSF rates at 9 years were identical. Importantly, pathologic complete response (pCR) was directly proportional to DFS and OS. Recently, dose dense adjuvant chemotherapy has shown a statistically significant improvement in DFS and OS. However, no data is available for the use of dose dense preoperative chemotherapy at this time. Methods: Women enrolled in the I-SPY correlative trial with newly diagnosed breast cancer, T ≥ 3cm, any N, M0 were evaluated to assess response rates and safety to dose dense neoadjuvant chemotherapy (doxorubicin 60 mg/m2 IV Q2 wks × 4, paclitaxel 175 mg/m2 IV Q2 wks × 4, and cyclophosphamide 600 mg/m2 IV Q2 wks × 4). Results: Since 02/2003, 43 pts have been treated with dose dense neoadjuvant chemotherapy on the I-SPY trial at UAB (mean age 47.9). 47% of the pts were ER+, 37% were PR+ and 5% were Her2+ by FISH. 2 pts dropped out for personal reasons and 9 pts are actively undergoing treatment. Overall, 32 pts received dose dense chemotherapy and proceeded to surgery. Of those, 31 received dose dense sequential ATC and 1 received dose dense concurrent AC followed by T. 34% had a pCR (breast & nodes) while an additional 10% had a pCR in the breast but residual disease in lymph nodes; 41% had a PR; 9% had SD; and 6% had PD. Hematologic toxicity consisted of grade 3 anemia in 2 pts, febrile neutropenia in 2 pts and no grade 4 thrombocytopenia. Non-hematologic grade 3–4 toxicity consisted of mediport-associated thrombosis in 2 pts, hyperglycemia in 2 pts, syncope in 1 pt, neuropathy in 1 pt, and disseminated varicella in 1 pt. Conclusion: Our results show that dose dense neoadjuvant chemotherapy achieves a pCR (breast & nodes) in about 1/3 of patients (34%) with tolerable toxicity. No significant financial relationships to disclose.

A new measurement of residual cancer burden to predict survival after neoadjuvant chemotherapy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 536-536 ◽  
Author(s):  
W. Symmans ◽  
F. Peintinger ◽  
C. Hatzis ◽  
H. Kuerer ◽  
V. Valero ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Cox Regression ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Continuous Measure ◽  
Residual Cancer ◽  
Cancer Burden ◽  
Residual Cancer Burden ◽  
Ajcc Stage

536 Background: The strength of association between tumor response and survival is critical for neoadjuvant chemotherapy trials. Pathologic complete response (pCR) reliably predicts survival benefit, but residual disease contains a range of pathologic responses that likely contain different prognostic groups, including near complete response and resistance. Methods: Pathologic slides and reports were reviewed from 432 patients in two completed neoadjuvant trials: 1) fluorouracil, doxorubicin and cyclophosphamide (FAC) in 189 patients, and 2) paclitaxel followed by FAC (T/FAC) in 243 patients. Paclitaxel was administered as twelve weekly (n=126) or four 3-weekly cycles (n=117). Residual cancer burden (RCB) was calculated as an index that combines pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size). We compared four RCB categories, from RCB-0 (pCR) to RCB-3 (chemoresistant), and post-treatment revised AJCC Stage (0-III) for prediction of distant relapse-free survival (DRFS) in multivariate Cox regression analyses (stratified by ER status). Results: The pCR rate was greater after T/FAC than FAC (24% vs. 16%, LR p<0.05), and after weekly (vs. 3-weekly) paclitaxel in T/FAC (30% vs. 16%, LR p<0.01). In patients with residual disease, RCB measurements were significantly lower after T/FAC than FAC (t-test, p<0.0001), but were not different between paclitaxel schedules in T/FAC. RCB was a continuous predictor of DRFS after T/FAC (HR=1.86, 95%CI 1.51–2.30) or FAC (HR=1.67, CI 1.38–2.01) with median follow-up 5 and 8 years, respectively. The resistant category RCB-3 predicted relapse more strongly than AJCC Stage III and identified a larger group of high-risk patients ( Table ). Conclusions: RCB is a new continuous measure of pathologic response that is defined from routine pathologic materials, represents the distribution of residual disease, is a significant predictor of DRFS, and defines chemotherapy resistance more effectively than revised AJCC Stage. [Table: see text] [Table: see text]

Effect of lenalidomide (LEN) on biochemical responses and clinical benefit (CB) as a single agent in chemotherapy-naive castration-resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 128-128 ◽  
Author(s):  
Chadi Nabhan ◽  
Anand Patel ◽  
Dana Villines ◽  
Kathy Tolzien ◽  
Susan K. Kelby ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Benefit ◽  
Single Agent ◽  
Complete Response ◽  
Median Number ◽  
Castration Resistant Prostate Cancer ◽  
Serious Adverse Events ◽  
Biochemical Responses ◽  
Grade 3 ◽  
Dose Reductions

128 Background: LEN has anti-angiogenesis and immunomodulatory properties making it ideal to investigate in CRPC. We report on a phase II study investigating LEN in chemotherapy-naïve CRPC patients (pts) Methods: Eligible pts received LEN at 25 mg daily on days 1 – 21 every 28-days until progression. Daily aspirin or coumadin were required. Responses were assessed every 2 cycles. Toxicity was assessed every cycle. Primary end point: The CB of LEN [Sum of complete response (CR), partial response (PR) and stable disease (SD)]. Secondary end points: Toxicity, time to radiographic and PSA progression (TTP and TTP-PSA), time to next treatment (TTNT), overall survival (OS), and LEN’s impact on quality of life (QOL). Results: 31 pts were enrolled; 27 response-evaluable (1 withdrew consent, 3 off per choice after adverse events). Median age is 74 (range 58-89) with 24 (77%) having Gleason ≥ 7 disease. Median PSA is 66 (2.1-918.6). Six pts (19%) had liver/lung involvement. Fourteen pts (51%) showed biochemical response with 4 (15%) having >50% PSA drop. TTP-PSA is 4 months (2-11). No radiographic responses seen but 17 pts had SD for a median of 4 months (2-16) (CB=55%). Median number of LEN cycles was 3 (2-15). With a median follow-up of 18 months (5-38), 17 patients (55%) remain alive; median OS of 18 months. Grade 3/4 hematologic toxicities were most common (neutropenia 41%, leukopenia 12%, anemia 9%, thrombocytopenia 9%). Other grade 3/4 toxicities: venothromboembolism, atrial fibrillation, and dehydration (6% each). Serious adverse events (SAEs) were witnessed in 10 pts (32%) with only 1 (3%, rash) definitely related to LEN. Others were not related or possibly related. Of 27 pts, 7 (26%) had a dose reduction and 2 (7%) required two dose reductions. Dose reductions occurred after cycle 3. QOL scales suggested no adverse impact. Median TTNT is 2 months (9 pts received chemotherapy, 10 pts went onto studies, 3 pts received hormonal therapies, 4 pts received radiation, 3 pts had no therapy yet, and 2 pts remain on LEN). Conclusions: LEN is active as monotherapy in CRPC. Biochemical responses are witnessed and clinical benefit is observed. Myelosuppression is the most common toxicity.

Results of randomized phase II trial of neoadjuvant carboplatin plus docetaxel or carboplatin plus paclitaxel followed by AC in stage I-III triple-negative breast cancer (NCT02413320).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 516-516
Author(s):  
Priyanka Sharma ◽  
Bruce F. Kimler ◽  
Anne O'Dea ◽  
Lauren Elizabeth Nye ◽  
Yen Y. Wang ◽  
...  
Keyword(s):  
Pathologic Complete Response ◽  
Complete Response ◽  
Drug Regimen ◽  
Stage I ◽  
Treatment Delivery ◽  
Residual Cancer Burden ◽  
Randomized Phase Ii ◽  
Grade 3 ◽  
Clinical Trial Information ◽  
Carboplatin Auc

516 Background: Addition of neoadjuvant carboplatin (Cb) to paclitaxel (T) followed by doxorubicin + cyclophosphamide (AC) improves pathologic complete response (pCR) rate compared to T/AC in TNBC. An anthracycline-free regimen of Cb plus docetaxel (D) also yields high pCR rates in TNBC, and patients achieving pCR with this regimen demonstrate excellent 3-year outcomes without adjuvant anthracycline. This study was designed to compare the efficacy of neoadjuvant regimens CbT→AC and CbD in TNBC. Methods: In this multicenter study, eligible patients with stage I–III TNBC were randomized (1:1) to either paclitaxel 80 mg/m2 every week X 12 + carboplatin (AUC 6) every 3 weeks X 4, followed by doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 every 2 weeks X 4 (CbT→AC, Arm A), or to carboplatin (AUC 6) + docetaxel (75 mg/m2) every 21 days X 6 cycles (CbD, Arm B). The primary endpoint was pCR (no evidence of invasive tumor in the breast and axilla). The two regimens were compared for differences in pCR, residual cancer burden (RCB), treatment delivery, and toxicity. Results: Between 2015 and 2018, 100 patients were randomized; 48 to Arm A and 52 to Arm B. Median age was 52 years, median tumor size was 2.7 cm, 30% were lymph node-positive and 17% carried a BRCA1/2 mutation. Baseline demographic and tumor characteristics were balanced between two arms. pCR was 55% (95%CI: 41%-59%) in Arm A and 52% (95%CI: 39%-65%) in Arm B, p =0.84. RCB 0+1 rate was 67% in both arms. Grade 3/4 adverse events were more common in Arm A compared to Arm B (73% vs 21%, p < 0.0001), with most notable differences in rates of G3/4 neutropenia (Arm A = 60%, Arm B = 8%, p = 0.0001), febrile neutropenia (Arm A = 18%, Arm B = 0%, p = 0.0001), and G3/4 anemia (Arm A = 46%, Arm B = 4%, p = 0.0001). 81% of Arm A patients completed all 4 doses of AC and 4 doses of Cb, and 71% completed > 9 doses of T. 90% of Arm B patients completed all 6 doses of CbD (p = 0.034). Conclusions: The non-anthracycline platinum regimen of CbD yields pCR and RCB 0+1 rates similar to 4-drug regimen of CbTàAC, but with a more favorable toxicity profile and higher treatment completion rate. The CbD regimen should be further explored as a way to de-escalate therapy in TNBC. Clinical trial information: NCT02413320.

CALGB (Alliance) 40603: Long-term outcomes (LTOs) after neoadjuvant chemotherapy (NACT) +/- carboplatin (Cb) and bevacizumab (Bev) in triple-negative breast cancer (TNBC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 591-591 ◽  
Author(s):  
William M. Sikov ◽  
Mei-Yin Polley ◽  
Erin Twohy ◽  
Charles M. Perou ◽  
Baljit Singh ◽  
...  
Keyword(s):  
Residual Disease ◽  
Clinical Stage ◽  
Tumor Grade ◽  
Distant Recurrence ◽  
Residual Cancer ◽  
Cancer Burden ◽  
Residual Cancer Burden ◽  
Dose Dense

591 Background: Both Cb and Bev demonstrate activity when combined with standard chemotherapy in TNBC. CALGB 40603 is a 2x2 randomized trial that previously demonstrated that adding Cb to NACT significantly increased pathologic complete responses in the breast/axilla (pCR), while adding Bev did not (Sikov, JCO 2015). Here we report 5-year LTOs and assess factors that influenced them. Methods: 443 patients with clinical stage II-III previously untreated TNBC received 12 weeks of paclitaxel (wP) +/- Cb then dose-dense AC, +/- Bev before surgery. The primary endpoint was pCR. Analyses of LTOs (event-free survival (EFS), distant recurrence-free interval (DRFI) and overall survival (OS)), impact of residual cancer burden and other variables were secondary. Results: Median follow-up was 5.7 years (y); 5y EFS was 70.9% (95% CI; 66.7%-75.4%), DRFI 76.3% (72.3%-80.5%) and OS 76.9% (72.9%-81.2%). Pretreatment clinical stage and achieving pCR correlated with LTOs, while age, race, subtype (basal-like vs. not) and tumor grade did not. Among pCR 5y EFS was 86.4% vs. 57.5% for non-pCR (HR 0.28, 0.19-0.43), OS was 88.7% vs 66.5% (HR = 0.28, 0.17-0.44). This relationship was similar in all trial arms. Any residual disease conferred poorer outcome; compared with pCR/Residual Cancer Burden (RCB) 0, EFS HRs were 2.29 (1.32-3.97), 3.01 (1.90-4.74), and 9.67 (5.66-16.51) for RCBI, II and III, respectively. There were no improvements in LTOs with Cb (EFS HR 0.99, 0.70-1.40) or Bev (EFS HR 0.91, 0.64-1.29). In an exploratory analysis, receipt of ≥11 doses of wP was associated with better EFS (HR 1.92, 1.33-2.77); this was particularly notable in Cb-treated arms. Conclusions: As expected, regardless of treatment arm pCR was associated with markedly better LTOs, and pts with any residual disease had significantly worse outcomes. The addition of Cb or Bev to standard NACT for TNBC did not improve LTOs in this trial, although it should be noted that the trial was not powered for this endpoint. Omission of chemotherapy doses may result in poorer outcomes, especially among Cb-treated pts, which may warrant further evaluation. Support: U10CA180821; U10CA180882; Genentech; https://acknowledgments.alliancefound.org ; NCT00861705 Clinical trial information: NCT00861705.

PrECOG 0105: Final efficacy results from a phase II study of gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1003-1003 ◽  
Author(s):  
Melinda L. Telli ◽  
Kristin C. Jensen ◽  
Allison W. Kurian ◽  
Shaveta Vinayak ◽  
Jafi A. Lipson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Early Stage ◽  
Clinical Stage ◽  
Pathologic Complete Response ◽  
Breast Conservation ◽  
Complete Response ◽  
Pathologic Response ◽  
Residual Cancer Burden

1003 Background: TN and BRCA1-deficient breast cancer (BC) cell lines exhibit enhanced sensitivity to DNA damaging agents. This study was designed to assess efficacy, safety and predictors of response to iniparib in combination with GC in early-stage TN and BRCA1/2 mutation-associated BC. Methods: This single-arm, phase II study (NCT00813956) enrolled pts with clinical stage I-IIIA (T ≥ 1cm by MRI) ER-negative (≤ 5%), PR-negative (≤ 5%), and HER2-negative or BRCA1/2 mutation-associated BC. Neoadjuvant G (1000 mg/m2; IV; D1, 8), C (AUC 2; IV; D1, 8), and iniparib (5.6 mg/kg; IV; D1, 4, 8, 11) were given every 21 days for 4 cycles, until the protocol was amended to increase the treatment duration to 6 cycles, with enrollment of 80 pts at multiple PrECOG institutions. The primary endpoint is pathologic complete response (pCR), defined as no invasive carcinoma in the breast and axilla. Pathologic response was centrally assessed by the residual cancer burden (RCB) index. Assuming 76/80 eligible and treated pts, the regimen would be deemed effective if the lower bound of a 90% exact binomial CI on the pCR rate exceeded 25%. Secondary endpoints are safety, MRI response, and breast conservation. Results: Among 80 eligible pts treated with 6 cycles, median age is 48 years, 19 pts have germline BRCA1/2 mutations (90% tested to date) and clinical stage is I (13%), IIA (36%), IIB (36%), IIIA (15%). Pathologic response data (ITT population) are detailed below. 69 pts completed treatment per protocol: 5 progressed, 5 discontinued due to an AE and 1 mutation carrier was lost to follow-up. Most common G3/4 adverse events are neutropenia (49%), elevated ALT/AST (14%), and anemia (10%). Conclusions: Preoperative GC plus iniparib is active in the treatment of early-stage TN and BRCA1/2 mutation-associated BC. Clinical trial information: NCT00813956. [Table: see text]

Neoadjuvant dose-dense sequential biweekly epirubicin and cyclophosphamide followed by docetaxel and trastuzumab for HER2+ operable breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 595-595
Author(s):  
L. Blakely ◽  
B. Somer ◽  
M. Keaton ◽  
R. Hermann ◽  
F. Schnell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Stage ◽  
Single Agent ◽  
Pathologic Complete Response ◽  
Skin Toxicity ◽  
Pathologic Response ◽  
Her2 Breast Cancer ◽  
Grade 3 ◽  
Dose Dense ◽  
Q 14

595 Background: Neoadjuvant (Neo) chemotherapy (CT) with trastuzumab (H) improves pathologic complete response (pCR) rate for HER2+ breast cancer. Dose-dense regimens improve outcome in the adjuvant setting but have not been fully evaluated as preoperative therapy. We designed this regimen to utilize full doses of active agents including docetaxel (T) and H in a novel biweekly schedule to explore efficacy and safety. Methods: Patients (pts) with biopsy proven, clinical stage IIA-IIIC, noninflammatory breast cancer were eligible. HER2+ by FISH was determined locally. CT consisted of epirubicin (E) 100 mg/m2 and cyclophosphamide (C) 600 mg/m2 Q 14 days x 4 followed by T 75 mg/m2 and H 6 mg/kg loading dose, then 4 mg/kg Q 14 days x 4, all with pegfilgrastim support. Surgery was scheduled 20–24 weeks from start after a fifth cycle of H 4mg/kg. EF was measured prior to CT, after EC, after TH and at 6, 12 and 24 months after surgery. Additional adjuvant H to complete 1 year of therapy by conventional schedule was recommended after surgery. The primary endpoint was pCR for invasive cancer in breast and lymph nodes. Results: 30 pts were enrolled at 5 centers: median age was 50.1 (range, 31–72); ethnicity African-American 14, Caucasian 14, other 2; clinical stage IIA, 14, IIB, 4, IIIA, 7, IIIB/C, 5; ER+ 18, PR+ 14; grade 3, 21 and grade 2, 8. Twenty eight pts were evaluable for pathologic response- 2 withdrew before completing treatment, 1 for toxicity. Dose delivery on schedule was >95% for all drugs. Clinical response prior to surgery was cCR 20; cPR 5; and stable 2 pts. Pathologic response: pCR 16 (57%) including 4 with residual DCIS only; 9 pPR, and 2 stable. Mean EF was 63.1 (range, 51–81) before treatment, 62.4 (49–75) after EC and 58.3 (35–74) after TH. Two pts had EF <50% during Neo, one with clinical CHF and 1 additional pt developed CHF during adjuvant single agent H. Both pts had symptomatic improvement with cessation of H. Adverse events were generally mild with 14 grade 3 AEs including 3 episodes of dyspnea and no grade 3 skin toxicity or any grade 4 toxicity noted. Conclusions: Sequential Neo dose-dense Q 14 day EC followed by Q 14 day TH yields a high pCR rate in HER2+ breast cancer with acceptable toxicity profile and no new safety signals noted. No significant financial relationships to disclose.

A phase I-II study of tipifarnib plus weekly paclitaxel (P) followed by dose-dense doxorubicin/cyclophosphamide (AC) in stage IIb-IIIc breast cancer (BC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1118-1118
Author(s):  
Eleni Andreopoulou ◽  
Ivette Sara Vigoda ◽  
Vicente Valero ◽  
Dawn L. Hershman ◽  
George Raptis ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Historical Data ◽  
Clinical Stage ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Stage I ◽  
Weekly Paclitaxel ◽  
Dose Dense ◽  
Phase I And Ii

1118 Background: Tipifarnib (T) is an orally bioavailable farnesyl transferase inhibitor (FTI) that has activity in metastatic BC (J Clin Oncol 2003; 21:2492-9). We previously showed that adding T (200 mg PO BID days 2-7) to preoperative AC was associated with a higher pathologic complete response (pCR) than expected compared with historical data (Clin Cancer Res. 2009;15;2942-8), and preclinical data suggest that FTIs enhance the antineoplastic effects of P (Cancer Res 2005; 65:3883-93). Methods: Eligible pts with HER2-negative clinical stage IIB-IIIC BC received 12 weekly doses of P (80 mg/m2) followed by AC (60/600 mg/m2 every 2 weeks and pegfilgrastim), plus T 100 mg or 200 mg on days 1-3 of each P dose in cohorts of 3-6 pts in the phase I (and T 200 mg PO BID on days 2-7 each AC cycle in both the phase I and II). Simon two-stage design used for the phase II in two strata generally resistant to neoadjuvant chemotherapy. The trial was powered to detect an improvement in breast pathologic complete response (pCR) from 15% to 35% in each stratum (alpha 0.10, beta 0.10), which required breast pCR in at least 4/19 eligible pts in stage I to proceed to stage II, and at least 8/33 pts in stage I and II to be considered promising. Results: Sixty patients accrued in both the phase I and II. Two patients were non evaluable. There were no DLTs in the first 6 evaluable patients treated at dose level 1 and 2.The recommended phase II dose of T identified in the phase I trial was 200 mg BID.All protocol therapy was completed in 43/55 pts (78%) in the phase II, and one pt died of pneumonitis during therapy of uncertain cause. The prespecified efficacy endpoint was not met for either stratum. Conclusions: The addition of the FTI tipifarnib to neoadjuvant sequential weekly paclitaxel followed by dose-dense AC did not result in a higher breast pCR rate compared with historical data. Clinical trial information: NCT00049114. [Table: see text]

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