A randomized, multicenter, double-blind phase III study of palbociclib (PD-0332991), an oral CDK 4/6 inhibitor, plus letrozole versus placebo plus letrozole for the treatment of postmenopausal women with ER(+), HER2(–) breast cancer who have not received any prior systemic anticancer treatment for advanced disease.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS652-TPS652 ◽  
Author(s):  
Richard S. Finn ◽  
Veronique Dieras ◽  
Karen A. Gelmon ◽  
Nadia Harbeck ◽  
Stephen E. Jones ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Postmenopausal Women ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Advanced Disease ◽  
Phase Iii ◽  
Double Blind ◽  
Patient Reported ◽  
To Receive

TPS652 Background: Palbociclib (PD-0332991) is an orally bioavailable selective inhibitor of CDK4/6 that prevents DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase. In a randomized phase II trial comparing palbociclib (PD-0332991) plus letrozole (P + L) to letrozole (L) in postmenopausal women with ER(+), HER2(–) advanced breast cancer (ABC) who had not received any prior systemic anticancer therapy for their advanced disease, P + L demonstrated significantly longer progression-free survival (PFS) vs L (26.1 vs 7.5 mo; HR = 0.37, P < .001) and was generally well tolerated, with uncomplicated neutropenia as the most frequent adverse event (Finn et al SABCS 2012). Methods: Based on phase II data, a global, randomized, double-blind, phase III clinical trial was designed to demonstrate that P + L provides superior clinical benefit compared with L + placebo in postmenopausal women with ER(+), HER2(–) ABC who have not received any prior systemic therapy for their advanced disease. The study aims to assess whether P + L improves median PFS over L at HR of at least 0.7. Approximately 450 eligible patients with locoregionally recurrent or metastatic, pathologically confirmed ABC who are candidates to receive L as first-line treatment for their advanced disease will be randomized 2:1 to receive either P (125 mg QD 3 wk on, 1 wk off) + L (2.5 mg QD) or L (2.5 mg QD) + placebo. Patients who received anastrozole or letrozole as part of their (neo)adjuvant regimen are eligible if their disease progressed more than 12 months from completion of adjuvant therapy. Tumor tissue is required for participation. Secondary endpoints include overall survival, objective response, duration of response, clinical benefit, safety and tolerability, and patient-reported outcomes of health-related quality of life and disease- or treatment-related symptoms. Clinical trial information: NCT01740427.

Phase II multicenter study of talazoparib for somatic BRCA1/2 mutant metastatic breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1110-TPS1110
Author(s):  
Neelima Vidula ◽  
Erica Blouch ◽  
Nora K. Horick ◽  
Erin Basile ◽  
Senthil Damodaran ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Patient Reported

TPS1110 Background: PARP inhibitors are approved for the treatment of HER2 negative metastatic breast cancer (MBC) with germline BRCA1/2 mutations, based on phase III studies demonstrating an improvement in progression-free survival (PFS) compared to chemotherapy in this population and better patient reported outcomes (Robson, NEJM, 2017; Litton, NEJM, 2018). However, germline BRCA1/2 mutations account for only 5-10% of breast cancer, limiting the current clinical applicability of PARP inhibitors. Somatic BRCA1/2 mutations are detectable in circulating cell-free DNA (cfDNA) in ̃13.5% of patients with MBC; in pre-clinical models, pathogenic somatic BRCA1/2 mutations have been shown to respond to PARP inhibition (Vidula, CCR, 2020). The purpose of this study is to evaluate the efficacy of talazoparib, a PARP inhibitor, in patients with MBC who have somatic BRCA1/2 mutations detectable in cfDNA, in the absence of a germline BRCA1/2 mutation, which we hypothesize will be effective in this setting. This study may help expand the population of patients with MBC who benefit from PARP inhibitors. Methods: This is an investigator initiated multicenter, single arm, phase II clinical trial studying the efficacy of talazoparib in 30 patients with MBC who have pathogenic somatic BRCA1/2 mutations detected in cfDNA. Patients with MBC who are found to have pathogenic somatic BRCA1/2 mutations detected in cfDNA in the absence of a germline BRCA1/2 mutation are eligible. Patients may have triple negative (with ≥ 1 prior chemotherapy), or hormone receptor positive/HER2 negative breast cancer (with ≥ 1 prior hormone therapy). Patients may have received any number of prior lines of chemotherapy, including a prior platinum (in the absence of progression). They must have adequate organ function and ECOG performance status ≤2, and should not have previously received a PARP inhibitor. Patients are treated with talazoparib 1 mg daily until disease progression or intolerability, with serial imaging using CT chest/abdomen/pelvis and bone scan performed at baseline and every 12 weeks, and cfDNA collection every 4 weeks. Primary endpoint is PFS by RECIST 1.1. Patients are being enrolled in a two-stage design with 80% power to demonstrate that the treatment is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety (NCI CTCAE v 5.0). Exploratory analyses include studying serial changes in cfDNA BRCA1/2 mutant allelic frequency and comparing pre-and post-treatment cfDNA for the emergence of BRCA1/2 reversion and resistance mutations. This study is activated and open at Massachusetts General Hospital, where 2 patients are completing screening. It is also opening soon at 6 other academic centers (NCT03990896). Grant support includes a Pfizer ASPIRE award and 2020 Conquer Cancer Foundation of ASCO – Breast Cancer Research Foundation – Career Development Award. Clinical trial information: NCT03990896 .

Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women With Hormone Receptor–Positive, Advanced Breast Cancer: Results From EFECT

2008 ◽  
Vol 26 (10) ◽  
pp. 1664-1670 ◽  
Author(s):  
Stephen Chia ◽  
William Gradishar ◽  
Louis Mauriac ◽  
Jose Bines ◽  
Frederic Amant ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Postmenopausal Women ◽  
Clinical Benefit ◽  
Hormone Receptor ◽  
Advanced Breast ◽  
Phase Iii ◽  
Pharmacokinetic Data ◽  
Double Blind ◽  
Hormone Receptor Positive

Purpose The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor–positive (HR+) breast cancer. Because many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure. Materials and Methods Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR+ advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily. Results A total of 693 women were randomly assigned to fulvestrant (n = 351) or exemestane (n = 342). Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups (hazard ratio = 0.963; 95% CI, 0.819 to 1.133; P = .6531). The overall response rate (7.4% v 6.7%; P = .736) and clinical benefit rate (32.2% v 31.5%; P = .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no significant differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant. Conclusion Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI.

Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer at high risk of disease recurrence (D-CARE): An international, placebo-controlled, randomized, double-blind phase III clinical trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS662-TPS662
Author(s):  
Paul E. Goss ◽  
Carlos H. Barrios ◽  
Arlene Chan ◽  
Dianne M. Finkelstein ◽  
Hiroji Iwata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
High Risk ◽  
Bone Metastasis ◽  
Early Stage ◽  
Early Stage Breast Cancer ◽  
Phase Iii ◽  
Double Blind ◽  
Free Survival ◽  
Patient Reported

TPS662 Background: In women with early-stage breast cancer, bone is a common site of distant recurrence and represents approximately 40% of all first recurrences. Preclinical studies demonstrated that inhibition of RANKL significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab is approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors. The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. The primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Additional endpoints include safety, breast density, time to first on-study SRE (following the development of bone metastasis), patient reported outcomes, and biomarkers. Methods: In this international, randomized, double-blind, and placebo-controlled phase 3 trial, 4509 women with stage II or III breast cancer at high risk for recurrence and with known hormone and HERE2 receptor status were randomized. High risk was defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size > 5 cm (T3), or locally advanced disease (T4). Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination, must be planned. Patients with a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, were not eligible. Patients were randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) were required. The trial, sponsored by Amgen Inc., began enrolling patients in June 2010 and completed enrollment in late 2012. Clinical trial information: NCT01077154.

scholarly journals National Cancer Institute of Canada – Clinical Trials Group (NCIC CTG)

2006 ◽  
Vol 9 (S1) ◽  
pp. 373-401
Author(s):  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Postmenopausal Women ◽  
Primary Breast Cancer ◽  
Randomized Study ◽  
Phase Iii ◽  
Adjuvant Tamoxifen ◽  
Double Blind ◽  
Node Negative ◽  
Increased Risk

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by National Cancer Institute of Canada – Clinical Trials Group (NCIC CTG). Clinical trials include: Double-blind randomized trial of tamoxifen versus placebo in patients with node-positive or high-risk node-negative (tumor ≥ 1 cm and either higher histological grade (poorly differentiated, or SBR grade III or MSBR grade V) or lymphatic/vascular invasion or both) breast cancer who have completed CMF, CEF or AC adjuvant chemotherapy. NCIC CTG Trial MA.12A randomized trial of antiestrogen therapy versus combined antiestrogen and octreotide LAR therapy in the adjuvant treatment of breast cancer in postmenopausal women. NCIC CTG Trial MA.14A phase III randomized double blind study of letrozole versus placebo in women with primary breast cancer completing five or more years of adjuvant tamoxifen. BIG 01-97/NCIC CTG MA.17NCIC CTG MA.17 Companion study (2): The influence of letrozole on bone mineral density in women with primary breast cancer completing five or more years of adjuvant tamoxifen. BIG 01-97/NCIC MA.17BNCIC CTG MA.17 Companion study (1): The influence of letrozole on serum lipid concentrations in women with primary breast cancer who have completed 5 years of adjuvant tamoxifen. BIG 01-97/NCIC CTG MA.17LNCIC CTG MA.17R A double blind re-randomization to letrozole or placebo for women completing 5 years of adjuvant letrozole in the MA.17 study.A phase III study of regional radiation therapy in early breast cancer. NCIC CTG trial MA.20A phase III adjuvant trial of sequenced EC + GCSF Taxol versus sequenced AC → Taxol versus CEF as therapy for premenopausal women and early postmenopausal women who have had potentially curative surgery for node positive or high-risk node negative breast cancer. NCIC CTG Trial MA.21A phase I/II study of increasing doses of epirubicin and docetaxel + pegfilgrastim for locally advanced or inflammatory breast cancer. NCIC CTG Trial MA.22A randomized phase III trial of exemestane versus anastrozole with or without celecoxib in postmenopausal women with receptor positive primary breast cancer. NCIC CTG Trial MA.27A randomized feasibility study of letrozole in postmenopausal women at increased risk for development of breast cancer as evidenced by high breast density. NCIC CTG Trial MAP.1A randomized study of the effect of exemestane (Aromasin) versus placebo on breast density in postmenopausal women at increased risk for development of breast cancer. NCIC CTG Trial: MAP.2A phase III randomized study of exemestane versus placebo in postmenopausal women at increased risk of developing breast cancer. NCIC CTG Trial: MAP.3

The study of tamoxifen and raloxifene (STAR): First report of patient-reported outcomes (PROs) from the NSABP P-2 Breast Cancer Prevention Study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. LBA561-LBA561 ◽  
Author(s):  
P. A. Ganz ◽  
S. R. Land ◽  
D. L. Wickerham ◽  
M. Lee ◽  
M. Ritter ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Statistical Power ◽  
Phase Iii ◽  
Double Blind ◽  
Mixed Effects Modeling ◽  
Sf 36 ◽  
Significant Difference ◽  
Patient Reported ◽  
Musculoskeletal Problems ◽  
Pre Treatment

LBA561 Background: STAR is a double-blind, randomized phase III prevention trial designed to evaluate the relative efficacy of raloxifene (R) compared to tamoxifen (T) in reducing the incidence of invasive breast cancer in high-risk postmenopausal women. In addition to standard safety monitoring, PROs were measured for quality of life (QOL) and symptoms (SXs). Methods: QOL was measured with the MOS SF-36, the CES-D, and the MOS Sexual Activity Questionnaire. SXs were measured using a modified checklist (SCL) from the NSABP P-1 BCPT. Primary endpoints were the SF-36 physical (PCS) and mental (MCS) component scales. A sample size of 1,670 provided statistical power of at least 0.8 (two-tailed test, alpha = .05). The QOL study was open to accrual at selected sites between 1/4/2000 and 5/31/2001, with questionnaires administered at baseline (pre-treatment), q 6 mos until 60 mos, and at 72 mos. SCL data were collected on all STAR participants. Longitudinal analyses used mixed effects modeling for the PCS, MCS, CES-D, and regression analyses were used to compare the average severity of SCL scores between T and R. Results: 19,747 participants enrolled in STAR and were eligible for the SCL assessment, with median follow-up time (mFU) 4.6 yrs. The QOL study enrolled 1,983 participants, 973 assigned to T and 1,010 assigned to R, mFU 5.4 yrs. QOL participants were comparable to women accrued concurrently at non-participating institutions. SCL and QOL forms compliance was high (with a low of 75% at 4.5 yrs for SCL and 74% for QOL). Mean PCS and MCS scores declined modestly over the 60 mos on study, with no significant difference between T and R. Mean CES-D scores worsened slightly on study, but with no significant difference between T and R. However, statistically significant differences (all p’s < .002) were noted between the T and R for severity of SXs, with R women reporting greater musculoskeletal problems, dyspareunia and weight gain and T women reporting greater vasomotor symptoms, leg cramps, bladder and gynecological problems. Conclusions: There were no significant differences between T and R in PROs for physical & mental health or depresson. While SX severity was generally low in this postmenopausal sample, the pattern of SXs differed between T and R. [Table: see text]

Results of ENCORE 301, a randomized, phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive (ER+) breast cancer progressing on a nonsteroidal aromatase inhibitor (AI).

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 268-268 ◽  
Author(s):  
D. A. Yardley ◽  
R. Ismail-Khan ◽  
P. Klein
Keyword(s):  
Breast Cancer ◽  
Postmenopausal Women ◽  
Hormonal Therapy ◽  
Stage Iv ◽  
Phase Iii ◽  
Controlled Study ◽  
Growth Factor Signaling ◽  
Intrinsic Resistance ◽  
Double Blind ◽  
The Impact

268 Background: Hormonal therapy, including AIs, is the mainstay of ER+ breast cancer (BC) treatment; however, both acquired and intrinsic resistance limits its clinical benefit. Entinostat is a novel, oral, class I selective histone deacetylase inhibitor that has been shown to inhibit growth factor signaling pathways that mediate AI resistance. This study was designed to evaluate the impact of the addition of entinostat to exemestane therapy on progression-free survival (PFS). Methods: Postmenopausal women with ER+ advanced BC who had progressed on a non-steroidal AI were randomized to exemestane 25 mg daily + entinostat 5 mg or placebo weekly. Results: A total of 130 women were enrolled (66 exemestane+placebo; 64 exemestane+entinostat). All but 1 patient had Stage IV disease, and 82% had measurable disease. All patients had received prior hormonal therapy (1 prior line 42%; >1 prior line 58%), and 62% had received prior chemotherapy (33% in the advanced BC setting). Analysis of the intent-to-treat population showed that PFS was significantly (defined prospectively as p <0.10) longer with exemestane+entinostat than with exemestane+placebo (4.28 versus 2.27 months, respectively; hazard ratio [HR] = 0.73; p=0.06). Entinostat combined with exemestane was well-tolerated with the most frequent adverse events (AEs) consisting of fatigue, gastrointestinal disturbances, and hematologic abnormalities. AEs with a ≥20% higher incidence with exemestane+entinostat than with exemestane+placebo were fatigue (46% versus 26%, respectively) and uncomplicated neutropenia (25% versus 0%, respectively). The serious AE rate was similar for exemestane+entinostat (13%) and exemestane+placebo (12%). Conclusions: Exemestane+entinostat significantly prolonged the median PFS and reduced the risk of disease progression by 27% versus exemestane+placebo (HR = 0.73). In light of these positive data, a phase III evaluation of this combination is planned.

TJ-107 for the prevention of oxaliplatin-induced peripheral neuropathy: Results of a phase II randomized placebo-controlled clinical trial.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 567-567
Author(s):  
Toru Kono ◽  
Taishi Hata ◽  
Yoshinori Munemoto ◽  
Takanori Matsui ◽  
Hiroshi Kojima ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Peripheral Neuropathy ◽  
Cancer Patients ◽  
Phase Ii ◽  
Gynecologic Oncology ◽  
Phase Iii ◽  
Chemotherapy Response ◽  
Gynecologic Oncology Group ◽  
Response To Chemotherapy ◽  
Patient Reported

567 Background: Oxaliplatin-induced peripheral neuropathy (OPN) continues to be a substantial problem for many cancer patients. In light of the promising data on TJ-107 from a previous pilot study (ASCO-GI, 2009), the present clinical trial was conducted to evaluate its efficacy for the prevention of OPN. To determine whether TJ-107 given as an adjuvant therapy effectively prevents oxaliplatin-induced peripheral neuropathy Methods: A phase II, randomized, double-blind, placebo-controlled trial was conducted in colorectal cancer patients undergoing therapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX). TJ-107 (7.5g) or matching placebo was orally administered three times daily. The primary endpoint was the incidence of grade 2 or greater OPN according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) criteria after 8 cycles of chemotherapy. Patient-reported neurotoxicity symptoms were also assessed using the neurotoxicity subscale of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity (FACT/GOG-Ntx, version 4). Secondary endpoints included the incidence of all grades of OPN after each cycle and chemotherapy response rates. Results: A total of 93 patients were enrolled from May 1, 2009 to March 31, 2010 at 37 participating GONE trial institutions in Japan. Eighty-nine evaluable patients were randomized to either the TJ-107 group (n = 44) or the placebo group (n = 45). Placebo patients showed a significantly higher rate of neurotoxicity than that of TJ-107 patients (p < 0.001), with the median difference in NTX-12 score of 3 and 3.5 at the 8th week and 26th week, respectively. There were no significant between-group differences in response to chemotherapy (55.5% in TJ-107, 39.1% in placebo). In addition, TJ-107 treatment was well tolerated overall. Conclusions: TJ-107 shows promise in reducing the incidence of OPN. Further investigation in a larger phase III trial is necessary before any conclusions can be drawn. [Table: see text]

Randomized, Placebo-Controlled, Double-Blind, Phase II Study of Axitinib Plus Docetaxel Versus Docetaxel Plus Placebo in Patients With Metastatic Breast Cancer

2011 ◽  
Vol 29 (18) ◽  
pp. 2459-2465 ◽  
Author(s):  
Hope S. Rugo ◽  
Alison T. Stopeck ◽  
Anil A. Joy ◽  
Stephen Chan ◽  
Shailendra Verma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Metastatic Breast ◽  
Double Blind ◽  
The Difference ◽  
To Receive

Purpose This multicenter, randomized, double-blind, phase II study assessed safety and efficacy of axitinib plus docetaxel in metastatic breast cancer (MBC). Patients and Methods Women with MBC were randomly assigned 2:1 to receive docetaxel 80 mg/m2 once every 3 weeks plus axitinib 5 mg twice per day (combination arm) or placebo (placebo arm), following a lead-in phase I trial. The primary end point was time to progression (TTP). Results In all, 168 patients were enrolled; 112 were randomly assigned to axitinib and 56 to placebo. Median TTP was numerically longer in the combination arm than in the placebo arm (8.1 v 7.1 months), but this difference was not statistically significant (hazard ratio, 1.24; 95% CI, 0.82 to 1.87; one-sided P = .156). The difference in median TTP was greatest among patients who had received prior adjuvant chemotherapy (9.2 v 7.0 months; P = .043, prespecified subgroup analysis). Objective response rate was higher in the combination arm (41.1% v 23.6%; P = .011). The most common grades 3 to 4 treatment-related adverse events (combination/placebo) included diarrhea (10.8%/0%), fatigue (10.8%/5.4%), stomatitis (12.6%/1.8%), mucositis (9.0%/0%), asthenia (7.2%/0%), and hypertension (4.5%/0%). Three patients in the combination arm experienced serious thromboembolic events (one death). Febrile neutropenia was more frequent in the combination arm (15.3% v 7.1%); rates of other hematologic toxicities were comparable. Increased toxicity with axitinib was generally managed by dose reduction and/or growth factor support. Conclusion The addition of axitinib to docetaxel did not improve TTP in first-line MBC treatment. Combination therapy may be more effective in patients previously exposed to adjuvant chemotherapy.

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