Results from VERONICA: A randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1004-1004
Author(s):  
Geoffrey J Lindeman ◽  
Rebecca Bowen ◽  
Katarzyna Joanna Jerzak ◽  
Xinni Song ◽  
Thomas Decker ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Single Agent ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Hazard Ratio ◽  
Clinical Activity ◽  
Primary Analysis ◽  
Biomarker Analysis ◽  
Er Positive

1004 Background: For patients (pts) with ER-positive, HER2-negative MBC, CDK4/6 inhibitors + endocrine therapy (ET) is standard first-line treatment, with single-agent ET considered for second-line. Nevertheless, most pts progress. A novel therapeutic target is the antiapoptotic protein BCL2, which is overexpressed in ̃85% of primary ER-positive breast cancers. VEN is a potent, selective BCL2 inhibitor that has shown promising clinical activity in pts with ER-positive and BCL2-positive MBC who have received prior ET. We report the prespecified primary and updated (for overall survival [OS]) analysis of VERONICA (NCT03584009), a phase II study of VEN + F vs F in ER-positive, HER2-negative LA/MBC. Methods: Pts were ≥18-year-old women with ER-positive, HER2-negative LA/MBC, who received ≤2 prior lines of ET and no prior chemotherapy in the LA/MBC setting and experienced disease recurrence/progression during/after CDK4/6 inhibitor therapy (received ≥8 weeks prior). Pts were randomized 1:1 to VEN (oral; 800 mg daily) + F (intramuscular; 500 mg day 1 and 15 of cycle 1; day 1 of subsequent 28-day cycles) or F, and were treated until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end. Pts were stratified by prior lines of therapy in the LA/MBC setting (1 vs 2) and BCL2 status (high vs low). Primary endpoint was clinical benefit rate (CBR; complete response, partial response, and stable disease ≥24 weeks). Secondary endpoints included progression-free survival (PFS) and OS; safety and exploratory subgroup analyses were also conducted. Results: At primary analysis (cutoff: Aug 5, 2020), 103 pts had been randomized (intention-to-treat [ITT] population). Median age was 58.0 and 59.5 years in the VEN + F and F arms, respectively. CBR was similar between arms (VEN + F: 11.8% [n = 6/51; 95% confidence interval (CI) 4.44–23.87]; F: 13.7% [7/51; 5.70–26.26]; risk difference: -1.96% [95% CI -16.86–12.94]). Median PFS was 2.69 months (95% CI 1.94–3.71) in the VEN + F vs 1.94 months (1.84–3.55) in the F arm (stratified hazard ratio: 0.94 [95% CI 0.61–1.45]). Results for CBR and PFS were similar in the BCL2-high and -low subgroups vs the ITT population. More grade 3–4 adverse events (AEs) were observed in the VEN + F vs F arm (n = 13/50 [26%] vs 6/51 [11.8%]). AEs observed with VEN + F were consistent with their individual safety profiles. At updated analysis (cutoff: Oct 22, 2020), OS data were not mature (35.0% event/pt ratio); median OS was 16.99 months in the VEN + F vs not reached in the F arm (stratified hazard ratio: 2.06 [1.04–4.09]). Conclusions: From the primary analysis, VERONICA did not show an improved CBR or PFS with VEN + F, vs F alone, in pts with endocrine- and CDK4/6 inhibitor-refractory LA/MBC. Biomarker analysis is ongoing. Clinical trial information: NCT03584009 .

Randomized, phase II study of two doses of pemetrexed as first-line chemotherapy for locally advanced or metastatic breast cancer (MBC): Clinical results and exploratory pharmacogenomic analysis

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3077-3077 ◽  
Author(s):  
A. Llombart-Cussac ◽  
M. Martin ◽  
N. Harbeck ◽  
R. Anghel ◽  
A. Eniu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Local Therapy ◽  
Response Rates ◽  
Vitamin Supplementation ◽  
Gene Expressions ◽  
Biomarker Analysis

3077 Background: Pemetrexed, a folate antimetabolite, has shown varied response in MBC, depending on the dose, vitamin supplementation, and patient pre-treatment status. We conducted a randomized, double-blind, phase II study, in patients with locally advanced or MBC to evaluate 2 doses of pemetrexed. Primary objective was to assess the response rates on the 2 arms. Methods: Women with histologic/cytologic diagnosis of breast cancer, evidence of locally recurrent disease or distant metastasis, not amenable to local therapy were eligible. Patients received pemetrexed (600 mg/m2 Arm A; or 900 mg/m2 Arm B), on D1 of a 21-day cycle. All patients received folic acid and vitamin B12 supplementation. Forty-three patients were planned on each arm. Results: Ninety-two patients (median age 57 years, range 33–81) enrolled: 47 on arm A and 45 on arm B. Arms A and B had response rates of 17.0% (95% CI, 7.7%-30.8%), and 15.6% (95% CI, 6.5%-29.5%), median progression free survival times of 4.2 and 4.1 months, and median times to tumor progression (TtTP) of 4.2 and 4.6 months, respectively. On both arms, a median of 6 cycles was delivered. Toxicity was mild (grade 3/4 toxicity on both arms; neutropenia <20%, leucopenia <9%). Primary tumor samples from 49 patients were assessed for 10 folate or pyrimidine metabolism related gene expressions by reverse transcriptase-polymerase chain reaction methodology. Two markers, folypolyglutamate synthase (FPGS) and thymidine phosphorylase (TP), showed significant results. Best response rates and median TtTP for high vs low FPGS expression subgroups were 37.5% vs 10.0% and 8.6 vs 3.0 months. The corresponding results for TP were 27.6% vs 6.3% and 5.4 vs 1.9 months. Conclusions: Efficacy and safety of the two pemetrexed doses were similar; thus, the lower dose (600 mg/m2) is suitable in patients with MBC. Exploratory biomarker analysis suggests efficacy correlation for FPGS and TP. Further evaluation of these markers appears warranted. [Table: see text]

Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER.

2018 ◽  
Vol 36 (18_suppl) ◽  
pp. LBA1006-LBA1006 ◽  
Author(s):  
Jose Baselga ◽  
Susan Faye Dent ◽  
Javier Cortés ◽  
Young-Hyuck Im ◽  
Véronique Diéras ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Pik3ca Mutation ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Primary Analysis ◽  
Double Blind ◽  
Er Positive ◽  
Phase Iii Study

LBA1006 Background: Taselisib, a potent, selective PI3K inhibitor, has enhanced activity in PIK3CA-MUT BC cell lines and confirmed partial responses in PIK3CA-MUT BC as a single-agent or with FULV. We assessed taselisib + FULV in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. Methods: SANDPIPER (NCT02340221) is a double-blind, placebo (PBO)-controlled, randomized, phase III study. Postmenopausal pts with disease recurrence or progression during or after an aromatase inhibitor were randomized 2:1 to receive taselisib (4 mg oral, qd) or PBO + FULV (500 mg). Stratification factors were: visceral disease, endocrine sensitivity, and geographic region. Pts with PIK3CA-MUT tumors, assessed by central cobas PIK3CA Mutation Test, were randomized separately from non-MUT tumors. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in pts with PIK3CA-MUT tumors. Secondary endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), duration of objective response (DoR), PFS by blinded independent central review (BICR-PFS), and safety. Results: 516 pts were randomized in the PIK3CA-MUT intention-to-treat (ITT) population. Efficacy is shown in the Table. Taselisib + FULV significantly improved INV-PFS (hazard ratio [HR] 0.70) as confirmed by BICR-PFS (HR 0.66). OS is immature. The most common grade ≥3 adverse events (AEs; preferred terms) in the taselisib + FULV arm in safety-evaluable pts who received ≥ 1 dose of treatment were diarrhea (12%), hyperglycemia (10%), colitis (3%), and stomatitis (2%). AEs led to more taselisib discontinuations (17% v 2%) and dose reductions (37% v 2%), v PBO. Conclusions: Taselisib + FULV significantly improved INV-PFS, v PBO + FULV, in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. The safety profile is largely consistent with previous studies. Clinical trial information: NCT02340221. [Table: see text]

scholarly journals M-VAC combination in locally advanced, locally recurrent or metastatic breast carcinoma. A phase II study

1994 ◽  
Vol 5 (1) ◽  
pp. 93-94 ◽  
Author(s):  
G. Bisagni ◽  
G. Cocconi ◽  
B. Di Blasio ◽  
G. Ceci ◽  
V. De Lisi ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Metastatic Breast Carcinoma ◽  
Locally Recurrent

A Multicentre Phase II Study of the Aminopeptidase Inhibitor, CHR- 2797, in the Treatment of Elderly and/or Previously Treated patients with Acute Myeloid Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 961-961 ◽  
Author(s):  
B. Lowenberg ◽  
F. Davies ◽  
C. Müller-Tidow ◽  
Ulrich Dührsen ◽  
A. Burnett ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Elderly Aml ◽  
Previously Treated Patients ◽  
Previously Treated

Abstract Tosedostat (TSD, CHR-2797) is an aminopeptidase inhibitor that selectively depletes amino acid pools in malignant cells, resulting in anti-proliferative, pro-apoptotic and antiangiogenic effects. In a phase I study, treatment with TSD resulted in complete remission in a number of refractory AML patients. The primary objective of this phase II study was to determine whether TSD was a sufficiently effective therapy to warrant pivotal studies. Methods. This was an open label, single agent, phase II study to assess clinical activity of TSD in elderly and/or previously treated patients with AML/MDS. Patients were treated with once daily oral doses of the maximum acceptable dose (130 mg) of TSD for up to 84 days. Further treatment was allowed if, in the opinion of the investigator, this was considered to be beneficial. Clinical responses were assessed by monthly bone marrow aspirates and weekly hematological assessments. Results. Of the 41 TSD-treated patients with AML (n=38) or MDS (n=3), who were enrolled between March and October 2007, 27 were male, 14 female, with a mean age of 67 years (range 34–82). The median performance status (ECOG) at baseline was 1 (range 0–2). Twelve (31.6%) AML patients and 2 (66.7%) MDS patients were chemotherapy naïve, and 9 (23.7%) AML patients had either secondary disease or adverse cytogenetics. For 16 (39%) patients, treatment with TSD was a second or later salvage attempt. Thirty two patients (30 AML, 2 MDS-RAEB1 and 2) received ≥28 days treatment, and 21 (51.2%) patients completed the formal 84-day study period (19 AML, 2 MDS). Nine (22%) of the patients (7 AML, 2 MDS) continued treatment with TSD after 84 days, and 6 (15%) patients were on TSD in total for more than 6 months (4 AML, 2 MDS). Ten (26.3%) of the AML patients responded to treatment; amongst these, 2 patients received TSD as 2nd/3rd salvage therapy, and a further 2 patients did not show a complete response (CR) after 2 previous induction courses of chemotherapy. Three AML patients achieved a CR (< 5% blasts in bone marrow), of whom 2 were in durable remission (232 days, continuing*; 171 days), and 7 had a partial response (PR, 5–15% blasts) lasting approximately 1–3 months. Two (66.7%) of the MDS patients also responded to treatment with TSD; these patients maintained stable disease for more than 6 months. All responders (CR, PR and SD) were >60 years at the time of the first dose. Median overall survival in AML patients was 130 days (range 8 – 478 days*). The most frequently reported adverse events were: fatigue (61%), thrombocytopenia (49%), pyrexia (39%), peripheral edema (39%) and diarrhea (34%); 9 (22%) patients withdrew due to drug related toxicity. TSD had no effect on hemoglobin or neutrophils. Conclusions. This study in patients with advanced AML/MDS with adverse prognosis demonstrates the anti-leukemic activity of TSD in elderly AML patients, as measured by CR and decreases in leukemic blasts. In addition, 2 relapsed high risk MDS patients achieved disease stabilization. TSD at 130mg qd is also very well tolerated over a long period of exposure (6–10 months). These results support further pivotal studies with TSD in elderly AML and MDS patients.

Phase II Study of the Histone Deacetylase Inhibitor Panabinostat (LBH589) in Patients with Low or Intermediate-1 Risk Myelodysplastic syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1731-1731
Author(s):  
Sophie Dimicoli ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Tapan Kadia ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Median Duration ◽  
Lower Risk ◽  
Response Rate ◽  
Phase Ii Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Number Of Patients ◽  
Deacetylase Inhibitor

Abstract Abstract 1731 Panabinostat is a very potent panhistone deacetylase inhibitor (HDACi) with activity in acute myelogenous leukemia (CCR 2006;12: 4628). We hypothesized that single agent panabinostat could be active in patients with low and intermediate-1 risk MDS. Oral route of administration and safety profile further increased interest in this approach. To test this concept we designed a phase II study of panabinostat for patients above 18 years of age with lower risk disease. Patients could have received prior therapy or be treatment naïve. Appropriate renal, hepatic and cardiac functions were required. Patients were excluded if they had previous HDACi treatment. Patients with history of cardiac pathology such as rhythm alterations were excluded from the study. Use of drugs that could induce QT prolongation and CYP3A4 inhibitors were not allowed. Panabinostat was used at dose of 20 mg orally three times a week for consecutive 3 weeks with cycles repeated every 4 weeks. The primary objective of the study was overall response rate defined by IWG. A maximum of 40 patients could be enrolled. The study was to stop early if the expected response rate was less than 15%. Stopping rules were as follows: Stop if the number of patients with hematologic improvement/the number of patients evaluated was 0/15 or 1/32. The study also contained a stopping rule for non-hematological toxicity. Thirteen patients were enrolled between August 2009 and December 2010. Median age was 70 years (range 47 to 84, 84% of patients older than 60), 70% were transfusion dependent, 70% had intermediate-1 risk MDS, most patients were diploid but one patient with del(5q), one with trisomy 8, one with complex cytogenetics and 2 with deletion of 20q were included. Median percent of marrow blasts was 1% (range 1 to 6%). At start of therapy, median hemoglobin was 9.5 (range 7.5–11.2 G/dL), median platelet count was 56 (range 6–431 k/uL) and median white blood cell count was 4.6 (range 0.8–20.3 k/uL). Approximately 40% had previous therapy for MDS including hypomethylating agents, lenalidomide and investigational agent. Median number of prior therapies for treated patients was 2 (range 1 to 4). Median duration of disease at time of enrollment was 10 months (range 1–50). Patients received a median of 4 cycles of panabinostat (range 1–9). Of 13 patients, 1(8%) achieved a hematological improvement including both an erythroid and platelet response that lasted for 3 months. No complete remissions or partial responses were documented. Six patients (46%) had stable disease for a median duration of 6 months (range 2–13.6). Median overall survival was 15 months (1–31 months). Two patients died because progression to AML. Therapy was well tolerated: no major adverse events were documented except for one patient that developed significant QTc prolongation. Adverse events included mild fatigue and gastrointestinal toxicity. As a biomarker of molecular activity, histone H3 acetylation was measured in 5 patients with variable results. Induction of acetylation was documented in 2. Despite the fact that the stopping rule for activity was not officially met, because of the very modest clinical activity observed, the study was closed to new patient entry. In conclusion, panabinostat given as a single agent orally at a dose of 20 mg thee times a week for 3 weeks followed by one week of rest has limited clinical activity in patients with lower risk MDS. Disclosures: No relevant conflicts of interest to declare.

Phase II study of letrozole in estrogen receptor (ER) positive relapsed epithelial ovarian cancer (EOC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5025-5025 ◽  
Author(s):  
C. Gourley ◽  
J. F. Smyth ◽  
M. Mackean ◽  
A. Stevenson ◽  
A. Williams ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Cytotoxic Agents ◽  
First Line ◽  
Peritoneal Cancer ◽  
Biomarker Analysis ◽  
Er Positive ◽  
Radiological Response

5025 Background: Letrozole is a potent oral aromatase inhibitor which rapidly suppresses circulating estrogen levels by 99% in postmenopausal women. By comparison with cytotoxic agents it is very well tolerated. We previously demonstrated an ‘endocrine sensitive’ subgroup of ovarian cancer patients with ER histoscore cutoff of ≥150 (Bowman et al, Clin Can Res 2002). Methods: This was a phase II study with a planned sample size of 33 patients. Eligible patients had relapsed EOC or primary peritoneal cancer with an ER histoscore of ≥150 and a rising CA125 that had progressed according to Rustin’s criteria. Patients were treated with letrozole 2.5mg daily until clinical or marker evidence of disease progression. The primary endpoint was response according to CA125 and RECIST criteria. Biomarker analysis by tissue microarray is also being performed. Results: 46 patients were accrued, 45 of whom were eligible. The median age was 61 (range 39–81). 24, 10 and 10 patients had received 1,2 and >2 previous lines of chemotherapy respectively. Of 43 patients evaluable for CA125 response, 7 (16%) had a response (decrease of >50%) and 16 (37%) patients had not progressed (doubling of CA125) following 12 weeks on treatment. In the CA125 responders, the nadir CA125 ranged from 0.7–49% of baseline (actual % of baseline: 0.7, 2.6, 11.1, 17.6, 23.6, 42.6, 49). Of the 7 responding patients, 5 had received only one previous line of chemotherapy. The time taken to achieve the nadir CA125 value ranged from 10 to 36 weeks, with a median of 13 weeks. Of 33 patients evaluable for radiological response, 3 (9%) had a PR and 14 (42%) had stable disease at 12 weeks. Overall, 11 patients (26%) had a PFS of >6 months and 2 patients (5%) had a PFS of ≥2 years. Conclusions: To our knowledge this is the first study of a hormonal agent in a selected ER +ve population of ovarian cancer patients. Promising efficacy of the agent is demonstrated in this population of pre-treated patients, many with a considerable bulk of disease. Given the median time of 13 weeks to response, we suggest that this strategy should be tested in ER+ve ovarian cancer patients in the adjuvant setting following first line chemotherapy No significant financial relationships to disclose.

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