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  • American Association for Cancer Research (AACR)  (43)
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  • 1
    Online Resource
    Online Resource
    Abstract GS3-01: A randomized placebo controlled phase III trial of low dose tamoxifen for the prevention of recurrence in women with operated hormone sensitive breast ductal or lobular carcinoma in situ
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. GS3-01-GS3-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. GS3-01-GS3-01
    Abstract: Background: Tamoxifen is an effective drug for breast cancer prevention and treatment, but the risk of endometrial cancer and venous thromboembolism has limited its broader use. We have repeatedly shown in biomarker trials that the minimal effective dose of tamoxifen is lower than 20 mg/day, but a definitive answer on efficacy and safety required a phase III trial. The optimal treatment of ductal carcinoma in situ (DCIS) is still controversial. Methods: We conducted a phase III trial of tamoxifen (T), 5 mg/day versus placebo (P) in women with operated hormone sensitive breast intraepithelial neoplasia (DCIS or LCIS). Women with G3, positive margins or comedo/necrosis DCIS received radiotherapy. Women were seen every 6 months with an annual mammography for at last 5 years after randomization. Initial statistical calculations were revised according to the lower than expected accrual, and the Independent Data Safety Monitoring Board recommended the disclosure of results as 80% of the originally expected events were observed. Results: Between November 1, 2008 and March 31, 2015 a total of 500 women were randomized to either T, 5 mg/day or P for 3 years. A total of 10 patients are not assessable becuse of consent withdrawal or drop out. The main subject characteristics were well balanced between arms. As of May 31, 2018, after a median follow-up of 5.1 years (interquartile range, 3.9-6.3), there were 14 recurrences in the T arm and 29 in the P arm (hazard ratio=0.48, 95% CI, 0.25-0.89, p=0.02). The incidence rate of events was 11.8/1000 py in the T arm and 24.9/1000 py in the P arm. Most recurrences were invasive breast cancers: 11/14 (78%) in the T arm and 16/29 (55%) in the P arm. There were 8 serious adverse events in the T arm and 12 in the P arm, including 2 arterial events in each arm, 2 superficial phlebitis in the T arm and 1 endometrial cancer (annual rate 0.85/1000 py) in the T arm. There were 6 versus 4 second primary cancers in the T and P arm, respectively, and 2 deaths in the P arm. Menopausal symptoms were more frequent in the T arm and will be reported in details at the conference. Baseline characteristics  Tamoxifen (n=246)Placebo (n=244)  mean (SD)mean (SD)Age (yrs) 54.0 (9.4)53.7 (9.1)Body Mass Index (kg/m2) 25.7 (4.8)25.3 (4.2)  n (%)n (%)Menopausal statusPre-110 (45)107 (44) Post-136 (55)137 (56)Type of lesionDCIS221 (89)220 (90) LCIS25 (10)24 (10)Type of surgeryConservative (Q/L)206 (84)200 (82) Mastectomy39 (16)44 (18) Axillary dissection1 (0)-SD=standard deviation; DCIS=ductal carcinoma in situ; LCIS=lobular carcinoma in situ; Q=quadrantectomy; L=lumpectomy Conclusions: Tamoxifen at the dose of 5 mg/day can halve the incidence of recurrence in women with operated hormone sensitive DCIS or LCIS with a limited toxicity, providing a valid treatment option in women with disease. In addition, this study has important implications for the preventive therapy of high risk unaffected women. ClinicalTrials.gov Identifier: NCT01357772; Supported by the Italian Ministry of Health - RFPS-2006-1-339898 and the Italian Association for Cancer Research (AIRC) - IG 2008 Grant no. 5611. Citation Format: DeCensi A, Puntoni M, Guerrieri Gonzaga A, Avino F, Cortesi L, Donadio M, Pacquola M, Falcini F, Gulisano M, Digennaro M, Tienghi A, Cagossi K, Pinotti G, Varicchio C, Caviglia S, Boni L, Bonanni B. A randomized placebo controlled phase III trial of low dose tamoxifen for the prevention of recurrence in women with operated hormone sensitive breast ductal or lobular carcinoma in situ [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-GS3-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 2
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    Efficacy and Determinants of Response to HER Kinase Inhibition in HER2 -Mutant Metastatic Breast Cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Discovery Vol. 10, No. 2 ( 2020-02-01), p. 198-213
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 10, No. 2 ( 2020-02-01), p. 198-213
    Abstract: HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. Significance: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer. This article is highlighted in the In This Issue feature, p. 161
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-19-0966
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
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    P2-19-04: Changes in Adjuvant Treatment of Early Breast Cancer in Italy between 2000 and 2008. The NEMESI Study Versus the NORA Study.
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 24_Supplement ( 2011-12-15), p. P2-19-04-P2-19-04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 24_Supplement ( 2011-12-15), p. P2-19-04-P2-19-04
    Abstract: Background: In the early 2000s, we identified treatment patterns of early breast cancer (EBC) in Italy (NORA study). To ascertain whether attitudes have changed, we conducted a similar study in 2008. Patients and methods: In this retrospective study (NEMESI), we recorded the clinical, tumour and treatment characteristics of 1.894 EBC patients in 63 Italian oncological centres in 2008, and compared the results with those of NORA, on 3.515 patients in 70 same/similar Italian institutions, in 2000–2003. Tumor stage, surgery and endocrine-responsiveness are not comparable because of different recruitment protocols, patients charactheristics and adjuvant treatment strategies are perfectly comparable as a reliable picture of adjuvant strategies in Italy. Results: There was no difference in age class distribution, menopausal status, ECOG performance status, tumor grade, ki67 and estrogen receptors content. HER2 status was simila but determined in 98% of cases in NEMESI vs 46.2% in NORA. The overall use of endocrine treatment (HT) increased from 80.3% in NORA to 83.5% in NEMESI (p = 0.005); the overall use of chemotherapy (CHT) decreased from 68.4% to 57.8% (p = 0.00001). HT alone increased from 31.6% to 42.2% (P = 0.00001) and CHT alone decreased from 18.8% to 16.2% (p = 0.017). The use of both treatments decreased from 49.2% to 41.6% (p = 0.00001). Trastuzumab was never given in NORA and in 15% of cases in NEMESI (85% of all HER2 positive cases). The choice for HT was tamoxifen for 5 years in 32.5% of cases in NEMESI and 86.6% in NORA (p = 0.000001), and aromatase inhibitors for 5 years in 55.2% vs 13.3% of cases, respectively (P = 0.000001). The “switch” from tamoxifen 2–3 years to aromatase inhibitors 2–3 years was planned in 10.1% of cases in NEMESI and actually done in 12.9% of cases in NORA (p = 0.001). The overall use of LHRH analogues was significantly higher in NEMESI vs NORA (26.7% vs 3.0%, p = 0.00001). CMF-like regimens decreased from 37.0% in NORA to 9.1% (p = 0.000001). Anthracycline-containing regimens decreased from 52.1% in NORA to 48.8% in NEMESI; p = 0.0001) in favour of of regimens containing anthracyclines and taxanes, either in combination or sequential (0.9% in NORA vs 38.4% in NEMESIS, p = 0.000001). The use of taxanes alone regimens remained low (3.5% vs 3.7%, ns). The overall use of anthracyclines and taxanes increased from 53.0% to 87.5% and from 4.3% to 42.1%, respectively (both p =0.00001). Conclusions: EBC treatment has changed significantly in 6 years. Adjuvant strategies are significantly different, with a great increase of aromatase inhibitors and LHRH analogues associated with tamoxifen; anthra-taxane combinations have also significantly increased. Financial Support by Sanofi Aventis Italy Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-19-04.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS11-P2-19-04
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 4
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    Abstract P5-11-01: Phamacodynamic and circulating tumor DNA evaluation in a phase I study of GDC-0927, a selective estrogen receptor antagonist/ degrader (SERD)
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P5-11-01-P5-11-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P5-11-01-P5-11-01
    Abstract: Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of ER positive breast cancer. However, despite the effectiveness of available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen. Based on preclinical and clinical data, SERDs are expected be effective in patients harboring ESR1 mutations. Biomarker analysis was performed on plasma and tumor samples from the Phase I study of GDC-0927 in metastatic breast cancer (Dickler et al, SABCS 2017) with the goal of evaluating activity in both ESR1 mutant and wildtype tumors, and to assess ER pathway modulation. Methods: Hotspot mutations in ESR1, PIK3CA, and AKT1 were analyzed in baseline, on-treatment and end of treatment plasma derived circulating tumor DNA (ctDNA) using the BEAMing assay in patients treated at multiple dose levels of GDC-0927. A subset of samples was analyzed with Foundation Medicine's next generation sequencing ctDNA assay (FACT), which covers genomic alterations in 62 commonly altered genes. Paired pre- and on-treatment biopsies were collected to assess ER pathway modulation. ER, PR, and Ki67 protein levels were analyzed by immunohistochemistry. Gene expression analysis was performed using Illumina's RNA Access library preparation kit followed by paired-end (2x50b, 50M reads) sequencing on the HiSeq. Results: Baseline and on-treatment plasma samples were available for 40 patients. ESR1 and PIK3CA mutations were observed in 52% and 33% of patient baseline samples, respectively (BEAMing method). Mutant allele frequencies (MAF) generally declined in the first on-treatment samples collected for both ESR1 (16 out of 21 samples) and PIK3CA (7 out of 12 samples). The majority of the reductions were greater than 95% relative to baseline. Increases in ESR1 MAFs were observed in later time-points and were not associated with any particular ESR1 mutation. There were six instances for which an ESR1 mutation was detected in an on-treatment sample that was not detected in the baseline sample, three at L536P and one each at D538G, L536H, and S463P, and four out of six with MAFs close to the limit of detection. The FACT assay also detected alterations in CDH1, NF1, PTEN, and TP53 in baseline samples. The relationship between MAF changes and clinical benefit to GDC-0927 will be presented. A predefined, experimentally-derived set of ER target genes were evaluated in pre- and on-treatment tumor biopsy pairs from six patients. Four of the six patients showed evidence of suppression in ER pathway activity, one patient treated at the 1000 mg dose level and three at the 1400 mg dose. The degree of pathway suppression was associated with pre-treatment pathway levels and decreases of ER and Ki67 protein levels. Conclusions: We report here evidence of consistent reduction of ESR1 and PIK3CA ctDNA in patients treated with GDC-0927. ER pathway suppression was observed at both the transcript and protein level confirming pharmacodynamic activity of the SERD. Citation Format: Spoerke JM, Daemen A, Chang C-W, Giltnane J, Metcalfe C, Dickler MN, Bardia A, Perez Fidalgo JA, Mayer IA, Boni V, Winer EP, Hamilton EP, Bellet M, Urruticoechea A, Gonzalez Martin A, Cortes J, Martin M, Gates M, Cheeti S, Fredrickson J, Wang X, Friedman LS, Liu L, Li R, Chan IT, Mueller L, Milan S, Lauchle J, Humke EW, Lackner MR. Phamacodynamic and circulating tumor DNA evaluation in a phase I study of GDC-0927, a selective estrogen receptor antagonist/ degrader (SERD) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-11-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P5-11-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 5
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    Abstract PD5-10: A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC)
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 4_Supplement ( 2018-02-15), p. PD5-10-PD5-10
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 4_Supplement ( 2018-02-15), p. PD5-10-PD5-10
    Abstract: Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of ER+ BC. However, despite the effectiveness of available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen. ER antagonists that are efficacious against ligand-dependent and ligand-independent, constitutively active ESR1 mutant tumors may be of substantial therapeutic benefit. GDC-0927 (formerly known as SRN-927) is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader (SERD) that induces tumor regression in ER+ BC patient-derived xenograft models. Methods: A phase I dose escalation study with 3+3 design was conductedin postmenopausal women with ER+ (HER2-) metastatic BC (progressing ≥ 6 months on endocrine therapy and with ≤ 2 prior chemotherapies in the advanced or metastatic setting) to determine the safety, pharmacokinetics (PK) and the recommended Phase 2 dose (RP2D) of GDC-0927. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans. Plasma PK samples (after single dose and at steady state), CT scans, and when feasible, pre and on-study tumor biopsies were obtained Results: From March 16, 2015 to March 17, 2017 patients (pts) with a median age of 53 years (range 44-69) and a median number of prior therapies for MBC 4 (range 1-7) were enrolled at 3 total daily dose levels (600, 1000, 1400 mg) once daily (QD) given orally with fasting (n = 12). Increases in GDC-0927 exposure were approximately dose proportional. Treatment related adverse events (AEs) were all grade 1 or 2. The most common treatment-related AEs were nausea (54%, n = 7), diarrhea (46%, n = 6), elevated aspartate aminotransferase (39%, n = 5) and anemia, constipation, (each 31%, n = 4). Treatment interruption was required for 2 pts due to nausea and vomiting. Of those pts with FES-PET avid disease at baseline (9 of 12), all post-therapy scans showed complete or near complete ( & gt; 90%) suppression of FES uptake to background levels, including pts with ESR1 mutations. Evidence of reduced ER levels and Ki67 staining was observed in on-treatment biopsies. Five of 12 pts (1 at 600 mg and 4 at 1400 mg) were on study ≥ 24 weeks (CBR = 41.6 %) with the best overall response of stable disease with 1 patient (ESR1 mt+ D538G) on study for over 490 days. There were no dose limiting toxicities and no SAEs related to study drug. R2PD was 1400 mg and was selected for single arm dose-expansion which is now complete with last patient enrolled on March 17, 2017. Updated results from dose-escalation and dose-expansion will be presented at the meeting (N = 43). Conclusions: GDC-0927 appears well-tolerated to date with PK exposure supporting QD dosing, evidence of robust PD target engagement, and encouraging anti-tumor activity in heavily pretreated pts with advanced or metastatic ER+ BC, including pts with ESR1 mutations. Citation Format: Dickler MN, Villanueva R, Perez Fidalgo JA, Mayer IA, Boni V, Winer EP, Hamilton EP, Bellet M, Urruticoechea A, Gonzalez-Martin A, Cortes J, Martin M, Giltnane J, Gates M, Cheeti S, Fredrickson J, Wang X, Friedman LS, Spoerke JM, Metcalfe C, Liu L, Li R, Morley R, McCurry U, Chan IT, Mueller L, Milan S, Lauchle J, Humke EW, Bardia A. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-10.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS17-PD5-10
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 6
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    First-in-Human Dose-Escalation Study of Cyclin-Dependent Kinase 9 Inhibitor VIP152 in Patients with Advanced Malignancies Shows Early Signs of Clinical Efficacy
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 7 ( 2022-04-01), p. 1285-1293
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 7 ( 2022-04-01), p. 1285-1293
    Abstract: To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor. Patients and Methods: Adults with solid tumors or aggressive non–Hodgkin lymphoma who were refractory to or had exhausted all available therapies received VIP152 monotherapy as a 30-minute intravenous, once-weekly infusion, as escalating doses (5, 10, 15, 22.5, or 30 mg in 21-day cycles) until the MTD was determined. Results: Thirty-seven patients received ≥ 1 VIP152 dose, with 30 mg identified as the MTD based on dose-limiting toxicity of grade 3/4 neutropenia. The most common adverse events were nausea and vomiting (75.7% and 56.8%, respectively), all of grade 1/2 severity. Of the most common events, grade 3/4 events occurring in & gt; 1 patient were neutropenia (22%), anemia (11%), abdominal pain (8%), increased alkaline phosphatase (8%), and hyponatremia (8%). Day 1 exposure for the MTD exceeded the predicted minimum therapeutic exposure and reproducibly achieved maximal pathway modulation; no accumulation occurred after multiple doses. Seven of 30 patients with solid tumors had stable disease (including 9.5 and 16.8 months in individual patients with pancreatic cancer and salivary gland cancer, respectively), and 2 of 7 patients with high-grade B-cell lymphoma with MYC and BCL2/BCL6 translocations (HGL) achieved durable complete metabolic remission (ongoing at study discontinuation, after 3.7 and 2.3 years of treatment). Conclusions: VIP152 monotherapy, administered intravenously once weekly, demonstrated a favorable safety profile and evidence of clinical benefit in patients with advanced HGL and solid tumors.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-3617
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 7
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    Abstract OT2-6-01: Phase 2 study of palbociclib (CDK 4/6 inhibitor) for ER positive, HER2- negative post-menopausal advanced breast cancer patients recurring after hormonal therapy (to reverse endocrine resistance - TREnd trial)
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 24_Supplement ( 2013-12-15), p. OT2-6-01-OT2-6-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 24_Supplement ( 2013-12-15), p. OT2-6-01-OT2-6-01
    Abstract: Background: Palbociclib (PD-0332991) is an orally active, potent and highly selective inhibitor of CDK4/6 that prohibits progression of the cell cycle from G1 into S phase and has shown activity in ER positive breast cancer in vivo and in vitro. Recently, in phase 2 settings, palbocilcib extended PFS in combination with letrozole as first-line hormonal treatment for advanced breast cancer (ABC) (Finn R.S. et al. Cancer Res., Dec 2012; 72: S1-6) and showed single agent activity in patients with ER positive ABC relapsed to several lines of therapy (DeMichele A. et al., ASCO 2013). Given pre-clinical evidence on the relevance of Cyclin D-CDK4/6-E2F signalling in the development of acquired resistance to hormonal therapy, CDK4-6 inhibition might be a strategy to overcome resistance in tumors who have progressed after hormonal therapy for metastatic disease. Study design: This is an investigator initiated, open-label, multicenter, randomized, Phase 2 trial for patients with ER+ HER2 negative ABC who have experienced progression on first or second line hormonal therapy. Other eligibility criteria include: ≤1 previous line of chemotherapy for ABC; measurable disease; and available archival tumor tissue for translational studies. Consenting patients are randomized (1:1) to receive, until progression of disease, unacceptable toxicity or consent withdrawal, either ARM A) palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment or ARM B) palbociclib in combination with the hormonal therapy to which the patient has experienced progression in the previous line of treatment (anastrozole 1 mg/d, letrozole 2.5 mg/d, exemestane 25 mg/d, fulvestrant 500mg/4 weeks). Patients are stratified according to: number or prior lines of hormonal therapy (1 vs. 2); disease site (visceral vs. non visceral); duration of prior line of hormonal therapy ( & gt;6 vs. ≤6 months); treating center. The primary endpoint is clinical benefit (CB) (i.e. complete response, partial response, stable disease≥ 24 weeks), based on local assessment of response using RECIST 1.1 criteria. Key secondary endpoints are: objective response rate, duration of response, time to progression, progression-free survival, overall survival and assessment of exploratory tissue markers of response. Statistical methods: A two-stage optimal phase 2 design is used to assess the activity of each of the two treatment regimens. Assuming P0≤20% (inactivity), P1≥ 40% (activity) and α = 10%, a sample size of 50 evaluable patients per treatment arm is required for a statistical power equal to 90%. In case of inactivity, enrolment could be stopped in each arm after 25 evaluable patients. This study does not provide adequate power for a two arm comparison. Target accrual: the study is actively recruiting in 3 Italian centers and is expected to involve additional 7 centers in Italy by the end of 2013. The first patient was enrolled in October 2012 and, as per June 2013, a total of 9 patients have been enrolled, 8 remain on treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS13-OT2-6-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 8
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    Abstract GS4-01: Pooled analysis of five randomized trials investigating temporary ovarian suppression with gonadotropin-releasing hormone analogs during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 4_Supplement ( 2018-02-15), p. GS4-01-GS4-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 4_Supplement ( 2018-02-15), p. GS4-01-GS4-01
    Abstract: Background The role of temporary ovarian suppression with gonadotropin-releasing hormone analogs (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients remains highly controversial. This option is considered experimental by the ASCO and ESMO guidelines on fertility preservation in cancer patients. The present pooled analysis aimed at elucidating the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients. Patients and methods This study included individual patient data from 5 trials (PROMISE-GIM6, POEMS/SWOG S0230, Anglo Celtic Group OPTION, GBG-37 ZORO, Moffitt-led trial) in which premenopausal women with early breast cancer were randomized to receive (neo)adjuvant chemotherapy alone or with concurrent administration of GnRHa. Efficacy endpoints were premature ovarian insufficiency (POI, according to the definition used as primary endpoint in the included trials), 1- and 2-year amenorrhea rates and post-treatment pregnancy rate. Safety endpoints were disease-free survival (DFS) and overall survival (OS). Odds ratio (OR), incidence rate ratio (IRR) and hazard ratio (HR) with 95% confidence intervals (CI) were calculated for the effect of adding GnRHa to chemotherapy alone. As each study represents a cluster, statistical analysis has been performed using a random effects model. The study is registered with the PROSPERO registration number CRD42014015638. Results A total of 873 patients from 5 randomized trials were included. Median age was 38 years (interquartile range: 34-42 years). POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted OR 0.38; 95% CI 0.26-0.57; p & lt; 0.001). The incidence of 1-year amenorrhea was 36.8% in the GnRHa group and 40.4% in the control group (adjusted OR 0.92; 95% CI 0.66-1.28; p = 0.623). The incidence of 2-year amenorrhea was 18.2% in the GnRHa group and 30.0% in the control group (adjusted OR 0.51; 95% CI 0.31-0.85; p = 0.009). A total of 37 patients had at least one post-treatment pregnancy in the GnRHa group and 20 in the control group (IRR 1.83; 95% CI 1.06-3.15; p = 0.030). There were no significant differences in DFS (adjusted HR 1.01; 95% CI 0.72-1.42; p = 0.999) or OS (adjusted HR 0.67; 95% CI 0.42-1.06; p = 0.083) between the GnRHa and control groups. Subgroup analyses of both efficacy and safety endpoints according to age of the patients, hormone receptor status, type and duration of chemotherapy will be presented at the conference. Conclusions This study provides level 1A of evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy in premenopausal early breast cancer patients. Given the findings of this pooled analysis, temporary ovarian suppression with GnRHa during chemotherapy should be considered as a new standard option to reduce the likelihood of chemotherapy-induced POF and possibly improve future fertility in premenopausal early breast cancer patients. Citation Format: Lambertini M, Moore HCF, Leonard RCF, Loibl S, Munster P, Bruzzone M, Boni L, Unger JM, Anderson RA, Mehta K, Minton S, Poggio F, Albain KS, Adamson DJA, Gerber B, Cripps A, Bertelli G, Seiler S, Ceppi M, Partridge AH, Del Mastro L. Pooled analysis of five randomized trials investigating temporary ovarian suppression with gonadotropin-releasing hormone analogs during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS17-GS4-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 9
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    A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody–Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 23 ( 2019-12-01), p. 6986-6994
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 23 ( 2019-12-01), p. 6986-6994
    Abstract: ADCT-402 (loncastuximab tesirine) is an antibody–drug conjugate comprising a CD19-targeting antibody and pyrrolobenzodiazepine dimers. A first-in-human study evaluated the safety and preliminary clinical activity of loncastuximab tesirine in patients with B-cell non-Hodgkin lymphoma (NHL). Patients and Methods: A multicenter, phase I, dose-escalation and dose-expansion study enrolled patients ages ≥18 years with relapsed/refractory (R/R) B-cell NHL. Patients received loncastuximab tesirine every 3 weeks at doses assigned by a 3+3 dose-escalation design. Dose escalation was used to assess the safety and tolerability of loncastuximab tesirine to determine the dose for expansion. Secondary objectives evaluated clinical activity, characterized the pharmacokinetic profile, and evaluated antidrug antibodies. Results: During dose escalation, 88 patients with R/R B-cell NHL were treated with loncastuximab tesirine at doses 15 to 200 μg/kg. Treatment-emergent adverse events (TEAEs) were experienced by 87/88 (98.9%) patients. Most common TEAEs (≥20% of patients) were hematologic abnormalities, fatigue, edema, liver test abnormalities, nausea, rash, and dyspnea. Grade ≥3 TEAEs (≥5% of patients) included hematologic abnormalities, liver test abnormalities, fatigue, and dyspnea. Overall response rate at doses ≥120 μg/kg was 59.4% (41 of 69 patients; 40.6% complete response; 18.8% partial response). Median duration of response, progression-free survival, and overall survival (all doses) were 4.8, 5.5, and 11.6 months, respectively. Drug exposure increased with increasing dose, showing moderate accumulation with multiple doses ≥150 μg/kg. There was no evidence of immunogenicity. Conclusions: Loncastuximab tesirine had promising activity with acceptable safety in this dose-escalation study. A phase II study with initial dosing at 150 μg/kg has been initiated based on these results.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-19-0711
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
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    A Phase II Trial of the CD40 Agonistic Antibody Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Confirmed Disease Progression on Anti-PD-1 Therapy
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research ( 2023-08-22), p. OF1-OF8
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), ( 2023-08-22), p. OF1-OF8
    Abstract: Disease progression during or after anti-PD-1-based treatment is common in advanced melanoma. Sotigalimab is a CD40 agonist antibody with a unique epitope specificity and Fc receptor binding profile optimized for activation of CD40-expressing antigen-presenting cells. Preclinical data indicated that CD40 agonists combined with anti-PD1 could overcome resistance to anti-PD-1. Patients and Methods: We conducted a multicenter, open-label, phase II trial to evaluate the combination of sotigalimab 0.3 mg/kg and nivolumab 360 mg every 3 weeks in patients with advanced melanoma following confirmed disease progression on a PD-1 inhibitor. The primary objective was to determine the objective response rate (ORR). Results: Thirty-eight subjects were enrolled and evaluable for safety. Thirty-three were evaluable for activity. Five confirmed partial responses (PR) were observed for an ORR of 15%. Two PRs are ongoing at 45.9+ and 26+ months, whereas the other three responders relapsed at 41.1, 18.7, and 18.4 months. The median duration of response was at least 26 months. Two additional patients had stable disease for & gt;6 months. Thirty-four patients (89%) experienced at least one adverse event (AE), and 13% experienced a grade 3 AE related to sotigalimab. The most common AEs were pyrexia, chills, nausea, fatigue, pruritus, elevated liver function, rash, vomiting, headache, arthralgia, asthenia, myalgia, and diarrhea. There were no treatment-related SAEs, deaths, or discontinuation of sotigalimab due to AEs. Conclusions: Sotigalimab plus nivolumab had a favorable safety profile consistent with the toxicity profiles of each agent. The combination resulted in durable and prolonged responses in a subset of patients with anti-PD-1-resistant melanoma, warranting further evaluation in this setting.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-23-0475
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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