Phase I trial of a sequence-specific combination of the HDAC inhibitor, vorinostat (SAHA) followed by doxorubicin in advanced solid tumor malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3502-3502 ◽  
Author(s):  
A. Daud ◽  
M. Schmitt ◽  
D. Marchion ◽  
E. Bicaku ◽  
S. Minton ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patient ◽  
Phase I ◽  
Histone Acetylation ◽  
Phase I Trial ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Grade 3 ◽  
Topo Ii

3502 Background: Preclinical cell culture and xenograft studies suggest that pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) may potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explores the safety, tolerability and maximum tolerated dose (MTD) of a weekly schedule of escalating vorinostat doses (twice daily days 1–3) followed by doxorubicin (20 mg/m2) on day 3 (3 out of 4 weeks). Histone acetylation and topo II expression are evaluated in pre-and post-vorinostat peripheral blood mononuclear cells and in tumor cells of the 30 patients treated at the MTD. Results: To date, 15 patients [median age 54 (38–73)] have been treated in 4 vorinostat cohorts: 200, 300, 400, 500 mg bid. Tumor types included: breast (3), melanoma (3), pancreatic (2) and one each of SCLC, sarcoma, endometrial, colon, prostate, renal cell and bladder cancer. Dose-limiting toxicities included a grade 3 thrombocytopenia (1/6) at the 400 mg bid dose. Non-dose limiting Grade 3 and 4 toxicities include neutropenia, thrombocytopenia, fatigue, pulmonary embolus, and anemia (1 pt each). Currently, vorinostat doses of 500 mg bid are being evaluated. One confirmed partial response in a breast cancer patient, as well as minor responses in a melanoma and a prostate cancer patient were seen in 10 evaluable patients. Patients received a median number of 2 (1–9+) treatment cycles. Doxorubicin is stopped after 6 cycles and patients continue on vorinostat alone. H3 and H4 histone acetylation and topo II expression will be correlated with vorinostat dose, plasma concentration and response. Conclusion: A sequence-specific combination of vorinostat and doxorubicin is active without exacerbation of doxorubicin toxicity. The tolerated vorinostat dose exceeds the proposed single agent dose for vorinostat derived from patients with hematological malignancies. Histone hyperacetylation occurs in peripheral blood mononuclear cells at all levels. The anti-tumor activity in breast cancer and melanoma will be further explored. No significant financial relationships to disclose.

A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3058-3058
Author(s):  
Amy Patricia Moore ◽  
Thach-Giao Truong ◽  
Kenneth Ted Thurn ◽  
Scott Thomas ◽  
Charles J. Ryan ◽  
...  
Keyword(s):  
Phase I ◽  
Histone Acetylation ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Phase I Trial ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Deacetylase Inhibitor ◽  
Grade 3

3058 Background: Preclinical and clinical data suggest pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) potentiates topoisomerase inhibitors. HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. In vitro data further suggest effective inhibition of HDAC2 is necessary for enhanced epirubicin-induced apoptosis. Methods: This phase I trial explores the safety, tolerability, and maximum tolerated dose (MTD) of escalating doses of panobinostat given orally on days 1, 3, and 5 followed by epirubicin administered intravenously at 75 mg/m2 on day 5 in 21-day cycles. Histone acetylation and HDAC2 expression are evaluated in pre- and post-treatment peripheral blood mononuclear cells (PBMCs) in all patients and in tumor cells of 16 patients treated at the MTD. Results: 36 patients have enrolled [10M/26F, median age 47 years (22-80)] in 5 panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types include melanoma (n=6), breast (n=6), sarcoma (n=16), ovarian (n=2), lung (n=2), and one each of neuroblastoma, pancreatic, testicular, and colon cancer. Prior to enrollment, patients received a median of 3 (0-8) prior chemotherapy regimens and 40% had anthracyclines. Dose-limiting toxicities (DLTs) included 1/3 grade 3 fatigue and 1/3 grade 4 thrombocytopenia at 60 mg of panobinostat, 1/6 patient experienced grade 3 atrial fibrillation at 50 mg, defining 50 mg panobinostat as the MTD. Non-dose–limiting grade 3/4 hematological toxicities include neutropenia (n=19, 53%), febrile neutropenia (n=6, 17%), thrombocytopenia (n=6, 17%), and anemia (n=4, 11%). Of 34 evaluable patients, 5 had partial responses and 14 had stable disease in anthracycline-refractory sarcomas (4) and Her2neu positive breast cancer (2), and small cell lung cancer. Correlative studies demonstrate increased H4 acetylation in PBMCs on day 3 and 5 suggesting sufficient histone deacetylase inhibition. Conclusions: Sequence-specific combination of panobinostat and epirubicin shows early activity without potentiating epirubicin toxicity. Dose expansion in anthracycline-pretreated sarcoma patients is ongoing.

scholarly journals Window-of-Opportunity Study of Valproic Acid in Breast Cancer Testing a Gene Expression Biomarker

2017 ◽  
pp. 1-11 ◽  
Author(s):  
Adam L. Cohen ◽  
Leigh Neumayer ◽  
Ken Boucher ◽  
Rachel E. Factor ◽  
Gajendra Shrestha ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Histone Acetylation ◽  
Triple Negative ◽  
Mononuclear Cells ◽  
Breast Tumors ◽  
Window Of Opportunity ◽  
Ki 67 ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Purpose The anticancer activity of valproic acid (VPA) is attributed to the inhibition of histone deacetylase. We previously published the genomically derived sensitivity signature for VPA (GDSS-VPA), a gene expression biomarker that predicts breast cancer sensitivity to VPA in vitro and in vivo. We conducted a window-of-opportunity study that examined the tolerability of VPA and the ability of the GDSS-VPA to predict biologic changes in breast tumors after treatment with VPA. Patients and Methods Eligible women had untreated breast cancer with breast tumors larger than 1.5 cm. After a biopsy, women were given VPA for 7 to 12 days, increasing from 30 mg/kg/d orally divided into two doses per day to a maximum of 50 mg/kg/d. After VPA treatment, serum VPA level was measured and then breast surgery or biopsy was performed. Tumor proliferation was assessed by using Ki-67 immunohistochemistry. Histone acetylation of peripheral blood mononuclear cells was assessed by Western blot. Dynamic contrast-enhanced magnetic resonance imaging scans were performed before and after VPA treatment. Results Thirty women were evaluable. The median age was 54 years (range, 31-73 years). Fifty-two percent of women tolerated VPA at 50 mg/kg/d, but 10% missed more than two doses as a result of adverse events. Grade 3 adverse events included vomiting and diarrhea (one patient) and fatigue (one patient). The end serum VPA level correlated with a change in histone acetylation of peripheral blood mononuclear cells (ρ = 0.451; P = .024). Fifty percent of women (three of six) with triple-negative breast cancer had a Ki-67 reduction of at least 10% compared with 17% of other women. Women whose tumors had higher GDSS-VPA were more likely to have a Ki-67 decrease of at least 10% (area under the curve, 0.66). Conclusion VPA was well tolerated and there was a significant correlation between serum VPA levels and histone acetylation. VPA treatment caused a decrease in proliferation of breast tumors. The genomic biomarker correlated with decreased proliferation. Inhibition of histone deacetylase is a valid strategy for drug development in triple-negative breast cancer using gene expression biomarkers.

scholarly journals Analysis of circulating breast cancer cell heterogeneity and interactions with peripheral blood mononuclear cells

2020 ◽  
Vol 59 (10) ◽  
pp. 1129-1139 ◽  
Author(s):  
Heather M. Brechbuhl ◽  
Kiran Vinod‐Paul ◽  
Austin E. Gillen ◽  
Etana G. Kopin ◽  
Kari Gibney ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Cell Heterogeneity ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

scholarly journals Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole

2018 ◽  
Vol 10 ◽  
pp. 175883591878685 ◽  
Author(s):  
Hiroshi Umehara ◽  
Yoshimi Maekawa ◽  
Fumito Koizumi ◽  
Makiko Shimizu ◽  
Toshio Ota ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Drug Combination ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Her2 Positive ◽  
Grade 3 ◽  
Mcf 7

Background: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Methods: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. Results: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. Conclusions: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated.

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

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

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

Sign in / Sign up

Export Citation Format

Share Document