scholarly journals The CDK9 Inhibitor, Alvocidib, Potentiates the Non-Clinical Activity of Azacytidine or Decitabine in an MCL-1-Dependent Fashion, Supporting Clinical Exploration of a Decitabine and Alvocidib Combination

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4355-4355
Author(s):  
Wontak Kim ◽  
Clifford Whatcott ◽  
Adam Siddiqui-Jain ◽  
Stephen Anthony ◽  
David J. Bearss ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Viability ◽  
Single Agent ◽  
Xenograft Model ◽  
Complete Response ◽  
Tumor Growth Inhibition ◽  
Phase 2 ◽  
Phase 1B ◽  
Cdk9 Inhibitor

Abstract The hypomethylating agents (HMAs) azacytidine and decitabine exert biological activity via two distinct mechanisms, namely, DNA damage and inhibition of DNA methyltransferases. Azacytidine and decitabine are indicated in the treatment of patients with myelodysplastic syndromes (MDS). As a result of DNA methyltransferase inhibition, it is hypothesized that HMAs may function by inducing re-expression of key pro-apoptotic proteins such as NOXA, which sequesters the anti-apoptotic protein MCL-1, preventing its association with the mitochondrial pore-forming proteins BAX/BAK. Activity of the potent CDK9 inhibitor, alvocidib, is largely driven by targeting of CDK9-dependent MCL-1 expression. Alvocidib is under active clinical investigation, but has also has demonstrated high complete response rates in newly diagnosed AML patients, particularly when administered as part of a cytarabine and mitoxantrone containing regimen (ACM regimen). Given the dual NOXA/MCL-1-targeting ability of combining alvocidib and azacytidine or decitabine, the combination may synergize therapeutically in the treatment of non-clinical models of AML or MDS by means of transcriptional induction of NOXA and repression of MCL-1 expression. Cell viability and induction of apoptosis was assessed following treatment with alvocidib, azacytidine, and decitabine in cells using the Celltiter-Glo and Caspase-Glo assays. Gene expression changes following treatment were assessed using quantitative RT-PCR. Protein expression changes with treatment were also measured using standard immunoblotting technique. To assess the in vivo anti-tumor activity of these compounds, xenograft studies in the MOLM13 and additional models of MDS, exploring sequencing and scheduling of alvocidib administration with HMAs, were performed. Treatment of AML cell lines with alvocidib inhibited both mRNA and protein expression of MCL-1 in a time and concentration-dependent fashion. Pre-treatment of cells with alvocidib, to repress MCL-1 expression prior to azacytidine treatment, reduced the azacytidine cell viability EC50 more than 2.5-fold, from 1.8 µM to 0.6 µM in MV4-11 cells. The alvocidib/azacytidine combination also resulted in synergistic increases in caspase activity relative to either single agent within the combination, at multiple dose levels. The combination of azacytidine or decitabine with alvocidib was active in the MOLM13 xenograft model, yielding up to 65.7 or 91.1% tumor growth inhibition (%TGI) in the azacytidine or decitabine combination, respectively. Taken together, the in vitro and in vivo studies indicated that decitabine was more effective at re-expressing NOXA and potentiating alvocidib activity compared to azacytidine. These non-clinical data suggest that an alvocidib/HMA combination may constitute a viable therapeutic regimen whose rationale focuses on hypertargeting of NOXA/MCL-1. Based on these non-clinical results, a Phase 1b/2 clinical study of alvocidib administered in sequence after decitabine in patients with intermediate to high risk MDS is being conducted (Zella 102). Patients will be enrolled in cohorts of 3-6 patients with decitabine administered as a 1-hour IV infusion daily on days 1 to 5 at a dose of 20 mg/m2 followed by a single alvocidib treatment on day 8 as a loading dose over 30 minutes followed by a 4-hour infusion. Treatment will be repeated every 28 days until disease progression or unacceptable toxicity. Enrollment will include MDS patients (Phase 1b) with previously untreated MDS and patients who received fewer than six (6) cycles of previous HMAs, as well as (Phase 2) untreated patients with de novo or secondary MDS. The primary objective is to determine the maximum tolerated dose and recommended Phase 2 dose of alvocidib when administered in sequence with decitabine. Key Phase 2 endpoints will include complete response rate and improvement in transfusion dependency. Disclosures Kim: Tolero Pharmaceuticals, Inc: Employment. Whatcott:Tolero Pharmaceuticals, Inc: Employment. Siddiqui-Jain:Tolero Pharmaceuticals, Inc: Employment. Anthony:Tolero Pharmaceuticals, Inc: Employment. Bearss:Tolero Pharmaceuticals, Inc: Employment. Warner:Tolero Pharmaceuticals: Employment.

Phase I trial of KOS-953, a heat shock protein 90 inhibitor, and trastuzumab (T)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 501-501 ◽  
Author(s):  
S. Modi ◽  
A. Stopeck ◽  
M. S. Gordon ◽  
D. Solit ◽  
W. Ma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Intracellular Signaling ◽  
Single Agent ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Tumor Growth Inhibition ◽  
Phase 2 ◽  
Drug Induced ◽  
Her2 Breast Cancer

501 Background: KOS-953 (17-AAG in Cremophor) is a potent Hsp90 inhibitor that in vivo induces rapid degradation of Her2, loss of pAKT and tumor growth inhibition in a Her2+ breast cancer xenograft. Objectives: Define the phase 2 dose of KOS-953 + T. Define toxicity and PK of KOS-953, its active metabolite and T. Assess changes in intracellular signaling proteins (such as Hsp70) in leucocytes. Describe antitumor activity. Methods: Eligible pts with advanced solid tumors (Her2 + was not required) received standard weekly doses of T followed by IV KOS-953 in escalating doses over 2 hrs. Results: 25 pts enrolled in 4 cohorts (225, 300, 375 and 450 mg/m2; 4, 3, 8 and 10 patients per cohort), receiving a total of 94 cycles (median 3, range <1 - 12+). Demographics: 21 female (17 with Her2+ metastatic breast cancer ‘MBC‘, 1 Her2 status unknown); median age/KPS 66 yrs/90; # prior T-containing regimens for MBC pts (n=18) equaled 2 (range 0–5). DLT was observed at the 3rd and 4th cohort (1 pt each): 2-week dose delay for recovery from Grade 4 fatigue/Grade 2 nausea & anorexia at 375 mg/m2; delayed recovery of platelets at 450 mg/m2. Drug-related Grade 3 toxicity: emesis, increased ALT and hypersensitivity (n=2); Grade 4 drug-induced thrombocytopenia in a pt with Hashimoto’s disease after 7 cycles. In general the drug was well tolerated. Grade 1 or 2 toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT and anorexia. Most toxicities (except headache) were not dose dependent. PK of parent (n=21): t½ 3.0 ± 2.1 h; clearance 31.8 ± 12.8 L/h; Vz 164 ± 101 L. Metabolite: Tmax 30–60 min after end-of-infusion with similar AUC and longer t½ of 6.1 ± 1.7 h. PK of T showed no changes compared to previous reports. Among 17 pts with Her2 + MBC s/p multiple regimens of T: PR= 1, MR = 3, 5 pts with SD (5, 7+, 9 and 12+ months). Pts with PR and MRs had confirmed progression of disease prior to study on T-containing regimen. Pharmacodynamic testing showed reactive induction of Hsp70/72 in leucocytes at all dose levels. Conclusions: KOS-953 added to T is active in refractory Her2 + MBC with no change in PK compared to single-agent therapy. The phase 2 dose of KOS-953 is 450 mg/m2; enrollment to the phase 2 trial of this combination in Her2+ MBC is on-going. [Table: see text]

341 Phase 1b/2 study of BXCL701, an oral activator of the systemic innate immunity pathway, combined with pembrolizumab (pembro), in men with metastatic castration-resistant prostate cancer (mCRPC)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A366-A366
Author(s):  
Rahul Aggarwal ◽  
Dan Costin ◽  
Jingsong Zhang ◽  
Paul Monk ◽  
Mark Linch ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Single Agent ◽  
Objective Response ◽  
Fixed Dose ◽  
Tumor Growth Inhibition ◽  
Low Grade ◽  
Phase 2 ◽  
Split Dose ◽  
Cytokine Activation ◽  
Phase 1B

BackgroundBXCL701 (talabostat) is an oral small molecule inhibitor of dipeptidyl peptidases (DPP) primarily DPP8 and DPP9, which triggers inflammasome mediated pyroptosis in macrophages leading to induction of IL-18 and IL-1beta, bridging between innate and adaptive immunity. PD-L1 expression correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor growth inhibition was observed with BXCL701 plus checkpoint inhibition. In a prior clinical study, single-agent BXCL701 resulted in objective responses in patients (pts) with Stage IV melanoma (unpublished).MethodsIn Phase 1b portion of this multicenter study, eligible pts had progressing mCRPC (PCWG3), at least 1 prior systemic therapy, ≤ 2 lines of cytotoxicchemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anticancertherapy. Using a 3+3 design, pts received fixed-dose pembro (200 mgIV q21-days) with escalating doses of BXCL701 on days 1–14. The primary endpoint was determination of the recommended Phase 2 dose (RP2D). Response (RECIST 1.1, PSA, CTC), plasma drug concentration and change in relevant immune effector cytokines were also evaluated.Results13 pts were treated in 3 cohorts of BXCL701: 0.4 mg qd (n = 3); 0.6 mg qd (n = 3) and 0.6 mg split dose (n=7). 7 pts had adenocarcinoma, 6 had small cell/neuroendocrine prostate cancer features. Prior treatment included ADT (n = 10), 2nd-generation androgen signaling inhibitors (n = 9), chemotherapy (n = 11), RT (n = 11). On-target AEs consistent with cytokine activation were seen at the highest dose levels. In the 0.6 mg qd cohort, all pts had events consistent with cytokine release: 3/3 had hypotension (including 1 grade 3 syncope (DLT)) and 2pts each had dizziness and LE edema. Splitting the 0.6 mg dose improved the tolerability while maintaining the TDD previously associated with objective response; 3/7 pts had fatigue, and 1pt each had low grade hypotension, dyspnea, chills, myalgia. Preliminary anti-tumor activity was seen with 1 pt achieving a PSA response and 3 pts with RECIST1.1 stable disease. BXCL701 was quantifiable in plasma. Consistent dose and time dependent increases in serum IL-18 levels were observed with 0.6 mg split dose.ConclusionsBXCL701 0.3 mg BID (0.6 mg TDD) administered on days 1–14 was identified as the RP2D when administered with pembro 200 mg every 21 days. Splitting the TDD was associated with improved tolerability as evidenced by no reported DLTs and lower rates of other adverse events of interest such as hypotension and peripheral edema. The Phase 2 portion of the study is enrolling.AcknowledgementsAll patients, their families, and caregivers who make this study possible; the participating investigators and their staff; Cedric Burg PhD and J. MacDougall PhD of BioXcel Therapeutics, Valery Chatikhine MD of Iqvia Biotech and the Iqvia Biotech team for assisting in the conduct of the study.Trial RegistrationNCT03910660EUDRACT 2018-003734-32Ethics ApprovalThis study was approved by Institution Review Boards or Ethics Committees affiliated with participating institutions.

scholarly journals Natural Antioxidant Resveratrol Suppresses Uterine Fibroid Cell Growth and Extracellular Matrix Formation In Vitro and In Vivo

Antioxidants ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 99 ◽  
Author(s):  
Chen ◽  
Lin ◽  
Shih ◽  
Wang ◽  
Hong ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Protein Expression ◽  
Cell Viability ◽  
Xenograft Model ◽  
B Cell Lymphoma ◽  
Nuclear Antigen ◽  
Mrna Levels ◽  
Messenger Ribonucleic Acid

Resveratrol (RSV) is a polyphenolic phytoalexin found in peanuts, grapes, and other plants. Uterine fibroids (UF) are benign growths that are enriched in extracellular matrix (ECM) proteins. In this study, we aimed to investigate the effects of RSV on UF using in vivo and in vitro approaches. In mouse xenograft models, tumors were implanted through the subcutaneous injection of Eker rat-derived uterine leiomyoma cells transfected with luciferase (ELT-3-LUC) in five-week-old female nude (Foxn1nu) mice. When the tumors reached a size of 50–100 mm3, the mice were randomly assigned to intraperitoneal treatment with RSV (10 mg·kg−1) or vehicle control (dimethyl sulfoxide). Tumor tissues were assayed using an immunohistochemistry analysis. We also used primary human leiomyoma cells as in vitro models. Cell viability was determined using the sodium bicarbonate and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The protein expression was assayed using Western blot analysis. The messenger ribonucleic acid (mRNA) expression was assayed using quantitative reverse transcription–polymerase chain reaction (qRT–PCR). Cell apoptosis was assayed using Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) and Hoechst 33342 staining. RSV significantly suppressed tumor growth in vivo and decreased the proportion of cells showing expression of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA). In addition, RSV decreased the protein expression of PCNA, fibronectin, and upregulated the ratio of Bax (Bcl-2-associated X) and Bcl-2 (B-cell lymphoma/leukemia 2) in vivo. Furthermore, RSV reduced leiomyoma cell viability, and decreased the mRNA levels of fibronectin and the protein expression of collagen type 1 (COL1A1) and α-SMA (ECM protein marker), as well as reducing the levels of β-catenin protein. RSV induced apoptosis and cell cycle arrest at sub-G1 phase. Our findings indicated the inhibitory effects of RSV on the ELT-3-LUC xenograft model and indicated that RSV reduced ECM-related protein expression in primary human leiomyoma cells, demonstrating its potential as an anti-fibrotic therapy for UF.

scholarly journals EXTH-46. ARTIFICIAL INTELLIGENCE-BASED IDENTIFICATION OF COMBINED VANDETANIB AND EVEROLIMUS IN THE TREATMENT OF ACVR1-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii97-ii97
Author(s):  
Diana Carvalho ◽  
Peter Richardson ◽  
Nagore Gene Olaciregui ◽  
Reda Stankunaite ◽  
Cinzia Emilia Lavarino ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Cell Viability ◽  
Xenograft Model ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Serine Threonine Kinase ◽  
Orthotopic Xenografts ◽  
Extended Survival

Abstract Somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2 receptor, are found in a quarter of children with the currently incurable brain tumour diffuse intrinsic pontine glioma (DIPG). Treatment of ACVR1-mutant DIPG patient-derived models with multiple inhibitor chemotypes leads to a reduction in cell viability in vitro and extended survival in orthotopic xenografts in vivo, though there are currently no specific ACVR1 inhibitors licensed for DIPG. Using an Artificial Intelligence-based platform to search for approved compounds which could be used to treat ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an approved inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd=150nM) and reduce DIPG cell viability in vitro, but has been trialed in DIPG patients with limited success, in part due to an inability to cross the blood-brain-barrier. In addition to mTOR, everolimus inhibits both ABCG2 (BCRP) and ABCB1 (P-gp) transporter, and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination is well-tolerated in vivo, and significantly extended survival and reduced tumour burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Based on these preclinical data, three patients with ACVR1-mutant DIPG were treated with vandetanib and everolimus. These cases may inform on the dosing and the toxicity profile of this combination for future clinical studies. This bench-to-bedside approach represents a rapidly translatable therapeutic strategy in children with ACVR1 mutant DIPG.

scholarly journals 846 Pre-clinical validation of a FLT3L-fusion protein for dendritic cell expansion and anti-tumor efficacy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A887-A887
Author(s):  
Michelle Kuhne ◽  
Hamlet Chu ◽  
Sarah Ng ◽  
Christopher Clarke ◽  
Brian Carr ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Fusion Protein ◽  
Tyrosine Kinase ◽  
Single Agent ◽  
Tumor Growth Inhibition ◽  
Cell Responses ◽  
Dose Dependent ◽  
Cell Death Protein

BackgroundThe ligand for the receptor tyrosine kinase FMS-like tyrosine kinase 3 (FLT3) plays an importantrole in hematopoiesis. FLT3 signaling is required for the differentiation andexpansion of dendritic cells. In the context of cancer immunity, the conventional dendritic cellsubtype 1 (cDC1) are required for the generation of tumor-specific T cell responses in mousepreclinical models. In human tumors cDC1 are often underrepresented in thetumor microenvironment, supporting the hypothesis that therapeutically increasing their number via FLT3 pathway stimulation has the potential to promote T cell-mediated anti-tumor efficacy.MethodsGS-3583 is a fusion protein composed of the extracellular domain (ECD) of human FLT3 ligand(FLT3L) combined with a modified fragment crystallizable (Fc) region of human IgG4. GS-3583was designed to induce cDC1 expansion and subsequently promote tumor-reactive T cell priming, activation and recruitment into the tumor microenvironment. To evaluate the therapeutic efficacy of FLT3 stimulation in vivo, a mouse surrogate mGS-3583was designed using the ECD of mouse FLT3L fused to an engineered mouse IgG2a Fc withattenuated binding to mouse FcgRs.Results mGS-3583 bound to recombinant mouse FLT3 with an estimated affinity of 15 nM, and to mouse FLT3-expressing cells with an EC50 of 0.15 nM. In vivo, mGS-3583 showed single agent dose-dependent tumor growth inhibition (TGI) in tumors that correlated with peripheral and intratumoral cDC1 expansion. In tumors with no initial immune infiltration, mGS-3583 led to an influx of T cells into the tumors. In addition to single agent efficacy, mGS-3583 combined effectively with programmed cell death protein (ligand)-1 (PD(L)-1) pathway blockade.ConclusionsIn vivo expansion of dendritic cells can convert uninflamed (cold) tumors to immunologically active (hot) tumors and initiate productive anti-tumor immune responses. These findings support the development GS-3583 as a promising candidate for cancer immunotherapy.

Effect of Auraptene on angiogenesis in Xenograft model of breast cancer

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Mohammad Reza Shiran ◽  
Elham Mahmoudian ◽  
Abolghasem Ajami ◽  
Seyed Mostafa Hosseini ◽  
Ayjamal Khojasteh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Animal Model ◽  
Protein Expression ◽  
Western Blot ◽  
Xenograft Model ◽  
Dependent Manner ◽  
Concentration Dependent Manner

Abstract Objectives Angiogenesis is the most important challenge in breast cancer treatment. Recently, scientists become interesting in rare natural products and intensive researches was performed to identify their pharmacological profile. Auraptene shows helpful effects such as cancer chemo-preventive, anti-inflammatory, anti-oxidant, immuno-modulatory. In this regard, we investigated the anti-angiogenesis effect of Auraptene in in-vitro and in-vivo model of breast cancer. Methods In this study, 4T, MDA-MB-231 and HUVEC cell lines were used. The proliferation study was done by MTT assay. For tube formation assay, 250 matrigel, 1 × 104 HUVEC treated with Auraptene, 20 ng/mL EGF, 20 ng/mL bFGF and 20 ng/mL VEGF were used. Gene expression of important gene related to angiogenesis in animal model of breast cancer was investigated by Real-time PCR. Protein expression of VCAM-1 and TNFR-1 gene related to angiogenesis in animal model of breast cancer was investigated by western-blot. Results Auraptene treatment led to reduction in cell viability of MDA-MB-231 in a concentration-dependent manner. Also, we observed change in the number of tubes or branches formed by cells incubated with 40 and 80 μM Auraptene. Auraptene effect the gene expression of important gene related to angiogenesis (VEGF, VEGFR2, COX2, IFNɣ). Moreover, the western blot data exhibited that Auraptene effect the protein expression of VCAM-1 and TNFR-1. Conclusions Overall, this study shows that Auraptene significantly suppressed angiogenesis via down-regulation of VEGF, VEGFR2, VCAM-1, TNFR-1, COX-2 and up-regulation of IFNγ.

scholarly journals Targeting REV7 effectively reverses 5-FU and oxaliplatin resistance in colorectal cancer

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Xianjun Sun ◽  
Wenhou Hou ◽  
Xin Liu ◽  
Jie Chai ◽  
Hongliang Guo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Viability ◽  
Research Effort ◽  
Translesion Synthesis ◽  
Xenograft Model ◽  
Mice Model ◽  
Cell Viability Assay ◽  
Viability Assay ◽  
Xenograft Mice Model

Abstract Background Despite an enormous research effort, patients diagnosed with advanced colorectal cancer (CRC) still have low prognosis after surgical resection and chemotherapy. The major obstacle for CRC treatment is chemoresistance to front line anti-cancer drugs, such as 5-fluorouracil (5-FU) and oxaliplatin. However, the mechanism of chemoresistance to these drugs remains unclear. Methods Cell viability to 5-FU and oxaliplatin was measured by the CellTiter-Glo® 2.0 Cell Viability Assay. The endogenous REV7 protein in CRC cells was detected by western blotting. The translesion synthesis (TLS) events were measured by plasmid-based TLS efficiency assay. Cell apoptosis was evaluated by caspase3/7 activity assay. The in vivo tumor progression was analyzed by HT29 xenograft mice model. Results In this study, we found that expression of REV7, which is a key component of translesion synthesis (TLS) polymerase ζ (POL ζ), is significantly increased in both 5-FU and oxaliplatin resistant CRC cells. TLS efficiency analysis revealed that upregulated REV7 protein level results in enhanced TLS in response to 5-FU and oxaliplatin. Importantly, inhibition of REV7 by CRISPR/Cas9 knockout exhibited significant synergy with 5-FU and oxaliplatin in cell culture and murine xenograft model. Conclusion These results suggest that combination of REV7 deficiency and 5-FU or oxaliplatin has strong inhibitory effects on CRC cells and identified REV7 as a promising target for chemoresistant CRC treatment.

scholarly journals Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial

Blood ◽  
2019 ◽  
Vol 133 (18) ◽  
pp. 1964-1976 ◽  
Author(s):  
Andrew D. Zelenetz ◽  
Gilles Salles ◽  
Kylie D. Mason ◽  
Carla Casulo ◽  
Steven Le Gouill ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Phase 2 ◽  
Non Hodgkin Lymphoma ◽  
Phase 1B ◽  
Grade 3

Abstract Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.

Phase I Trial of Sphingosomal Vincristine (SV, Marqibo®) and Dexamethasone in Relapsed or Refractory Acute Lymphocytic Leukemia (ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4539-4539
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Leonard Heffner ◽  
Wendy Stock ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Phase I ◽  
Single Agent ◽  
Dose Intensity ◽  
Complete Response ◽  
Antifungal Prophylaxis ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Dependent Manner ◽  
Pulse Dexamethasone

Abstract Delivery of standard therapeutics in formulations which allow increased drug delivery with equivalent or less toxicity may improve outcome. Vincristine is an essential component of ALL therapy. Its cytotoxicity occurs in a time and dose-dependent manner, but the dose needs to be capped at 2 mg to prevent severe neurotoxicity. SV is a form of vincristine encapsulated in sphingomyelin liposomes or “sphingosomes” with an increased circulation half-life of 12 hours compared with 6–12 minutes for free vincristine. In vivo, SV has more anti-tumor activity than free vincristine in mice bearing P388 and L1210 leukemias. A previous study of single agent SV 2.0 mg/m2 given every 2 weeks (without dose capping) was conducted in 16 patients (pts) with relapsed or refractory ALL. Objective responses were observed in 14% (1 complete response [CR], 1 partial response [PR]); 36% had transient reduction in marrow leukemia infiltrate with very minimal toxicity (Thomas et al., Cancer106:1641, 2006). An increase in dose intensity was considered the strategy for future trials. A standard 3 + 3 phase I study of weekly escalating doses of SV (1.5 mg/m2, 1.825 mg/m2, 2 mg/m2, 2.25 mg/m2, 2.4 mg/m2) with pulse dexamethasone (D) 40 mg daily days 1–4 and 11–14 was initiated. Pts with active grade 2 or greater central or peripheral neuropathy (PN) were excluded. Pts were evaluated for dose-limiting toxicities (DLT) after 1 course (defined as 4 weekly doses of SV + D). To date, 36 pts with relapsed/refractory ALL were enrolled. Median age was 34 years (range, 21–62). Median number of prior salvage regimens was 2 (range, 1–3); all pts had prior vincristine. SV was discontinued early for progressive disease (n=5), death due to sepsis (n=3) or other toxicities (n=3). Thus, twenty-five pts (71%) completed 1 full course and were considered evaluable. DLTs were observed at the 2.4 mg/m2 dose level (grade 3 PN, seizure with intracranial hemorrhage, grade 4 hepatotoxicity). The tentative MTD is 2.25 mg/m2 (expansion of cohort ongoing). Expected toxicities included infections related to neutropenia, grade 1–3 constipation, grade 1–2 PN and transient grade 1–3 elevations in hepatic transaminases related to azole antifungal prophylaxis. Six pts (24%) achieved CR (2 at 1.5 mg/m2, 1 at 1.825 mg/m2, 2 at 2.25 mg/m2, 1 at 2.4 mg/m2), 1 a PR (at 2.25 mg/m2), and 3 (12%) hematological improvements (of platelets at 1.825 mg/m2 and 2 mg/m2 or clearance of marrow blasts at 2.25 mg/m2). Five responders proceeded to allogeneic stem cell transplant. In conclusion, SV with pulse dexamethasone demonstrated encouraging activity in relapsed or refractory ALL. Phase II and III studies of SV in ALL are planned.

Phase 1b Evaluation of the Safety and Efficacy of a 30-Minute IV Infusion of Carfilzomib In Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3024-3024 ◽  
Author(s):  
Kyriakos Papadopoulos ◽  
David Samuel diCapua Siegel ◽  
Seema B. Singhal ◽  
Jeffrey R. Infante ◽  
Edward A. Sausville ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Blood ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Proteasome Inhibition ◽  
Response Assessment ◽  
Phase 2 ◽  
Peripheral Blood Mononuclear ◽  
Phase 1B

Abstract Abstract 3024 Background: Carfilzomib (CFZ) is a novel, highly selective, epoxyketone proteasome inhibitor. In two separate Phase 2 trials in patients (pts) with relapsed and/or refractory (R/R) multiple myeloma (MM), single-agent CFZ administered as an IV bolus over 1–10 minutes has demonstrated durable activity at 20/27 mg/m2 and is well-tolerated with no clinically significant cumulative toxicity. In rats, significantly improved tolerability of CFZ was obtained following administration as a 30 min infusion as compared to a rapid IV bolus. Notably, a dose of 48 mg/m2 via IV bolus resulted in 50% lethality, compared to minimal toxicity without lethality at the same dose via a 30 min infusion. The reduced toxicity with 30-min infusion may reflect the role of Cmax (45 μM for bolus vs. 1.5 μM for infusion), since proteasome inhibition in blood and tissue was equivalent in both groups. Here we report on the results of administration of CFZ as a 30-minute IV infusion in a Phase 1b study in pts with R/R MM. The goals of this study are to determine the maximum recommended dose for infusion, safety, efficacy, pharmacokinetics (PK), and pharmacodynamic (PD) parameters. Methods: This Phase 1b trial is enrolling pts with R/R MM after ≥2 prior treatment failures. CFZ is given as a 30-minute IV infusion on days (D) 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C) until progression. Dosing in all cohorts is initiated at 20 mg/m2 for the first two doses, with subsequent escalation to 36, 45, 56, or 70 mg/m2. Dose escalation follows standard 3+3 rules. Dexamethasone (4 mg for doses up to 45 mg/m2) is given prior to each infusion, with 8 mg given at higher doses. Responses by IMWG Uniform Response Criteria are measured at every C. Plasma samples for PK analysis and peripheral blood samples for PD analysis were obtained from pts at C1D1 (20 mg/m2) and C2D1 (all dose cohorts). Results: To date, 16 pts with R/R MM have been enrolled in the Phase 1b infusion study (4 at 36 mg/m2; 3 at 45 mg/m2; 7 at 56 mg/m2 and 2 at 70 mg/m2). Pts have remained on study for a median of 4 cycles (range 1–13+). Dose Limiting Toxicity (DLT) was observed in both pts treated at 70 mg/m2: reversible Grade (G) 3 renal failure in one pt within 24-hours following his first dose at 70 mg/m2 (C1D8); reversible G3 fatigue with fevers 4 days following four doses of 70 mg/m2 (C1 D20). Both pts were successfully rechallenged and continue on treatment. Seven patients have started dosing at 56 mg/m2; to date, one DLT (reversible G3 hypoxia with fevers) was observed. Thirteen pts are evaluable for efficacy (2 pts withdrew prior to 1st response assessment; 1 pt is too early to assess). Responses, time on study and prior regimens are detailed in the following table. Preliminary PK analysis demonstrates that the Cmax with 30-minute infusion is lower than obtained with a 5–10 minute IV bolus of the same dose. Inhibition of proteasome activity in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) was >80% at 20 mg/m2 and >90% at 36 mg/m2 and above. Common adverse events (AEs) with CFZ delivered as a 30-minute infusion have included fatigue, fevers, myalgias, diarrhea, nausea, thrombocytopenia, and reversible elevations in serum creatinine. There have been no episodes of worsening of baseline peripheral neuropathy or hepatotoxicity. Conclusions: In pts with R/R MM, single-agent CFZ as 30-minute IV infusion is both active and well-tolerated at doses ≥36 mg/m2; the dose level of 56 mg/m2 is being expanded as the recommended phase 2 dose on this schedule. Responses were seen in 8 out of 13 evaluable MM pts, including three VGPRs in pts who had received 5–7 prior regimens. Similar to animal studies, improved safety outcomes in MM patients can be achieved with near complete proteasome inhibition when CFZ is administered as a 30-minute infusion. An additional schedule of CFZ using weekly dosing (30-minute infusion for 5 weeks out of every 6) will be investigated in this trial. Disclosures: Papadopoulos: Onyx Pharmaceuticals: Consultancy, Research Funding. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Gordon:Onyx Pharmaceuticals: Research Funding. Kauffman:Onyx Pharmaceuticals: Employment. Woo:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Bui:Onyx Pharmaceuticals: Employment. Hannah:Onyx Pharmaceuticals: Consultancy.

Sign in / Sign up

Export Citation Format

Share Document