Interleukin-21 (IL-21): Tolerability and anti-tumor activity following two 5-day cycles in patients with stage IV melanoma (MM) or renal cell carcinoma (RCC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2505-2505 ◽  
Author(s):  
J. A. Thompson ◽  
B. D. Curti ◽  
B. G. Redman ◽  
J. S. Weber ◽  
S. S. Agarwala ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Nk Cell ◽  
Phase 1 ◽  
Cell Activity ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Study Results ◽  
Initiation Of Therapy ◽  
Anti Tumor Activity

2505 Background: IL-21 enhances NK cell activity and the proliferation and activation of CD8+ T cells. A Phase 1 outpatient dose-escalation trial of IL-21 in patients with MM or RCC established a maximum tolerated dose and demonstrated biologic effects as measured by increased soluble CD25 levels and decreased lymphocyte counts. Partial responses (PR) were observed in 2 patients with RCC (J Immunother. 2005; 28:641–642). Methods: IL-21 was administered by intravenous push at 30 μg/kg/day for two 5-day cycles separated by a 9- or 16-day rest to a total of 34 patients (18 MM and 16 RCC) to further characterize safety and evaluate preliminary signs of anti-tumor activity. Results: All patients received 2 cycles of treatment with the exception of one patient who discontinued secondary to pleural effusion. Common drug-related Grade 1–2 adverse events (AEs) included pyrexia (n=27), fatigue (n=25), chills (n=18), headache (n=18), and rash (n=16). Related Grade 3 AEs included pleural effusion, abdominal pain, hypophosphatemia, and thrombocytopenia (n=1 each). Laboratory abnormalities commonly observed were decreased lymphocytes (n=31), platelets (n=31), albumin (n=29), and hemoglobin (n=27); increased triglycerides (n=27) and ALT (n=26). Except for lymphopenia (an expected pharmacodynamic response), most toxicities were Grade 1–2. AEs and laboratory abnormalities were generally transient. Final study results, including response data, will be presented. To date, of 28 patients evaluable for response (i.e., those who received at least 8 of 10 doses and have had a final evaluation), one PR has been confirmed in a patient with MM and 18 patients have stable disease two months following initiation of therapy. Conclusions: Two 5-day outpatient cycles of IL-21 at 30 μg/kg/day have been reasonably well tolerated and have demonstrated preliminary evidence of anti-tumor activity in patients with advanced MM or RCC. [Table: see text]

Anti-tumor activity of recombinant human Interleukin-21 (rIL-21): Preliminary data from a phase 2a study in patients with stage IV malignant melanoma (MM) without prior treatment

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3055-3055
Author(s):  
I. D. Davis ◽  
B. Brady ◽  
M. Millward ◽  
B. K. Skrumsager ◽  
U. Mouritzen ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Performance Status ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Two Stage ◽  
Two Phase ◽  
Study Results

3055 Background: rIL-21 is a pleiotropic class I cytokine that activates CD8+ T cells and NK cells. The safety and pharmacologic profile of rIL-21 was characterized in two phase 1 dose escalation studies including patients with MM, performed in Australia and the US, respectively. Two dosing schedules were tested: “5+9” (5 days of dosing followed by 9 days of rest) and “3/wk” (dosing 3 times per week for 6 weeks). The maximum tolerated dose (MTD) was determined to be 30 μg/kg for both dosing regimens and two complete remissions (at the 30 μg/kg dose level) were observed in the MM patients. A phase 2a study was initiated to estimate the preliminary efficacy of rIL-21 in patients with advanced MM. Methods: The phase 2a study design is an open-label, two-stage trial. Primary objective: antitumor efficacy as determined by response rate. Secondary objectives: safety, effects on blood biomarkers, and measurement of anti-rIL-21 antibodies. Eligible patients had unresectable MM with measurable disease, no prior systemic therapy (adjuvant interferon was permitted), adequate major organ function, good performance status, no brain metastases, and no evidence of significant autoimmune disease. rIL-21 was administered by i.v. bolus injection using the “5+9” regimen for 6 weeks (= three cycles) at 30 μg/kg dose level. Results: At the time of writing (January 2007), all 14 patients have entered the first stage of the phase 2a study and currently seven patients are evaluable for response after completion of 3 treatment cycles (6 weeks). One patient had a complete remission, five patients had stable disease, and one patient had progressive disease. So far, six patients have gone on to receive further treatment with rIL-21. Similar to the phase 1 experience, treatment with rIL-21demonstrated an acceptable safety profile. Updated interim study results, including response data, will be presented. Conclusions: rIL-21 administered at 30 μg/kg/day using the “5+9” regimen is well tolerated by patients with MM. Preliminary evidence of clinical response has been observed and the second stage of the two-stage phase 2a study has opened for accrual. [Table: see text]

scholarly journals NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Patrick J. Mansky ◽  
Dawn B. Wallerstedt ◽  
Timothy S. Sannes ◽  
Jamie Stagl ◽  
Laura Lee Johnson ◽  
...  
Keyword(s):  
Clinical Response ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Stage Iv ◽  
Dosage Level ◽  
Maximum Tolerated Dose ◽  
Stage I ◽  
Fixed Dose ◽  
Mistletoe Lectin ◽  
Mistletoe Extract

Purpose.European Mistletoe (Viscum albumL.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM.Methods.Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery.Results.DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m2and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high.Conclusion.GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.

Adrenal tumors provide insight into the role of cortisol in NK cell activity

2021 ◽  
Author(s):  
Andrew E. Greenstein ◽  
Mouhammed Amir Habra ◽  
Subhagya A. Wadekar ◽  
Andreas Grauer
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Phase 1 ◽  
Cell Activity ◽  
The Cancer Genome Atlas ◽  
Adrenal Tumors ◽  
Steroid Synthesis

Elevated glucocorticoid (GC) activity may limit tumor immune response and immune checkpoint inhibitor (ICI) efficacy. Adrenocortical carcinoma (ACC) provides a unique test case to assess correlates of GC activity, as approximately half of ACC patients exhibit excess GC production (GC+). ACC multi-omics were analyzed to identify molecular consequences of GC+ and assess the rationale for combining the glucocorticoid receptor (GR) antagonist relacorilant with an ICI. GC status, mRNA expression, and DNA mutation and methylation data from 71 adrenal tumors were accessed via The Cancer Genome Atlas. Expression of 858 genes differed significantly between GC- and GC+ ACC cases. KEGG pathway analysis showed higher gene expression of 3 pathways involved in steroid synthesis and secretion in GC+ cases. Fifteen pathways, most related to NK cells and other immune activity, showed lower expression. Hypomethylation was primarily observed in the steroid synthesis pathways. Tumor-infiltrating CD4+ memory (P=.003), CD8+ memory (P=.001), and NKT-cells (P=.014) were depleted in GC+ cases; tumor-associated neutrophils were enriched (P=.001). Given the pronounced differences between GC+ and GC- ACC, the effects of cortisol on NK cells were assessed in vitro (NK cells from human PBMCs stimulated with IL-2 or IL-12/15). Cortisol suppressed, and relacorilant restored, NK cell activation, proliferation, and direct tumor cell killing. Thus, GR antagonism may increase the abundance and function of NK and other immune cells in the tumor microenvironment, promoting immune response in GC+ ACC and other malignancies with GC+. This hypothesis will be tested in a phase 1 trial of relacorilant + ICI.

IPH2101, a Novel Anti-Inhibitory KIR Monoclonal Antibody, and Lenalidomide Combine to Enhance the Natural Killer (NK) Cell Versus Multiple Myeloma (MM) Effect.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3870-3870 ◽  
Author(s):  
Don Benson ◽  
Courtney E Bakan ◽  
Shuhong Zhang ◽  
Lana Alghothani ◽  
Jing Liang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Phase 1 ◽  
Granzyme B ◽  
Cell Activity ◽  
Target Cells ◽  
Nk Cell Activity ◽  
Immune Complex Formation

Abstract Abstract 3870 Poster Board III-806 Background NK cell activity against tumor cells is regulated by a balance of inhibitory and activating signals mediated by receptors on NK cells that recognize inhibitory and activating ligands expressed by cancer cells. IPH2101 (1-7F9) is a novel monoclonal anti-inhibitor KIR blocking antibody that has been shown to augment NK cell function against MM targets. Moreover, lenalidomide has been shown to expand and activate NK cells in vivo and in vitro. We have previously reported that the combination of IPH2101 and lenalidomide enhances NK cell mediated cytotoxicity against MM cells compared to each agent alone (Zhang et al., AACR 2009). We expand our studies to investigate potential mechanisms for the enhancement of NK cell activity by the combination of IPH2101 and lenalidomide. Methods The effects of IPH2101 and lenalidomide alone and in combination were studied using primary human NK cells from healthy donors as well as from MM patients. The MM cell lines U266 and RPMI 8226 as well as primary tumor cells from marrow aspirates of MM patients served as target cells. The effect of lenalidomide on MM activating and inhibitory ligand expression was studied by flow cytometry. NK cell trafficking was investigated with standard transwell plate migration assay. Immune complex formation between NK cell effectors and MM tumor targets was characterized by flow cytometry in control conditions and with NK cells pre-treated with IPH2101 and lenalidomide. The effects of IPH2101 and lenalidomide were studied regarding interferon-gamma and granzyme B production by ELISPOT and target-specific cytotoxicity studies were conducted to complement effector-based assays. Results IPH2101 (30 ug/ml) significantly enhanced cytotoxicity against U266 cells and primary MM tumor cells by both purified NK cells at effector:target (E:T) ratios of 10:1 or less, and also of freshly isolated peripheral blood mononuclear cells (PBMC) at E:T ratios of 60:1 or less, from more than 10 random donors. In addition, treatment of PBMC with 5-10 μmol/L lenalidomide for 72h without interleukin (IL)-2 increased NK cell lysis of U266. Treatment of PBMC from normal donors did not enhance the expression of the NK receptors KIR, NKG2D, NCR, TRAIL, and DNAM-1. Incubation of U266 cells with lenalidomide (5 uM) for 3-5 days resulted in significant enhancement of cytotoxicity by normal donor NK cells. This was associated with upregulation of the activating ligands, MICA, ULBP-2, DR4, and CD112. Using blocking antibodies to NKG2D, TRAIL, and DNAM-1, lenalidomide enhancement of MM cell killing was abrogated indicating the importance of the modulation of the ligands to the latter receptors by lenalidomide. Although IPH2101 and lenalidomide did not significantly increase NK cell migration into normal media, migration was enhanced 2.98-fold (+/− 0.36, p < 0.05) towards U266 cell targets (n= 3, p < 0.05) and MM patient serum 3.2-fold (+/− 0.4, n=3, p < 0.05). IPH2101 and lenalidomide also led to a 2.3-fold (+/− 0.43, p < 0.05) increase in immune complex formation between NK cells and MM tumor cells. IPH2101 and lenalidomide also augmented NK cell interferon gamma production against MM (control mean 303 spots/well +/− 13 versus 525 +/− 83, n=3, p < 0.05) and granzyme B production (control mean 115 +/− 98 versus 449 +/−72, n=3, p < 0.05). Importantly, in all experiments described herein, the effects of IPH2101 and lenalidomide together were greater than either agent alone. Conclusions Taken together, our data suggest that IPH2101 and lenalidomide may exert complementary mechanisms on both effector and target cells to enhance NK cell mediated killing of MM cells. Moreover, these agents have no predicted clinical cross-toxicities. A single-agent phase 1 clinical trial of IPH2101 has shown the mAb to be safe and well tolerated in MM patients. These findings support a phase 1/2 clinical trial of IPH2101 with lenalidomide as a first dual-innate immunotherapy for patients with MM. Disclosures: Andre: Innate Pharma: Employment. Squiban:Innate pharma: Employment. Romagne:Innate Pharma: Employment.

A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 48-48 ◽  
Author(s):  
Michael Friedlander ◽  
Tarek Meniawy ◽  
Ben Markman ◽  
Linda R. Mileshkin ◽  
Paul Harnett ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Autoimmune Hepatitis ◽  
Solid Tumors ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Study Results

48 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that may potentially increase the efficacy of BGB-A317. A phase 1 study identified 60 mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, pharmacokinetic (PK) profile, and preliminary antitumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6–12 patients with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1–3, BGB-290 doses ranged between 20–60 mg PO BID with BGB-A317 2 mg/kg IV Q3W. In DLs 4–5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 31 March 2017, 43 patients [median age 63 years (34–75)] were treated in DLs 1–5. Three patients experienced four dose-limiting toxicities: grade 2 nausea (DL4), grade 2 nausea and grade 2 vomiting (DL5), and grade 4 autoimmune hepatitis (DL5). MTD was identified as BGB-A317 200 mg IV Q3W + BGB-290 40 mg PO BID. The most common adverse event (AE) considered related to both study drugs was fatigue. Immune-related AEs of Grade ≥3 were elevated alanine aminotransferase/aspartate aminotransferase (n = 3), autoimmune hepatitis (n = 3), and hepatitis (n = 1). Complete or partial response was observed in 11 patients, 4 of whom had confirmed PR or CR. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: The combination of BGB-A317 and BGB-290 was generally well tolerated in patients with advanced solid tumors. These results support the continuation of this trial with enrollment into the disease-specific cohorts. Clinical trial information: NCT02660034.

Updated results from a phase Ib trial of regorafenib plus nivolumab in patients with advanced colorectal or gastric cancer (REGONIVO, EPOC1603).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 135-135
Author(s):  
Kohei Shitara ◽  
Hiroki Hara ◽  
Naoki Takahashi ◽  
Takashi Kojima ◽  
Akihito Kawazoe ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase 1 ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Significant Difference ◽  
One Year ◽  
Anti Tumor Activity

135 Background: In the phase 1 REGONIVO study, regorafenib of 80 mg/day plus nivolumab showed manageable safety profiles and encouraging anti-tumor activity for advanced colorectal cancer (CRC) or gastric cancer (GC) with objective response rate (ORR) of 36% in CRC and 44% in GC (Fukuoka, et al. ASCO 2019). Updated efficacy results are presented. Methods: Enrolled patients (pts) received regorafenib plus nivolumab in a dose-finding phase to estimate the maximum tolerated dose (MTD). Additional pts were enrolled in a dose-expansion phase. Regorafenib of 80 to 160 mg was administered once daily for 21 on 7 days off with nivolumab 3 mg/kg every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during cycle one to estimate the MTD and the recommended dose. PD-L1 combined positive score (CPS) was assessed using the anti–PD-L1 28-8 antibody. Tumor mutation burden (TMB) was measured using Oncomine tumor mutation load assay. Results: Fifty pts were enrolled (25 CRC; 25 GC) until October 2018 with median prior treatment line of 3. Efficacy results were updated as of September 1st 2019. One CRC pt was with MSI-high but all other pts were with MSS or MMR-proficient. Among the 20 pts (9 CRC and 11 GC) with objective response (40%), responses are still ongoing in 13 pts (7 CRC and 6 GC) and the median duration of response was not reached (NR). Median progression free survival (PFS) was 7.8 months in CRC (95% CI, 2.8- NR) and 5.5 months (95% CI, 2.6-10.2 months) in GC. One-year PFS rate was 41.7% in CRC and 22.4% in GC. Median overall survival (OS) was not reached in CRC (95% CI, 9.7-NR) and 12.1 months (95% CI, 5.2-NR) in GC. One-year OS rate was 68% in CRC and 55.3% in GC. No significant difference of PFS and ORR was observed in CRC according to PD-L1 and TMB. Conclusions: Encouraging anti-tumor activity of the combination of regorafenib plus nivolumab had been maintained with long-term follow-up. A randomized study for MSS CRC is under planning. Clinical trial information: NCT03406871.

Safety and antitumor activity of AMG 706 in patients (pts) with thyroid cancer (TC): A subset analysis from a phase 1 dose-finding study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3030-3030 ◽  
Author(s):  
D. Boughton ◽  
L. Rosen ◽  
A. Van Vugt ◽  
R. Kurzrock ◽  
M. Eschenberg ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Finding Study ◽  
Stage Iv Disease ◽  
Modified Recist ◽  
Dose Finding Study

3030 Background: AMG 706 is an investigational, oral, small molecule multi-kinase inhibitor with both antiangiogenic and direct antitumor activity that selectively targets VEGF, PDGF, and Kit receptors. From a phase 1 study (Rosen ASCO 2005; Herbst EORTC 2005), encouraging antitumor activity was seen in pts with TC. In this analysis, we report on the TC subset from the study. Methods: Pts with refractory solid tumors received oral AMG 706 QD (50, 100, 125, 175 mg) or BID (25 mg) intermittently or continuously for 28-day cycles. Study objectives were to assess safety, establish the maximum tolerated dose (MTD), and generate pharmacokinetic profiles of AMG 706 in these pts. Tumor response (modified RECIST) was evaluated at wk 8 and Q12W thereafter. Data from Oct 2005 were analyzed. Results: In this study, 7 of 71 pts enrolled had TC. Baseline demographics for this subset were 4 W/3 M, median (range) age of 58 (41, 78) yrs, ECOG 1 (71%), and all had stage IV disease. Histologies were papillary (3: PTC), follicular (1; FTC), Hürthle cell (1), anaplastic (1), and medullary TC (1; MTC). All pts received prior external radiotherapy, radioiodine, chemotherapy, and/or surgery. Initial doses of AMG 706 were 125 mg and 175 QD and 25 mg BID. The MTD for the study was 125 mg QD. Median (range) time on treatment for the TC pts was 141 (14, 564) days. Treatment-related adverse events are summarized ( table ). Best objective responses were 3 pts with partial response (PR), 3 with stable disease (SD), and 1 with progressive disease. PR was seen in pts with MTC, PTC and FTC. Two pts with PR did not have confirmation of response (1 had a PR during the last assessment). The 3 pts with PR received AMG 706 for 338, 366, and 564 days; 2 pts are still receiving AMG 706. Time to response for these 3 pts were 210, 217, and 304 days. Conclusion: In patients with TC, AMG 706 appears to be relatively well tolerated and displays promising antitumor activity for some pts. Based on these favorable findings, a phase 2 study of AMG 706 for the treatment of advanced TC is ongoing. [Table: see text] [Table: see text]

Phase I study of oral LBH589, a novel deacetylase (DAC) inhibitor in advanced solid tumors and non-hodgkin’s lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3500-3500 ◽  
Author(s):  
H. M. Prince ◽  
D. George ◽  
A. Patnaik ◽  
M. Mita ◽  
M. Dugan ◽  
...  
Keyword(s):  
Parotid Gland ◽  
Solid Tumors ◽  
Phase 1 ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Peripheral Blood Lymphocytes ◽  
Advanced Solid Tumors ◽  
Post Dose ◽  
Western Blots

3500 Background: LBH589 is a novel deacetylase inhibitor (DACi) which induces apoptosis of tumor cells at nanomolar levels. In this phase 1 study, we evaluated the safety and tolerability of LBH589 in pts with advanced solid tumors or non-hodgkins lymphoma. Methods: LBH589 was administered orally on Monday, Wednesday, and Friday (MWF) weekly. Western blots on peripheral blood lymphocytes were used to study histone acetylation (HA). Plasma PK profiles were analyzed on Days 1 and 15. Results: Thirty two pts have been treated (Median age 63 years; 18 M, 14 F). Pts received 15 mg (3), 30 mg (10), the dose-limiting toxicity level (DLT), or 20 mg (19), the maximum tolerated dose (MTD). Tumor types included: CTCL (10), renal cell (6), melanoma (6), prostate (4), hepatic (1), rhabodomyosarcoma (1), mesothelioma (1), colon (1), bladder (1), and parotid gland (1). Three DLTs were reported; G3 diarrhea and transient G4 thrombocytopenia at 30 mg and G3 fatigue at 20 mg. The most common adverse events were anorexia, nausea, fatigue, diarrhea and transient thrombocytopenia. Of the 1,057 ECGs, 1 pt (20 mg) had a QTcF of 503 msec, an isolated event after the first dose with no recurrence on continued therapy. The mean change in QTcF from baseline was < 10 msec during the first cycle in all cohorts. No increase in HA was seen at 15 mg, but did increase in 50% of pts at 72 hrs post dose in both the 20 mg and 30 mg cohorts. LBH589 was rapidly absorbed in plasma (Tmax 1.5 hr), then declined with a mean terminal half-life of 16 hrs. Cmax and AUC increased linearly with doses between 15–30 mg. Two cutaneous T- cell lymphoma (CTCL) pts achieved a complete response (5 and 7 months) and 4 CTCL pts attained a partial response (6.5, 8, 9 and 18+ months). Stable disease was achieved in 7 pts: CTCL-2 pts (2 and 3 months); RCC-2 pts (3.5 and 7 months); melanoma-1 pt (4 months), mesothelioma-1 pt (2.5 months) and parotid gland-1 pt (5 months). Fifteen pts progressed on treatment and 4 pts were not evaluable for response. Conclusions: At 20 mg MWF every week, LBH589 oral produced a sustained pharmacodynamic effect on HA for ≥72 hours post dose in 50% of pts. Cardiac data indicates no clinically-significant effect on QTcF. Preliminary evidence of tumor response was observed at this dose and schedule in CTCL pts. No significant financial relationships to disclose.

Phase 1 with expansion cohorts in a study of NEO-201 in adults with chemo-resistant solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2645-TPS2645
Author(s):  
Maria Pia Morelli ◽  
Justin M. David ◽  
Nicole D. Houston ◽  
Stan Lipkowitz ◽  
Jung-min Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Delayed Type Hypersensitivity ◽  
Tumor Type ◽  
Vaccine Platform ◽  
Anti Tumor Activity

TPS2645 Background: NEO-201 is a novel humanized IgG1 monoclonal antibody (mAb) generated against the Hollinshead allogenic colorectal cancer vaccine platform. Briefly, tumor-associated antigens (TAA) derived from tumor membrane fractions pooled from colorectal cancer surgical specimens were screened for delayed-type hypersensitivity and evaluated in clinical trials. The original vaccine was used to generate monoclonal antibodies, one of which is NEO-201. In preclinical data generated in our laboratory, we have demonstrated that NEO-201 exert anti-tumor activity by natural killer (NK)-mediated antibody-dependent cytotoxicity (ADCC) against several tumor type including colorectal and pancreatic cancer models (Fantini, et al. 2018). We have identified NEO-201 antigen as a glycosylated form of CEACAM-5 and -6, which is expressed by tumor tissue but is not present in the surrounding healthy tissue (David, et al. 2018). This could result in a specific anti-tumor activity without significant normal tissue toxicity. Nevertheless, toxicity was further assessed in non-human primates and transient neutropenia was the only adverse event observed. Based on this data we designed a first in human phase I trial to evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) of the humanized monoclonal antibody NEO-201. Methods: This is a first-in-human phase 1 study with expansion cohort to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NEO-201 in adults with advanced solid tumors that have high likelihood pof expression NEO201 antigen and have progressed to standard of treatments and have a PS0-2 ECOG. Study design is a classic Fibonacci (3+3) dose escalation, with a cohort expansion at the MTD. NEO-201 is administered intravenously every two weeks, and four different dose levels will be explored (DL1 = 1mg/kg, DL2 = 2mg/kg, DL3 = 4mg/kg and DL4 = 6mg/kg). No intra-patient dose escalation is allowed. Patients will be evaluated for safety every two weeks, with weekly laboratory testing, according to CTCAEv4.0. and with a DLT window of 28 days (cycle 1). Response will be assessed every 8 weeks (2 cycles of treatment) according to RECISTv1.1. Additionally, biological samples will be collected to understand NEO-201 pharmacokinetic, the effect on the immune process and their correlation with treatment toxicity and response. As of February 2019 we have completed enrollment in the first DL and are evaluating for DLT. Clinical trial information: NCT03476681.

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