Model-driven metronomic vinorelbine in heavily pre-treated metastatic NSCLC and PM patients: Results of a phase I/II study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20505-e20505
Author(s):  
Joseph Ciccolini ◽  
Elissa Cousin ◽  
Laure Deyme ◽  
Diane-Charlotte Imbs ◽  
Sylvanie Bonnet ◽  
...  
Keyword(s):  
Phase I ◽  
Tumor Size ◽  
Drug Exposure ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Tumor Burden ◽  
Oral Vinorelbine ◽  
Large Variability ◽  
Heavily Pretreated ◽  
Metronomic Vinorelbine

e20505 Background: A phase I/II trial (NCT02555007) of oral metronomic Vinorelbine derived from a mathematical model was performed in heavily pretreated metastatic Non-Small Cell Lung Cancer or Pleural Mesothelioma patients. Progression free survival, toxicity and PK/PD endpoints were the main objectives. Methods: Metronomic scheduling was selected using a simplified phenomenological model to identify the best continuous scheduling and dosing of oral vinorelbine with a total dose of 150 mg QW. Patients were monitored on a weekly basis, efficacy was evaluated by CT scans (RECIST). Toxicity was monitored using standard CTCAE criteria. Total tumor size (TTS) was the sum of diamaters of all lesions. Computation of individual PK parameters was done with Monolix software using population approach. Results: The PK/PD model proposed the following schedule: 60 mg D1, 30 mg D2, 60 mg D4. A total of 36 patients (30 evaluable) were enrolled (22M, 13F, 24 NSCLC, 11 mesothelium, median age 69.5, range 33-85.2). Patients were all heavily pre-treated (median 3 lines, range 1-9). Grade 3+ Neutropenia was observed in 30% patients. Median PFS was 11 weeks (range: 6-16.9). Best responses included 4 PR (13%) and 18 SD (60%). Baseline total tumor size was associated with reduced PFS (HR: 1.09, p = 0.026). A large variability in drug exposure (AUC 53 %, range 26 – 501 ng.h/ml) and PK parameters (Cl 82 %, range 45-605 l/h) was observed among patients. Exposure was not associated with efficacy, apart in patients with larger TTS (i.e., > 70 mm) who seemed to have longer PFS (125 days VS. 40 days, p = 0.057). Vinorelbine exposure tended to be associated with higher risk for grade 2+ neutropenia, especially in patients with BSA < 1.8 m² (60% VS. 25.5%, p = 0.055). A non-significant trend towards baseline NLR and PFS was observed (i.e., NLR < 4: 80 days, NLR > 4: 60 days, p = 0.077). Conclusions: Metronomic vinorelbine was characterized by huge variability in drug exposure among patients. However and despite being all heavily pre-treated, 60% of stable disease and 13% of PR were achieved in these patients. Plasma exposure yielded conflicting results depending on the initial tumor burden, suggesting that patients should be carefully selected prior to be scheduled for metronomic regimen. Possible role NLR could play as a predictive marker is intriguing and should be confirmed in larger cohort.

A phase I/II study of CR011-vcMMAE, an antibody-drug conjugate (ADC) targeting glycoprotein NMB (GPNMB) in patients (pts) with advanced melanoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9032-9032 ◽  
Author(s):  
P. Hwu ◽  
M. Sznol ◽  
A. Pavlick ◽  
H. Kluger ◽  
K. B. Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Human Monoclonal Antibody ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Advanced Melanoma ◽  
Antibody Drug Conjugate ◽  
Tubulin Inhibitor ◽  
Duration Of Response ◽  
Heavily Pretreated

9032 Background: GPNMB is expressed on melanoma cells and represents a potential target for ADCs. CR011-vcMMAE is a fully-human monoclonal antibody to GPNMB conjugated to the tubulin inhibitor monomethylauristatin E (MMAE). Dose limiting toxicity in Phase I (n=32) was rash; tumor shrinkage including one partial response (PR) was observed. We now report Phase II data at the maximum tolerated dose of 1.88 mg/kg iv q3w. Methods: Eligible pts had unresectable stage III or stage IV melanoma and had received no more than 1 prior cytotoxic regimen but any number of other therapies. Pts received CR011-vcMMAE until disease progression (PD) or intolerable toxicity. The primary endpoint was overall response (ORR) by RECIST using a minimax two-stage design (p0=0.5; p1=0.2, α=β=0.1) with 18 patients in the first stage and a total of 32 pts. Secondary endpoints included progression free survival (PFS) and duration of response. Results: 36 pts (median age 67 years [range 37–79]; 94% stage IV; 68% M1c) were treated for a median of 2.4 months (m)(range 0.5–7.5m). 18 pts discontinued (14 PD, 2 consent, 1 adverse event [AE], 1 stable disease [SD]) and 18 pts were ongoing. The study met the criteria for advancement to the second stage; 4 PRs (1 unconfirmed) and 19 SD (range 1.7–7.5 mo) have been observed; final ORR is pending. The unconfirmed PR was in a pt with 96% tumor reduction and PD 6 weeks later. Median PFS was 4m. The most common AEs were rash (81%), fatigue (72%), alopecia (63%) and pruritus (56%). The most common grade 3/4 AEs were neutropenia (22%) and rash (19%). Grade 2 or higher rash was associated with longer PFS. Conclusions: CR011-vcMMAE is active and well-tolerated in heavily pretreated pts with advanced melanoma. Rash may be a useful biomarker for activity. More frequent dosing is being explored. [Table: see text]

scholarly journals PET-CT Standard uptake value predict bevacizumab-containing chemotherapy response and prognosis for unresectable colorectal cancer liver-limited metastasis

2019 ◽  
Author(s):  
Yang Lv ◽  
QingYang Feng ◽  
WenTao Tang ◽  
YuQiu Xu ◽  
SongBin Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Size ◽  
Metabolic Response ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Metastatic Tumor ◽  
Standard Uptake Value ◽  
Primary Lesion ◽  
Chemotherapy Response ◽  
Pet Ct

Abstract Background: Standard uptake value (SUV) is an indicator of tumor metabolic response. In this paper, we aim to explore the value of SUV on unresectable colorectal cancer liver-limitedmetastasis (CRLM) patients receiving bevacizumab-containing chemotherapy. Method: This study was performed retrospectively. A total of 185 CRLM patients between April 2011 to December 2015 with complete clinical data were included in this study. All enrolled patients were assigned into two treatment cohorts (bevacizumab plus chemotherapy cohort and chemotherapy only cohort). All clinical variables, and various PET/CT parameters were statistically compared with progression-free survival (PFS) and overall survival (OS). Primary and Metastatic tumor SUV were selected for analysis. Results: Among the 185 patients, 101 patients received chemotherapy plus bevacizumab ( beva cohort ), 84 patients only received chemotherapy ( CMT cohort ). Baseline characteristics of two cohorts showed no statistical difference (P>0.05). Primary SUV level was correlated with primary tumor size, while metastatic SUV was statistically correlated with metastatic tumor number and tumor size (P=0.000). Primary lesion, metastatic lesion SUV and elevation of SUV demonstrated prognostic role for OS (P<0.05). SUV gap were statistically associated with optimal response in beva cohort (P=0.03) and no-PD status in CMT cohort (P=0.019), respectively. After multivariate analysis, elevated SUV is an independent risk factor for OS (P=0.000). Besides, elevation of SUV between metastatic and primary lesion can be a predictive factor for bevacizumab survival benefit. Conclusion: PET-CT scan is important for CRLM patients. Our study demonstrated that an elevation of SUV was a better prognostic and predictive marker for CRLM patients.

Combinations of the Phosphatidylinositol 3-Kinase-Delta (PI3Kδ) Inhibitor Gs-1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Previously Treated, Indolent Non-Hodgkin Lymphoma: Results From a Phase I Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3645-3645 ◽  
Author(s):  
Nathan H Fowler ◽  
Sven de Vos ◽  
Marshall T. Schreeder ◽  
John P. Leonard ◽  
Ian W. Flinn ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Progression Free Survival ◽  
Tumor Control ◽  
Advisory Committees ◽  
Heavily Pretreated ◽  
Previously Treated

Abstract Abstract 3645 Introduction: PI3Kδ drives proliferation and survival in malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor of PI3Kδ that has shown considerable monotherapy activity when given at dose levels of ≥100 mg BID in patients with heavily pretreated indolent non-Hodgkins lymphoma (iNHL). Methods and Patients: This Phase 1 combination study has evaluated repeated 28-day cycles of GS-1101 with rituximab and/or bendamustine in patients with previously treated iNHL. GS-1101 was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m2 given weekly for 8 doses) (GS-1101/R regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/B regimen), or in combination with R (375 mg/m2, on Day 1 of each cycle for 6 cycles) and B (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles (GS-1101/BR regimen). Initial cohorts received a GS-1101 dose of 100 mg/dose BID. Thereafter, all patients received a GS-1101 dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Cheson 2007). Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays. Results: The study enrolled 76 patients with iNHL. Patient characteristics, histological sub-typing, safety, and efficacy results are depicted in the table. The majority of patients were >60 years of age and had undergone extensive prior therapy. Grade ≥3 adverse events and lab abnormalities were generally consistent with those expected with each of the single agents. Lymph node shrinkage was rapid and all evaluable patients had reductions in lymphadenopathy, resulting in overall response rates (ORR) of 77%, 85%, and 77% for the GS-1101/R, GS-1101/B, and GS-1101/BR regimens, respectively. Complete responses (with bone marrow confirmation) were observed in 13%, 16%, and 30% of patients. With median follow-up duration ranging from 28 to 48 weeks, 1-year progression- free survival (PFS) rates were >75% in all treatment groups. Disease-associated chemokines/cytokines were commonly elevated at baseline and were significantly reduced by GS-1101-based combination treatment. Conclusions: A lack of overlapping toxicities allows the oral PI3Kδ inhibitor, GS-1101, to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with iNHL. GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy. All 3 regimens provide durable tumor control. The data from this trial support the development of Phase 3 combination trials of GS-1101 with rituximab- and/or bendamustine-containing regimens in patients with iNHL. Disclosures: Fowler: Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Phase I trial of GS-1101, a PI3K delta inhibitor, in B cell malignancies. de Vos:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Schreeder:Gilead Sciences: Research Funding. Leonard:Gilead: Consultancy. Coutre:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Sharman:Gilead: Honoraria, Research Funding. Boccia:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Holes:Gilead: Employment. Lannutti:Gilead Sciences Inc: Employment. Johnson:Gilead Sciences: Employment. Jahn:Gilead: Employment. Miller:Gilead: Employment. Godfrey:Gilead Sciences: Employment.

A phase I dose escalation safety and pharmacokinetic (PK) study of SSR244738 administered as a one-hour intravenous (IV) infusion every 3 weeks in patients (pt) with refractory solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2518-2518
Author(s):  
F. G. De Braud ◽  
N. Isambert ◽  
G. Curigliano ◽  
G. Spitaleri ◽  
E. Ferrant ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Liver Function Tests ◽  
Large Variability ◽  
Cyp2c9 Genotype ◽  
Cell Cycle Inhibitor ◽  
Heavily Pretreated ◽  
Ecog Ps ◽  
Tumor Types ◽  
Dose Levels

2518 Background: This phase I study of SSR244738, a G2-cell cycle inhibitor cytotoxic agent, was aimed to establish the dose limiting toxicities (DLT), the maximum administered dose (MAD) and to characterize the PK profile of the proposed schedule. Methods: SSR244738 was administered as one-hour IV infusion every 3 weeks in pts (selected according common phase I criteria) starting with a modified accelerated dose escalation scheme. PK profiles (up to day 8) were obtained in each pt after the 1st administration. CYP2C9 and CYP3A5 genotypes were analyzed to identify pts’ metabolizer status. Results: 2 centers enrolled 14 heavily pretreated pts: 5 females, 9 males, median age: 52 years (32–67), ECOG PS: 0 (93% pts); main tumor types: head and neck, lung, melanoma, and breast. 40 cycles (median = 2, range: 1–11) were administered in 6 dose levels (DL) ranging from 165 to 1,300 mg/m2. Accelerated dose escalation was stopped at 660 mg/m2 for non-proportionally increase of PK parameters respect to the dose administered . SSR244738 was well tolerated up to 1,300 mg/m2: one DLT (abnormal liver function tests ALFT) was reported in one breast cancer pt with liver metastases. Only one pt (hepatocarcinoma) was withdrawn from the study due to toxicity (ALFT) after 3 cycles at 1,000 mg/m2. 2 stable diseases were reported. PK data: mean T1/2 of 23h (range: 9.20–127), mean Vss: 11.1 L (6.43–15.8) and mean Clearance (CL): 0.71 L/h (0.041–1.43). This large variability of the CL (CV% =63%) could in part be explained by CYP2C9 genotype: so far CL is <0.4 in 2 poor metabolizers (PM) and >0.6 in extensive metabolizers. Conclusion: Due to the high CL variability, 1300 mg/m2 is considered as the MAD. 3 pts will be accrued at 1,300mg/m2 to complete the DL (a reduced dose will be given to CYP2C9 PM). Weekly and twice-weekly schedules will be tested. No significant financial relationships to disclose.

Phase I expansion study of cabozantinib plus nivolumab (CaboNivo) in metastatic urothelial carcinoma (mUC) patients (pts) with progressive disease following immune checkpoint inhibitor (ICI) therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5037-5037
Author(s):  
Daniel da Motta Girardi ◽  
Scot Anthony Niglio ◽  
Amir Mortazavi ◽  
Primo Lara ◽  
Sumanta K. Pal ◽  
...  
Keyword(s):  
Phase I ◽  
Progressive Disease ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Median Number ◽  
Primary Objective ◽  
Best Response ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Expansion Cohort

5037 Background: Previous treatment with ICI is more common in clinical practice since recent FDA-approval of 5 ICIs in second-line and 2 in first-line for mUC. There is lack of data regarding the use of ICI after progression on a prior ICI. Cabozantinib has been shown to have immunomodulatory properties and may have synergistic effect with ICI. Methods: This is a phase I expansion cohort of mUC pts, who received prior ICI, treated with Cabozantinib 40mg daily and Nivolumab 3mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary objective was to determine the efficacy and tolerability of CaboNivo. Results: Twenty-nine mUC pts were treated. Median follow-up was 14.1 months (mo). The majority of pts were male (75.8%); 27 were White (93.1%), and 2 were Asian (6.9%). Primary tumor was bladder in 21 pts (72.4%) and upper tract in 8 (27.6%). Twenty-two pts (75.9%) had visceral metastasis (mets), 4 (13.8%) had lymph node only mets and 13 (44.8%) had liver mets. The median number of prior lines of treatment for mUC was 2 (range 0-8) with 17 pts (58.6%) receiving 2 prior lines of treatment. The majority of pts (86.2%) received prior chemotherapy for mUC and all pts received prior ICI. The median number of cycles of prior ICI was 7 (range 1-20) and median time between previous ICI and CaboNivo was 2.5 mo (range 1-18). The best response to previous ICI was partial response (PR) in 1 pt (3.4%), stable disease (SD) in 13 (44.9%), progressive disease (PD) in 14 (48.3%) and one (3.4%) was not evaluable (NE). The overall response rate for CaboNivo was 13.8% with 4 pts achieving PR (13.8%), 15 SD (51.7%), 7 PD (24.2%) and 3 NE (10.3%). Responses were seen in the liver, lung, and lymph nodes. Among 4 pts with PR, 2 were primary refractory to previous ICI and 2 had SD. At cutoff date the median duration of response was not reached and 3 PR were still ongoing: 1 had just began and the other 2 were ongoing at 12.3 and 26.4 mo. Among 15 pts with SD, 4 had SD for more than 6 mo and 2 were still ongoing at 8.1 and 25.1 mo. Median progression-free survival was 3.6 mo (95% CI: 2.1 – 5.3 mo) and median overall survival was 10 mo (95% CI: 5.8 – 16.7 mo). Grade 1/ 2 treatment related adverse events (AEs) occurred in 28 pts (97%) and >Grade 3 (G>3) AEs occurred in 14 pts (48%). The most common G>3 AEs were fatigue (14%), hypophosphatemia (14%), lymphocyte count decrease (14%), hypertension (7%) and hyponatremia (7%). Conclusions: CaboNivo is clinically active and safe in heavily pretreated pts with progressive mUC following ICI. Clinical trial information: NCT02496208 .

A phase I/II trial of trifluridine/tipiracil in combination with irinotecan in patients with advanced gastric cancer refractory to fluoropyrimidine, platinum, and taxane.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 210-210
Author(s):  
Hiroki Hara ◽  
Takuro Mizukami ◽  
Keiko Minashi ◽  
Tomohiro Nishina ◽  
Naoki Takahashi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Advanced Gastric Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

210 Background: Trifluridine/tipiracil (FTD/TPI) or irinotecan is a treatment option in the heavily pretreated patients with advanced gastric cancer (AGC) with the limited efficacy. Thus, we investigated the recommended dose of trifluridine/tipiracil (FTD/TPI) and irinotecan for these patients. Methods: Patients who refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) used a escalated dose of irinotecan [100 (Level 1) or 125 mg/m2 (Level 2) on Days 1 and 15 of a 28-day schedule] with 2 dosage schedules of FTD/TPI:35 mg/m2/dose, twice daily (bid), on days 1-5 and 8-12 of a 28-day cycle (Level A) or on days 1-5 and days 15-19 of a 28-day cycle (Level B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D) for phase I part and the evaluation of disease control rate (DCR) targeting > 55% in all enrolled patients for phase II part. Results: Eleven patients were enrolled from 4 institutions in Japan; 2 at Level 1A, 3 at Level 1B and 6 at Level 2B. DLTs occurred in 2/2 patient at Level 1A (Grade 3 gum infection and Grade 3 febrile neutropenia on Day 29, outside the 28-day DLT assessment period, determined equivalent to DLT), and 2/6 patients at Level 2B (Grade 3 mucositis oral and Grade 3 febrile neutropenia). Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved partial response and the DCR was 72.7% (95% CI 39.0- 94.0%). The median progression-free survival and overall survival was 3.0 months (95% CI 0.92- not reached) and 10.2 months (95% CI 2.2- not reached), respectively. Conclusions: The RP2D was determined to be Level 1B although further investigation to explore optimal regimen is needed. Clinical trial information: UMIN000031346.

Perifosine Plus Bortezomib and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma Previously Treated With Bortezomib: Results of a Multicenter Phase I/II Trial

2011 ◽  
Vol 29 (32) ◽  
pp. 4243-4249 ◽  
Author(s):  
Paul G. Richardson ◽  
Jeff Wolf ◽  
Andrzej Jakubowiak ◽  
Jeff Zonder ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progression Free Survival ◽  
Phase Iii ◽  
The Novel ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Heavily Pretreated ◽  
Previously Treated

Purpose Novel agents have improved patient outcome in relapsed or relapsed/refractory multiple myeloma (MM). Preclinical data show that the novel signal transduction modulator, perifosine, enhances the cytotoxicity of dexamethasone and bortezomib. Clinical data suggest that perifosine in combination with dexamethasone has activity in relapsed or relapsed/refractory MM. Patients and Methods In a phase I/II study, perifosine in combination with bortezomib with or without dexamethasone was prospectively evaluated in 84 patients with relapsed or relapsed/refractory MM. All were heavily pretreated and bortezomib exposed; 73% were refractory to bortezomib, and 51% were refractory to bortezomib and dexamethasone. The dose selected for the phase II study was perifosine 50 mg/d plus bortezomib 1.3 mg/m2, with the addition of low-dose dexamethasone at 20 mg if progression occurred on perifosine plus bortezomib alone. Results An overall response rate (ORR; defined as minimal response or better) of 41% was demonstrated with this combination in 73 evaluable patients, including an ORR of 65% in bortezomib-relapsed patients and 32% in bortezomib-refractory patients. Therapy was generally well tolerated; toxicities, including gastrointestinal adverse effects and fatigue, proved manageable. No treatment-related mortality was seen. Median progression-free survival was 6.4 months, with a median overall survival of 25 months (22.5 months in bortezomib-refractory patients). Conclusion Perifosine–bortezomib ± dexamethasone demonstrated encouraging activity in heavily pretreated bortezomib-exposed patients with advanced MM. A phase III trial is underway comparing perifosine–bortezomib plus dexamethasone with bortezomib–dexamethasone in patients with relapsed/refractory MM previously treated with bortezomib.

Phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4090-4090
Author(s):  
Teresa Macarulla ◽  
Victor Moreno ◽  
Li-Tzong Chen ◽  
Michael B. Sawyer ◽  
Lipika Goyal ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Progression Free Survival ◽  
Therapeutic Benefit ◽  
Clinical Activity ◽  
Drug Discontinuation ◽  
Prior Therapy ◽  
Heavily Pretreated ◽  
Recommended Phase Ii Dose ◽  
Ecog Ps

4090 Background: Evidence suggests that hyperactivated fibroblast growth factor 4 (FGFR4) signaling pathway leads to enhanced tumor growth. Targeting FGFR4 may have therapeutic benefit in tumors with altered FGF19 signaling. A phase I study (NCT02834780) was undertaken to assess H3B-6527, a highly selective covalent FGFR4 inhibitor, in patients with HCC/ICC. Methods: Adults with advanced HCC/ICC, ECOG PS 0-1, well compensated liver function, who progressed after > one prior therapy, received H3B-6527 po daily (QD) or twice-daily (bid) on a 21-day cycle following a 3+3 design. Doses ranged from 300-2000mg QD or 500-700mg BID. Patients in dose escalation were treated regardless of FGF19 status. Patients in expansion had FGF19+ tumors by mRNA testing. Adverse events (AEs), and pharmacokinetics (PK) were assessed. Response was determined by RECIST 1.1/mRECIST imaging every 6 weeks. Results: Study enrollment is complete at 128 patients. Ninety HCC patients were treated (QD = 48, bid = 42). ICC enrollment was suspended after 38 patients due to limited efficacy. No dose-limiting toxicities were seen and no grade 4-5 treatment related AEs have been observed. Recommended Phase II dose for H3B-6527 is 1000mg QD based upon safety, efficacy, and PK data. Grade 3 TEAEs have occurred in 12.5% of patients on QD dosing. Treatment related TEAEs were seen in 62.5% of patients on the QD schedule, with diarrhea (45.8%), fatigue (12.5%), and nausea (12.5%) most frequent. Drug discontinuation due to AEs for QD dosing was 8.3%. Interim data analysis shows that, for HCC patients with >2 prior lines of therapy treated on QD schedule, overall survival was 10.6m, progression-free survival 4.1m, overall response rate 16.7% (all partial responses), and clinical benefit rate 45.8% (responders + durable stable disease >17 weeks). H3B-6527 Cmax and AUC were lower at 300 mg dose but then similar across 500–2000 mg doses. Following oral administration of 1000 mg fasted, H3B-6527 plasma concentration reached peak at a Tmax of ̃2-3 hours and then decayed exponentially, with terminal half-life of ̃4-5 hours. There was no accumulation following QD dose. Dosing with food did not meaningfully change H3B-6527 plasma exposure. Conclusions: H3B-6527 was well tolerated and demonstrated a favorable toxicity and safety profile and encouraging clinical activity in heavily pretreated HCC patients. Final trial results will be presented at conference. Clinical trial information: NCT02834780.

scholarly journals Phase II study of metronomic treatment with daily oral vinorelbine as first-line chemotherapy in patients with advanced/metastatic HR+/HER2− breast cancer resistant to endocrine therapy: VinoMetro—AGO-B-046

2021 ◽  
Author(s):  
Slavomir Krajnak ◽  
Thomas Decker ◽  
Lukas Schollenberger ◽  
Christian Rosé ◽  
Christian Ruckes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
First Line ◽  
Open Label ◽  
Oral Vinorelbine ◽  
Her2 Breast Cancer ◽  
Line Chemotherapy

Abstract Purpose Metronomic chemotherapy (MCT) is an increasingly used treatment option in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced/metastatic breast cancer (MBC) after failure of endocrine-based therapies. Methods VinoMetro was a multicentre, open-label, single-arm, phase II study of metronomic oral vinorelbine (VRL; 30 mg/day) as a first-line chemotherapy (CT) in patients with HR+/HER2− MBC after endocrine failure. The primary endpoint was the clinical benefit rate (CBR) at 24 weeks. Results Between January 2017 and April 2019, nine patients were enrolled. The CBR was 22.2% (90% confidence interval [CI] 4.1–55.0), p = 0.211. The median progression-free survival (PFS) was 12.0 weeks (95% CI 11.3–12.7). Grade 3–4 adverse events (AEs) occurred in 22.2% of patients. One patient died of febrile neutropenia. Conclusion VinoMetro (AGO-B-046) was closed early after nine patients and occurrence of one grade 5 toxicity in agreement with the lead institutional review board (IRB). Metronomic dosing of oral VRL in HR+/HER2− MBC as first-line CT after failure of endocrine therapies showed only limited benefit in this population. Trial registration number and date of registration ClinicalTrials.gov Identifier: NCT03007992; December 15, 2016.

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