Phase I-II open label multicenter study of PD0332991 in BRAFV600mut metastatic melanoma patients harboring CDKN2A loss and RB1 expression and treated with vemurafenib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9545-9545
Author(s):  
Baptiste Louveau ◽  
Matthieu Resche-Rigon ◽  
Thierry Lesimple ◽  
Marc Pracht ◽  
Barouyr Baroudjian ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Phase I ◽  
Clinical Response ◽  
Metastatic Melanoma ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Open Label ◽  
Melanoma Patients ◽  
Group 2 ◽  
Group 1

9545 Background: Among mechanisms of resistance to BRAF inhibitors (BRAFi), cell cycle effectors including CDK4 have been involved in ERK reactivation. In this phase I-II open label study, we aimed to establish the Maximum Tolerated Dose (MTD) of PD0332991, an inhibitor of CDK4/6, when added to vemurafenib (VM) in metastatic melanoma patients. Methods: Patients with BRAFV600E/K mutated metastatic melanoma harbouring CDKN2A loss and RB1 expression were included. Patients were treated with a 14 days followed by 7 days rest daily dosing schedule of PD0332991 + continuous BID dosing of VM, and stratified into 2 groups according to previous BRAFi treatment (no group 1, yes group 2). Dose levels (PD0332991 (mg/QD)/VM (mg/BID) ranged from 25/720 to 200/960. The primary endpoint was the occurrence of a DLT within the first 2 cycles of therapy. Secondary endpoints included best response (RECIST), OS, PFS, pharmacokinetics parameters, tumour molecular profiling on baseline lesions using transcriptomic and NGS analysis. Results: Nineteen patients were enrolled, among them 16 (84%) in group 2, with 18.5 months median follow-up. Characteristics at baseline were: male 11 (58%), median age 54.4 years, unresectable stage IIIC 2 (11%), stage IV 17 (89%), M1C 12 (67%), high LDH 9 (47%), median time from advanced melanoma diagnosis to inclusion 26.8 months, ≥ 2 lines therapy 13 (68%). A DLT was observed for 1 and 5 patients in group 1 and 2 respectively, defining the MTD at PD0332991 25mg and VM 960mg in group 2. No significant evidence for drug-drug interaction between PD0332991 and VM was highlighted. In group 2, ORR was estimated to 4 (25%), SD to 8 (50%), median PFS to 9.3 months and median OS to 13.2 months. Baseline transcriptomic analysis revealed high alteration rate associated with clinical response and enrichment in genes related to MAPK, cell cycle and apoptosis pathways. Conclusions: While combination of fixed dose of PD0332991 + VM did not allow us to increase PD0332991 dosage above 25mg, significant clinical benefit was achieved in heavily pretreated patients; baseline molecular analysis revealed an association between transcriptomic data and clinical response. Clinical trial information: NCT02202200.

scholarly journals Phase I-II open label multicenter study of palbociclib + vemurafenib in BRAFV600MUT metastatic melanoma patients: uncovering CHEK2 as a major response mechanism

2021 ◽  
pp. clincanres.4050.2020
Author(s):  
Baptiste Louveau ◽  
Matthieu Resche-Rigon ◽  
Thierry Lesimple ◽  
Laetitia Da Meda ◽  
Marc Pracht ◽  
...  
Keyword(s):  
Phase I ◽  
Metastatic Melanoma ◽  
Multicenter Study ◽  
Response Mechanism ◽  
Open Label ◽  
Major Response ◽  
Melanoma Patients

A phase I study of the combination of intravenous Reolysin (REO) and gemcitabine (GEM) in patients (pts) with advanced cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3584-3584
Author(s):  
H. Arkenau ◽  
J. Evans ◽  
M. Lokelma ◽  
P. Roxburgh ◽  
R. Morisson ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Control ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Open Label ◽  
Enveloped Virus ◽  
Trial Entry ◽  
Wide Range ◽  
Label Dose ◽  
Secondary Endpoints

3584 Background: REO (reovirus serotype 3) is a Dearing strain, naturally occurring, non-enveloped virus with limited pathogenecity in humans. REO replicates specifically in transformed Ras-activated cells due to inhibition of the dsRNA-activated protein kinase, resulting in cell-lysis. GEM has shown efficacy in a wide range of tumors commonly driven by activated Ras, and causes cell cycle arrest in S phase. Results from isobologram analysis suggest potential synergies of REO and GEM. Methods: This open-label, dose-escalating, two-centre phase-I trial studied the combination of iv REO, d1–5 and iv GEM, d1 and 8, qw3. The REO starting dose was 3x109 TCID50 over 1-hour, increasing in successive cohorts and GEM was given at a fixed dose of 1,000 mg/m2 over 30-min. Endpoints were the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and safety profile of REOGEM and to establish a RP2D. Secondary endpoints were to evaluate the immune response, to evaluate pharmacokinetics of REOGEM and to describe any antitumor activity. Results: Since July 2007, 15 heavily pre-treated pts with disease progression prior to trial entry (9M/6F, median age 56 years, ECOG 0/1: 3/12) were entered into this trial. After 2 pts had Grade >3 toxicities during the first cycle (1 pt: GGT and Trop-I increase and PD; 1 pt: Trop-I increase and unspecific ST-changes) considered probably related to both agents the protocol was amended and the dose of REO was adjusted to 1x109 TCID50, d1 of each cycle (C-1) and increased in subsequent cohorts to 3x109, 1x1010, and 3x1010 TCID50. In total 45 cycles were administered (median 3) resulting in mild and expected toxicities including fever, headaches, rhinorrhea, fatigue and myelosupression. The MTD was not reached. Of the 10 pts evaluable for response, 2 pts (breast and nasopharyngeal) had PR and/or clinical response and 5 pts had SD for 4–8 cycles, amounting for a total disease control rate (CR+PR+SD) of 70%. Conclusions: The combination of REOGEM was well tolerated and resulted in disease control for a majority of pts. A RP2D, of REO 3x1010, d1 and GEM 1000mg/m2, d1 and 8, qw3, was recommended and phase-2 trials are underway. [Table: see text]

A phase I study of an IDO inhibitor (SHR9146) plus camrelizumab and in combination with/without apatinib in patients with advanced solid tumors: Safety and efficacy analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3101-3101
Author(s):  
Ying Cheng ◽  
Ying Liu ◽  
Jinhua Xu ◽  
Jing Zhu ◽  
Ying Wang ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Renal Cancer ◽  
Phase I Study ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Safety And Efficacy

3101 Background: IDO is an enzyme of interest in immuno-oncology because of the immunosuppressive effects that result from its role in tryptophan catabolism. Clinical trials of IDO inhibitors with immunotherapy are under active investigation. The addition of angiogenesis inhibitor may further enhance the anti-tumor immune responses. Here we report the safety and efficacy results of SHR9146 (IDO inhibitor) plus camrelizumab (PD-1 antibody) with/without apatinib (VEGFR-2 inhibitor) in patients (pts) with advanced solid cancers who failed standard antitumor therapies. Methods: This was an open-label, phase I study. Eligible puts would receive SHR9146 (escalated dose) plus camrelizumab (200 mg IV, q2w) alone (Cohort A) or in combination with apatinib (250 mg p.o. qd) (Cohort B). Each cohort was conducted according to a 3+3 dose escalation design. The starting dose of SHR9146 was 100mg bid, followed by 200, 400, 600 mg bid. The two primary endpoints were Dose-limiting Toxicity (DLT) and Maximum Tolerated Dose (MDT). The secondary objective was to analysis the incidence of Adverse Events (AEs) and efficacy. Results: As of Oct 31, 2020, 23 pts have been enrolled (Cohort A:14, Cohort B: 9; median age: 54 years; median prior therapies: 2 lines;). Cohort A was escalating at 600mg, and Cohort B was escalating at 400mg. Two pts experienced DLTs: one DLT (G4 hypercalcemia) was observed at 600mg in Cohort A; the other DLT (G3 rash) was observed at 400mg in Cohort B. MDT was not reached and the study was still ongoing. In Cohort A, ORR and DCR in evaluable pts were 21.4% (3/14, all confirmed) and 42.9% (6/14). Partial response was observed in 3 pts with liver cancer (1/3), renal cancer (1/3), and cervix cancer (1/3). In Cohort B, ORR and DCR in evaluable pts were 33.3%(3/9, all confirmed) and 77.8%(7/9). Partial response was observed in 3 pts with SCLC (1/3), prostate cancer (1/3) and renal cancer (1/3). The incidence of pts with TRAEs and grade>=3 TRAEs were 91.3% (21/23) and 39.1% (9/23) respectively. The most common grade>=3 TRAEs were hypercalcemia (26.1%, 6/23), fatigue (17.4%, 4/23) and nausea (13.0%, 3/23). No fatal AEs were observed. G3 nausea, G3 lipase increased and G2 GGT increased resulted in SHR9146 dose reduction in 3 pts (Cohort A). Conclusions: SHR9146 plus camrelizumab in combination with/without apatinib demonstrated promising anti-tumor activity with acceptable safety in pts with advanced solid tumors. Further study is needed to validate the efficacy and safety. Clinical trial information: NCT03491631.

The use of antiviral drug based on technologically processed antibodies to interferon-γ, CD4 receptor and histamine in the treatment of influenza in adults: results of a multicenter open-label randomized comparative trial with oseltamivir

2021 ◽  
Vol 19 (1) ◽  
pp. 39-57
Author(s):  
K.V. Zhdanov ◽  
◽  
R.F. Khamitov ◽  
V.V. Rafalsky ◽  
M.P. Mikhaylusova ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cell ◽  
Open Label ◽  
Virus Elimination ◽  
Antiviral Immune Response ◽  
Cd4 Receptor ◽  
Antiviral Efficacy ◽  
Ifn Γ ◽  
Group 2 ◽  
Group 1

Objective. A multicenter open-label randomized controlled clinical trial was aimed to compare the efficacy of the study drug (SD) containing technologically processed affinity purified antibodies (high dilutions) to IFN-γ, CD4 receptor and histamine (Ergoferon) with oseltamivir, and evaluate the influence of SD on the antiviral immune response in adults with seasonal influenza. Patients and methods. 184 outpatients aged 18–70 with confirmed influenza of mild/moderate severity were included and randomized into 2 groups (in a 1:1 ratio). Patients received SD (Group 1, n = 92) or oseltamivir (Group 2, n = 92), according to the instructions for medical use for 5 days. As the primary endpoint, the percentage of patients with recovery/improvement was assessed (according to the data of the patient's diary on days 2–7 and according to the clinical examination on days 3 and 7). Additionally, the duration and severity of influenza symptoms, the percentage of patients with virus elimination (according to RT-PCR of nasopharyngeal samples), the percentage of patients with complications, the percentage of patients prescribed antipyretic drugs, the change in concentration of T cell (IL-2, IL-18, IFN-γ) and B cell antigen-specific (IL-4, IL-16) immune response regulators in serum, the leukocyte phenotypes on days 1, 3 and 7 were evaluated. Statistical analysis was performed using a “Non-Inferiority” design (or no less efficiency/safety). Intention-to-Treat (ITT) analysis data are presented. Results. According to patients’ self-assessment, 53.3% of patients in Group 1 recovered/improved on the 6th day in the morning and 65.2% – in the evening (vs. 53.3% and 57.6% in Group 2, respectively). There were 73.9% recovered/ improved patients on the 7th day in the morning (vs. 67.4% in Group 2). A generalized analysis showed that the treatment results in both groups were comparable (p < 0.0001). According to objective medical examination, 79.3% of patients in the SD group and 74.0% of patients in the Оseltamivir group recovered/improved on the 7th day (p < 0.0001). The antiviral efficacy of SD was not inferior to oseltamivir, which was confirmed by comparable periods of virus elimination, duration and severity of fever and other influenza symptoms. A moderate activating effect of SD on the immune system was evaluated. A significant, compared to oseltamivir, increase in the concentration of IL-2 and IL-4 on the 3rd day of treatment (p = 0.03 and p = 0.04 vs. the oseltamivir group), and IFN-γ on the 3rd and the 7th days (p = 0.012 and p < 0.0001, respectively, vs. the oseltamivir group). No stimulating effect of SD on the growth and differentiation of immune cells was found. Conclusion. SD is effective and safe in the treatment of patients with influenza. The therapeutic and antiviral efficacy of SD is comparable to that of oseltamivir. The antiviral activity of SD affects the interferon system and the concentration of the cytokines IL-2 and IL-4, regulators of the T and B cell immune response. At the same time, there is no significant stimulation of interferon production with further development of hyporeactivity. Key words: influenza, oseltamivir, therapy, cytokines, Еrgoferon

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.

Phase I/II Study of Ipilimumab for Patients With Metastatic Melanoma

2008 ◽  
Vol 26 (36) ◽  
pp. 5950-5956 ◽  
Author(s):  
Jeffrey S. Weber ◽  
Steven O’Day ◽  
Walter Urba ◽  
John Powderly ◽  
Geoff Nichol ◽  
...  
Keyword(s):  
Phase I ◽  
Metastatic Melanoma ◽  
Complete Response ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Clinical Activity ◽  
Multiple Doses ◽  
Group A ◽  
Group B

PurposeThe primary objective of this phase I/II study was to determine the safety and pharmacokinetic profile of either transfectoma- or a hybridoma-derived ipilimumab. Secondary objectives included determination of a maximum-tolerated dose and assessment of clinical activity.Patients and MethodsEighty-eight patients with unresectable stage III or IV melanoma with at least one measurable lesion were treated. Mean age was 59 years, with 65% male and 35% female patients, and 79% of patients had received prior systemic therapy. Single doses of ipilimumab up to 20 mg/kg (group A, single dose), multiple doses up to 5 mg/kg (group A, multiple dose), and multiple doses up to 10 mg/kg (group B) were administered.ResultsSingle dosing up to 20 mg/kg of transfectoma antibody was well tolerated, as were multiple doses up to 10 mg/kg without a maximum-tolerated dose. In group B, dose-limiting toxicity was seen in six of 23 melanoma patients. Grade 3 or 4 immune-related adverse events (irAEs) were observed in 14% of patients (12 of 88 patients), and grade 1 or 2 irAEs were seen in an additional 58%. The half-life of ipilimumab was 359 hours. In group B, there was one partial response (23+ months), one complete response (21+ months), and seven patients with stable disease (SD), for a disease control rate of 39%. Two patients in group B with SD had slow, steady decline in tumor burden that was ongoing at 1 year of observation.ConclusionIpilimumab has activity in patients with metastatic melanoma. Late responses were observed in patients with prolonged SD.

334 DNA SYNTHESIS DURING THE FIRST CELL CYCLE OF PORCINE OOCYTES FOLLOWING DIFFERENT ACTIVATION TREATMENTS

2007 ◽  
Vol 19 (1) ◽  
pp. 282
Author(s):  
S.-A. Ock ◽  
D. Kang ◽  
J. Han
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Molecular Signaling ◽  
Oocyte Activation ◽  
Group 4 ◽  
Group 3 ◽  
Group 2 ◽  
Nuclear Ploidy ◽  
High Level ◽  
Group 1

Inhibitors of protein synthesis and phosphorylation have been widely used for oocyte activation and have been reported to induce abnormalities in nuclear ploidy due to aberrant DNA synthesis (DNAS). The present experiment was designed to compare the DNAS during the first cell cycle of porcine parthenotes following different activation treatments. Cumulus–oocyte complexes were cultured in TCM-199 supplemented with 0.5 �g mL-1 LH and FSH, 10 ng mL-1 EGF, and 0.1% PVA for 22 h, and additionally cultured in media without LH and FSH for 22 h. MII oocytes were then electrically pulsed twice in 0.28 M mannitol containing 0.05 mM CaCl2 and 0.1 mM MgSO4 at 1.8 kV cm-1 for 30 �s (group 1), followed by 7.5 �g mL-1 cytochalasin B (CCB, group 2), 10 �g mL-1 cycloheximide (CHX, group 3), or 1.9 mM 6-dimethylaminopurine (6-DMAP, group 4) for 3 h. Eggs were incubated with 100 �M 5-bromo-222-deoxyuridine (BrdU) for 1 h at 0, 2, 4, 6, 8, 10, and 12 h after activation to evaluate DNAS (Adenot et al. 1997 Development 124, 4615–4625) by determining the BrdU signal under a fluorescence microscope. Experiments were replicated 4 times; results were expressed as mean � SD and analyzed using one-way ANOVA by SPSS 10.0. The percentage of DNAS was calculated by dividing the number of BrdU-positive eggs by the total number of eggs used. DNAS in groups 1, 3, and 4 initiated at 2–3 h post-activation (hpa) but at 4–5 hpa in group 2. In group 1, DNAS was faint until 3 hpa, gradually increasing thereafter until 11 hpa (20.7 � 19.6, 29.4 � 17.0, 41.3 � 16.7, and 64.4 � 6.2, at 4–5, 6–7, 8–9, and 10–11 hpa, respectively). There was a significant (P &lt; 0.05) increase in DNAS at 10–11 h, but a significant (P &lt; 0.05) decrease (34.3 � 6.4) at 12–13 hpa. In groups 2 and 3, after 4–5 hpa, DNAS gradually increased until 7 h (6.2 � 1.4 and 29.8 � 16.6 at 4–5 hpa, and 21.1 � 13.7 and 40.0 � 18.7 at 6–7 hpa, respectively), but a DNAS peak was observed at 8–9 h (44.6 � 9.0) in group 2 and at 10–11 h (40.5 � 22.1) in group 3. Interestingly, group 4 parthenotes showed a different DNAS pattern compared with other groups, as it started at 2–3 hpa (24.8 � 11.7), reached a significantly (P &lt; 0.05) high level at 4–5 hpa (56.3 � 9.0), and gradually decreased at 6–7 hpa (42.7 � 10.3) until 12–13 hpa (29.5 � 14.9). In conclusion, CCB, CHX, and 6-DMAP used for oocyte activation exhibited different patterns of DNA synthesis during the first cell cycle of porcine parthenotes. Therefore, further experiments are required to evaluate the molecular signaling that regulates DNAS, embryonic developmental velocity, and ploidy of 2-cell parthenotes.

E7389, a novel anti-tubulin, in patients with refractory breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 653-653 ◽  
Author(s):  
J. BlumL. Forero ◽  
M. K. Heiskala ◽  
N. Meneses ◽  
K. Chandrawansa ◽  
F. Fang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Performance Status ◽  
Safety Data ◽  
Synthetic Analog ◽  
Open Label ◽  
Ecog Performance Status ◽  
Group 2 ◽  
Grade 3 ◽  
Cycle Group ◽  
Group 1

653 Background: E7389 is a synthetic analog of halichondrin B, with a broad anti- proliferative activity against tumor cells. Methods: E7389 was evaluated in an open-label, single-arm Phase II trial as monotherapy for patients with refractory breast cancer (≥2 prior chemotherapy regimens, which must have included an anthracycline and a taxane). E7389 was administered as an IV bolus of 1.4 mg/m2 on Days 1, 8, and 15 of a 28-day cycle (group 1), or on Days 1 and 8 of a 21-day cycle (group 2). The primary efficacy endpoint was ORR. Results: As of 9 December 2005, 88 patients had received treatment, 68 in group 1 and 20 in group 2. Median age was 55 yrs (range 36–84) and ECOG performance status 0–1. Sixty-six percent of the tumors were ductal carcinomas, 6% lobular, and 27% were unclassified. Sixty percent of the tumors were ER+, 47% PR+, and 17% Her2/neu 3+. The patients had received at least two previous regimens, with a median number of 5 (range 2–14). Forty-eight percent of the patients had also used hormonal therapy. Forty-nine patients in group 1 and 12 patients in group 2 had completed their 2nd cycle of treatment, and twenty-one in group1 and 1 in group 2 their 4th cycle. Safety: The major toxicity related to study drug was neutropenia. Among 73 patients with preliminary safety data available, two patients had Grade 3 febrile neutropenia, and 31 had Grade 3 or 4 neutropenia or leukopenia. The other Grade 3 toxicities encountered in more than two patients were dehydration (4 patients) and dyspnea (4 patients). Grade 3 peripheral neuropathy was reported in 2 patients. Efficacy: At the end of cycle four there were 10 (15.2%) confirmed partial responses (PRs) out of 66 evaluable patients in group 1, and 1 confirmed PR (5.6%) out of 18 evaluable patients in group 2. The median duration of confirmed responses was 113 days. Conclusions: Based on the safety and efficacy in this refractory breast cancer population, E7389 appears to be a therapy worthy of continued investigation in patients with heavily pretreated breast cancer. In order to comply with the current demand for individualized cancer care, bio-markers which would predict the sensitivity to E7389 are being searched in the tumor samples of the patients in the current and forthcoming studies. [Table: see text]

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