scholarly journals A phase I study of a dual PI3-Kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

2020 ◽  
Author(s):  
Fabian Lang ◽  
Lydia Wunderle ◽  
Susanne Badura ◽  
Eberhard Schleyer ◽  
Monika Brüggemann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Leukemia ◽  
Phase I ◽  
Mtor Inhibitor ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Prolonged Treatment ◽  
Small Subset ◽  
Serious Adverse Events ◽  
Efficient Treatment

Abstract Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single centre open lable study was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia.Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300-400 mg BID (cohort -1/1)) to assess safety, tolerability, preliminary efficacy and pharmakokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3+3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. Results Twenty-four patients with ALL (n=11) or AML (n=12) or CML-BP (n=1) were enrolled. All patients had failed one (n=5) or more lines of therapy (n=5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. Trial registration ClinicalTrials.gov, identifier NCT01756118. registered 19th Decembre 2012, https://clinicaltrials.gov/ct2/show/NCT01756118

scholarly journals A phase I study of a dual PI3-Kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

2020 ◽  
Author(s):  
Fabian Lang ◽  
Lydia Wunderle ◽  
Susanne Badura ◽  
Eberhard Schleyer ◽  
Monika Brüggemann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Leukemia ◽  
Phase I ◽  
Mtor Inhibitor ◽  
Primary Objective ◽  
Prolonged Treatment ◽  
Small Subset ◽  
Open Label ◽  
Serious Adverse Events ◽  
Efficient Treatment

Abstract Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300-400 mg BID (cohort -1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3+3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase.Results Twenty-four patients with ALL (n=11) or AML (n=12) or CML-BP (n=1) were enrolled. All patients had failed one (n=5) or more lines of therapy (n=5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML.Trial registration ClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.

scholarly journals A phase I study of a dual PI3-Kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

2020 ◽  
Author(s):  
Fabian Lang ◽  
Lydia Wunderle ◽  
Susanne Badura ◽  
Eberhard Schleyer ◽  
Monika Brüggemann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Leukemia ◽  
Phase I ◽  
Mtor Inhibitor ◽  
Primary Objective ◽  
Prolonged Treatment ◽  
Small Subset ◽  
Open Label ◽  
Serious Adverse Events ◽  
Efficient Treatment

Abstract Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300-400 mg BID (cohort -1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3+3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase.Results Twenty-four patients with ALL (n=11) or AML (n=12) or CML-BP (n=1) were enrolled. All patients had failed one (n=5) or more lines of therapy (n=5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML.Trial registration ClinicalTrials.gov, identifier NCT01756118. registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118

scholarly journals A phase I study of a dual PI3-Kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

2020 ◽  
Author(s):  
Fabian Lang ◽  
Lydia Wunderle ◽  
Susanne Badura ◽  
Eberhard Schleyer ◽  
Monika Brüggemann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Leukemia ◽  
Phase I ◽  
Mtor Inhibitor ◽  
Primary Objective ◽  
Prolonged Treatment ◽  
Small Subset ◽  
Open Label ◽  
Serious Adverse Events ◽  
Efficient Treatment

Abstract Background: Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia.Methods: Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300-400 mg BID (cohort -1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3+3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase.Results: Twenty-four patients with ALL (n=11) or AML (n=12) or CML-BP (n=1) were enrolled. All patients had failed one (n=5) or more lines of therapy (n=5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability.Conclusions: Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML.Trial registration: ClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.

scholarly journals A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Fabian Lang ◽  
Lydia Wunderle ◽  
Susanne Badura ◽  
Eberhard Schleyer ◽  
Monika Brüggemann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Leukemia ◽  
Phase I ◽  
Mtor Inhibitor ◽  
Prolonged Treatment ◽  
Small Subset ◽  
Open Label ◽  
Serious Adverse Events ◽  
Efficient Treatment ◽  
Link Type

Abstract Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300–400 mg BID (cohort − 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. Results Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. Trial registration ClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.

A phase I/Ib study of crenolanib with ramucirumab (RAM)/paclitaxel (PTX) as second-line therapy (2L tx) for advanced esophagogastric adenocarcinoma (EGA).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 116-116
Author(s):  
Megan Greally ◽  
Sujata Jha ◽  
Sam S. Yoon ◽  
Jia Li ◽  
Avni Mukund Desai ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Objective Response ◽  
Study Drug ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Serious Adverse Events ◽  
Ecog Ps ◽  
Higher Doses

116 Background: PTX/RAM as 2L tx for patients (pts) with EGA is a standard-of-care based on the RAINBOW trial (Lancet Oncol 2014;15:1224). However, benefit is modest. Upregulation of the platelet-derived growth factor (PDGF)/PDGF receptor-β (PDGFR-β) pathway causes resistance to VEGF inhibition. Crenolanib is a selective inhibitor of PDGFR-β. We report initial results of the dose escalation phase of a study of crenolanib plus RAM/PTX in pts with previously treated advanced EGA. Methods: This phase I/Ib study is enrolling ECOG PS 0-1 EGA pts with progression on first-line chemo. PTX 80 mg/m2/ day on day 1, 8, 15 and RAM 8mg/kg q 14 days were administered with escalating doses of crenolanib (60, 80, 100 mg BID) after a 7 day “run-in” of crenolanib to assess crenolanib-related toxicities. The primary objective was to determine the maximum tolerated dose (MTD) of crenolanib plus RAM/PTX. Safety and preliminary efficacy were examined. Results: 15 pts were treated; 12 male, median age 58 (32-73), 66% were ECOG PS 1. Primary site was gastric in nine pts, GEJ in 4 pts and esophageal in two pts. Three pts each received crenolanib 60mg BID and 80mg BID, six pts received 100mg BID and three pts received higher doses. At data cutoff, eight pts continued on treatment. 12 pts have completed the DLT evaluation period across 3 dose levels (60 to 100 mg BID). Median treatment duration was 76 days (35-191). The combination was well tolerated, with no DLTs or serious adverse events (SAEs) attributed to study drug. Treatment related adverse events occurred in two pts (17%), all grade 1. These were fatigue, nausea, vomiting and hypertension. Disease progression was the most common reason for treatment discontinuation; no pt discontinued due to study drug related AEs. Nine pts were evaluable for response. One pt had objective response; the disease control rate was 78%. Median PFS and OS were 4.1 and 11.9 months respectively. Conclusions: Crenolanib plus RAM/PTX appears well tolerated at a dose level of 100mg BID. Further evaluation is needed to determine efficacy. Accrual is ongoing at higher doses. Once the MTD is defined, the dose expansion phase will enroll 25 pts. Updated data with pharmacokinetics and biomarkers will be presented. Clinical trial information: NCT03193918.

scholarly journals Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma

2021 ◽  
Vol 9 (4) ◽  
pp. e002203
Author(s):  
Georgia M Beasley ◽  
Smita K Nair ◽  
Norma E Farrow ◽  
Karenia Landa ◽  
Maria Angelica Selim ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Phase I Trial ◽  
Clinical Investigation ◽  
Objective Response ◽  
Complete Response ◽  
Primary Objective ◽  
Mitogen Activated Protein Kinase ◽  
Open Label ◽  
Serious Adverse Events

BackgroundWhile programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation.MethodsAn open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections.ResultsPVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months.ConclusionIntratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients.Trial registration numberNCT03712358

scholarly journals Prospective Phase I Multi-Center Trial Incorporating Lenalidomide (LEN) into Dose-Adjusted EPOCH Plus Rituximab (DA-EPOCH-R) in Patients with Double Hit (DHL) or Double Expressing (DEL) Lymphomas: Final Results

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4191-4191 ◽  
Author(s):  
Chadi Nabhan ◽  
Theodore Karrison ◽  
Justin Kline ◽  
Kenneth Cohen ◽  
Michael R. Bishop ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Maximum Tolerated Dose ◽  
Sales Force ◽  
Primary Objective ◽  
Dose Finding ◽  
Hematologic Toxicity ◽  
Serious Adverse Events ◽  
Ecog Ps

Abstract Background: There are no prospective studies that define best therapy for DHL (presence of c-MYC and BCL-2 translocations) or DEL (co-expression of c-MYC ³40% and BCL-2 ³50% by IHC). Retrospective data for both entities show suboptimal outcomes with R-CHOP and perhaps improved outcomes with intensified regimens such as DA-EPOCH-R. We conducted a phase I prospective multicenter study adding escalating doses of LEN to DA-EPOCH-R in pts with DHL or DEL. Herein, we report the final results of the dose-finding portion of this ongoing clinical trial. Patients and Methods: Eligible pts had DHL or DEL as defined above. They were allowed to receive radiotherapy for neurologic compromise or one cycle of R-CHOP prior to enrollment at the investigator's discretion. Pts had measurable disease, ECOG PS 0-2, and adequate liver, kidney, and marrow function and no known HIV or CNS involvement. Either aspirin or warfarin prophylaxis was required. Primary objective was to determine the maximum-tolerated dose (MTD) of LEN when added to DA-EPOCH-R. We utilized a standard (3+3 design) where LEN was started at 10mg (days 1-14, Q21-days) with each cycle of DA-EPOCH-R, and escalated to a maximum of 25 mg unless a MTD was reached at an earlier dose. Dose-limiting toxicities (DLTs) were assessed during cycle 1; DA-EPOCH-R administration and dose modifications were conducted as per usual protocol. Cycles were repeated every 3-weeks for a maximum of 6 cycles and were followed by an end of therapy PET scan. CNS prophylaxis was strongly encouraged with 12.5 mg IT-methotrexate for 4 doses during induction. Patients attaining PET negativity after induction were continued on maintenance LEN 10 mg (days 1-14 Q21 days) for 12 cycles. During the LEN dose escalation portion of the study, a hematologic toxicity did not count as a DLT to allow DA-EPOCH-R dose adjustments. Results: 15 pts (6: DHL and 9: DEL; 13 DLBCL and 2 BCL-U) were enrolled; median age was 62 years (range: 26-83). There were 5 males and 10 females (11 whites, 3 African Americans, and 1 Asian pts). Two pts had ECOG PS 2 while all others were 0-1. All pts (100%) had stage III/IV disease, 13 pts (86%) had high-risk IPI score, and median LDH was 673 (range: 193-1,835). All ptsare assessable for toxicity. Serious adverse events (SAEs) per dose levels are summarized in the Table. DA-EPOCH-R dose escalation was feasible in 10 pts (67%), one pt (6.7%) maintained the same dose throughout, and another (6.7%) required dose de-escalation. Two DLTs were observed (grade 4 sepsis and hypotension for both) at dose-level 20 mg of LEN leading to 15 mg being the MTD and RP2D. Most common grade 1 and/or 2 non-hematologic toxicities were fatigue (70%), constipation (47%), alopecia (53%), nausea (47%), peripheral sensory neuropathy (40%), diarrhea (33%), and hypokalemia (33%). The only grade 3 and/or 4 non-hematologic toxicity occurring in ³2 pts (13%) was hypokalemia. All others occurred in 1 pt (6%) and were: constipation, fever, hyperglycemia, hypertension, mucositis, and hypoalbumenemia. One pt (6%) developed treatment-related myelodysplasia, (T-MDS), 18 months after treatment initiation. Twelve patients are evaluable for response at time of analysis, (1 patient lost to follow-up, and 2 with ongoing therapy). Best responses at completion of induction based on PET were 6 complete responses (CR: 50%), 3 partial responses (PR: 25%) and 1 pt with progressive disease (8%). All CR pts received LEN maintenance but only 1 completed 12 cycles to date (1 came off due to cytopenias found later to have T-MDS, 1 due to AE, 1 due to finding of unrelated colon cancer, 2 on active maintenance). With median follow up 10.7 months (range: 1.3-18.6 months), 14 pts remain alive and one pt has died for an OS of 93%. Conclusions: LEN can safely be added to DA-EPOCH-R in DHL and DEL patients at a dose of 15 mg (days 1-14 Q21 days). Chemotherapy dose escalation was not compromised and preliminary safety/efficacy data appear promising. A phase II study in this pt population with LEN+DA-EPOCH-R is underway. Disclosures Nabhan: Celgene, Genentech, Seattle Genetics, Astellas: Research Funding; Celgene, Genentech, Abbvie, Infinity, Cardinal Health: Consultancy. Karmali:Celgene: Speakers Bureau. Fishkin:Biogen: Other: Owns Stocks. Smith:Genentech: Consultancy, Other: on a DSMB for two trials ; Juno: Consultancy; TGTX: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Amgen: Other: Educational lecture to sales force; Portola: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy.

Phase I Trial of Intravenous Administration of PV701, an Oncolytic Virus, in Patients With Advanced Solid Cancers

2002 ◽  
Vol 20 (9) ◽  
pp. 2251-2266 ◽  
Author(s):  
Andrew L. Pecora ◽  
Naiyer Rizvi ◽  
Gary I. Cohen ◽  
Neal J. Meropol ◽  
Daniel Sterman ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Intravenous Administration ◽  
Single Agent ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Repeat Dose ◽  
Tumor Cell Membrane ◽  
Dosing Regimens ◽  
Higher Doses

PURPOSE: PV701, a replication-competent strain of Newcastle disease virus, causes regression of tumor xenografts after intravenous administration. This phase I study was designed to define the maximum-tolerated dose (MTD) and safety of single and multiple intravenous doses of PV701 as a single agent in patients with cancer. PATIENTS AND METHODS: Seventy-nine patients with advanced solid cancers that were unresponsive to standard therapy were enrolled. Four PV701 intravenous dosing regimens were evaluated: (1) single dose: one dose every 28 days; (2) repeat dose: three doses in 1 week every 28 days; (3) desensitizing: one lower dose followed by two higher doses in 1 week every 28 days; and (4) two week: one lower dose followed by five higher doses over 2 weeks every 21 days. RESULTS: A 100-fold dose intensification was achieved over 195 cycles. A first-dose MTD of 12 × 109 plaque-forming units (PFU)/m2 was established for outpatient dosing. After an initial dose of 12 × 109 PFU/m2, patients tolerated an MTD for subsequent doses of 120 × 109 PFU/m2. The most common adverse events were flu-like symptoms that occurred principally after the first dose and were decreased in number and severity with each subsequent dose. Tumor site–specific adverse events and acute dosing reactions were also observed but not cumulative toxicity. Objective responses occurred at higher dose levels, and progression-free survival ranged from 4 to 31 months. Tumor tissue from one patient was obtained after 11 months of therapy and showed evidence of PV701 particles budding from the tumor cell membrane by electron microscopy and a pronounced lymphoplasmacytic infiltrate by histologic examination. CONCLUSION: PV701 warrants further study as a novel therapeutic agent for cancer patients.

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.

scholarly journals Risk assessment based on the Risk Index for Serious Adverse Events (SAEs) in Phase I trials

2017 ◽  
Vol 28 ◽  
pp. ix108
Author(s):  
Sigehiro Koganemaru ◽  
Yasutoshi Kuboki ◽  
Kohei Shitara ◽  
Shogo Nomura ◽  
Hideaki Takahashi ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Adverse Events ◽  
Phase I ◽  
Risk Index ◽  
Phase I Trials ◽  
Serious Adverse Events
Sign in / Sign up

Export Citation Format

Share Document