Assessing the safety, tolerability and efficacy of PLGA-based immunomodulatory nanoparticles in patients with advanced NY-ESO-1-positive cancers: a first-in-human phase I open-label dose-escalation study protocol

IntroductionThe undiminished need for more effective cancer treatments stimulates the development of novel cancer immunotherapy candidates. The archetypical cancer immunotherapy would induce robust, targeted and long-lasting immune responses while simultaneously circumventing immunosuppression in the tumour microenvironment. For this purpose, we developed a novel immunomodulatory nanomedicine: PRECIOUS-01. As a PLGA-based nanocarrier, PRECIOUS-01 encapsulates a tumour antigen (NY-ESO-1) and an invariant natural killer T cell activator to target and augment specific antitumour immune responses in patients with NY-ESO-1-expressing advanced cancers.Methods and analysisThis open-label, first-in-human, phase I dose-escalation trial investigates the safety, tolerability and immune-modulatory activity of increasing doses of PRECIOUS-01 administered intravenously in subjects with advanced NY-ESO-1-expressing solid tumours. A total of 15 subjects will receive three intravenous infusions of PRECIOUS-01 at a 3-weekly interval in three dose-finding cohorts. The trial follows a 3+3 design for the dose-escalation steps to establish a maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Depending on the toxicity, the two highest dosing cohorts will be extended to delineate the immune-related parameters as a readout for pharmacodynamics. Subjects will be monitored for safety and the occurrence of dose-limiting toxicities. If the MTD is not reached in the planned dose-escalation cohorts, the RP2D will be based on the observed safety and immune-modulatory activity as a pharmacodynamic parameter supporting the RP2D. The preliminary efficacy will be evaluated as an exploratory endpoint using the best overall response rate, according to Response Evaluation Criteria in Solid Tumors V.1.1.Ethics and disseminationThe Dutch competent authority (CCMO) reviewed the trial application and the medical research ethics committee (CMO Arnhem-Nijmegen) approved the trial under registration number NL72876.000.20. The results will be disseminated via (inter)national conferences and submitted for publication to a peer-reviewed journal.Trial registration numberNCT04751786.

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Results of a Phase I Study of GRN163L, a Direct Inhibitor of Telomerase, in Patients with Relapsed and Refractory Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v112.11.3688.3688 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3688-3688 ◽

Cited By ~ 3

Author(s):

Asher Alban Chanan-Khan ◽

Nikhil C. Munshi ◽

Mohamad A. Hussein ◽

Laurence Elias ◽

Fabio Benedetti ◽

...

Keyword(s):

Phase I ◽

Telomere Length ◽

Dose Escalation ◽

Plasma Concentrations ◽

Clinical Signs ◽

Telomerase Activity ◽

Maximum Tolerated Dose ◽

Dose Finding ◽

Hematologic Toxicity ◽

Dose Escalation Study

Abstract Telomerase over-expression is the predominant mechanism by which cancer cells maintain adequate telomere length to achieve immortalization. Telomere length is often decreased and telomerase activity is often increased in MM. GRN163L is a 13-mer oligonucleotide that directly inhibits telomerase activity and has demonstrated anticancer effects in various preclinical models. We are conducting a phase I dose escalation study to define the maximum tolerated dose (MTD), safety, tolerability, efficacy as well as pharmacokinetics of GRN163L in patients with relapsed or refractory MM. Each treatment cycle consisted of 3 weekly 2 hr i.v. infusions of GRN163L. Dose escalation followed standard “3+3” dose finding rules. To date, 12 patients, median age 61 years, have been treated in 3 dose cohorts (3.2, 4.8 and 7.2 mg/kg). Patients had received a median of 4.0 prior treatment regimens. All patients had normal baseline neutrophil and 10 had normal baseline platelet counts. Patients completed a median of 2 cycles of GRN163L treatment, with one receiving 4 and another 6 cycles. GRN163L has been generally well-tolerated to date. One patient had Gr 3 anorexia however all other related or possibly related non-hematologic AEs to date were Gr 1 or 2. Treatment related events included thrombocytopenia, neutropenia, aPTT prolongation, anemia, fatigue, nausea, anorexia, and dizziness. No dose limiting toxicity (DLT) occurred among patients in the first 2 cohorts. All patients exhibited transient dose-related aPTT prolongations, which resolved in parallel with decreasing GRN163L plasma levels. There were no bleeding episodes or clinical signs of complement activation. Two of the 5 patients in the 7.2 mg/kg cohort had transient prolongation of aPTT to > 3 fold of the upper limit of normal. One patient in the highest dose group had Gr 4 thrombocytopenia in Cycle 1, which constituted a DLT. Delayed (cycle 2 or later) Gr 3 or 4 neutropenia or thrombocytopenia was noted in 5 additional patients with no episodes of febrile neutropenia. Maximal post-infusion plasma concentrations (Cmax) of GRN163L have been linear with respect to dose. Mean (± SD) plasma concentration of GRN163L declined by 41.1 ±17.6 %, N=9, over the 2 hours following the first infusion, consistent with other previously reported studies. DLTs observed in this study were thrombocytopenia and aPTT prolongation. The MTD for continuous weekly dosing of GRN163L in this heavily pretreated, relapsed and refractory MM population appears to be ≥ 4.8 and < 7.2 mg/kg. The most marked hematologic toxicity was observed in two patients with prior autologous stem cell transplantation. Exploration of intermediate dose levels in this range is continuing. Additional studies exploring alternative dosing schedules will be initiated.

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A phase I open-label, dose escalation study to determine the maximum tolerated dose and to evaluate the safety profile of lenalidomide with every three week docetaxel in subjects with androgen independent prostate cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.14618 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 14618-14618 ◽

Cited By ~ 1

Author(s):

R. A. Moss ◽

G. Shelton ◽

J. Melia ◽

S. G. Mohile ◽

D. P. Petrylak

Keyword(s):

Prostate Cancer ◽

Phase I ◽

Dose Escalation ◽

Specific Antigen ◽

Maximum Tolerated Dose ◽

Open Label ◽

Narcotic Analgesics ◽

Dose Escalation Study ◽

Measurable Disease ◽

Androgen Independent

14618 Background: Based on the known efficacy of docetaxel (D) in Androgen Independent Prostate Cancer (AIPC), and demonstrated activity of the antiangiogenesis agent thalidomide in combination with docetaxel, a Phase I trial in patients (pts) with AIPC with evidence of progression by unidimensionally measurable disease or rising serum Prostate Specific Antigen (PSA) levels after antiandrogen withdrawal was designed. The study evaluates the combination of escalating doses of D and lenalidomide (Ln), a derivative of thalidomide with immunomodulatory and antiangiogenic properties. Pts were permitted to have no more than two prior chemotherapy regimens. Methods: Pts were given D and Ln on a q3 week dose-escalation schedule. Dose Levels of D (mg/m2): Level (L) 1 = 60 L2-L5 =75, given IVPB over 60 minutes in combination with prednisone 5mg po bid. Decadron 20 mg was given 12, 6 hrs and 15 minutes prior to D on D#1. Dose of Ln (mg/day) on D#1–14 of 21-day cycle: L 1 = 10 mg, L2= 10 mg, L3 = 15 mg, L4–20 mg L5 = 25 mg. Patient Characteristics: L1: N = 5. Median Age 66.2 yrs. Median PSA = 101.9 (range 5.9–164.0). Prior CT: none. Prior palliative RT: none. Patients with unidimensionally measurable disease: 4, all in lymph nodes. Patients with bone metastases: 5. Pre-treatment, 1 patient required narcotic analgesics. Results: Five L1 patients are evaluable for toxicity and response. Median number of cycles administered = 4 (range 2–5). Toxicity: There have been no Grade (G) 3 or 4 toxicities. Anti-tumor activity: Two pts (40%) have had a greater than 50% decline in serum PSA on 2 consecutive measurements at least 2 weeks apart. Of 4 pts with unidimensionally measurable disease, all have stable disease by RECIST criteria. Conclusions: At L1, D + Ln has been well tolerated in AIPC. Further dose escalation to L2 and above is planned. [Table: see text]

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A phase I study of Debio 0932, an oral HSP90 inhibitor, in patients with solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3026 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3026-3026 ◽

Cited By ~ 1

Author(s):

Nicolas Isambert ◽

Antoine Hollebecque ◽

Yann Berge ◽

Hein van Ingen ◽

Silvano Brienza ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Phase I Study ◽

Maximum Tolerated Dose ◽

Hsp90 Inhibitor ◽

Treatment Withdrawal ◽

Advanced Solid Tumors ◽

Open Label ◽

Dose Escalation Study

3026 Background: Debio 0932 is an oral second-generation heat shock protein 90 (HSP90) inhibitor that has shown extended tumor retention, blood-brain-barrier penetration, and promising anti-tumor activity both as monotherapy and combination against a broad range of tumors in pre-clinical models. Here we report the results of the dose escalation part of a phase I study in patients with advanced solid tumors or lymphoma (NCT01168752). Methods: This was an open-label, non-randomized, 3 + 3 dose-escalation study to determine the maximum tolerated dose (MTD) of Debio 0932 when given QD or Q2D during the first 30 days of treatment in patients with advanced solid tumours or lymphoma resistant to standard therapy. The starting dose in both treatment groups was 50mg. Doses were increased according to an algorithm based on observed toxicity and dose limiting toxicities (DLT). Tumor assessments were performed every 8 weeks. Results: Patient characteristics and results are summarized below. DLTs occurred at 1600mg in both dose groups. Adverse events (AE) were mostly CTCAE grade 1 or 2, with no apparent dose relationship. No ocular or cardiac toxicity was observed. The main reason for treatment withdrawal was progressive disease. Investigator-reported cases of SD and PR were observed. Conclusions: Debio 0932 mono-therapy was generally well tolerated and showed promising signs of efficacy in patients with advanced solid tumors. The recommended phase II dose, established at 1000mg QD, will be tested in an additional 30 patients in an ongoing expansion study. A phase I-II study of Debio 0932 in combination with standard of care in the first- and second-line treatment of NSCLC is planned. [Table: see text]

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A phase I study of the safety and activity of K-001 in patients with advanced pancreatic ductal adenocarcinoma

BMC Cancer ◽

10.1186/s12885-021-08375-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jiujie Cui ◽

Haiyan Yang ◽

Jue Liu ◽

Donghui Chen ◽

Jiong Hu ◽

...

Keyword(s):

Antitumor Activity ◽

Phase I ◽

Pancreatic Ductal Adenocarcinoma ◽

Dose Escalation ◽

Objective Response ◽

Maximum Tolerated Dose ◽

Ductal Adenocarcinoma ◽

Marine Microorganisms ◽

Open Label ◽

Dose Escalation Study

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that lack of effective therapeutic drugs. K-001 is an oral antitumor drug made from active ingredients of marine microorganisms. The current study aimed to evaluate safety and antitumor activity of K-001 in patients with advanced PDAC. Methods In this phase I, open-label trial, patients with advanced PDAC were recruited to a dose-escalation study in a standard 3 + 3 design. K-001 was administered twice daily in four-week cycles, and dose escalation from 1350 mg to 2160 mg was evaluated twice daily. Physical examination and laboratory tests were done at screening and then weekly. The safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of K-001 were assessed while tumor response was estimated by Response Evaluation Criteria in Solid Tumor (RECIST). Results Eighteen patients with advanced PDAC were screened, and twelve eligible patients were analyzed in the study. No DLT was observed. Totally, 47 adverse events (AEs) presented, and 14 drug-related AEs were reported in 7 patients, including 8 grade 1 events (57.1%) and 6 grade 2 events (42.9%). There was no grade 3 or 4 drug-related AE. In these 14 drug-related AEs, the most frequent ones were dyspepsia (21.4%), followed by flatulence, constipation, and hemorrhoid bleeding (above 10% of each). Among all 12 patients, 10 patients (83.3%) maintained stable disease (SD), and 2 patients (16.7%) had progressive disease (PD). The objective response rate (ORR) was 0% and the disease control rate (DCR) was 83.3%. Conclusions K-001 manifests satisfactory safety and tolerability, as well as meaningful antitumor activity in advanced PDAC patients. Further evaluation of K-001 in phase II/III appears warranted. Trial registration NCT02720666. Registered 28 Match 2016 - Retrospectively registered.

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A phase I, open label, multicenter dose escalation study of AZD2811 nanoparticle in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3098 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3098-3098

Author(s):

Melissa Lynne Johnson ◽

Jan G. C. E. Cosaert ◽

Gerald Steven Falchook ◽

Suzanne Fields Jones ◽

Donald Strickland ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Maximum Tolerated Dose ◽

Mucosal Inflammation ◽

Advanced Solid Tumors ◽

Open Label ◽

Dose Escalation Study ◽

Total Blood ◽

Aurora Kinase B

3098 Background: Aurora kinase B (AURKB) represents a potential target for therapy in solid and hematological malignancies. AURKB inhibitor AZD1152 (barasertib) was previously investigated in solid tumor pts in a phase I setting. AZD2811-nanoparticle (np) is a novel, encapsulated slow release AURKB inhibitor offering several advantages over AZD1152 (Ashton S et al., Sci Transl Med 2016). We report the completed dose-escalation safety, pharmacokinetics (PK), preliminary activity and defined maximum tolerated dose (MTD) of AZD2811-np in pts with advanced solid tumors (NCT02579226). Methods: Adult pts with advanced solid tumors received AZD2811-np IV on Day 1 (D1) and 4 (D4) Q4 week (wk) in six cohorts 15-200 mg/infusion without the use of g-csf in cycle 1. D1 Q4wk and Q3wk schedules were investigated up to 600 mg/infusion (including cohorts with mandatory g-csf prophylaxis on day 8). A standard 3+3 design was used. PK was assessed in cycle 1. Results: 50 pts were recruited into 12 cohorts. D1, D4 Q4wk schedule: 24 pts (15, 25,38, 50, 100 mg/infusion (n=3/cohort), 200 mg/infusion (n=9)). All cohorts were tolerated. Transient grade 4 neutropenia was observed in 7/9 pts at 200 mg/infusion, including 1 DLT (gr4 > 7 days) D1 Q4wk: 200 mg(n=3) was tolerated. D1 Q3wk: 23 pts were evaluated (200/400 mg (n=3,7), and 400/600/500 mg with mandatory g-csf (n=3/5/6)). 400 mg without g-csf was not tolerated (1 gr3 mucosal inflammation & 1 gr4 neutropenia > 7 days). 600 mg with g-csf was not tolerated (gr3 febrile neutropenia & gr3 fatigue). 25/50 pts experienced AE ≥gr 3 (21 considered AZD2811-np-related, 19 neutropenia-related, no deaths within-DLT period). AZD2811-np caused transient gr1/2 fatigue, nausea, diarrhoea and mucosal inflammation. AZD2811 total blood PK appears dose proportional with a t1/2 of 30-50 hours irrespective of schedule. Released AZD2811 concentrations ~1% of total. 14 pts (28%) had disease stabilisation. 1 prostate ca. pt had a confirmed partial response (PR) (continued tx to 451 days). Conclusions: The MTD for AZD2811-np is 500 mg D1 Q3wk. AZD2811-np is now being investigated in a small cell lung cancer expansion. Clinical trial information: NCT02579226.

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A Phase I Study of K-001 in Patients with Advanced Pancreatic Ductal Adenocarcinoma

10.21203/rs.3.rs-394558/v1 ◽

2021 ◽

Author(s):

Jiujie Cui ◽

Haiyan Yang ◽

Jue Liu ◽

Donghui Chen ◽

Jiong Hu ◽

...

Keyword(s):

Antitumor Activity ◽

Phase I ◽

Pancreatic Ductal Adenocarcinoma ◽

Dose Escalation ◽

Objective Response ◽

Maximum Tolerated Dose ◽

Ductal Adenocarcinoma ◽

Marine Microorganisms ◽

Open Label ◽

Dose Escalation Study

Abstract Background:K-001 is an oral antitumor drug made from active ingredients of marine microorganisms. The current study aimed to evaluate safety and antitumor activity of K-001 in patients with advanced pancreatic ductal adenocarcinoma (PDAC).Methods:In this phase I, open-label trial, patients with advanced PDAC were recruited to a dose-escalation study in a standard 3+3 design. K-001 was administered twice daily in 4-week cycles, and dose escalation from 1350mg to 2160mg twice daily was evaluated. Physical examination and laboratory tests were done at screening and then weekly. The safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of K-001 were assessed, and tumor response was estimated by Response Evaluation Criteria in Solid Tumor (RECIST).Results:Eighteen patients with advanced PDAC were screened, and twelve eligible patients were analyzed in the study. No DLT was observed. Totally, 47 adverse events (AEs) presented, and 14 drug-related AEs were reported in 7 patients, including 8 grade 1 events (57.1%) and 6 grade 2 events (42.9%). There was no grade 3 or 4 drug-related AE. In these 14 drug-related AEs, the most frequent ones were dyspepsia (21.4%), followed by flatulence, constipation, and haemorrhoids bleeding (above 10% of each). Among all 12 patients, 10 patients (83.3%) maintained stable disease (SD), and 2 patients (16.7%) had progressive disease (PD). The objective response rate (ORR) was 0% and the disease control rate (DCR) was 83.3%.Conclusions:K-001 has satisfactory safety and tolerability, as well as meaningful antitumor activity in advanced PDAC patients. Further evaluation of K-001 in phase II/III appears warranted.Trial registration: NCT02720666. Registered 28 Match 2016 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02720666.

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Phase I study of tomuzotuximab, a glycoengineered therapeutic antibody against the epidermal growth factor receptor, in patients with advanced carcinomas

ESMO Open ◽

10.1136/esmoopen-2017-000303 ◽

2018 ◽

Vol 3 (2) ◽

pp. e000303 ◽

Cited By ~ 7

Author(s):

Walter Fiedler ◽

Sara Cresta ◽

Henning Schulze-Bergkamen ◽

Sara De Dosso ◽

Jens Weidmann ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Phase I ◽

Dose Escalation ◽

Antitumour Activity ◽

Growth Factor Receptor ◽

Maximum Tolerated Dose ◽

Dose Escalation Study ◽

Epidermal Growth

BackgroundChanges in glycosylation of the constant domain (Fc) of monoclonal antibodies (mAbs) enhance antibody-dependent cell-mediated cytotoxicity independently of downstream effects following receptor blockade by the antibody, thus extending their indication. We investigated the safety, pharmacokinetics, pharmacodynamics and antitumour activity of tomuzotuximab, an IgG1 glycoengineered mAb against the epidermal growth factor receptor with enhanced tumour cytotoxicity in a phase I dose-escalation study (NTC01222637).Patients and methodsForty-one patients with advanced solid tumours refractory to standard therapies received tomuzotuximab weekly (12–1370 mg) or two-weekly (990 mg) on a three-plus-three dose escalation design.ResultsA maximum tolerated dose was not reached. The most frequent treatment-related adverse events were infusion-related reactions in 31 (76%) patients (grade 3, 12%), mainly confined to the first dose, and skin toxicities (grade 1 or 2) in 30 (73%) patients. Hypomagnesaemia was observed in 9 out of 23 evaluable patients (39%). Similar to cetuximab, tomuzotuximab concentrations increased proportionally to dose from doses≥480 mg with a median terminal half life (t½) of 82 hours, range 55–113 hours. Antitumour activity included one complete response ongoing since more than 4.5 years in a patient with non-small-cell lung cancer and one partial response lasting 353 days in a patient with colorectal cancer. Twelve patients achieved stable disease (median, 166 days, range, 71–414 days) and two patients had prolonged control (>1 year) of their non-measurable disease.ConclusionTomuzotuximab was safe and showed promising antitumour activity in heavily pretreated patients with advanced metastatic disease. A phase IIb trial of chemotherapy and weekly tomuzotuximab or cetuximab followed with maintenance therapy with the corresponding mAb in patients with recurrent or metastatic head and neck squamous cell carcinoma is ongoing.

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