scholarly journals ACTR-47. TPI 287, A BRAIN PENETRABLE ANTI-MICROTUBULE AGENT, PLUS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: RESULTS FROM A DOSE ESCALATION PHASE 1/2 CLINICAL TRIAL

2016 ◽  
Vol 18 (suppl_6) ◽  
pp. vi12-vi12
Author(s):  
Samuel Goldlust ◽  
Burt Nabors ◽  
J. Paul Duic ◽  
Nimish Mohile ◽  
Tara Benkers ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Phase 1 ◽  
Recurrent Glioblastoma

CTNI-01. A PHASE 1-2 CLINICAL TRIAL OF EO1001 (APL-122), A NOVEL IRREVERSIBLE PAN-ERBB INHIBITOR WITH PROMISING BRAIN PENETRATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi58-vi58
Author(s):  
Sophia Frentzas ◽  
Gary Richardson ◽  
Jeffrey Bacha ◽  
Sarath Kanekal ◽  
Neil Sankar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Phase 1 ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Cns Metastases ◽  
Once Daily ◽  
Adult Participants ◽  
Xenograft Models ◽  
Cns Penetration

Abstract CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive crosstalk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models. We report on a first-in-human Phase 1-2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, with adequate bone marrow, renal and liver function are eligible. ESCALATION: One subject per dose cohort is enrolled in an accelerated dose-escalation design until drug-related toxicity (≥G2) is observed in the first cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Cycle 1: Patients receive a single oral dose of EO1001 on day 1; single-dose pharmacokinetics are measured. Beginning on day 8, EO1001 is administered once daily for 21 days; multi-dose pharmacokinetics are measured. Cycles 2-6: EO1001 is administered once daily in continuous 28-day cycles for up to 20 weeks. EXPANSION: EO1001 will be administered once daily to 20 patients at the MTD in continuous 28-day cycles for up to 6 cycles to determine a recommended Phase 2 dose (RP2D) for further study. Toxicity is assessed based on NCI CTCAEv5 and tumor response is assessed by RECIST 1.1. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.

Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1540-1540 ◽  
Author(s):  
Sheeba K. Thomas ◽  
Wael A. Harb ◽  
Joseph Thaddeus Beck ◽  
Gabrail Nashat ◽  
M. Lia Palomba ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Open Label ◽  
Label Dose ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

Abstract Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation. Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006). Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented. Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. Disclosures Thomas: Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

Phase I/II dose escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS24-TPS24
Author(s):  
William Ho ◽  
Nicole Nasrah ◽  
Dan Johnson
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
Receptor Occupancy ◽  
Open Label ◽  
Ligand Expression

TPS24 Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects will be enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of November 6, 2018, Cohort 1 has been completed without DLT. Clinical trial information: NCT03674567.

An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2671-TPS2671
Author(s):  
Mark R. Middleton ◽  
Joseph J. Sacco ◽  
Jaime R. Merchan ◽  
Brendan D. Curti ◽  
Ari M. Vanderwalde ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Phase 2 ◽  
Biomarker Analysis ◽  
Tumor Types

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.

scholarly journals Phase 1 dose-escalation study of the antiplacental growth factor monoclonal antibody RO5323441 combined with bevacizumab in patients with recurrent glioblastoma

2015 ◽  
Vol 17 (7) ◽  
pp. 1007-1015 ◽  
Author(s):  
Ulrik Lassen ◽  
Olivier L. Chinot ◽  
Catherine McBain ◽  
Morten Mau-Sørensen ◽  
Vibeke Andrée Larsen ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Dose Escalation ◽  
Phase 1 ◽  
Recurrent Glioblastoma ◽  
Dose Escalation Study

scholarly journals Mesenchymal Stem Cells for Bronchopulmonary Dysplasia: Phase 1 Dose-Escalation Clinical Trial

2014 ◽  
Vol 164 (5) ◽  
pp. 966-972.e6 ◽  
Author(s):  
Yun Sil Chang ◽  
So Yoon Ahn ◽  
Hye Soo Yoo ◽  
Se In Sung ◽  
Soo Jin Choi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bronchopulmonary Dysplasia ◽  
Dose Escalation ◽  
Phase 1

scholarly journals Phase 1/2 Trial of Durvalumab and Lenalidomide in Patients with Cutaneous T Cell Lymphoma (CTCL): Preliminary Results of Phase I Results and Correlative Studies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2931-2931
Author(s):  
Christiane Querfeld ◽  
Jasmine M. Zain ◽  
Devin L. Wakefield ◽  
Tijana Jovanovic-Talisman ◽  
Sung Hee Kil ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Immune Checkpoint ◽  
Phase 1 ◽  
Super Resolution ◽  
Advisory Committees ◽  
Skin Biopsies ◽  
Super Resolution Microscopy

Abstract Background: In CTCL, intratumoral T cells are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. To this end, we initiated a phase 1/2 clinical trial of lenalidomide and durvalumab to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, with mechanisms of action that target the exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses. Methods: A Phase 1 portion is ongoing to characterize the safety and tolerability of durvalumab and lenalidomide combination. Patients (pts) are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (cohort 1 = 10 mg; cohort 2 = 15 mg; subsequent planned dose increments of 5 mg) to evaluate safety, efficacy and antitumor activity. Serial skin and blood samples were collected to assess the impact on the tumor micro-environment. We examined the correlation between clinical response and resistance and the following biological factors: PD1 clustering at the single molecule level using super-resolution microscopy, and expression of PD-L1 and ICOS at the tissue level by means of multiplex immunohistochemistry on pre-treatment primary cells (migrated from skin explants), and skin tissue (formalin-fixed and paraffin-embedded) from clinical trial subjects. Results: Six patients (5 males/1female, age 32-57 years) with refractory/advanced CTCL (mycosis fungoides/Sezary syndrome subtype), clinical stage IB (1), IIA (1), IIB (3), IIIA (1) have been enrolled as of July 2018. Duration time on treatment was 4 to 13+ months. Four patients showed improvement of skin disease with 2 patients achieved partial response with > 90% improvement of skin disease by mSWAT. Two patients developed progressive disease. No serious adverse events (AEs) were observed. The most frequently reported AEs were fatigue (n=6), skin pain (n=4), anemia (n=3) chills (n=4), and decreased appetite (n=3). All treatment-related AEs were Grade 1 or 2 in severity. One grade 3 fatigue occurred in one patient. No dose limiting toxicity has been observed to date. Using multispectral microscopy, we analyzed expression panels of several checkpoints: PD1, PD-L1, and ICOS on lesional skin biopsies at baseline. Strong PD-L1 and ICOS expression is observed from non-responders. Detectable levels of PD-L1, but low levels of ICOS is observed in responding patients. Quantitative super-resolution microscopy detected nanoscale clusters of PD1 in T cells from responders and no PD1 clustering was observed in T cells from non-responders. Conclusions: Durvalumab/lenalidomide has significant clinical activity in patients with refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion of this trial. Responses were durable and ongoing, and treatment was well tolerated with a low toxicity profile. Dose escalation is planned up to lenalidomide 20 mg daily. Our preliminary results from patients on trial demonstrated that immune signatures on skin biopsies at baseline may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. Disclosures Querfeld: Acelion: Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees; Bioniz: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals TRLS-06. A Phase 1–2 clinical trial of EO1001 (APL-122), a novel irreversible pan-ErbB inhibitor with promising brain penetration

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii6-iii7
Author(s):  
Sophia Frentzas ◽  
Gary Richardson ◽  
Jeffrey Bacha ◽  
Sarath Kanekal ◽  
Neil Sankar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Phase 1 ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Cns Metastases ◽  
Once Daily ◽  
Adult Participants ◽  
Xenograft Models ◽  
Cns Penetration

Abstract CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive cross-talk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models. We report on a first-in-human Phase 1–2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, with adequate bone marrow, renal and liver function are eligible. Materials and methods Escalation: One subject per dose cohort is enrolled in an accelerated dose-escalation design until drug-related toxicity (≥G2) is observed in the first cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Cycle 1: Patients receive a single oral dose of EO1001 on day 1; single-dose pharmacokinetics are measured. Beginning on day 8, EO1001 is administered once daily for 21 days; multi-dose pharmacokinetics are measured. Cycles 2–6: EO1001 is administered once daily in continuous 28-day cycles for up to 20 weeks. Expansion: EO1001 is administered once daily to 20 patients at the MTD in continuous 28-day cycles for up to 6 cycles to determine a recommended Phase 2 dose (RP2D) for further study. Toxicity is assessed based on NCI CTCAEv5 and tumor response is assessed by RECIST 1.1. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.

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