First in-human phase 1 trial of a novel amino-peptidase inhibitor, CHR-2797

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3537-3537
Author(s):  
A. Protheroe ◽  
A. Reid ◽  
G. Attard ◽  
A. Davies ◽  
J. Spicer ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Patient ◽  
Once Daily ◽  
Apoptotic Protein ◽  
Peptidase Inhibitor ◽  
Orally Bioavailable ◽  
Ecog Ps ◽  
Continuous Dosing ◽  
Visual Disturbances ◽  
Potent Tumor

3537 Background: CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn++-dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, Noxa. CHR-79888 is an active metabolite of CHR-2797. Patients and Methods: This study was conducted according to an accelerated titration design to define the MTD, DLT, toxicity profile and PK of CHR-2797 when administered orally for 28 days or longer. Patients (ECOG PS = 2) with histologically confirmed advanced solid tumors resistant or refractory to standard therapy were eligible. Results: 37 pts (median age 61.5 years [range 22.4–80.1]; 30M/7F; median ECOG PS 1; median prior regimens 2, range 0–6) enrolled in 12 cohorts (doses between 10 and 320mg). The first four patients received a 10 mg dose for 7, 14, 21 or 28 days respectively. Subsequent cohorts received 28 days continuous dosing, with dose doubling in single patient cohorts until drug-related toxicity = Grade 2. Thereafter the study followed a 3+3 design with = 40% dose increments. Common (gr 1–2) toxicity included fatigue (47%), diarrhea (47%), dizziness (24%), constipation, vomiting, abdominal pain (all 21%), and thrombocytopenia (18%). Toxicities show dose dependency for thrombocytopenia and fatigue. MTD was declared at 320 mg after 2 DLT’s were reported: 2 patients were unable to complete 28 days of daily dosing due to syncope/anemia, and dizziness/visual disturbances/thrombocytopenia, respectively. Patients recovered fully after cessation of the drug. The dose level below (240 mg) was expanded to 13 patients. Plasma PK was determined for both CHR-2797 and -79888, on days 1 and 28, which showed dose proportional increases in AUC and Cmax. Intracellular and intratumoral levels of both the parent and metabolite were also measured. So far 4 patients continued therapy for 7–9 months: one patient (RCC [130 mg]) achieved a PR, and 3 patients (ovarian ca [40 mg], NSCLC [130 mg], and breast ca [180 mg] had confirmed SD (> 3 months). Conclusion: Once daily oral CHR-2797 can be administered safely for 28 days in doses up to 240 mg and exhibits favorable PK. No significant financial relationships to disclose.

An Ongoing Phase 1/2a Study of ABT-263; Pharmacokinetics (PK), Safety and Anti-Tumor Activity in Patients (pts) with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 883-883 ◽  
Author(s):  
Andrew W. Roberts ◽  
John F Seymour ◽  
Jennifer R Brown ◽  
William G Wierda ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Platelet Count ◽  
Research Funding ◽  
Phase 1 ◽  
Absolute Lymphocyte Count ◽  
Lymphocytic Leukemia ◽  
Partial Recovery ◽  
Orally Bioavailable ◽  
The Impact ◽  
Continuous Dosing

Abstract Abstract 883 ABT-263, a novel orally bioavailable BH3 mimetic, binds with high affinity (Ki ≤ 1nM) and inhibits multiple antiapoptotic Bcl-2 family proteins. In vitro, ABT-263 potently induces apoptosis (EC50 ≤ 1μM) in Bcl-2 overexpressing human lymphoma cell lines and primary CLL cells. Preclinical mechanism-based toxicities include inhibition of spermatogenesis, reduction in circulating lymphocytes and decreased survival of circulating platelets, reflecting inhibition of Bcl-w, Bcl-2 and Bcl-XL, respectively. Study M06-873 is a phase 1/2a dose-escalation trial employing a continuous reassessment method (CRM) to evaluate ABT-263 PK, safety and antitumor activity of two dosing schedules in pts with relapsed or refractory CLL. Tumor responses were evaluated by the NCI-WG criteria. Pts were initially dosed on d1-14 of a 21d cycle with 10-250 mg ABT-263. To ameliorate the impact of thrombocytopenia (TCP) due to on-target Bcl-XL inhibition-induced platelet apoptosis, a 100 mg lead-in dose for 7d followed by continuous 21/21d dosing (up to 300mg/d) was investigated. This study has completed enrollment at 300 mg with 29 pts (15 on a 14/21d; 14 on a 21/21d schedule) as of June 2009. The PK exposure of ABT-263 was approximately dose-proportional from 10-300 mg with a terminal half-life of 11 h. Platelet nadirs were transient, occurring on d3-5 followed by partial recovery due to compensatory increased megakaryopoiesis during continued dosing. Lead-in dosing reduced the early platelet nadir, and minimized fluctuations in platelet count observed with intermittent dosing. Circulating platelet count dropped maximally during cycle 1 by an average 12%, 57%, 68% and 70% from baseline at 10 mg, 110 mg, 200 and 250 mg for the 14/21d schedule, and an average of 52%, 63%, 63% and 68% from baseline at 125 mg, 200 mg, 250 mg and 300 mg for the 21/21d schedule. Of the 21 evaluable pts, 2 had radiographically confirmed partial responses (99% and 79% reductions) and 3 had as yet unconfirmed nodal regression (100%, 71% and 55%). 7 pts maintained a ≥50% decrease in circulating absolute lymphocyte count for ≥ 2 months with 2 pts having PR by physical examination; the overall response rate was 33%. Stable disease was noted in 8 pts and 2 pts had progressive disease. Responses tend to be durable, with the median PFS not yet reached while the median time on study is 9 mos (range 0.63 - 18.4 mos). The most common adverse events (AE) were diarrhea (52%), nausea (44%), vomiting (24%), fatigue (24%) thrombocytopenia (TCP; 20%) and neutropenia (12%). Dose limiting toxicities (DLT) were observed in 3 pts on the 14/21d schedule; 2 at 110mg (hospitalization & Grade 4 TCP) and 1 at 250 mg (Grade 4 TCP). Among the 14 pts on the 21/21d schedule, 3 pts experienced DLT; 1 at 200 mg (Grade 4 TCP); 1 at 250 mg (Grade 2 nausea) and 1 at 300 mg (Grade 4 TCP). ABT-263 was well-tolerated and had favorable PK and acceptable safety profiles. One week 100mg/d lead-in followed by continuous dosing minimizes platelet nadir and cycle variability. Based on the 21/21d continuous dosing data, the CRM model projection for MTD converged. The recommended phase 2 dose is 100 mg 7-d lead-in followed by 250 mg/d continuous dosing. Disclosures: Roberts: Abbott : Research Funding; Genentech: Research Funding. Off Label Use: ABT-263 is an experimental drug that is not yet registered. It is designed to induce apoptosis in tumor cells.. Brown:Celgene: Research Funding; Genzyme: Research Funding. Wierda:GSK: Consultancy; Ligand: Consultancy; Genentech: Consultancy; MEDIMMUNE: Consultancy; ABBOTT: Consultancy; TRUBION: Consultancy; BAYER, SANOFI-AVENTIS, MEMGEN, GENITOPE, GENMAB, SUNESIS, ABBOTT, GSK: Research Funding; GENENTECH: Honoraria; CELGENE: Speakers Bureau. Xiong:Abbott: Employment. Cui:Abbott: Employment. Busman:Abbott: Employment. Enschede:Abbott: Employment. Krivoshik:Abbott: Employment. Humerickhouse:Abbott: Employment.

A phase 1 dose finding study of CHR-2797, an inhibitor of M1 aminopeptidases, in patients with advanced solid tumours

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3053-3053
Author(s):  
A. Reid ◽  
A. Protheroe ◽  
G. Attard ◽  
C. Cowsill ◽  
J. Spicer ◽  
...  
Keyword(s):  
Phase 1 ◽  
Plasma Concentrations ◽  
Dose Finding ◽  
Fixed Dose ◽  
10Mg Dose ◽  
Finding Study ◽  
Orally Bioavailable ◽  
Two Phases ◽  
Ecog Ps

3053 Background: CHR-2797 is a novel, orally bioavailable inhibitor of the M1 family of aminopeptidases, in particular PuSA, and LTA4 hydrolase. Exposure of cancer cells to CHR-2797 results in the generation of the active metabolite CHR-79888 which is poorly membrane-permeable, resulting in intracellular accumulation. CHR-2797 has shown anti-proliferative activity in syngeneic (rat) and xenograft (mouse) cancer models, and is anti-angiogenic in vitro. Methods: Patients (pts) (ECOG PS ≤ 2) with histologically confirmed advanced solid tumors resistant or refractory to standard therapy were eligible. The accelerated titration design of the trial involved two phases for evaluation of schedule and dose: 1) fixed dose with increasing duration, and 2) dose escalation over a fixed duration (28 days). Results: 16 pts (median age: 64.5 years [range 48.8–80.1], 13M/3F)were treated with once daily doses ranging from 10mg to 130mg. The first four patients received a 10mg dose for 7, 14, 21 or 28 days respectively. Five subsequent cohorts received 28 days continuous dosing, with dose doubling in single patient cohorts until drug-related toxicity ≥ Grade 2. Thereafter dose was escalated in ≤ 40% increments in 3-patient cohorts. The most frequent adverse events were: gr 1–2 thrombocytopenia (44%), gr 1 diarrhea (25%), gr 1–2 transaminitis (19%), gr 1–2 fatigue (13%), gr 1 hot flushes (13%), and gr 1 lightheadedness (13%). There were no DLTs. Five patients continued therapy after 28 days; stable disease has been achieved in 1 pt for 6 months with granulosa cell carcinoma of ovary, who was progressing prior to study entry. CHR-2797 and CHR-79888 demonstrate dose proportional increases in AUC and Cmax. The terminal half-life for CHR-2797 is around 1–2 hours, whereas it is between 9 and 11 hours for CHR-79888. Intracellular (packed blood cells) exposure to both CHR-2797 and CHR-79888 is good, with CHR-79888 accumulating over 28 days, such that by day 28 the intracellular levels are comparable to plasma. Conclusions: CHR-2797 is well tolerated and can be safely administered at doses that reach plasma concentrations associated with activity in pre-clinical models. Accrual into the study continues. No significant financial relationships to disclose.

An Ongoing Phase 1 Study of ABT-263; Pharmacokinetics, Safety and Anti-Tumor Activity in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3177-3177 ◽  
Author(s):  
Andrew W. Roberts ◽  
Jennifer Brown ◽  
John F. Seymour ◽  
William G. Wierda ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Lymphocytic Leukemia ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Dosing Schedule ◽  
Orally Bioavailable ◽  
Anti Tumor Activity ◽  
Continuous Dosing

Abstract ABT-263 is a novel, orally bioavailable BH3 mimetic that binds with high affinity (Ki≤ 1nM) and inhibits multiple antiapoptotic Bcl-2 family proteins. In vitro, this novel class of drug (ABT-263 and ABT-737) potently induces apoptosis (EC50 ≤ 1μM) in Bcl-2 overexpressing human lymphoma cell-lines and primary CLL cells. On target toxicities observed preclinically include inhibition of spermatogenesis, reduction in circulating lymphocytes and decreased survival of circulating platelets, reflecting inhibition of Bcl-w, Bcl-2 and Bcl-XL, respectively. Study M06-873, a phase 1 dose-escalation study, is employing a continuous reassessment method to assess ABT-263 safety and anti-tumor activity of two dosing schedules in patients with relapsed or refractory CLL. Enrollment continues with 18 patients (15 on a 14/21 and 3 on a 21/21 dosing schedule) enrolled. Dose escalation of ABT-263 given on a 14/21 day dosing schedule began at 10 mg and continued to 250 mg. ABT-263 given on a 21/21 day dosing schedule continues at the 200 mg/day dose level following a one week lead-in dose of 100 mg/day. The pharmacokinetic profile of ABT-263 was linear from 10 – 250 mg. As expected with Bcl-xL inhibition, a dose-dependent reduction in circulating platelet counts was observed. Circulating platelet count dropped maximally by an average of 12%, 61%, 66%, and 70% from baseline at 10, 110, 200 and 250 mg, respectively. Typically, platelet nadirs were transient, occurring on days 3–5 followed by subsequent recovery during continued dosing, consistent with preclinical in vivo animal data demonstrating accelerated platelet apoptosis and compensatory increased production. With the 14 day on/7 day off schedule, DLT’s included one patient receiving 110 mg experienced events of tumor lysis (per laboratory values only) and grade 4 thrombocytopenia and 1 patient receiving 250 mg experienced an event of grade 4 thrombocytopenia. To date, the dose limiting toxicity (DLT) has not been defined for the continuous dosing schedule. For patients with bulky lymphadenopathy, a 92% reduction in the target lesion was noted in 1 subject dosed at 200 mg. Radiographic tumor reductions of less than 50% were observed in 2 additional subjects and there were 2 additional patients with stable disease without radiographic reductions. For subjects with lymphocytosis, 7 experienced ≥ 50% decreases in peripheral lymphocytes. At this time there are 10 active patients; 8 are off study as indicated: progressive disease (3), serious adverse events (3), withdrawal of consent (1) or other (1). ABT-263 is a novel, orally bioavailable and active small molecule Bcl-2 family protein inhibitor with predictable and manageable toxicity and anti-tumor activity in relapsed or refractory CLL patients. The thrombocytopenia is predictable and manageable. A one week lead-in dose of 100mg/day to minimize the depth of the initial platelet nadir, along with continuous dosing is now being explored.

A phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) patients (pts).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4095-4095 ◽  
Author(s):  
Teresa Macarulla Mercade ◽  
Victor Moreno ◽  
Binu John ◽  
John Charles Morris ◽  
Michael B. Sawyer ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Stable Disease ◽  
Phase 1 ◽  
Therapeutic Benefit ◽  
Clinical Activity ◽  
Once Daily ◽  
Downstream Signaling ◽  
Prior Therapy ◽  
Prior Systemic Therapy ◽  
Ecog Ps

4095 Background: FGF19 overexpression is hypothesized to hyperactivate FGFR4 and its downstream signaling pathway leading to enhanced tumor growth in HCC/ICC. Targeting FGFR4 may have therapeutic benefit in HCC/ICC with altered FGF19 signaling. A phase 1 study (NCT02834780) was initiated to assess H3B-6527, an investigational highly selective covalent FGFR4 inhibitor. Methods: Adult pts with advanced HCC or ICC, ECOG PS 0-1, well compensated liver function, and who progressed after at least one prior therapy, were administered H3B-6527 orally QD (once daily) on a 21-day cycle following a 3+3 design. Patients in the dose escalation phase were treated regardless of FGF19 status. Adverse events (AEs), pharmacokinetics (PK), and pharmacodynamics (PD) were assessed. Response was determined by RECIST 1.1 or modified RECIST every 6 weeks. Results: As of 06-Jan-2019, 37 pts have been treated with H3B-6527 at doses of 300 to 1400 mg QD (23 pts in escalation; 14 in expansion). In dose escalation, a total of 17 patients with HCC, Child-Pugh A received prior systemic therapy including 100% with prior TKI and 35% with prior IO. 12% had hepatitis B virus and 47% had hepatitis C virus. H3B-6527 plasma levels increased with dose from 300 to 1000 mg QD and plateaued. H3B-6527 was rapidly absorbed with a tmax of ~2-3 h and showed a terminal half-life of ~4-5 h, following administration of 1000 mg (fasted). No dose-limiting toxicities or ≥ Grade 3 treatment-related AEs (TRAE) have been observed in escalation. Most common TRAEs (≥ 10%) were diarrhea, nausea, and vomiting. Based on safety, PK, and PD, 1000 mg QD was the recommended phase 2 dose. Durable stable disease and partial responses (PR) have been observed on the once daily fasted schedule; 2 of 17 pts with HCC achieved PRs and an additional 7 with stable disease were on treatment for ≥ 5 months. Conclusions: H3B-6527 is well tolerated and demonstrates early signs of clinical activity. Dose expansion on QD schedule and exploration of BID (twice daily) schedule is ongoing. Clinical trial information: NCT02834780.

Phase 1 study of OKI-179, an oral class 1-selective depsipeptide HDAC inhibitor, in patients with advanced solid tumors: Final results.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3075-3075
Author(s):  
Jodi A. Kagihara ◽  
Bradley Corr ◽  
Jose Maria Pacheco ◽  
S. Lindsey Davis ◽  
Christopher Hanyoung Lieu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Significant Inhibition ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Human Dose ◽  
Continuous Dosing

3075 Background: OKI-179 is a novel, oral pro-drug analog of largazole, a compound in the romidepsin-depsipeptide class of natural products. OKI-006, the active metabolite of OKI-179, inhibits HDAC 1,2,3 (IC50 = 1.2, 2.4, 2.0 nM, respectively), with no significant inhibition of Class IIa HDACs and has shown promising activity in preclinical models of solid tumors. We conducted a first-in-human dose escalation study of OKI-179 in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, ECOG ≤1, normal QTc, and disease refractory to or with no available standard therapy options were treated with OKI-179 with either intermittent dosing (once daily for 4 days on 3 days off) or continuous dosing (once daily). Dose escalation was conducted using a standard 3+3 design. Pharmacokinetic (PK) and pharmacodynamic (PD) testing was performed at various time points after dosing. Results: As of Feb 4, 2021, 26 patients (19 female, 7 male) were enrolled with mean age of 63 (range 41-83). Patients received a median of 5 (range 1-11) prior lines of therapy and most common tumor types included pancreatic (N = 5), breast (N = 4), lung (N = 4), and ovarian cancer (N = 4). Twenty patients were treated in intermittent dosing cohorts from 30-450 mg. One DLT (Grade 2 [G2] thrombocytopenia) occurred in the 450 mg cohort which was expanded to 6 patients without subsequent DLTs. Six patients were treated in 2 continuous dosing cohorts of 200 mg and 300 mg. Two of 3 patients in the 300 mg cohort had DLTs of G3-4 thrombocytopenia and no DLTs were observed in 3 patients treated at 200 mg PO daily. The most common adverse events (AEs) were nausea (62%), fatigue (42%), anemia (39%), anorexia (27%), and vomiting (23%). These AE’s were G1-2 except for G3 anemia (12%), G3 fatigue (12%), and G3 anorexia (4%). No other G4-5 treatment-related AEs occurred. Median time on study was 79 days and best response was stable disease (SD) in 10 of 24 patients evaluable for efficacy (42%). Prolonged SD was observed in patients with platinum-resistant serous ovarian cancer (446 days) and adenoid cystic nasopharyngeal carcinoma (256 days). OKI-006 achieved consistent exposure with Cmax > 2,000 ng/ml and AUC > 8,000 hr*ng/ml, well above the targeted exposure for efficacy based on pre-clinical studies in murine models. Tmax was 2 hours and T1/2 was 6-8 hours. OKI-179 treatment resulted in > 3X increased T cell histone H3K9 and H3K27 acetylation within circulating PBMCs at doses of 180 - 450 mg. Conclusions: OKI-179 has a manageable safety profile, with thrombocytopenia being the on-target DLT. It has a favorable PK profile and demonstrated on-target PD effects at tolerable doses. The MTD and RP2D for OKI-179 was 450 mg daily for intermittent dosing and 200 mg daily for continuous dosing. Phase 2 studies are being designed, with a focus on combination with endocrine therapy in ER+ breast cancer and in NRAS-mutant melanoma. Clinical trial information: NCT03931681.

scholarly journals Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers

Pituitary ◽  
2022 ◽  
Author(s):  
Ajay Madan ◽  
Stacy Markison ◽  
Stephen F. Betz ◽  
Alan Krasner ◽  
Rosa Luo ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Single Dose ◽  
Neuroendocrine Tumors ◽  
Multiple Dose ◽  
Phase 1 ◽  
Somatostatin Receptor ◽  
Plasma Concentrations ◽  
Receptor Subtype ◽  
Once Daily ◽  
Orally Bioavailable

Abstract Purpose Evaluate the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors. Methods A randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral paltusotine capsules once daily 5 mg (× 7 days), 10, 20, and 30 mg (× 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability. Results Single-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo. Conclusions Paltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors. Trial registration NCT03276858, registered September 8, 2017, retrospectively registered.

Abstract PS11-26: A phase 1 study of D-0502, an orally bioavailable SERD, for advanced or metastatic HR-positive and HER2-negative breast cancer

2021 ◽  
Author(s):  
Cynthia Osborne ◽  
Donald A Richards ◽  
Sharon T Wilks ◽  
Sami Diab ◽  
Dejan Juric ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Orally Bioavailable

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.

Oral Sildenafil in the Treatment of Erectile Dysfunction

2021 ◽  
pp. 245-250
Author(s):  
Joshua Bodie
Keyword(s):  
Erectile Dysfunction ◽  
Side Effects ◽  
Sexual Activity ◽  
Once Daily ◽  
Higher Doses ◽  
Different Doses ◽  
Visual Disturbances ◽  
Better Than

This chapter summarizes the results of a landmark trial comparing different doses of oral sildenafil versus placebo to treat erectile dysfunction. Patients received either an identical placebo or 25- mg, 50-mg, or 100-mg tablets of sildenafil to be taken approximately one hour before planned sexual activity (but not more than once daily) for 24 weeks. Higher doses of sildenafil resulted in higher mean score for frequency of penetration and maintenance of erection, which were also consistently better than placebo. The most common side effects were headaches, flushing, dyspepsia, rhinitis, and visual disturbances. This study established sildenafil as an effective, reasonably well-tolerated treatment for men with erectile dysfunction of varying etiologies.

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