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

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.

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Phase I dose-escalation study of pasireotide LAR in patients with advanced neuroendocrine tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e15126 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e15126-e15126 ◽

Cited By ~ 1

Author(s):

Alexandria T. Phan ◽

Edward M. Wolin ◽

Jennifer A. Chan ◽

Jerry M. Huang ◽

Michelle Hudson ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Somatostatin Receptor ◽

Plasma Concentrations ◽

Median Number ◽

Maximum Tolerated Dose ◽

Dose Escalation Study ◽

Best Response ◽

Long Acting

e15126 Background: Somastatin analogs (SSA), including octreotide and lanreotide, bind predominantly to somatostatin receptor (SSTR) 2 and form the foundation of treatment for symptomatic neuroendocrine tumors (NET). Pasireotide, a novel SSA with a broad binding affinity (SSTR 1-3 and 5), is being explored for treatment of NET. A phase 1 dose-escalation study (NCT01364415) of pasireotide long-acting release (LAR; starting dose of 80 mg) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) and to characterize safety, tolerability, pharmacokinetics, and efficacy in pts with advanced NET. Methods: Pts with advanced, well- or moderately differentiated NET received pasireotide LAR beginning at a dose of 80 mg q28d. Successive cohorts will receive doses (up to 220 mg) guided by a Bayesian logistic regression model until MTD/RP2D is reached. Results: To date, 15 pts have been treated at 80 mg (n=6) and 120 mg (n=9). Median age is 59 (44-76) years. Primary tumor sites include small intestine (40%), pancreas (20%), and lung (13.3%). All pts received prior antineoplastic therapy; 93% received prior SSA. Median number of cycles of pasireotide was 6.68 (2-14) (1 cycle=28 days). 10 (67%) pts remain on treatment: 3 on 80 mg and 7 on 120 mg. 5 (33%) have discontinued (disease progression, 2 pts; withdrew consent, 2 pts; adverse event [AE], 1 pt). Median plasma concentrations of pasireotide increased with dose. No dose-limiting toxicities have been reported. Most frequent AEs were similar in both dose groups and included hyperglycemia (87%), diarrhea (53%), abdominal pain (47%), nausea (40%), anemia (33%), and fatigue (33%). Most AEs were mild/moderate. 2 pts (1 in each group) had grade 3 hyperglycemia. 4 (27%) and 2 (13%) pts had HbA1C increase from <6.5% at baseline to 6.5-<8% and ≥8%, respectively. 13 (87%) pts had radiographically stable disease as best response. More pts at 120 mg (50%) vs 80 mg (33%) achieved ≥50% reduction in chromogranin A. Conclusions: Pasireotide LAR up to 120 mg appears to be well tolerated in patients with advanced NET. The study is ongoing. Pasireotide represents a promising therapy for pts with NET. Clinical trial information: NCT01364415.

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Involvement of the Sst1 Somatostatin Receptor Subtype in the Intrahypothalamic Neuronal Network Regulating Growth Hormone Secretion: Anin Vitroandin VivoAntisense Study1

Endocrinology ◽

10.1210/endo.141.3.7349 ◽

2000 ◽

Vol 141 (3) ◽

pp. 967-979 ◽

Cited By ~ 16

Author(s):

Christophe Lanneau ◽

Marie Thérèse Bluet-Pajot ◽

Philippe Zizzari ◽

Zsolt Csaba ◽

Pascal Dournaud ◽

...

Keyword(s):

Growth Hormone ◽

Neuronal Network ◽

Somatostatin Receptor ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Receptor Subtype

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Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study

Acta Endocrinologica ◽

10.1530/eje-09-0170 ◽

2009 ◽

Vol 161 (1) ◽

pp. 119-130 ◽

Cited By ~ 101

Author(s):

Gudmundur Johannsson ◽

Ragnhildur Bergthorsdottir ◽

Anna G Nilsson ◽

Hans Lennernas ◽

Thomas Hedner ◽

...

Keyword(s):

Single Dose ◽

Replacement Therapy ◽

Plasma Cortisol ◽

Plasma Concentrations ◽

Pharmacokinetic Studies ◽

Double Blind ◽

Once Daily ◽

Physiological Serum ◽

Cortisol Levels ◽

Dual Release

BackgroundEndogenous plasma cortisol levels have a well-defined circadian rhythm. The aim of this project is to develop a once daily oral dual-release formulation for cortisol replacement therapy that mimics the diurnal variation in the plasma cortisol profile.ObjectiveTo determine single-dose plasma pharmacokinetics and dose-proportionality of oral 5 and 20 mg dual-release hydrocortisone tablets in healthy volunteers. In addition, the effect of food intake was investigated for the 20 mg dose.DesignA randomised, controlled, two-way cross-over, double-blind, phase I study of oral hydrocortisone (modified (dual) release; 5 and 20 mg) with an open food-interaction arm.MethodsThe single dose pharmacokinetic studies were performed with betamethasone suppression. The two first study days were blinded and randomised between morning administration of 5 and 20 mg tablet in a fasting state. The third day was open with a 20 mg tablet taken 30 min after a high-calorie, high-fat meal. The plasma samples were assayed using both a validated LC–MS/MS and an immunoassay. The plasma pharmacokinetic variables were calculated using non-compartmental data analysis.ResultsThe time to reach a clinically significant plasma concentration of cortisol (>200 nmol/l) was within 20 min and a mean peak of 431 (s.d. 126) nmol/l was obtained within 50 min after administration of the 20 mg tablet. Plasma cortisol levels remained above 200 nmol/l for around 6 h thereafter and all plasma concentrations 18–24 h after intake were below 50 nmol/l. In the fed state the time to reach 200 nmol/l was delayed by 28 and 9 min based on LC–MS/MS and immunoassay, respectively. The 5 and 20 mg tablets produced an increase in plasma exposure of cortisol that was not fully dose proportional.ConclusionThe dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.

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70. A PHASE 1–2 CLINICAL TRIAL OF EO1001, A NOVEL IRREVERSIBLE pan-ErbB INHIBITOR WITH PROMISING BRAIN PENETRATION

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa073.057 ◽

2020 ◽

Vol 2 (Supplement_2) ◽

pp. ii14-ii15

Author(s):

Helen Wheeler ◽

Jeffrey Bacha ◽

Sarath Kanekal ◽

Harry Pedersen ◽

Neil Sankar ◽

...

Keyword(s):

Single Dose ◽

Dose Escalation ◽

Rapid Development ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Erbb Receptors ◽

Brain Penetration ◽

Once Daily ◽

Erbb Family ◽

Cns Disease

Abstract CNS metastasis has become a prominent driver of morbidity and mortality in recent years as new targeted therapies have improved systemic outcomes. Mutations in the ErbB family of kinases are known oncodrivers in many of these cancers. ErbB family member “crosstalk” is associated with rapid development acquired resistance to ErbB TKIs. The development of agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor with superior CNS penetration targeting ErbB1, ErbB2 and ErbB4. Preclinical data suggests a favorable pharmacokinetic and safety profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. Male or female adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver function are eligible. An accelerated dose-escalation design is employed. One subject per dose cohort will be recruited until drug related toxicity (≥G2) is observed in the first dosing cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Dose Escalation: Cycle 1: Patients will receive a single dose EO1001 on day 1 and single dose pharmacokinetics will be performed. Beginning on day 8, EO1001 will be administered once daily for 21 days; multi-dose pharmacokinetics will be performed. Cycles 2–6: Oral EO1001 will be administered once daily in continuous 28-day cycles for up to 20 weeks. MTD Expansion: Oral EO1001 will be administered once daily at the MTD in continuous 28-day cycles for up to 6 cycles (24 weeks). Toxicity is assessed based on NCI CCTCAEv5 and tumor response will be assessed by RECIST 1.1 or RANO for CNS disease. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.

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Pharmacokinetics of Sativex® in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders

Biomolecules ◽

10.3390/biom10020279 ◽

2020 ◽

Vol 10 (2) ◽

pp. 279

Author(s):

María Fernández-Trapero ◽

Carmen Pérez-Díaz ◽

Francisco Espejo-Porras ◽

Eva de Lago ◽

Javier Fernández-Ruiz

Keyword(s):

Veterinary Medicine ◽

Single Dose ◽

Multiple Dose ◽

Plasma Concentrations ◽

Beagle Dogs ◽

Blood Samples ◽

Dose Treatment ◽

Pathological Conditions ◽

Sublingual Delivery ◽

Progressive Accumulation

The phytocannabinoid-based medicine Sativex® is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pathologies, including human-like pathological conditions. With the purpose of assessing different dosing paradigms for using Sativex in Veterinary Medicine, we investigated its pharmacokinetics when administered to naïve dogs via sublingual delivery. In the single dose arm of the study, adult Beagle dogs were treated with 3 consecutive sprays of Sativex, and blood samples were collected at 12 intervals up to 24 h later. In the multiple dose arm of the study, Beagle dogs received 3 sprays daily for 14 days, and blood samples were collected for 24 h post final dose. Blood was used to obtain plasma samples and to determine the levels of cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC) and its metabolite 11-hydroxy-Δ9-THC. Maximal plasma concentrations of both Δ9-THC (Cmax = 18.5 ng/mL) and CBD (Cmax = 10.5 ng/mL) were achieved 2 h after administration in the single dose condition and at 1 h in the multiple dose treatment (Δ9-THC: Cmax = 24.5 ng/mL; CBD: Cmax = 15.2 ng/mL). 11-hydroxy-Δ9-THC, which is mainly formed in the liver from Δ9-THC, was almost undetected, which is consistent with the use of sublingual delivery. A potential progressive accumulation of both CBD and Δ9-THC was detected following repeated exposure, with maximum plasma concentrations for both cannabinoids being achieved following multiple dose. Neurological status, body temperature, respiratory rate and some hemodynamic parameters were also recorded in both conditions, but in general, no changes were observed. In conclusion, this study demonstrates that single or multiple dose sublingual administration of Sativex to naïve dogs results in the expected pharmacokinetic profile, with maximal levels of phytocannabinoids detected at 1–2 h and suggested progressive accumulation after the multiple dose treatment.

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Dose and schedule selection for the anti-CTLA4 monoclonal antibody ticilimumab in patients (pts) with metastatic melanoma

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.8032 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 8032-8032 ◽

Cited By ~ 5

Author(s):

J. Gomez-Navarro ◽

A. Sharma ◽

V. Bozon ◽

C. Bulanhagui ◽

D. Pavlov ◽

...

Keyword(s):

Single Dose ◽

Metastatic Melanoma ◽

Clinical Benefit ◽

Dose Regimen ◽

Multiple Dose ◽

Phase 1 ◽

Phase 2 ◽

Phase 1 Trial ◽

Clinical Dose ◽

Anti Tumor Activity

8032 Background: Ticilimumab therapy has demonstrated anti-tumor activity in pts with metastatic melanoma. Its indirect, immune-mediated antitumor effects pose unique challenges for dose/regimen selection. Methods: It was our original intention to select the clinical dose/regimen of ticilimumab based on (1) clinical safety and tolerability and (2) attainment of target plasma concentrations derived from pre-clinical work using an ex vivo assay of ticilimumab-induced enhancement of cytotoxic T-cell function. Because numerous pts with metastatic melanoma experienced clinical benefit (i.e., durable objective responses [OR] and/or long-term survival) in early clinical trials of ticilimumab, we are using (1) safety and tolerability and (2) clinical benefit to guide dose/regimen selection. Data for evaluating these criteria come from a single-dose Phase 1 trial (0.01, 0.1, 1, 3, 6, 10 and 15 mg/kg) and an ongoing multiple-dose Phase 1/2 trial in pts with melanoma (Phase 1 portion: 3, 6 and 10 mg/kg Q1M; Phase 2 portion: 10 mg/kg Q1M and 15 mg/kg Q3M). Results: In the single-dose Phase 1 trial, 10 mg/kg was the Protocol-defined MTD but a high rate of clinical benefit was seen in the 15 mg/kg dose cohort (6/6 pts). Because the DLTs seen at 15 mg/kg (Gr 3 diarrhea, Gr 3 rash) were moderate and resolved completely within 3 months of dosing, 15 mg/kg Q3M was proposed as a safe and tolerable dose and is being studied in the Phase 2 portion of the multiple-dose Phase 1/2 trial. The Phase 1 portion of the multiple-dose Phase 1/2 trial revealed that 10 mg/kg is safe and tolerable with monthly dosing so 10 mg/kg Q1M is also being studied in the Phase 2 portion of the trial. At the end of the Simon Optimum-defined Stage 1 of the Phase 2 portion of the ongoing trial, the OR rate (3/18 pts) is the same for both dosing regimens. However, with 15 mg/kg Q3M, Gr 3/4 adverse events were less frequent (6% versus 34%). Conclusions: 15 mg/kg Q3M is proposed as the clinical dose/regimen for ticilimumab in metastatic melanoma. This dose/regimen appears to have anti-tumor activity approximately equal to 10 mg/kg Q1M but it appears to have a superior safety profile. [Table: see text]

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

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3537 ◽

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.

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Dopamine receptor subtype 2 and somatostatin receptor subtype 5 expression influences somatostatin analogs effects on human somatotroph pituitary adenomas in vitro

Journal of Molecular Endocrinology ◽

10.1677/jme.1.01876 ◽

2005 ◽

Vol 35 (2) ◽

pp. 333-341 ◽

Cited By ~ 29

Author(s):

M C Zatelli ◽

D Piccin ◽

F Tagliati ◽

A Bottoni ◽

M R Ambrosio ◽

...

Keyword(s):

Growth Hormone ◽

Primary Culture ◽

Pituitary Adenomas ◽

Somatostatin Receptor ◽

Somatostatin Analogs ◽

Receptor Subtype ◽

Inhibitory Effects ◽

Gh Secretion ◽

Secretion Inhibition

Dopamine (DA) and somatostatin (SRIF) receptor agonists inhibit growth hormone (GH) secretion by pituitary adenomas. We investigated DA subtype 2 receptor (DR2) and SRIF receptor (sst) subtypes 2 and 5 expression in 25 GH-secreting pituitary adenomas and tested in primary culture the effects on GH and prolactin (PRL) secretion of sst agonists selectively interacting with sst2 (BIM-23120), sst5 (BIM-23206), and sst2 and sst5 (BIM-23244). All adenomas expressed sst2; eight adenomas expressed both sst5 and DR2, eight sst5 but not DR2, and eight DR2 but not sst5. One tissue lacked expression of DR2 and sst5. GH secretion was inhibited by BIM-23120 in all samples, while it was reduced by BIM-23206 only in adenomas not expressing DR2. BIM-23120’s inhibitory effects correlated with sst2 and DR2 expression, whereas DR2 expression correlated inversely with BIM-23206 inhibitory effects on GH secretion. In seven mixed GH-/PRL-secreting pituitary adenomas, PRL secretion was inhibited in sst5-expressing tumors by BIM-23206, but not by BIM-23120. BIM-23244 reduced PRL secretion only in adenomas expressing sst2, sst5 and DR2. sst5 and DR2 expression correlated directly with BIM23206 inhibitory effects on PRL secretion. Our results suggest that adenomas expressing DR2 are less likely to respond to clinically available SRIF analogs in terms of GH secretion inhibition. Therefore, drugs interacting also with DR2 might better control secretion of pituitary adenomas.

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