What is the efficacy of switching to weekly pegvisomant in acromegaly patients well controlled on combination therapy?

Abstract Context Although combination therapy of acromegaly with long-acting somatostatin analogs (LA-SSAs) and pegvisomant (PEGV) normalizes insulin-like growth factor-1 (IGF1) levels in the majority of patients, it requires long-term adherence. Switching from combination therapy to monotherapy with weekly PEGV could improve patients’ comfort, but the efficacy is unknown. Objective To assess the efficacy of switching to PEGV monotherapy in patients well controlled on combination therapy of LA-SSAs and PEGV. Design Single-center, open-label observational pilot study. LA-SSA therapy was discontinued at baseline and all patients were switched to PEGV monotherapy for 12 months. If IGF1 levels exceeded 1.0 times upper limit of normal (ULN), PEGV dose was increased by 20 mg weekly. Subjects and methods The study included 15 subjects (eight males), with a median age of 58 years (range 35 – 80) on combination therapy of high-dose LA-SSAs and weekly PEGV for >6 months, and IGF1 levels within the normal range. Treatment efficacy was assessed by measuring serum IGF1 levels. Results After 12 months of weekly PEGV monotherapy, serum IGF1 levels of 73% of the subjects remained controlled. In one patient, LA-SSA had to be restarted due to recurrence of headache. IGF1 levels increased from a baseline level of 0.62 × ULN (range 0.30 – 0.84) to 0.83 × ULN (0.30 – 1.75) after 12 months, while the median weekly PEGV dose increased from 60 (30 – 80) mg to 80 (50 – 120) mg. Conclusion Our results suggest that switching from combination therapy of LA-SSAs and PEGV to PEGV monotherapy can be a viable treatment option for acromegaly patients without compromising efficacy.

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A comparison between octreotide-LAR and lanreotide-SR in the chronic treatment of acromegaly

Acta Endocrinologica ◽

10.1530/eje.0.1410267 ◽

1999 ◽

pp. 267-271 ◽

Cited By ~ 33

Author(s):

R Cozzi ◽

D Dallabonzana ◽

R Attanasio ◽

M Barausse ◽

G Oppizzi

Keyword(s):

Chronic Treatment ◽

Somatostatin Analogs ◽

Somatostatin Analog ◽

Normal Range ◽

First Line ◽

Hormonal Change ◽

Upper Limit ◽

Igf I ◽

Long Acting ◽

Active Disease

BACKGROUND: At present long-acting somatostatin analogs represent the first-line medical treatment of acromegaly. These drugs produce stable suppression of GH in most sensitive patients and IGF-I normalization in many; they also increase the compliance of acromegalic patients. The recent availability of octreotide (OC)-LAR, a somatostatin analog to be administered at 28-day intervals, has prompted us to compare, in the same group of patients, its effects and those of another somatostatin analog already available, lanreotide-SR (LSR, to be administered at 14-day intervals). PATIENTS: Twelve somatostatin analog-sensitive acromegalic patients with active disease were enrolled in a prospective open sequential study after giving their informed consent. After chronic treatment with LSR (6-24 months), the patients were changed to treatment with OC-LAR, without wash-out. LSR had been administered at individually tailored dosages (30 mg i.m. at 7-21-day intervals, median 10 days - every 7 days in seven patients, 10 days in two patients, 14 days in two patients and 21 days in one patient) according to GH and IGF-I responses. Disease stability was obtained, as shown by maximal GH/IGF-I suppression without any significant hormonal change between the last two control measurements. OC-LAR was administered i.m. at 28-day intervals six times at the dosage of 20 mg for the first three times and 10 or 30 mg for the last three times (according to individual GH/IGF-I responses). GH (mean of three, hourly samples) and IGF-I concentrations were evaluated on the same day as each administration of the drug, before its injection. RESULTS: GH and IGF-I values were significantly decreased by LSR treatment. GH decreased from 41.6 +/- 14.6 microg/l (mean +/- s.e.) to 7.2 +/- 1.5 microg/l (P < 0.02), whereas IGF-I values declined from 959 +/- 95 microg/l to 460 +/- 61 microg/l (P < 0.00001), expressed as absolute values, and from 287 +/- 30% to 137 +/- 19% expressed as percentage of the upper limit of normal range (% ULNR). At the end of the last cycle, OC-LAR treatment achieved a significant further suppression both in GH (to 5.1 +/- 1.1 microg/l, P < 0.05 compared with LSR) and in IGF-I concentrations (to 374 +/- 60 microg/l, P<0.05 compared with LSR, and to 112 +/- 19% as % ULNR). LSR decreased GH concentrations to less than 2.5 microg/l in one patient and normalized IGF-I concentrations in four patients. OC-LAR decreased GH concentrations to less than 2.5 microg/l in four patients and normalized or near-normalized IGF-I concentrations (i.e. to < 110% ULNR) in eight patients. CONCLUSIONS: These preliminary results show that the once-monthly OC-LAR administration schedule proved more efficacious than LSR given every 7-21 days, in a greater number of acromegalic patients.

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177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial

The Lancet Oncology ◽

10.1016/s1470-2045(21)00572-6 ◽

2021 ◽

Cited By ~ 1

Author(s):

Jonathan R Strosberg ◽

Martyn E Caplin ◽

Pamela L Kunz ◽

Philippe B Ruszniewski ◽

Lisa Bodei ◽

...

Keyword(s):

Overall Survival ◽

Neuroendocrine Tumours ◽

High Dose ◽

Open Label ◽

Phase 3 ◽

Long Acting ◽

Randomised Controlled

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Efficacy and safety of high-dose long-acting repeatable octreotide as monotherapy or in combination with pegvisomant or cabergoline in patients with acromegaly not adequately controlled by conventional regimens: results of an open-label, multicentre study

Endokrynologia Polska ◽

10.5603/ep.a2019.0023 ◽

2019 ◽

Vol 70 (4) ◽

pp. 305-312 ◽

Cited By ~ 2

Author(s):

Annamaria Colao ◽

Wojciech Zgliczyński ◽

Jan Komorowski ◽

Beata Kos-Kudła ◽

Antoine Tabarin ◽

...

Keyword(s):

Multicentre Study ◽

High Dose ◽

Efficacy And Safety ◽

Open Label ◽

Long Acting

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Combined treatment for acromegaly with long-acting somatostatin analogs and pegvisomant: long-term safety for up to 4.5 years (median 2.2 years) of follow-up in 86 patients

Acta Endocrinologica ◽

10.1530/eje-08-0843 ◽

2009 ◽

Vol 160 (4) ◽

pp. 529-533 ◽

Cited By ~ 81

Author(s):

SJCMM Neggers ◽

WW de Herder ◽

JAMJL Janssen ◽

RA Feelders ◽

AJ van der Lely

Keyword(s):

Combined Therapy ◽

Combined Treatment ◽

Somatostatin Analogs ◽

Pituitary Surgery ◽

Median Dosage ◽

Previously Treated ◽

Long Acting

BackgroundWe previously reported on the efficacy, safety, and quality of life (QoL) of long-acting somatostatin analogs (SSA) and (twice) weekly pegvisomant (PEG-V) in acromegaly and improvement after the addition of PEG-V to long-acting SSA.ObjectiveTo assess the long-term safety in a larger group of acromegalic patients over a larger period of time: 29.2 (1.2–57.4) months (mean (range)).DesignPegvisomant was added to SSA monotherapy in 86 subjects (37 females), to normalize serum IGF1 concentrations (n=63) or to increase the QoL. The median dosage was 60.0 (20–200) mg weekly.ResultsAfter a mean treatment period of 29.2 months, 23 patients showed dose-independent PEG-V related transient liver enzyme elevations (TLEE). TLEE occurred only once during the continuation of combination therapy, but discontinuation and re-challenge induced a second episode of TLEE. Ten of these patients with TLEE also suffered from diabetes mellitus (DM). In our present series, DM had a 2.28 odds ratio (CI 1.16–9.22; p=0.03) higher risk for developing TLEE. During the combined therapy, a clinical significant decrease in tumor size by more than 20% was observed in 14 patients. Two of these patients were previously treated by pituitary surgery, 1 with additional radiotherapy and all other patients received primary medical treatment.ConclusionLong-term combined treatment with SSA and twice weekly PEG-V up to more than 4 years seems to be safe. Patients with both acromegaly and DM have a 2.28 higher risk of developing TLEE. Clinical significant tumor shrinkage was observed in 14 patients during combined treatment.

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Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE in patients with midgut neuroendocrine tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4112 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4112-4112

Author(s):

Jonathan R. Strosberg ◽

Martyn E Caplin ◽

Pamela L. Kunz ◽

Philippe B Ruszniewski ◽

Lisa Bodei ◽

...

Keyword(s):

Overall Survival ◽

Neuroendocrine Tumors ◽

High Dose ◽

Radioligand Therapy ◽

Phase 3 ◽

Long Term Follow Up ◽

Long Acting ◽

Safety Signals

4112 Background: As demonstrated in the primary analysis of the phase 3 NETTER-1 trial, 177Lu-DOTATATE significantly prolonged progression-free survival (PFS) versus high-dose long-acting octreotide, with a HR of 0.18 (95% CI: 0.11, 0.29; p < 0.0001), in patients with advanced, progressive, well-differentiated, somatostatin receptor-positive midgut neuroendocrine tumors (NETs). Here we report final overall survival (OS) for NETTER-1. Methods: In this international open-label trial, eligible patients were randomized to receive either four cycles of 177Lu-DOTATATE 7.4 GBq (200 mCi) every 8 ± 1 weeks plus long-acting octreotide 30 mg or high-dose long-acting octreotide 60 mg every 4 weeks (control arm), both on top of best supportive care. After disease progression on randomized treatment or completion of an 18-month treatment period, patients in both arms entered long-term follow-up and could receive further anti-cancer treatment as recommended by their physicians. The primary endpoint was PFS per RECIST 1.1 and OS was a key secondary endpoint. Primary intention-to-treat analysis of OS was prespecified to take place after 158 deaths or 5 years after the last patient was randomized, whichever occurred first. Results: Of 231 randomized patients, 101/117 (86.3%) in the 177Lu-DOTATATE arm and 99/114 (86.8%) in the control arm entered long-term follow-up. Final analysis occurred 5 years after the last patient was randomized, following 142 deaths, with a median follow-up of more than 76 months. During long-term follow-up, 41/114 (36%) of patients in the control arm received subsequent radioligand therapy (“cross-over”), the majority (22.8%) within 24 months. Median OS was 48.0 months (95% CI: 37.4, 55.2) in the 177Lu-DOTATATE arm and 36.3 months (95% CI: 25.9, 51.7) in the control arm. HR was 0.84 (95% CI: 0.60, 1.17) with p = 0.30 (unstratified 2-sided log-rank test). A total of 2/112 (1.8%) 177Lu-DOTATATE treated patients in the study developed myelodysplastic syndrome (MDS). No new cases of MDS or acute leukemia were reported in the long-term follow-up. Overall, no new safety signals emerged during long-term follow-up. Conclusions: Median OS was 48.0 months in the 177Lu-DOTATATE arm of the NETTER-1 trial and 36.3 months in the control arm. This difference was not statistically significant, potentially impacted by a high rate (36%) of cross-over of patients in the control arm to radioligand therapy after progression. In overall conclusion, the NETTER-1 study demonstrated that 177Lu-DOTATATE yielded a clinically and statistically significant improvement in PFS as a primary endpoint (HR: 0.18, p < 0.0001) as well as a clinically meaningful trend towards improvement in median OS of 11.7 months. No new safety signals emerged during the 5-year long-term follow-up. Clinical trial information: NCT01578239.

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Long-Term (1 Year) Safety and Efficacy of Methylphenidate Modified-Release Long-Acting Formulation (MPH-LA) in Adults with Attention-Deficit Hyperactivity Disorder: A 26-Week, Flexible-Dose, Open-Label Extension to a 40-Week, Double-Blind, Randomised, Placebo-Controlled Core Study

CNS Drugs ◽

10.1007/s40263-014-0180-4 ◽

2014 ◽

Vol 28 (10) ◽

pp. 951-962 ◽

Cited By ~ 4

Author(s):

Y. Ginsberg ◽

T. Arngrim ◽

A. Philipsen ◽

P. Gandhi ◽

C.-W. Chen ◽

...

Keyword(s):

Modified Release ◽

Open Label ◽

Double Blind ◽

Safety And Efficacy ◽

Hyperactivity Disorder ◽

Open Label Extension ◽

Core Study ◽

Long Acting ◽

Flexible Dose

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Evaluation of the pharmacoeconomics of drugs used for the treatment of long-term complications of sulfur mustard

Italian Journal of Medicine ◽

10.4081/itjm.2016.743 ◽

2016 ◽

Vol 10 ◽

Author(s):

Yunes Panahi ◽

Mostafa Ghanei ◽

Milad Vakili Zarch ◽

Zohreh Poursaleh ◽

Shahram Parvin ◽

...

Keyword(s):

Cost Effectiveness ◽

Inhaled Corticosteroids ◽

Sulfur Mustard ◽

Cost Effective ◽

Chemical Warfare Agent ◽

Pulmonary Complications ◽

High Dose ◽

Chemical Injuries ◽

Long Acting

Sulfur mustard (SM), a cytotoxic vesicant chemical warfare agent, has powerful irritant and blistering effects on the skin, eyes and respiratory tract. Since during the Iraq-Iran war, many Iranian soldiers and civilians were exposed to SM, there are several victims still suffering from long-term cutaneous, ocular and pulmonary complications. Currently, there is no definite treatment for long-term complications of SM, and only supportive medical care is being taken to minimize the symptoms. In this study, we compared the cost-effectiveness of common drugs that are used against long-term SM-induced complications in Iranian patients. In this review article, electronic databases were checked using the following key words: sulfur mustard, lung, skin, eye, cost-effectiveness, pharmacoeconomics and treatment. Abstracts of non-English papers and proceedings of congresses on SM were also assessed. Among the studied drugs, high-dose oral N-acetyl cysteine and long-acting inhaled corticosteroids against respiratory complications, topical corticosteroids and oral antihistamines against cutaneous complications and NSAIDS and corticosteroids ophthalmic drops against ocular complications were found to be cost-effective. Usage of different drugs in the treatment of SM injuries in Iran, have imposed a significant economic burden to patients and their families because many drugs that are effective against chemical injuries are not covered by insurance. In addition, development of more effective drugs in this field is considered as an urgent demand that should be noticed by the pharmaceutical industry.

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A case report of long-term complete remission following cessation of romiplostim dosing in a previously severe ITP patient.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e17001 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e17001-e17001

Author(s):

Allison Ashley Baxley ◽

James N George ◽

Deirdra Terrell ◽

Meredith Moorman ◽

Jennifer L. Holter

Keyword(s):

Clinical Trial ◽

Platelet Count ◽

Case Report ◽

Bleeding Complications ◽

Drug Discontinuation ◽

High Dose ◽

Platelet Response ◽

Open Label ◽

Platelet Production

e17001 Background: Primary Immune thrombocytopenia(ITP) is a chronic autoimmune disorder characterized by low platelet counts and bleeding complications. Platelet destruction together with insufficient platelet production occur through an antibody-mediated process and early treatment options revolve around targeting antibodies and immunologic pathways. Such therapies may not produce long-term responses and may be accompanied by considerable adverse effects which can lead to complications and/or drug discontinuation. Romiplostim is a thrombopoietic agent that stimulates platelet production and offers an alternative method for treatment of patients with ITP. In clinical trials, patients have achieved durable platelet count responses without clinically important side effects. Methods: We report the case of a 44 year-old female with refractory ITP who has achieved successful remission following treatment with romiplostim. Results: As previously described in Haematologica (2008;93:1445) this patient presented with purpura, menorrhagia, and a platelet count of 7,000. Throughout 2005 she had only transient responses to high dose dexamethasone, intravenous immunoglobulin, rituximab, and splenectomy. She was placed on romiplostim in August 2005 as part of a clinical trial and received a dose of 7 mcg/kg/week for approximately 50 weeks. She was able to tolerate dose reductions and by May 2007 her dose had been de-escalated to 3 mcg/kg/week, which she continued through 2009 as part of an open-label continuation study. In January 2010, after completion of the clinical trial, she began receiving romiplostim by prescription. She was able to gradually tolerate extended dosing intervals due to sustained platelet response. Her last dose was administered on October 27, 2010 and she has maintained a platelet count above 197,000 without further therapy. Conclusions: This case represents, to our knowledge, one of the longest maintained durable responses to romiplostim therapy. Romiplostim provides an alternative approach of treatment for ITP, and as evidenced by this case report, in some patients it may also lead to disease remission and eliminate the need for further treatment.

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Pazopanib (PZP) in germ cell tumors (GCT) after chemotherapy (CT) failure: Final results of the open label, single-group, phase II Pazotest trial.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.414 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 414-414 ◽

Cited By ~ 1

Author(s):

Andrea Necchi ◽

Salvatore Lo Vullo ◽

Patrizia Giannatempo ◽

Daniele Raggi ◽

Giuseppina Calareso ◽

...

Keyword(s):

Kinase Inhibitor ◽

Significant Proportion ◽

Germ Cell Tumors ◽

High Dose ◽

Open Label ◽

Term Survival ◽

Baseline Serum ◽

Grade 3 ◽

Disease Stages

414 Background: Therapeutic options for patients (pts) with chemoresistant GCT are limited and prognosis is poor. PZP is a potent and selective tyrosine kinase inhibitor (TKI) with distinct antiangiogenic activity. Methods: In Pazotest trial (NCT01743482), pts were given PZP 800 mg/day until disease progression (PD) or unacceptable toxicity. Eligibility included failure of ≥ 2 platinum-based CT, including high-dose (HD)-CT. Baseline serum tumor markers (STM), computed tomography and FDG-PET were repeated after 4 wks and q8 weeks thereafter. The primary endpoint was PFS (H0: 3-m PFS ≤ 10%, H1: ≥ 25%, α = 5%/β = 20%). PD was defined as rising STM, increasing size of nonteratomatous masses (RECIST v1.1), or the appearance of new lesions. Translational analyses included circulating IL8 levels and next generation sequencing of pre-PZP tissue from extreme responders. Results: 43 pts were enrolled from 05/2013 to 07/2016. 35 pts (81.4%) had nonseminoma, 6 (14%) primary mediastinal GCT. The number of failed CT regimen was: 2 (11.6%), 3 (51.2%), > 3 (37.2%). 53.5% had failed HDCT. 39 pts had elevated STM: 56.4% AFP, 43.6% HCG. Grade 3-4 adverse events were seen in 4 pts (increased AST/ALT). 26/39 pts (66.7%) had STM reduction (38.5% > 50% from baseline) after 4 wks. RECIST results: 1 partial response, 20 stable disease, 16 PD (6 not evaluable). 12 (27.9%) had a decreased FDG uptake. Median follow-up was 29.6 months. 3-m PFS was 12.8% (95%CI: 5.7-28.9), median PFS was 2.5 m (IQR: 1.0-3.0). 24-m OS was 14.2% (95%CI: 6.0-33.7). In pts with > 50% STM decline, 24-m OS was 24.1% (95%CI: 8.3-69.6). Univariably, STM was associated with OS (HCG vs AFP: HR: 2.73, 95%CI: 1.24-6.02, p = 0.042). Baseline and +4wks IL8 levels did not predict for PFS/OS. In 2 responding pts, new mutations were found ( FLT3, G846V and RAD50 E448Q classified as damaging; TSC2, R197M and TNF A16V classified as benign). Conclusions: PZP was well tolerated and showed predictable activity, with early but short-living STM decline. Long term survival was obtained in a significant proportion of pts. Based on the present results, PZP may be investigated in earlier disease stages as an optimal bridging therapy preceding salvage curative treatment. Clinical trial information: NCT01743482.

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