scholarly journals Safety and Efficacy of Oral Octreotide in Acromegaly: Results of a Multicenter Phase III Trial

2015 ◽  
Vol 100 (4) ◽  
pp. 1699-1708 ◽  
Author(s):  
Shlomo Melmed ◽  
Vera Popovic ◽  
Martin Bidlingmaier ◽  
Moises Mercado ◽  
Aart Jan van der Lely ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Phase Iii ◽  
Dose Titration ◽  
Controlled Study ◽  
Open Label ◽  
The Core ◽  
End Of Treatment ◽  
Label Dose ◽  
Somatostatin Receptor Ligand ◽  
Oral Therapeutic

Background: A novel oral octreotide formulation was tested for efficacy and safety in a phase III, multicenter, open-label, dose-titration, baseline-controlled study in patients with acromegaly. Methods: We enrolled 155 complete or partially controlled patients (IGF-1 <1.3 × upper limit of normal [ULN], and 2-h integrated GH <2.5 ng/mL) receiving injectable somatostatin receptor ligand (SRL) for ≥3 months. Subjects were switched to 40 mg/d oral octreotide capsules (OOCs), and the dose escalated to 60 and then up to 80 mg/d to control IGF-1. Subsequent fixed doses were maintained for a 7-month core treatment, followed by a voluntary 6-month extension. Results: Of 151 evaluable subjects initiating OOCs, 65% maintained response and achieved the primary endpoint of IGF-1 <1.3 × ULN and mean integrated GH <2.5 ng/mL at the end of the core treatment period and 62% at the end of treatment (up to 13 mo). The effect was durable, and 85 % of subjects initially controlled on OOCs maintained this response up to 13 months. When controlled on OOCs, GH levels were reduced compared to baseline, and acromegaly-related symptoms improved. Of 102 subjects completing the core treatment, 86% elected to enroll in the 6-month extension. Twenty-six subjects who were considered treatment failures (IGF-1 ≥1.3 × ULN) terminated early, and 23 withdrew for adverse events, consistent with those known for octreotide or disease related. Conclusions: OOC, an oral therapeutic peptide, achieves efficacy in controlling IGF-1 and GH after switching from injectable SRLs for up to 13 months, with a safety profile consistent with approved SRLs. OOC appears to be effective and safe as an acromegaly monotherapy.

A randomized, multicenter, open-label, phase III study of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) versus ofatumumab in patients (pts) with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): RESONATE.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS8619-TPS8619
Author(s):  
John C. Byrd ◽  
Jacqueline Claudia Barrientos ◽  
Stephen Devereux ◽  
Jennifer R. Brown ◽  
Neil E. Kay ◽  
...  
Keyword(s):  
Package Insert ◽  
Cell Receptor ◽  
Primary Objective ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Controlled Study ◽  
Open Label ◽  
Pivotal Phase ◽  
Phase Iii Study ◽  
Line Of Therapy

TPS8619 Background: Chemoimmunotherapy (CIT) treatment approaches such as FCR have markedly improved outcomes for CLL pts when administered as initial or second-line therapy. Despite this progress, virtually all pts relapse and effective salvage regimens that induce durable remissions or can be administered safely to elderly pts or those with comorbidities are lacking. BTK, an essential mediator of B-cell receptor signaling, is a novel target in CLL. Ibrutinib, a first-in class inhibitor of BTK, promotes apoptosis and inhibits proliferation, migration and adhesion in CLL cells. Phase II data of ibrutinib monotherapy in RR CLL demonstrated an estimated PFS and OS of 75% and 83% respectively at 26 months (Byrd Abst #189 ASH 2012). These findings confirmed BTK as an important target in CLL and supported initiation of a pivotal phase III study in pts with RR CLL/SLL. Methods: PCYC-1112-CA is an ongoing international Phase 3 randomized controlled study of ibrutinib versus ofatumumab for treatment of pts with RR CLL/SLL. The study is enrolling 350 planned pts in 9 countries. Pts are randomized 1:1 to receive ibrutinib 420 mg orally once daily or ofatumumab per the package insert at 300 mg for the first dose, then 2000 mg for a total of 12 doses over 24 weeks. Pts are stratified based on del 17p and disease refractory to purine analogs. Key inclusion criteria include RR CLL/SLL with >= 1 prior line of therapy including pts who experienced a short remission duration to purine analog based CIT, pts who are older or have comorbidities, and pts with del 17p. Pts must have active disease meeting criterion for requiring therapy and measurable nodal disease by CT. Key exclusion criteria include Richter’s transformation, stem cell transplantation within 6 months, GVHD or immunosuppression, platelet count <30,000 cells/ul or use of warfarin The primary objective of the study is PFS evaluated by an IRC. Other outcomes include ORR, OS, hematologic improvement, and safety. An independent DMC is monitoring the study. Clinical trial information: NCT01744691.

Phase III randomized, open-label, active-controlled study of momelotinib versus best available therapy in ruxolitinib-treated patients with myelofibrosis.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. TPS7102-TPS7102
Author(s):  
Vikas Gupta ◽  
Maria R. Baer ◽  
Stephen T. Oh ◽  
Carole Brennan Miller ◽  
Susie Jun ◽  
...  
Keyword(s):  
Phase Iii ◽  
Controlled Study ◽  
Open Label

A phase III study of xilonix in refractory colorectal cancer patients with weight loss.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 685-685 ◽  
Author(s):  
George A. Fisher
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Human Monoclonal Antibody ◽  
Well Being ◽  
Phase Iii ◽  
Controlled Study ◽  
Open Label ◽  
Risk Of Death ◽  
Increased Risk ◽  
Median Change

685 Background: Xilonix, an anti-interleukin-1α true human monoclonal antibody is being assessed as cancer therapy to improve overall survival (OS) in advanced colorectal cancer (CRC) patients. Methods: An open label multicenter randomized comparator controlled study to evaluate efficacy and safety of Xilonix in CRC complicated with cachexia. Eligible patients had metastatic CRC, failed oxaliplatin or irinotecan based chemotherapy, and lost ≥5% total body weight in the previous 6 months (m). Patients were 1:1 randomized to Xilonix (3.75 mg/kg intravenously every two weeks) or megestrol acetate (MA, oral 800 mg daily) until progression. Primary endpoint was OS. Secondary endpoints included assessment of patient well-being using the EORTC QLQ-C30 questionnaire. Platelets support tumor growth and metastasis and platelet counts increase during cancer progression. IL-1α on platelets may be a target of Xilonix and thus platelet count was a key pharmacodynamic measure. Results: 40 patients were enrolled between March 2013 and July 2014, at which time the study was halted to revise inclusion criteria to reduce screen failures. An eligibility violation excluded 1 Xilonix patient from analysis (Xilonix n=19, MA n=20). MA treatment arm had a 39% shorter median OS (2.0 versus 2.8 months) and a trend in increased risk of death (hazard ratio 2.17, p=0.17). Physical and role function worsened in patients receiving megesterol (median change of -13.3 (p=0.02), -16.7 (p=0.02) respectively), whereas in Xilonix treated patients these functions did not decline during therapy (median change 0, p=0.88 and 0, p=0.69, respectively). Xilonix patients had treatment-related reduction in platelets compared to the MA group (median -60,000/mm3, vs 10,000/mm3, p=0.03). No infusion reactions, no discontinuations due to adverse events (AEs) and no related SAEs were reported for Xilonix. Conclusions: The trend in OS for Xilonix patients was encouraging and consistent with improved function and intended pharmacodynamic activity. An amended Phase III protocol has been developed to simplify enrollment for an ongoing study of Xilonix in an advanced CRC population. (NCT01767857) Clinical trial information: NCT01767857.

scholarly journals Insulin Growth Factor-Based Dosing of Growth Hormone Therapy in Children: A Randomized, Controlled Study

2007 ◽  
Vol 92 (7) ◽  
pp. 2480-2486 ◽  
Author(s):  
Pinchas Cohen ◽  
Alan D. Rogol ◽  
Campbell P. Howard ◽  
George M. Bright ◽  
Anne-Marie Kappelgaard ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Primary Outcome Measure ◽  
Target Range ◽  
Dose Titration ◽  
Controlled Study ◽  
Growth Responses ◽  
Open Label ◽  
Gh Treatment ◽  
Short Children ◽  
Igf I

Abstract Context: Weight-based dosing of GH is the standard of care for short children, although IGF-I is thought to be the main mediator of GH actions on growth. Objective: The objective of the study was to test whether IGF-I levels achieved during GH therapy are determinants of the growth responses to GH treatment. Design: This was a 2-yr, open-label, randomized, IGF-I concentration-controlled trial. Prepubertal short children [n = 172, mean age 7.53 yr, mean height sd score (HT-SDS) −2.64] with low IGF-I levels (mean IGF-I SDS −3.56) were randomized to receive one of two GH dose-titration arms in which GH dosage was titrated to achieve an IGF-I SDS at the mean [IGF(low) group, n = 70] or the upper limit of the normal range [+2 SDS, IGF(high) group, n = 68] or to a comparison group of conventional GH dose of 40 μg/kg/d (n = 34). Setting: The study was conducted in a multicenter, outpatient setting. Primary Outcome Measure: Change in HT-SDS over 2 yr was measured. Results: One hundred forty-seven patients completed the trial. Target IGF-I levels were achieved in the dose-titration arms within 6–9 months. The changes in HT-SDS were +1.0, +1.1, and +1.6 for conventional, IGF(low), and IGF(high), respectively, with IGF(high) showing significantly greater linear growth response (P &lt; 0.001, compared with the other two groups). The IGF(high) arm required higher doses (&gt;2.5 times) than the IGF(low) arm, and these GH doses were highly variable (20–346 μg/kg/d). Multivariate analyses suggested that the rise in the IGF-I SDS significantly impacted height outcome along with the GH dose and the pretreatment peak-stimulated GH level. Conclusion: IGF-I-based GH dosing is clinically feasible and allows maintaining serum IGF-I concentrations within the desired target range. Titrating the GH dose to achieve higher IGF-I targets results in improved growth responses, although at higher average GH doses.

scholarly journals Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years

2012 ◽  
Vol 18 (9) ◽  
pp. 1278-1289 ◽  
Author(s):  
Christian Confavreux ◽  
David K Li ◽  
Mark S Freedman ◽  
Philippe Truffinet ◽  
Hadj Benzerdjeb ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Opportunistic Infections ◽  
Oral Disease ◽  
Controlled Study ◽  
Phase 2 ◽  
Open Label ◽  
The Core ◽  
Open Label Extension ◽  
Sensory Disturbances ◽  
Long Term Follow Up

Background: Teriflunomide, an oral disease-modifying therapy in development for patients with relapsing forms of multiple sclerosis (RMS), was well tolerated and effective in reducing magnetic resonance imaging (MRI) lesions in 179 RMS patients in a phase 2 36-week, placebo-controlled study. Methods: A total of 147 patients who completed the core study entered an open-label extension. Teriflunomide patients continued their assigned dose, and placebo patients were re-allocated to teriflunomide, 7 mg/day or 14 mg/day. An interim analysis was performed at a cut-off on January 8 2010. Results: The mean and median duration of study treatment, including both the core and extension phase, from baseline to the interim cut-off, was 5.6 years (standard deviation: 2.7 years) and 7.1 years (range: 0.05–8.5 years), respectively. Of 147 patients, 62 (42.2%) discontinued (19% due to treatment-emergent adverse events (TEAEs)). The most common TEAEs were mild infections, fatigue, sensory disturbances and diarrhoea. No serious opportunistic infections occurred, with no discontinuations due to infection. Asymptomatic alanine aminotransferase increases (≤3× upper limit of normal (ULN)) were common (7 mg, 64.2%; 14 mg, 62.1%); increases >3×ULN were similar across groups (7 mg, 12.3%; 14 mg, 12.1%). Mild decreases in neutrophil counts occurred; none led to discontinuation. The incidence of malignancies was comparable to that of the general population, and cases were not reminiscent of those observed in immunocompromised patients. Annualised relapse rates remained low, minimal disability progression was observed, with a dose-dependent benefit with teriflunomide 14 mg for several MRI parameters. Conclusion: Teriflunomide had a favourable safety profile for up to 8.5 years.

scholarly journals Initial response of young people with thyrotoxicosis to block and replace or dose titration thionamide

2022 ◽  
Vol 11 (1) ◽  
Author(s):  
Claire L Wood ◽  
Niamh Morrison ◽  
Michael Cole ◽  
Malcolm Donaldson ◽  
David B Dunger ◽  
...  
Keyword(s):  
Initial Response ◽  
Patient Characteristics ◽  
Thyroid Stimulating Hormone ◽  
Phase Iii ◽  
Dose Titration ◽  
Rank Test ◽  
Z Score ◽  
Open Label ◽  
Dose Time ◽  
Open Label Trial

Objective Patients with thyrotoxicosis are treated with anti-thyroid drug (ATD) using block and replace (BR) or a smaller, titrated dose of ATD (dose titration, DT). Design A multi-centre, phase III, open-label trial of newly diagnosed paediatric thyrotoxicosis patients randomised to BR/DT. We compared the biochemical response to BR/DT in the first 6 months of therapy. Methods Patients commenced 0.75 mg/kg carbimazole (CBZ) daily with randomisation to BR/DT. We examined baseline patient characteristics, CBZ dose, time to serum thyroid-stimulating hormone (TSH)/free thyroxine (FT4) normalisation and BMI Z-score change. Results There were 80 patients (baseline) and 78 patients (61 female) at 6 months. Mean CBZ dose was 0.9 mg/kg/day (BR) and 0.5 mg/kg/day (DT). There was no difference in time to non-suppressed TSH concentration; 16 of 39 patients (BR) and 11 of 39 (DT) had suppressed TSH at 6 months. Patients with suppressed TSH had higher mean baseline FT4 levels (72.7 vs 51.7 pmol/L; 95% CI for difference 1.73, 31.7; P = 0.029). Time to normalise FT4 levels was reduced in DT (log-rank test, P = 0.049) with 50% attaining normal FT4 at 28 days (95% CI 25, 32) vs 35 days in BR (95% CI 28, 58). Mean BMI Z-score increased from 0.10 to 0.81 at 6 months (95% CI for difference 0.57, 0.86; P < 0.001) and was greatest in patients with higher baseline FT4 concentrations. Conclusions DT-treated patients normalised FT4 concentrations more quickly than BR. Overall, 94% of patients have normal FT4 levels after 6 months, but 33% still have TSH suppression. Excessive weight gain occurs with both BR and DT therapy.

scholarly journals A Phase III, Randomized, Multi-Center, Open-Label, Fixed Dose, Neulasta Active-Controlled Clinical Trial of F-627, a Novel G-CSF, in Women with Breast Cancer Receiving Myelotoxic Chemotherapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4290-4290
Author(s):  
John Glaspy ◽  
William Daley ◽  
Igor Bondarenko ◽  
Dean Rutty ◽  
Jianmin Chen
Keyword(s):  
Breast Cancer ◽  
Study Drug ◽  
Phase Iii ◽  
Chemotherapy Cycle ◽  
Severe Neutropenia ◽  
Fixed Dose ◽  
Controlled Study ◽  
Open Label ◽  
Treatment Groups ◽  
The Mean

Abstract Background - Chemotherapy-induced neutropenia (CIN) is the primary dose-limiting toxicity in patients receiving myelotoxic chemotherapy which is associated with increased morbidity and early mortality. Ryzneuta TM (F-627), a recombinant fusion protein containing human granulocyte-colony stimulating factor (G-CSF) and IgG2-Fc fragment, is intended to reduce CIN by utilizing the neutrophilic proliferating and activating properties of G-CSF. F-627 was designed as a novel, non-pegylated molecule with dimeric G-CSF, which may possess stronger G-CSF receptor activating properties and improved efficacy compared to filgrastim and pegfilgrastim. The primary objective of this study was to evaluate the safety and efficacy of F-627 given as a single fixed dose (20 mg) pre-filled syringe (PFS) as compared to Neulasta® (6 mg) in the first chemotherapy cycle. Methods - This was a phase III, multi-center, randomized, open-label, two-arm, active-controlled study that randomized female patients with Stage I to III invasive breast cancer who received 4 cycles of myelotoxic taxane + cyclophosphamide chemotherapy treatment. Forty-one (41) sites across 5 countries participated in the trial, including Bulgaria, Hungary, Russia, Ukraine, and US. Patients were randomized to F-627 or Neulasta® in a 1:1 ratio on the day of chemotherapy and administered study drug 24 hours after chemotherapy administration in each cycle. A total of 393 patients were randomized and analyzed for efficacy and safety. Clinical assessments were cycle-specific and included physical examination, serum samples for immunogenicity before each chemotherapy cycle, laboratory assessments, hematology and CBC with differentials, urinalysis, body weight, vital signs, adverse event (AE) collection, and concomitant medications. The pharmacokinetics (PK) and the pharmacodynamics (PD) of F-627 were also assessed. The primary efficacy endpoint was the duration in days of Grade 4 (severe) neutropenia (ANC &lt;0.5 × 10 9/L) during cycle 1 of chemotherapy. Results - The mean duration of Grade 4 neutropenia in chemotherapy cycle 1 was 0.2 days for both F-627 and Neulasta®. F-627 was non-inferior compared to Neulasta® for the duration of Grade 4 neutropenia in chemotherapy cycle 1 with a mean difference of 0.0 days (95% CI: -0.1, 0.1), utilizing a non-inferiority margin of 0.6 days. The incidence of Grade 4 neutropenia in chemotherapy cycle 1 was comparable between F-627 and Neulasta®, 11.7% for both treatment groups. For chemotherapy cycles 2, 3, and 4, the incidence and duration of Grade 4 neutropenia was generally lower than in chemotherapy cycle 1. The mean durations of Grade 4 neutropenia were 0.1, 0.0, and 0.0 days for F-627 and 0.1, 0.1, and 0.1 days for Neulasta® in chemotherapy cycles 2,3,4, respectively. The incidence of Grade 4 neutropenia was 4.6%, 2.6%, and 1.6% for F-627 and 5.1%, 6.3%, and 5.3% for Neulasta® in chemotherapy cycles 2, 3, and 4, respectively. Across all chemotherapy cycles and for each chemotherapy cycle, the mean duration and the incidence of IV antibiotic use and hospitalization due to febrile neutropenia or any infection were low and comparable between F-627 and Neulasta®. The depth of ANC nadir was comparable in each chemotherapy cycle between F-627 and Neulasta®. For each chemotherapy cycle, time to ANC nadir was slightly longer for patients treated with F-627 than those with Neulasta®; the mean time to ANC nadir was 6.4, 6.1, 6.2, and 6.2 days for F-627, compared to 6.1,5.3, 5.7, and 5.5 days for Neulasta® in cycles 1, 2, 3, and 4, respectively. F-627 was well tolerated, with a low incidence of serious AEs and AEs leading to discontinuation, comparable to the profile for Neulasta®. There were 3 deaths during the study (1 for F-627 and 2 for Neulasta®). None of the deaths were related to study drug treatment. Clinical laboratory abnormalities were observed to be similar between the two treatment groups. Conclusion - Once-per-cycle F-627, given as a fixed 20 mg dose, was non-inferior to Neulasta® in reducing the duration of severe neutropenia following TC chemotherapy. F-627 was well tolerated during the study with an overall safety profile comparable to that for Neulasta®. F-627 is a safe, effective, and easy to use alternative to current CIN therapy. Disclosures Daley: Evive: Current Employment, Current holder of stock options in a privately-held company. Chen: Evive: Current Employment.

An open-label, randomized, phase III trial of zalutumumab, a human monoclonal EGF receptor (EGFr) antibody, versus best supportive care, in patients with noncurable squamous cell carcinoma (SCCHN) of the head and neck who have failed standard platinum-based chemotherapy (ZALUTE).

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA5506-LBA5506 ◽  
Author(s):  
J. H. Machiels ◽  
S. Subramanian ◽  
A. Ruzsa ◽  
G. Repassy ◽  
I. Lifrenko ◽  
...  
Keyword(s):  
Supportive Care ◽  
Egf Receptor ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Dose Titration ◽  
Controlled Study ◽  
Rank Test ◽  
Meaningful Improvement ◽  
Platinum Based Chemotherapy ◽  
Ecog Ps

LBA5506 Background: Zalutumumab is a novel, fully human IgG1 mAb targeting the EGFr that has shown encouraging activity in SCCHN. Methods: Patients with noncurable SCCHN with an ECOG PS of 0-2 and centrally documented radiographic progressive disease (PD) within 6 months after platinum-therapy were randomized between zalutumumab monotherapy and best supportive care (BSC) in a 2:1 ratio. Stratification parameter was ECOG PS. Methotrexate (MTX) was allowed in the BSC arm only. Individual dose-titration of zalutumumab was applied (max. exposure 16 mg/kg). The primary endpoint was overall survival (OS), with progression free survival (PFS) as the only secondary endpoint to be compared between groups, using log-rank test. 231 deaths were required to statistically differentiate OS between groups with 80% power. Results: 286 patients (34F, 252M) were randomized. The median age was 57 years (range 18-78), 65% had distant metastasis and 17% were ECOG PS 2, all similar between groups. 78% of patients in BSC arm received MTX. Although a median OS of 6.7 months was observed in the zalutumumab group compared to 5.2 in the BSC group, this was not statistically significant (p=0.065). A clear improvement in PFS (P=0.001) was demonstrated. Zalutumumab showed a safety profile as expected within this drug class. Conclusions: This is the first controlled study to demonstrate that an EGFr-targeted antibody given as monotherapy induces a clinically meaningful improvement in PFS in patients with SSCHN who have failed platinum-based chemotherapy. [Table: see text] [Table: see text]

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