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 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.

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 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 &lt;1.3 × upper limit of normal [ULN], and 2-h integrated GH &lt;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 &lt;1.3 × ULN and mean integrated GH &lt;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.

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.

scholarly journals Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis

2020 ◽  
Vol 38 (28) ◽  
pp. 3252-3260 ◽  
Author(s):  
Efstathios Kastritis ◽  
Xavier Leleu ◽  
Bertrand Arnulf ◽  
Elena Zamagni ◽  
María Teresa Cibeira ◽  
...  
Keyword(s):  
Overall Survival ◽  
Light Chain ◽  
Response Rate ◽  
Alkylating Agents ◽  
Standard Of Care ◽  
Phase Iii ◽  
Controlled Study ◽  
Al Amyloidosis ◽  
Open Label ◽  
Hematologic Response

PURPOSE Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016 . RESULTS A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.

Nail Psoriasis and Biologics

2009 ◽  
Vol 13 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Kristin Noiles ◽  
Ronald Vender
Keyword(s):  
Clinical Trials ◽  
Literature Review ◽  
Severity Index ◽  
Phase Iii ◽  
Controlled Study ◽  
Extensive Literature ◽  
Open Label ◽  
Double Blind ◽  
Nail Psoriasis ◽  
Percent Improvement

Background: Since the advent of biologic therapies for psoriasis, reports of efficacy in nail psoriasis have appeared in the literature and at international conferences with increasing frequency. Objective: This article aims to review the existing literature on the use of biologics in the treatment of nail psoriasis. Methods: An extensive literature review was conducted using OVID Medline. Studies examining the efficacy of biologics in the treatment of nail psoriasis were documented. Results: A literature review revealed few clinical trials specifically concentrating on nail psoriasis; however, nails have been assessed in larger clinical trials for cutaneous psoriasis. A large, multicenter, phase III, double-blind, placebo-controlled study of infliximab administered as a brief induction regimen at weeks 0, 2, and 6 followed by a single infusion every 8 weeks revealed statistically significant mean percent improvement in the Nail Psoriasis Severity Index (NAPSI) score over placebo at both week 10 (26.8% vs −7.7%, respectively; p < .001) and week 24 (57.2% vs −4.1%, respectively; p < .001). For other biologics, evidence has thus far been largely anecdotal, appearing as either case studies or extracted secondarily from open-label prospective trials in plaque psoriasis or psoriatic arthritis. Conclusion: Infliximab appears to be the most effective treatment for nail psoriasis to date.

A Phase II Study Of Aprepitant As Anti-Emetic Prophylaxis In Patients Receiving Induction Chemotherapy For AML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5035-5035
Author(s):  
Joseph Brandwein ◽  
Karen W.L. WL Yee ◽  
Andre C Schuh ◽  
Vikas Gupta ◽  
Jack T Seki
Keyword(s):  
Induction Chemotherapy ◽  
Phase Ii ◽  
Cumulative Incidence ◽  
Retrospective Cohort ◽  
Phase Iii ◽  
Controlled Study ◽  
Open Label ◽  
Open Label Study ◽  
Secondary Endpoints ◽  
Additional Therapy

Abstract Background Standard AML induction chemotherapy includes an anthracycline plus cytarabine (3+7); the former is considered moderately emetogenic. Such patients typically received anti-emetic prophylaxis using a 5-HT3 antagonist; however, many patients continue to experience chemotherapy-induced nausea and vomiting (CINV) requiring additional therapy. Aprepitant is a neurokinin inhibitor with documented efficacy against CINV, but has not been evaluated to date in the setting of AML induction therapy. Patients and Methods Patients with previously untreated AML, receiving induction chemotherapy with daunorubicin 60 mg/m2 IV daily on Days 1-3 plus cytarabine 200 mg/m2 IV daily (100 mg/m2 for patients age 60 and over) as a continuous IV infusion x 7 days, were enrolled in a Phase II single arm open label study. All patients received 5-HT3 antagonist prophylaxis using either granisetron 1 mg IV daily or ondansetron 8 mg IV q12h on the 3 daunorubicin dosing days. In addition, patients received aprepitant 125 mg PO on Day 1 followed by 80 mg PO daily on Days 2-5. No corticosteroids were used. Additional anti-emetic therapy was given as needed, at the discretion of the medical staff, for any nausea or vomiting. The primary endpoint was any vomiting or retching, while secondary endpoints included nausea requiring supplemental anti-emetics. Results were compared to a retrospective cohort of 40 patients who had received the same AML induction chemotherapy and 5-HT3 antagonist prophylaxis, but without aprepitant. Results At a pre-planned interim analysis, 27 patients receiving aprepitant on study were evaluated. By the end of Day 5, 3/27 patients (11%) had experienced at least one episode of vomiting or retching, while by the end of Day 8 four additional patients had experienced vomiting/retching, for a cumulative incidence of 26%. In comparison, the cumulative incidence of vomiting or retching by the end of Day 5 in the retrospective cohort was 50% (20/40), and 53% by Day 8. The proportion of patients experiencing vomiting was below 8% per day on aprepitant dosing days, but increased to11% on Day 6.  The cumulative incidence of nausea and/or vomiting in the aprepitant group was 52% by the end of Day 5 and 60% at the end of Day 8, as compared to 78% at both time points in the retrospective cohort. There were no toxicities attributable to aprepitant. Conclusion The results indicate that aprepitant is highly effective, when combined with a 5-HT3 antagonist, in preventing vomiting in patients receiving AML induction chemotherapy with 3+7. The combination appears less effective in controlling nausea. The results warrant further evaluation in a Phase III randomized placebo controlled study. Disclosures: Brandwein: Merck: Honoraria, Research Funding. Off Label Use: Aprepitant as anti-emetic prophylaxis for AML induction. Seki:Merck: Honoraria.

KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (PBO) + chemo for previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer (mTNBC).

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS18-TPS18 ◽  
Author(s):  
Javier Cortés ◽  
Zifang Guo ◽  
Vassiliki Karantza ◽  
Gursel Aktan
Keyword(s):  
Antitumor Activity ◽  
Disease Recurrence ◽  
Phase Iii ◽  
Controlled Study ◽  
Adjuvant Setting ◽  
Open Label ◽  
Double Blind ◽  
End Points ◽  
Phase Iii Study ◽  
Locally Recurrent

TPS18 Background: In the phase Ib KEYNOTE-012 study, the anti–PD-1 antibody pembro demonstrated promising antitumor activity and acceptable safety as monotherapy in pretreated patients (pts) with PD-L1+ mTNBC. Adding pembro to chemo may enhance antitumor activity. KEYNOTE-355 (NCT02819518) is a global phase III study of pembro+chemo vs PBO+chemo in pts with previously untreated, locally recurrent, inoperable TNBC/mTNBC. Methods: Eligible pts are ≥18 y and have centrally confirmed, locally recurrent, inoperable TNBC or mTNBC not previously treated with chemo (prior chemo in [neo]adjuvant setting is allowed); measurable disease per RECIST v1.1; ECOG PS 0-1; ≥6 mo between definitive surgery or last dose of adjuvant chemo, whichever was last; and first disease recurrence (≥12 mo if prior treatment with same-class agent). Part 1 is an open-label, unblinded safety run-in of ~30 pts in 3 arms (pembro+nab-paclitaxel, pembro+paclitaxel, pembro+gemcitabine/carboplatin). Part 2 is a double-blind, PBO-controlled study of ~828 pts randomized 2:1 to pembro 200 mg every 3 weeks + chemo (nab-paclitaxel 100 mg/m2 on d 1, 8, and 15 every 28 d; paclitaxel 90 mg/m2 on d 1, 8, and 15 every 28 d; or gemcitabine 1000 mg/m2+ carboplatin AUC 2 on d 1 and 8 every 21 d) or PBO+chemo. Crossover is not allowed. Stratification factors are study chemo (taxane vs gemcitabine/carboplatin), tumor PD-L1 expression (+/-), and prior therapy with same-class agent in the (neo)adjuvant setting (yes/no). Treatment will occur for ≤35 administrations (pembro/PBO only) or until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or decision to discontinue. Primary end points are safety in part 1 and PFS (by RECIST v1.1, central radiology review) and OS in part 2; secondary end points include ORR (by RECIST v1.1, central radiology review) and duration of response. AEs will be graded per NCI CTCAE v4.0. Response will be assessed at wk 8, 16, 24, then at 9-wk intervals up to 1 y, and at 12-wk intervals thereafter. Interim safety analysis will occur after pts complete 1 treatment cycle in part 1. Clinical trial information: NCT02819518.

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