What is this summary about?
This is a plain language summary of an article originally published in the Journal of Bone and Mineral Research. People with fibrodysplasia ossificans progressiva (FOP) ...become physically disabled over time as new bone forms in places where it is not usually found, such as in muscles and ligaments. Until recently, there were no treatments for FOP that had been proven through clinical trials; however, a drug called palovarotene has been tested in clinical trials and may be effective. Here, we describe the MOVE trial, which investigated how effectively palovarotene works, as well as its safety in treating patients with FOP.
What were the results?
Results from MOVE suggest that palovarotene may reduce extra bone formation outside the normal skeleton. Patients with FOP who took palovarotene formed less new bone than those who did not take palovarotene. The most common side effects involved the skin, and included dryness and irritation. Some children who were still growing when they took palovarotene had a side effect that resulted in the (normal) growth of their skeleton stopping too soon.
What do the results of the trial mean?
Palovarotene may be a useful treatment option for FOP. Patients, caregivers, and doctors would need to consider the benefits and risks of treatment with palovarotene, particularly with growing children.
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361
Background: TIVO-1, a randomized Phase III trial in first-line targeted therapy for patients (pts) with ccRCC, demonstrated significant improvement in progression-free survival ...(PFS) in pts receiving tivozanib hydrochloride (T) vs. sorafenib (S) (11.9 vs. 9.1 months 12.7 vs. 9.1 in treatment-naïve pts). To further characterize molecular ccRCC subtypes and assess relationships between subtypes and vascular endothelial growth factor tyrosine kinase inhibitor activity, we characterized available molecularly annotated datasets from TIVO-1. Methods: Tumor subtypes were established using hierarchical clustering and evaluated in two microarray ccRCC datasets using gene set enrichment analysis with 51 signatures representing a set of molecular phenotypes. A 9-gene signature comprising genes associated with hypoxia-inducible factor (HIF) transcription was quantified by RT-PCR on all available (69/517) formalin-fixed, paraffin-embedded material from patients using a predefined classifier score and cutoff. Results: Hierachical clustering generated 3 distinct tumor classes. Molecular clusters defining HIF gene expression (low), endothelial cell content (low), extracellular matrix (low), proliferation (high) epithelial cell phenotype (high), and metabolism (high) were differentially expressed in cluster 3 tumors, which represented approximately 15% of the populations. Based on predefined analysis, the hypoxia signature was significantly associated with better PFS on T using a previously established classifier (Table). The hypoxia signature was not significantly associated with PFS on S. There was no significant correlation to single largest diameter for either agent. Conclusions: A novel molecular subtype of ccRCC is characterized by a distinct molecular profile and can be classified by a low hypoxia signature. This hypoxia gene signature may help identify T responders. This signature is seen in subsets of other solid tumors supporting the broad exploration of this candidate T response biomarker. Clinical trial information: NCT01030783. Table: see text
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364
Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life ...and has shown superior efficacy, measured as progression-free survival (PFS), as first-line, targeted therapy vs. sorafenib in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma (J Clin Oncol2012;30suppl:Abstract 4501). Patients who progressed (PD) on sorafenib could receive tivozanib in an open-label, prospective multicenter extension study of TIVO-1. We report preliminary efficacy and safety data for patients who had PD on sorafenib and subsequently received tivozanib in this extension study. Methods: Patients with PD on sorafenib, per RECIST version 1.0, were eligible to receive tivozanib dosed at 1.5 mg/day PO for 3 weeks followed by a 1-week rest, in repeated 4-week cycles, until PD or unacceptable toxicity. Patients were to have been no more than 4 weeks from last dose of sorafenib until initiation of tivozanib, and have an ECOG performance status of ≤2. Dose adjustments were performed as previously reported. Objectives included assessing objective response rate (ORR), duration of response, PFS for tivozanib following PD on sorafenib, and overall survival. Results: As of January 20, 2012, 127 patients (72.4% male) were evaluable for response. Median age was 59.0 years (range: 23–85 years). ORR was 7.9% (95% CI 3.8–14.0%; partial response PR=7.9%; stable disease SD=65.4%; PD=18.9%), and 71.3% of patients showed tumor shrinkage. Median duration of PR was 11.1 months (95% CI ≥7.5 months). Median duration of SD was 12.7 months (95% CI ≥7.4 months). Median PFS was 5.6 months (95% CI 5.4–9.1 months). Median OS was not yet reached. Most commonly reported treatment-emergent adverse events (all grades/Grade ≥3) were hypertension (22.4%/10.2%), asthenia (11.0%/3.1%), fatigue (11.0%/3.9%), palmar-plantar erythrodysesthesia (11.0%/1.6%), and diarrhea (10.2%/1.6%). Conclusions: Tivozanib has anti-tumor activity after PD on sorafenib. The adverse-event profile of tivozanib after sorafenib is similar to that observed in TIVO-1. Clinical trial information: NCT01076010.
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355
Background: Tivozanib hydrochloride (T) was superior to sorafenib (S) in progression-free survival (medians of 11.9 vs. 9.1 months, respectively; 12.7 vs. 9.1 months, respectively, ...for metastatic treatment-naïve pts) in the phase III TIVO-1 study in pts with mRCC. T showed a differentiated safety profile with lower rates of dose interruptions/reductions v S (18/12 vs. 35/43, respectively; p<0.001). TIVO-1 also evaluated patient self-reported HRQoL. Methods: Pts with mRCC were randomized 1:1 to receive T (1.5 mg PO once daily for 3 weeks on, 1 week off) or S (400 mg bid, continuously). HRQoL was assessed on Cycle 1/Day1 (baseline BL) and at the beginning of each cycle, using the Functional Assessment of Cancer Therapy–General (FACT-G), FACT–Kidney Symptom Index Disease Related Symptoms (FKSI-DRS), and EuroQol 5-dimensional (EQ-5D) questionnaires; EQ-5D scores are not reported here. Pts with BL and ≥1 post-BL evaluable forms were analyzed. Changes from BL in FACT-G and FKSI-DRS scores over 18 treatment cycles were analyzed using repeated measures mixed-effects models. QoL improvement/deterioration was defined as an increase/decrease from BL of ≥3 points for FACT-G subscales and FKSI-DRS total score and 7 points for the FACT-G total score during the study. Results: In the mixed effects analyses, no significant differences in HRQoL (FACT-G and FKSI-DRS) were noted between T and S. More pts receiving T vs. S experienced a significant improvement during the study in physical well-being (PWB) (25.7% vs. 16.4%; p=0.011) and a favorable trend in all other FACT-G and FKSI scores (p values: 0.078–0.405). FKSI improvement was greater with T than S in treatment-naïve pts (34.1% vs. 23.6%; p=0.023), pts with ≥2 metastases (32.9% vs. 24.7%; p=0.054), or pts <65 years old (33.0% vs. 22.8%; p=0.022). Median time to QoL deterioration was usually longer with T (3.75-7.66 months) than S (2.04-8.80 months). Conclusions: HRQoL was generally similar for T and S. Non-significant numeric differences usually favored T over S, and PWB improvement occurred significantly more often with T. These results support the previously-reported PFS advantage of T over S. Clinical trial information: NCT01030783.
Introduction: Hemophilia A and B are congenital bleeding disorders caused by insufficient thrombin generation due to deficiency in factor VIII or IX, respectively. In the presence of normal levels of ...endogenous anticoagulants, deficiency of factor VIII or IX results in an imbalance of the hemostatic system toward a bleeding phenotype. ALN-AT3 is a subcutaneously administered investigational RNAi therapeutic aimed at reducing the levels of antithrombin (AT) with the purpose of increasing thrombin generation and thereby restoring hemostatic balance in hemophilia.
Material and methods: Preclinical studies in hemophilia mouse models were used to investigate the ability of ALN-AT3 to reduce AT, increase thrombin generation, restore thrombus formation after microvascular laser injury, and control traumatic bleeding after saphenous vein transection. A study in an induced hemophilia A model in non-human primates was used to investigate the ability of ALN-AT3 to enhance thrombin generation in the setting of inhibitors to factor VIII.
A Phase 1 clinical study in healthy volunteers and severe/moderate hemophilia A or B is ongoing. Part A, a single ascending dose study in healthy volunteers, has been completed and Part B, a multiple ascending dose study in hemophilia patients, is currently ongoing. Primary endpoints are safety and tolerability. Secondary endpoints are pharmacokinetics, relative reduction in levels of AT and change in thrombin generation as measured by Calibrated Automated Thrombin (CAT) generation.
Results: ALN-AT3 treatment resulting in residual AT levels of 20-40% in hemophilia A and B mouse models increased thrombin generation, restored real-time localized thrombus formation in the laser-injury model comparable to treatment with full-length recombinant factor VIII. ALN-AT3 controlled traumatic bleeding in the saphenous vein model with an increase in number of hemostatic events equivalent to that achieved with infusion of 25 IU/kg full-length recombinant factor VIII. ALN-AT3 treatment targeting 20% residual AT levels normalized thrombin generation in non-human primates with induced high titer inhibitor hemophilia A.
In Part A of the phase 1 study, a total of 4 human volunteer subjects were randomized to receive a single subcutaneous dose of ALN-AT3 0.03 mg/kg or placebo (3:1) and were followed for at least 70 days. No serious adverse events (SAEs) were observed. A total of 5 mild AEs were recorded. Four out of 5 mild AEs were considered unlikely/not related to study drug. One mild AE of temporary self-limiting headache was considered possibly related to study drug. In Part A, per protocol, the maximum allowable level of AT relative reduction was set at 40%. Results in healthy volunteers show that a single, low subcutaneous dose of ALN-AT3 at 0.03 mg/kg resulted in an up to 28-32% knockdown of AT activity at nadir, and the treatment effect was statistically significant relative to placebo (p < 0.01 by ANOVA). This led to a statistically significant (p < 0.01) increase in peak thrombin generation, that was temporally associated and consistent with the degree of AT knockdown. The AT reduction was stable and durable for up to 70 days post single dose. In the ongoing Part B, cohorts of 3 hemophilia patients will receive 3 weekly doses of ALN-AT3, with dosing commenced at 0.015 mg/kg. Up-to-date results from Part B will be presented.
Conclusion: Collectively, these data suggest that the use of a novel RNAi therapeutic targeting AT is a promising approach for restoring hemostatic balance in hemophilia, and potentially, other bleeding disorders. Further, the subcutaneous route of administration, infrequent dosing, and applicability to persons with hemophilia who have inhibitors, make this a particularly encouraging potential therapy.
Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership. Off Label Use: ALN-AT3 is an investigational drug for potential treatment of hemophilia. The data represent phase 1/2 data. Mant:Quintiles phase 1 unit, London: Employment. Akinc:Alnylam Pharmaceuticals: Employment. Simon:Alnylam Pharmaceuticals: Employment, Equity Ownership. Melton:Alnylam Pharmaceuticals: Employment, Equity Ownership. Lynam:Alnylam Pharmaceuticals: Employment. Strahs:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sehgal:Alnylam Pharmaceuticals: Employment, Equity Ownership. Hutabarat:Alnylam Pharmaceuticals: Employment, Equity Ownership. Chaturvedi:Alnylam Pharmaceuticals: Employment, Equity Ownership. Barros:Alnylam Pharmaceuticals: Employment, Equity Ownership. Vaishnaw:Alnylam Pharmaceuticals: Employment, Equity Ownership. Investigators:Alnylam Pharmaceuticals: Clinical investigators in phase 1/2 study Other, Consultancy.
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350
Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor targeting all three vascular endothelial growth factor receptors, with a long ...half-life. Tivozanib has shown tolerability and superior progression-free survival and overall response rate versus sorafenib in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma. Final overall survival (OS) data (August 27, 2012) from TIVO-1 and its open-label, multicenter extension study are reported. Methods: A total of 517 patients were randomized 1:1 to tivozanib 1.5 mg/d (3 weeks on, 1 week off) or sorafenib 400 mg/d (twice a day, continuously) (J Clin Oncol2012;30suppl:Abstract 4501). In the extension study, patients who progressed (PD) on sorafenib based on investigator assessment were eligible to receive tivozanib, and patients with PD on tivozanib received subsequent treatment according to regional standards of care. Final OS analysis was planned to be conducted after all patients had died or were lost to follow-up, or when all patients in follow-up had been on study for at least 2 years, whichever occurred first. OS was compared using the stratified log-rank test. OS distribution was estimated using the Kaplan-Meier method. Hazard ratio (HR) was estimated using the Cox proportional hazard regression model. Results: At the time of final OS analysis (2 years after last patient was enrolled), 219 deaths had occurred (tivozanib, n=118 45.4%; sorafenib, n=101 39.3%) (stratified HR=1.245; 95% confidence interval CI 0.954–1.624; p=0.105), trending in favor of the sorafenib arm. Median OS (95% CI) was 28.8 months (22.5–NA) for tivozanib and 29.3 months (29.3–NA) for sorafenib. Of the 257 patients on sorafenib, 155 (60.3%) had started next-line tivozanib at the time of the analysis. Conclusions: There was no significant difference in OS between the two treatment arms. The high rate of utilization of second-line tivozanib in patients following PD on sorafenib may have affected the OS outcome. Clinical trial information: NCT01030783.
Abstract
Background: FOP is an ultra-rare, severely disabling genetic disorder characterized by episodic flare-ups and heterotopic ossification (HO) leading to restricted movement, physical ...disability, and early death. FOP may initially be misdiagnosed in ~90% of individuals leading to unnecessary and often harmful interventions. Patients with FOP are diagnosed and managed by multiple specialties, including endocrinologists.
Data from an ongoing, prospective, longitudinal, global, natural history study (NCT02322255) were used to investigate the progression of FOP, HO formation, and impact on physical functioning over time. We present results from the first 12 months of the 3-year study.
Methods: Males and females with FOP and a documented ACVR1 R206H mutation participated. HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding the head. All imaging was interpreted at a blinded, central laboratory using pre-specified procedures. Functional outcomes were evaluated using the Cumulative Analogue Joint Involvement Scale (CAJIS; for each joint: score=0 represents <10% involvement, score=1 represents 10–90% involvement, and score=2 represents >90% ankylosed across 15 major joints; total score range 0 to 30 higher scores indicate more severe mobility limitations) and the FOP Physical Function Questionnaire (FOP-PFQ; percent total score). Changes from Baseline at Month 12 were evaluated for new HO volume, CAJIS, and FOP-PFQ.
Results: Of 114 participants (pts) with Baseline data, 99 (4 to 56 years at enrollment; mean 17 years of age; 56% male) also had a Month 12 assessment. A total of 93 pts had evaluable WBCT scans at Baseline and Month 12 and were included in the HO analysis.
In total, 40% (37/93) of pts had new HO over 12 months; the mean volume of new HO in these pts was 57,706 mm3 (SD=100,079 mm3; median=20,753 mm3; range: 522 to 438,826 mm3). Of the pts with new HO, 65% (24/37) reported at least one flare-up (mean rate of 2.3 flare-ups/year).
Over 12 months, 60% (56/93) of pts did not have new HO; 43% (24/56) of them reported at least one flare-up (mean rate of 1.8 flare-ups/year).
Mean changes from Baseline in CAJIS and FOP-PFQ were minimal: CAJIS: 0.6 (SD=2.4; median=1.0; n=99) and FOP-PFQ: 4.4% (SD=11.2; median=3.7%; n=90); and were similar across pts with or without new HO.
Conclusions: In participants with FOP, although deterioration of physical function is expected over a patient’s lifetime, CAJIS and FOP-PFQ scores did not worsen significantly in the relative short-term of this study. However, HO volume, quantified by WBCT, increased over the course of 12 months. These results show that measuring HO may be a viable way to monitor changes in FOP over short periods of time.
Background and Objective
: For patients with advanced cancers, it is important that treatment improves the quality as well as the quantity of survival. This quality-adjusted time without symptoms of ...progression or toxicity (Q-TWiST) analysis provides a combined measure of both the overall survival interval and the quality of survival for patients with advanced renal cell carcinoma (RCC) receiving temsirolimus, interferon (IFN)-α or the combination of these agents, using data from a phase III clinical trial.
Methods
: Overall survival was partitioned into three distinct health states: time with serious toxicity (TOX), time after progression (REL) and time without symptoms of progression or toxicity (TWiST). Health states were quality weighted by patient-reported EQ-5D measures collected while receiving treatment.
Results
: All 626 patients from the trial were included in computation of health-state durations. EQ-5D questionnaires were obtained from 260 patients upon progression and from 230 after a grade 3 or 4 adverse event, and from 278 patients in the TWiST state. Patients receiving temsirolimus had 38% longer TWiST than those receiving IFNα (6.5 vs 4.7 months, respectively; p = 0.0005). Patients receiving temsirolimus had 25% longer qualityadjusted survival in terms of Q-TWiST than those receiving IFNa (7.0 vs 5.6 months, respectively; p = 0.0015). Differences between the combination (temsirolimus + IFNα) and IFNα groups were not statistically significant.
Threshold utility analysis indicated that temsirolimus was the preferred alternative for all possible utility weights for REL and TOX health states.
Conclusion
: Temsirolimus resulted in significantly longer Q-TWiST (qualityadjusted survival) in patients with advanced RCC than IFNα therapy.
Abstract
Background: Tivozanib is a potent, selective, long half-life tyrosine kinase inhibitor of vascular endothelial growth factor receptors-1, -2, and -3 that is currently being tested in a Phase ...III study in patients with renal cell carcinoma and Phase I/II studies of other solid tumors. Previous preclinical and clinical studies have shown that tivozanib displays strong antiangiogenic and antitumor effects. Preclinical and retrospective electrocardiogram (ECG) analyses did not suggest an effect of tivozanib on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. This open-label, non-randomized, single-arm study prospectively investigated the proarrhythmogenic potential of tivozanib on the QTcF interval and its morphology on the ECG and ECG-pharmacokinetic (PK) relationship in patients with advanced solid tumors.
Methods: Patients with advanced solid tumors, an ECOG score ≤1 and life expectancy ≥3 months were eligible. Patients received 1.5 mg of tivozanib orally, once daily for 21 days. Patients with a repeated baseline QTcF >480 ms were excluded. Serial blood samples and time-matched, triplicate, 12-lead ECGs were collected on: Day 1 20–30 minutes pre-dose (no blood sample collected), immediately pre-dose, and at 2.5, 4, 5, 6, 8, and 10 hours post dose; Day 2 pre-dose evaluation was taken approximately 24 hours post Day 1 dose; Day 8 (±1 day) pre-dose, and at 2.5, 5, and 8 hours post dose; Day 21 pre-dose and at 2.5, 4, 5, 6, 8, and 10 hours post dose; and Day 22 at approximately 24 hours post Day 21 dose. Additional safety parameters were evaluated by assessment of clinical laboratory tests, physical examinations, vital signs, and recording of adverse events.
Results: Fifty patients with advanced solid tumors (males, 17; median age, 63 years; 94% white) who received at least one dose of tivozanib were evaluable for the present study. Preliminary adverse event data showed that there were no clinically significant changes in QTcF from baseline. Further analysis will be completed, and final safety and ECG-PK modeling will be presented.
Conclusions: Preliminary data suggest that tivozanib at 1.5 mg daily over a 21-day period does not cause clinically significant prolongation of QT/QTc over baseline. Data from this study suggest that the safety and PK profile of tivozanib was similar to that observed in previous studies, and that the findings are consistent with the ECG evaluation in a monkey telemetry study.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C121.
Abstract
Background: Tivozanib is a potent, selective, long half-life tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3. Tivozanib has demonstrated ...antitumor activity in a Phase II study in subjects with renal cell carcinoma. This study was conducted to determine the absorption, metabolism, and excretion of a single 1.5 mg dose of 14C-tivozanib administered to healthy male subjects.
Methods: This study was approved by an independent institutional review board and enrolled 8 healthy male subjects; each received a single 1.5 mg (∼160 μCi) dose of oral 14C-tivozanib. Whole blood, serum, urine, and feces were collected for up to 28 days post dose for assessment of total radioactivity and/or for determination of 14C-tivozanib concentrations. All subjects were kept confined as inpatients for the duration of the study. Safety assessments included laboratory tests, electrocardiograms, physical examinations, vital signs, and recording of adverse events. Pharmacokinetic data were analyzed by noncompartmental methods.
Results: Subjects had a mean age of 32 years (range 19 to 46 years) and mean body mass index of 25 kg/m2 (range: 23 to 29 kg/m2). Of the 8 subjects enrolled, 7 completed the study. 14C-tivozanib and total radioactivity were slowly absorbed and eliminated from serum; median Tmax was 10.0 hours, and mean (±SD) t1/2 for 14C-tivozanib and total radioactivity in serum was 89.3 hours (± 23.5 hours) and 99.1 hours (± 32.5 hours), respectively. Mean (±SD) Cmax and AUC0−∞ values for 14C-tivozanib were 12.1 ng/mL (±46.9 ng/mL) and 1084 ng*hr/mL (±417 ng*hr/mL), respectively; these values were approximately 93% and 80% of the values for total radioactivity in serum, respectively. Mean blood to serum concentration ratios ranged from 0.495 to 0.615 through 312 hours post dose, indicating minimal association of radioactivity with red blood cells. Overall, mean (±SD) recovery of total radioactivity was 91.1% (±11.0%), with 11.8% (±4.6%) recovered in urine and 79.3% (±8.8%) recovered in feces. No unchanged tivozanib was found in the urine. A single therapeutic dose of tivozanib was well tolerated in healthy subjects.
Conclusion: These results indicate that after an oral dose of 1.5 mg (∼160 μCi) of 14C-tivozanib, the majority of circulating drug in the systemic circulation was unchanged tivozanib. The main route of elimination of 14C-tivozanib was via feces, with at least 11.8% of the administered total radioactive dose being absorbed into systemic circulation. No unchanged tivozanib was found in the urine, indicating that tivozanib does not undergo renal excretion. In this study, the mean half-life of 14C- tivozanib was 89.3 hours, one of the longest half-lives among VEGF TKIs. Tivozanib is currently being tested in a Phase III study in subjects with RCC and Phase I/II studies in other solid tumors.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C123.
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