Efficacy of add-on treosulfan and melphalan high-dose therapy in patients with high-risk metastatic Ewing sarcoma: Report from the International Ewing 2008R3 trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11501-11501
Author(s):  
Uta Dirksen ◽  
Vivek Bhadri ◽  
Bénédicte Brichard ◽  
Trude Butterfass-Bahloul ◽  
Sona Cyprova ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Primary Endpoint ◽  
Ewing Sarcoma ◽  
Adaptive Design ◽  
Phase Iii ◽  
Controlled Clinical Trial ◽  
High Dose ◽  
Type I ◽  
Hematopoietic Stem

11501 Background: Ewing 2008R3 (EudraCT2008-003658-13) was conducted in 12 countries. It evaluated the effect of treosulfan and melphalan high dose chemotherapy followed by re-infusion of autologous hematopoietic stem cells (HDTreoMel) on event-free (EFS, primary endpoint) and overall survival (OS) in high-risk Ewing Sarcoma (EwS). Methods: Phase III, open label, prospective, multi-center, randomized controlled clinical trial. Eligible patients (pts) had disseminated EwS with metastases to bone and/or other sites, excluding pts with only pleuropulmonary metastases. Pts received 6 cycles of VIDE induction and 8 cycles of VAC consolidation therapy. Patients were randomized to receive additional HDTreoMel chemotherapy or no further treatment (control), They were further stratified by number of bone metastases (1, 2-5, > 5). One-sided adaptive inverse-normal 4-stage design, changed after the 1st interim analysis via Müller-Schäfer method. Initial sample size 185 pts, type I error rate 2.5%, power 80%. Results: 109 pts were randomized between 2009 and 2018: 55 were randomized to HDTreoMel. With a median follow-up of 3.3 years, the primary endpoint EFS was not significantly different between HDTreoMel and control in the adaptive design (HR 0.85, 95% CI 0.55-1.32, intention-to-treat). 3-year (3y) EFS was 20.9 % (95% CI 11.5-37.9%) in HDTreoMel and 19.2 % (95% CI 10.8-34.4%) in control pts. Results were similar in the per protocol collective. Subgroup analyses showed that independent of treatment, male patients had a worse outcome than female patients: 3y EFS 13.3% (95% CI 5.7-31.1%) vs 25.2% (95% CI 15.5-40.8%); p = 0.07. Patients aged < 14 had a better outcome when treated in the HDTreoMel group: 3y EFS 39.3% (95% CI 20.4-75.8%) vs 9% (95% CI 2.4-34%); p = 0.016; HR 0.40 (0.19-0.87). These effects were similar in the per protocol collective. Severe toxicities of hematology, gut, general condition and infection were more pronounced in the HDTreoMel group (p < 0.05). Conclusions: In patients with very high risk EwS, additional HDTreoMel was of no benefit for the entire cohort of patients. HDTreoMel may be of benefit for children age < 14. This observation is supported by comparable results from a non-randomized trial EE99 R3 (Ladenstein et al. JCO, 2010). Clinical trial information: NCT00987636 .

Efficacy of maintenance therapy with zoledronic acid in patients with localized Ewing sarcoma: Report from the international Ewing 2008 trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11523-11523
Author(s):  
Uta Dirksen ◽  
Raphael Koch ◽  
Vivek Bhadri ◽  
Bénédicte Brichard ◽  
Trude Butterfass-Bahloul ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Zoledronic Acid ◽  
Maintenance Therapy ◽  
Primary Endpoint ◽  
Ewing Sarcoma ◽  
Adaptive Design ◽  
Phase Iii ◽  
Controlled Clinical Trial ◽  
Type I ◽  
Standard Risk

11523 Background: Ewing 2008R1 (EudraCT2008-003658-13, Sponsor UKM) was conducted in 12 countries. It evaluated the effect of zolendronic acid (ZOL) maintenance therapy on event-free (EFS, primary endpoint) and overall survival (OS) from randomization in standard risk Ewing Sarcoma (EwS). Methods: Phase III, open label, prospective, multi-center, randomized controlled clinical trial. Eligible patients (pts) had localized EwS with either good histological response to induction chemotherapy and/or small tumors ( < 200ml). Pts received 6 cycles VIDE induction and 8 VAI (male) or 8 VAC consolidation (female) and were randomized to receive either 9 cycles of maintenance ZOL or no further treatment (control;ctrl). ZOL cycles started parallel to the 6th consolidation cycle. Randomization was stratified by tumor site (pelvis/no pelvis). Two-sided adaptive inverse-normal 4-stage design, changed after the 1st interim analysis via Müller-Schäfer method. Initial sample size 448 pts, type I error rate 5%, power 80%. Results: 284 pts were randomized between 2009 and 2018 (142 ZOL / 142 ctrl). With a median follow-up of 3.9 years, the primary endpoint EFS was not significantly different between the ZOL and ctrl group in the adaptive design (HR 0.74, 95% CI 0.43-1.28, intention to treat). 3-year (3y) EFS rates were 84.0% (95% CI 77.7-90.8%) for ZOL vs 81.7% (95% CI 75.2-88.8%) for ctrl. Results were similar in the per protocol collective. Cause-specific HR for local recurrence in ZOL was csHR 0.30 (95% CI 0.08 -1.09; p = 0.07), for metastatic progress/new metastases csHR 1.0 (CI 0.5-2.2), for combined relapse/progress csHR 0.3 (95% CI 0.1-1.7), for second malignancies csHR 4.0 (95% CI 0.45-36.1) compared to ctrl. The 3y OS was 92.8% (95% CI 88.4-97.5%) for ZOL and 94.6% (95% CI 90.9-98.6%) for ctrl. For ZOL the 5y OS was 87.3% (95% CI 80.7-94.5%) and 89% (95% CI 83.7-95.9%) for ctrl. Noticeable more renal, neurological and gut toxicities were observed for ZOL (p < 0.05), with severe renal toxicities occurring more often in the ZOL arm (p = 0.003). Conclusions: In patients with standard risk localized Ewing Sarcoma there is no benefit from maintenance treatment with zoledronic acid, but significant side effects were observed. Clinical trial information: NCT00987636 .

Efficacy of dose intensification in induction therapy for localized Ewing sarcoma: Italian Sarcoma Group (ISG) and Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) ISG/AIEOP EW-1 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11501-11501
Author(s):  
Roberto Luksch ◽  
Giuseppe Maria Milano ◽  
Francesco Barretta ◽  
Alessandra Longhi ◽  
Emanuela Palmerini ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Ewing Sarcoma ◽  
Phase Iii ◽  
Secondary Outcome ◽  
Poor Responders ◽  
High Dose ◽  
Type I ◽  
Tumour Site ◽  
Dose Intensification ◽  
The Impact

11501 Background: The role of dose intensification of chemotherapy in Ewing sarcoma (ES) is under evaluation in prospective trials. This is a controlled, randomized phase III study evaluating the impact on event-free survival (EFS) of two arms at different intensity of induction therapy in localized ES at onset. Methods: Newly diagnosed localized ES patients aged 2-40 were eligible. They were randomized to receive 4-courses induction therapy - 1 every 21 days - either with a standard arm (arm A) as per ISG/SSGIII protocol (Ferrari S, et at, Ann Oncol. 2011;22(5):1221) or with an intense arm B, consisting of vincristine 1,5mg/sqm+ doxorubicin 80mg/sqm+ifosfamide 9g/sqm for each course. After induction, patients underwent surgery and/or radiotherapy,followed by an adaptive treatment. Good responders received standard courses chemotherapy: arm A pts received 9 courses, while arm B pts received 5 courses. Poor responders in both arms received 4 courses followed by high-dose busulfan/melphalan+autologous stem cell rescue. The primary outcome measure was EFS for the 2 arms in the intention-to-treat population. Kaplan-Meier curves compared with log-rank test and Cox model were performed to assess differences between study arms. A secondary outcome was toxicity differences, assessed by means of the Fisher’s exact test. Initial sample size was 230 pts, type I error rate 5%, power 80%. Results: Between 2009 and 2019, 234 patients were randomized (arm A-115; arm B-119). M:F ratio was 1.8; median age 14 years (range 2-40); tumour site extremity in 55%, axial/pelvis in 45%; tumour volume < 200ml in 31% and ≥200ml in 69%. A good response was obtained in 56% in arm A and 60% in arm B. Median follow-up was 68 months. EFS was not significantly different between arms; HR: 0.85; 95% CI: 0,51-1,41, 5-year EFS (95% CI) was 73% (64-82%) in arm A and 75% (67-83%) in arm B ( p = 0.526). Good responders in arm A and in arm B and poor responders in arm B had comparable results: 5-year EFS (95% CI) was 80% (71-91%), 77% (67-88%), and 72% (59-86%), respectively, while poor responders in arm A showed a worse, not statistically significant (p = 0.164) performance (63%; 50-78%). Subgroup analyses showed similar outcome for age, tumour site and volume in both arms. Hematological, gastrointestinal, and cardiovascular grade ≥3 toxicities were more pronounced in arm B (p < 0.05). Conclusions: Intense induction therapy with arm B did not improve 5-year EFS when compared with the standard arm A. The higher toxicity observed in arm B than in arm A was counterbalanced, in good responders, by a similar outcome with a shorter treatment plan. For poor responders, with almost 30 patients per arm event-free and with < 48-month FUP, better 5-year EFS in arm B than in arm A was observed but needs further observation. Clinical trial information: NCT02063022.

Aprepitant Vs. Placebo Plus Oral Ondansetron and Dexamethasone for the Prevention of Nausea and Vomiting Associated with Highly Emetogenic Preparative Regimens Prior to Hematopoietic Stem Cell Transplantation: A Prospective, Randomized Double-Blind Phase III Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2267-2267 ◽  
Author(s):  
Patrick Stiff ◽  
Mary Fox-Geiman ◽  
Karen Kiley ◽  
Nancy Porter ◽  
Karen Rychlik ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Primary Endpoint ◽  
Phase Iii ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Phase Iii Trial ◽  
Preparative Regimen ◽  
Oral Ondansetron

Abstract Abstract 2267 Poster Board II-244 Introduction: Both acute and delayed nausea and vomiting are a major problem for patients undergoing highly emetic high dose preparative regimens prior to hematopoietic stem cell transplant (HSCT). Aprepitant (APR) is an NK-1 antagonist FDA approved for the prevention of N/V due to standard dose highly and moderately emetogenic chemotherapy. While several small Phase II studies have suggested its benefit in HSCT, no completed prospective comparisons have been reported. In addition as APR is known to interact with cytochrome P450 isoenzymes involved in the bioactivation of high dose cyclophosphamide, and may interfere with etoposide pharmacokinetics, its impact on regimen related toxicity and long term survival post transplant is unknown. Patients and Methods: We performed a randomized (1:1 randomization) blinded Phase III trial to determine the safety and efficacy of APR for N/V due to ablative preparative regimens. Patients received either placebo (PBO) or oral APR 125mg PO day 1 then 80mg daily during and for 3 days after the preparative regimen was completed, in addition to oral ondansetron 8 mg PO q 8hrs + IV dexamethasone daily during and for 1 day after the preparative regimen. Only PRN lorazepam was permitted for nausea. Due to a known drug interaction between APR and dexamethasone, patients also received blinded dexamethasone doses of 10mg on the placebo arm and 7.5mg on the APR arm. Patients were stratified based on gender, and patients with heavy ETOH use were excluded. Clinical evaluations were performed daily during therapy with the primary endpoint being a CR, defined as: no emesis and no or mild nausea [less than grade (gr) 3 using CTC 2.0 criteria]. Other endpoints included; major response (MR): 1 episode of emesis or moderate nausea; minor response (mR): 2–4 episodes of emesis; and failure (F) : >4 episodes of emesis. Major efficacy (ME) = CR + MR. Other analyses performed included subjective nausea based on a 100 mm visual analog scale (VAS) with 0 = no nausea; amount of PRN antiemetics used to control breakthrough N/V and no emesis all days.. Safety analyses performed included time to engraftment, 30 day survival and progression free survival (PFS) and overall survival (OS). The study began 9/20/04 and completed enrollment 7/18/08. The study was powered (90 pts per arm) to detect a difference of 20 % between the two groups with a significance level of 0.05 using a two-sided t-test. The 181 randomized patients were balanced with respect to age, weight, donor source and h/o N/V with prior chemotherapy. Patients received one of 5 ablative prep regimens: CY/TBI/VP16 (36), CY/TBI (79), IV BU/CY (14), PO BU/CY (34), and BCV(16) Two pts never proceeded to transplant so only 179 pts are eligible for analysis. Ten pts (6 APR/4 PBO) failed to complete the study; data were analyzed as intent to treat. Results: Efficacy: There was a difference in CR rate (primary endpoint) in favor of APR: 81.9% vs 65.8 % for those receiving PBO with 48.9% vs 14.6% respectively meeting this endpoint for the entire study period (p<0.001). In addition, 73.3% of the APR group never experienced a single episode of emesis during the study vs 22.5% of the PBO group (p<0.001). Other response rates were as follows: MR: APR 16% PBO 21.6% (p= 0.011); mR: APR 2.0% PBO 10.3% (p<0.001); F: APR 0.1% PBO 2.2% (p<0.001) ME: APR 97.9% PBO 87.4% (p<0.001). Ave VAS was 16.5 % for the APR group vs 16.9% for the PBO group (0.892). Heartburn was more common in the APR arm (12/90) vs. PBO (6/89) Safety: Days to engraftment for the PBO vs APR groups: ANC: 11.7 vs 11.5d (p = NS), PLT: 14.1 vs 16.4d (p = NS); 30 day survivals were the same for the two groups. The PFS was 28.3 vs 28.6 months for the APR and PBO groups (p=0.8206) and overall survival was identical in the two groups as well (p = 0.5446). Conclusions: When used daily up to 10 days with ablative preparative regimens, aprepitant significantly improved control of acute and delayed regimen-related N/V with a major impact on emesis rates. It appears safe for this indication with no impact on WBC and PLT engraftment as well as PFS and OS. Disclosures: Stiff: Merck: Research Funding. Off Label Use: Aprepitant in BMT setting.

scholarly journals YF-H-2015005, a CXCR4 Antagonist, for the Mobilization of Hematopoietic Stem Cells in Non-Hodgkin Lymphoma Patients: A Randomized, Controlled, Phase 3 Clinical Trial

2021 ◽  
Vol 8 ◽  
Author(s):  
Weiping Liu ◽  
Yufu Li ◽  
Quanshun Wang ◽  
Hang Su ◽  
Kaiyang Ding ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Hodgkin Lymphoma ◽  
Primary Endpoint ◽  
Phase Iii ◽  
Cxcr4 Antagonist ◽  
Double Blind ◽  
Hematopoietic Stem ◽  
Non Hodgkin Lymphoma

Background: YF-H-2015005, a novel CXCR4 antagonist, has been proven to increase the quantities of circulating hematopoietic stem cells (HSCs), which results in an adequate collection of HSCs in non-Hodgkin lymphoma (NHL) patients.Methods: This was a multicenter, double-blind, randomized (1:1), placebo-controlled phase III clinical trial. All patients received granulocyte colony-stimulating factor (G-CSF) for up to 8 consecutive days. YF-H-2015005 or placebo was administrated on the evening of day 4 and continued daily for up to 4 days. Apheresis was conducted 9–10 h after each dose of YF-H-2015005 or placebo. The primary endpoint was the proportion of NHL patients procuring ≥5 × 106/kg CD34+ HSCs within ≤4 apheresis sessions.Results: In total, 101 patients with NHL were enrolled. The proportions of patients achieving primary endpoint were 57 and 12% in YF-H-2015005 and placebo groups, respectively (P &lt; 0.001). Moreover, a higher proportion of YF-H-2015005-treated patients reached a minimum target collection of ≥2 × 106/kg CD34+ HSCs in ≤4 apheresis days compared to placebo-treated patients (86 vs. 38%, P &lt; 0.001). Furthermore, the median time to collect ≥2 or 5 × 106/kg CD34+ HSCs were 1 and 3 days in YF-H-2015005-treated patients, but 4 days and not reached in placebo-treated patients, respectively. No severe treatment emergent adverse events were observed in both YF-H-2015005 treatment and placebo groups.Conclusions: YF-H-2015005 plus G-CSF regimen was a tolerable combination with high efficacy, which might be used to rapidly mobilize and collect HSCs in NHL patients.

United States Intergroup E1609: A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon-α2b for resected high-risk melanoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9504-9504 ◽  
Author(s):  
Ahmad A. Tarhini ◽  
Sandra J. Lee ◽  
F. Stephen Hodi ◽  
Uma N. M. Rao ◽  
Gary Irvin Cohen ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Therapy ◽  
Primary Endpoint ◽  
Randomized Study ◽  
Phase Iii ◽  
High Dose ◽  
High Risk Melanoma ◽  
Relative Safety ◽  
Risk Melanoma ◽  
Systemic Adjuvant Therapy

9504 Background: Phase III adjuvant trials reported significant benefits in relapse-free survival (RFS) for 6 FDA-approved regimens and overall survival (OS) for HDI and ipi10 versus observation or placebo. E1609 evaluated the relative safety and efficacy of ipi at 3 and 10 mg/kg compared to HDI, which was the adjuvant standard until recently. Methods: E1609 had 2 co-primary endpoints: OS and RFS; considered positive if either co-primary endpoint comparison was positive. Activated on 5/25/2011 and completed accrual 8/15/2014. A 2-step hierarchical approach evaluated ipi3 vs HDI followed by ipi10 vs HDI. Patients were stratified by AJCC7 stage (IIIB, IIIC, M1a, M1b). Based on protocol criteria, the primary evaluation was conducted using a data cutoff of 2/15/2019. Results: Final adult patient accrual was 1670; 523 randomized to ipi3, 636 to HDI and 511 to ipi10. Treatment related adverse events (AEs) Grade 3 or higher were experienced by 37% pts with ipi3, 79% with HDI and 58% with ipi10, and those of any grade leading to treatment discontinuation were 35% with ipi3, 20% HDI and 54% ipi10. AEs were mostly immune related and consistent with the known toxicity profiles of these agents. Gr5 AEs considered at least possibly related were 3 with ipi3, 2 with HDI and 8 with ipi10. First step comparison of OS and RFS of ipi3 vs. HDI utilized an ITT analysis of concurrently randomized cases (N = 1051) and showed significant OS difference in favor of ipi3; HR 0.78, 95.6% RCI (.61, 1.00); p = 0.044. The prespecified efficacy boundary was crossed. For RFS, HR 0.85, 99.4% CI (.66, 1.09), p = 0.065. In the 2nd step comparison of ipi10 vs. HDI (N = 989), there were trends towards improvement in OS [HR 0.88, 95.6% CI (.69, 1.12)] and RFS [HR 0.84, 99.4% CI (.65, 1.09)] in favor of ipi10 that were not statistically significant. Conclusions: Adjuvant therapy with ipi3 benefits survival of resected high-risk melanoma pts; for the first time in the history of melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in the primary endpoint of OS against an active control regimen previously shown to have OS and RFS benefits, supporting early systemic adjuvant therapy for high-risk melanoma. Clinical trial information: NCT01274338.

Abstract TP236: The Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial: A Case Study of a Bayesian Trial Design

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Kristine R Broglio ◽  
Jason T Connor ◽  
William J Meurer ◽  
Valerie L Durkalski ◽  
Karen C Johnston ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Sample Size ◽  
Primary Endpoint ◽  
Trial Design ◽  
Type I Error ◽  
Phase Iii ◽  
Absolute Difference ◽  
Type I ◽  
Operating Characteristics ◽  
Patient Resources

Introduction: The “Adaptive Designs Accelerating Promising Trials into Treatments (ADAPT-IT)” project is a collaborative effort supported by the NIH and FDA to explore how adaptive clinical trial design might improve the evaluation of drugs and medical devices. We use the NINDS-supported Neurological Emergencies Treatment Trials network as a "laboratory" in which to study the development of adaptive clinical trial designs. The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial was fully funded by the NIH-NINDS at the start of ADAPT-IT and is a currently ongoing phase III trial of tight glucose control in hyperglycemic acute ischemic stroke patients. Within ADAPT-IT, a Bayesian alternative design was developed. The primary endpoint is a severity-adjusted dichotomized 90-day modified Rankin scale (mRS). Objective: To present both designs and compare their operating characteristics. Methods: 10000 trials are simulated under treatment effects ranging from 0% to 7%. We present the mean sample size and probabilities of trial success or futility. Results: The SHINE trial design includes a group sequential procedure with 4 interim analyses to monitor for early efficacy and futility. A maximum of 1400 patients provide 80% power to detect a 7% absolute difference between treatment arms with an overall Type I error rate of 5%. The expected sample size is 1050 patients. This design also incorporates sample size re-estimation and response adaptive randomization. The Bayesian alternative would enroll a maximum of 1400 patients, equally randomized, but employs more frequent interim looks based on predictive probabilities and incorporates a longitudinal model of the primary endpoint. This design has similar power and Type I error and would enroll a mean of 733 and 979 patients under the null and alternative hypotheses respectively. Conclusions: Simulations suggest that the designs have similar power and Type I error. The Bayesian alternative, with more frequent looks, has a greater chance of stopping early for overwhelming efficacy or futility. The Bayesian alternative will be retrospectively executed upon completion of SHINE to later compare the designs based on their use of patient resources, time, and strength of conclusions in a real world setting.

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