787 Phase III clinical trial to test the safety and efficacy of autologous tumor lysate-loaded dendritic cells in patients with newly diagnosed glioblastoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A836-A836
Author(s):  
Marnix Bosch ◽  
Linda Liau ◽  
Keyoumars Ashkan
Keyword(s):  
Clinical Trial ◽  
Dendritic Cells ◽  
Tumor Cell ◽  
Disease Progression ◽  
Autologous Tumor ◽  
Newly Diagnosed ◽  
Tumor Lysate ◽  
Phase 3 ◽  
Link Type ◽  
To Receive

BackgroundGlioblastoma (GBM) is an incurable form of brain cancer with a high mortality rate in which multiple treatment attempts over the past decade have proven unsuccessful at extending survival. Early stage data have suggested that immunization against tumor cell antigens may be effective in GBM. In this Phase 3 study we aimed to assess whether autologous dendritic cells (DCs) loaded with autologous tumor cell lysate, is able to improve survival in these patients.MethodsWe conducted a randomized, double-blind, placebo-controlled international Phase 3 clinical trial with autologous tumor lysate-loaded DCs (DCVax-L) in 331 patients with histologically confirmed newly diagnosed GBM. Following surgery and chemoradiation, patients were randomized 2:1 to receive temozolomide plus DCVax-L or temozolomide plus placebo (i.e., autologous PBMC). Eligibility criteria included an intent for significant tumor resection (not biopsy only), sufficient doses of DCVax-L manufactured for 5 or more immunizations, and no radiographic evidence of apparent disease progression at the end of chemoradiation. A crossover option allowed all patients to receive the autologous vaccine at the time of disease progression. As a result, 90% of the randomized patients received DCVax-L at some point during their participation in the trial. Study subjects received immunizations with 2.5 million DCs or placebo at days 0, 10 and 20, followed by immunizations at months 2, 4, 8, 12, 18, 24 and 30. All subjects were assessed for progression-free survival(PFS) and overall survival (OS). This trial is registered with clinicaltrials.gov, number NCT00045968.Trial RegistrationThe study was registered as NCT00045968Ethics ApprovalThe study was approved by all applicable Institutional Review Boards or Ethics Committees

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase 3 trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9500-9500
Author(s):  
Alexander M. Eggermont ◽  
Andrey Meshcheryakov ◽  
Victoria Atkinson ◽  
Christian U. Blank ◽  
Mario Mandalà ◽  
...  
Keyword(s):  
Disease Progression ◽  
Objective Response ◽  
Stage Iv ◽  
Median Number ◽  
Complete Resection ◽  
Stage Iii ◽  
Phase 3 ◽  
Double Blind ◽  
Grade 3 ◽  
To Receive

9500 Background: The phase 3 double-blind EORTC 1325/KEYNOTE-054 trial evaluated pembrolizumab (pembro) vs placebo in stage III cutaneous melanoma patients (pts) with complete resection of lymph nodes. Pembro improved RFS (hazard ratio [HR] 0.57) and DMFS (HR 0.60) (Eggermont, NEJM 2018, TLO 2021). In the pembro group, the incidence of immune related AE (irAE) grade 1-5 was 37%, and of grade 3-5 was 7%. We present the safety profile, response rate and PFS for the subset of pts who had a recurrence and crossed over or were rechallenged with pembrolizumab, within protocol. Methods: Pts were randomized to receive iv. pembro 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year). Upon recurrence with no brain metastases, pts with an ECOG PS 0-2 were eligible to enter part 2 of the study, i.e. to receive pembro 200 mg iv. every 3 weeks for a maximum of 2 years, for crossover (those who received placebo) or rechallenge (those who recurred ≥6 months after completing one year of pembro therapy). Treatment was stopped in case of disease progression (RECIST 1.1) or unacceptable toxicity. Results: At the clinical cut-off (16-Oct-2020), 298 (59%) pts had a disease recurrence in the placebo group; 155 pts participated in the crossover part 2 of the trial. A total of 297 (58%) pts completed the 1-yr pembro adjuvant treatment, of whom 47 had a recurrence ≥6 mths from the stop of treatment and 20 entered in the rechallenge part of the trial. Among 175 pts who started pembro in Part 2, 160 discontinued due to completion of therapy (N=24), disease progression (N=88), toxicity (N=20), investigator's decision (N=21), or other reason (N=7); 15 pts were still on-treatment. Results for the 2 groups are provided in the table. The median number of doses was 12 and 5.5, respectively (resp), and the median follow-up was 41 and 19 mts, resp. Among the 175 pts, 51 (29%) had a grade 1-4 irAE (by group: 47 [30%] and 4 [20%] resp) and 11 (6%) a grade 3-4 irAE. Conclusions: Pembrolizumab treatment after crossover yielded a 39% ORR in evaluable pts and an overall 3-yr PFS of ̃32%, but after rechallenge the efficacy was lower. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA The median PFS (95% CI) from start of Part 2 was 14 (5-27) and 8 (5-15) mts for stage III-resected and III/IV various, resp. Among the 80 stage IV crossover pts with evaluable disease, 31 (39%) had an objective response: 14 (18%) CR, 17 (21%) PR. The 2-yr PFS rate from response was 69% (95% CI 48-83%). For these 80 pts, the median PFS was 6.1 mts and the 3-yr PFS rate was 31% (95% CI 21-41%). Among 9 stage IV rechallenged pts with an evaluable disease, 1 (11%) reached CR, 3 had SD and 5 PD. Clinical trial information: NCT02362594. [Table: see text]

SAFETY AND TOLERABILITY OF TERIFLUNOMIDE IN CLINICAL STUDIES

2015 ◽  
Vol 86 (11) ◽  
pp. e4.26-e4
Author(s):  
David Barnes ◽  
Thomas Leist ◽  
Mark Freedman ◽  
Tomas Olsson ◽  
Aaron Miller ◽  
...  
Keyword(s):  
Pregnancy Outcomes ◽  
Clinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Double Blind ◽  
Link Type ◽  
Relapsing Remitting ◽  
Tolerability Data ◽  
Relapsing Remitting Multiple Sclerosis ◽  
To Receive

IntroductionTeriflunomide, approved for the treatment of relapsing-remitting multiple sclerosis, has a well-characterized safety profile based on individual clinical studies. We report pooled safety and tolerability data from four, double-blind, placebo-controlled trials of teriflunomide. Post-approval updates on hair thinning and pregnancy outcomes, sometimes concerns for patients initiating teriflunomide, are reported.MethodsData were pooled from phase 2 (NCT01487096) and phase 3 TEMSO (NCT00134563), TOWER (NCT00751881), and TOPIC (NCT00622700) studies. Patients were randomized to receive teriflunomide 14 mg, 7 mg, or placebo. Safety analyses were performed for all patients exposed to teriflunomide.ResultsThe pooled dataset included 3044 patients. Commonly reported adverse events (AEs) were in accordance with individual clinical studies, most being transient and mild-to-moderate in intensity. Incidence of hepatic AEs was higher in teriflunomide groups; however, serious hepatic AEs were similar across groups (∼2–3%). Hair thinning was higher in teriflunomide than placebo groups, but typically resolved on treatment without intervention and led to discontinuation in <2% of patients. No structural or functional abnormalities were reported in 42 newborns from teriflunomide-exposed parents.ConclusionsThese data from >6800 patient-years of teriflunomide exposure were consistent with individual studies and no new, unexpected safety signals were observed. (Study supported by Genzyme, a Sanofi company).

scholarly journals ATIM-13. ALLOGENEIC TUMOR LYSATE/AUTOLOGOUS DENDRITIC CELL VACCINES IN NEWLY DIAGNOSED GLIOBLASTOMA: RESULTS OF CLINICAL TRIAL MC1272

2017 ◽  
Vol 19 (suppl_6) ◽  
pp. vi28-vi29 ◽  
Author(s):  
Ian F Parney ◽  
Michael P Gustafson ◽  
Timothy Peterson ◽  
Susan M Steinmetz ◽  
Allan B Dietz
Keyword(s):  
Clinical Trial ◽  
Dendritic Cell ◽  
Newly Diagnosed ◽  
Autologous Dendritic Cell ◽  
Tumor Lysate ◽  
Allogeneic Tumor ◽  
Dendritic Cell Vaccines ◽  
Newly Diagnosed Glioblastoma

Induction of T cell precursors in advanced melanoma treated with autologous tumor lysate loaded dendritic cells

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 2623-2623
Author(s):  
T. S. Crocenzi ◽  
C. G. Tretter ◽  
J. Fisher ◽  
N. Crosby ◽  
D. Truman ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Advanced Melanoma ◽  
Autologous Tumor ◽  
Tumor Lysate

A prospective, randomized, blinded, placebo-controlled, phase IIb trial of an autologous tumor lysate + yeast cell wall particles (YCWP) + dendritic cells (DC) vaccine vs unloaded YCWP + DC and embedded phase I/IIa trial with tumor lysate particle only (TLPO) vaccine in stage III and stage IV (resected) melanoma to prevent recurrence.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS201-TPS201 ◽  
Author(s):  
John W Myers ◽  
Garth S Herbert ◽  
Guy T Clifton ◽  
Timothy J Vreeland ◽  
Tommy A Brown ◽  
...  
Keyword(s):  
Cell Wall ◽  
Dendritic Cells ◽  
High Risk ◽  
Yeast Cell ◽  
Yeast Cell Wall ◽  
Stage Iii ◽  
Autologous Tumor ◽  
Tumor Lysate ◽  
Risk Of Recurrence ◽  
Disease Free

TPS201 Background: Melanoma is a potentially lethal skin malignancy; patients with stage III/IV resected disease have a recurrence rate of 50-90%. Adjuvant checkpoint inhibitor immunotherapy decreases the risk of recurrence but also causes significant immune-related toxicity. Vaccines are a promising strategy for patients with high risk melanoma. The optimal time to intervene may be in the adjuvant setting after attaining a disease-free state through standard of care therapies. Our strategy uses autologous tumor lysate (TL) in a yeast cell wall particle (YCWP) to load dendritic cells (DC) ex vivo. The tumor lysate particle loaded dendritic cell (TLPLDC) vaccine is then given to prevent melanoma recurrences. An alternate vaccine delivery method that we are evaluating utilizes the tumor lysate particle-only (TLPO) technique, in which tumor lysate is loaded into capped YCWP and injected intradermally, allowing an in vivo uptake by the patient’s dendritic cells. Methods: We are performing a prospective, randomized, blinded, placebo-controlled phase IIb trial in patients with resected stage III/IV melanoma who have been rendered disease-free but remain at high risk of recurrence. The study will utilize the TLPLDC strategy vs placebo (2:1) in 120 patients, followed by a bridging study of TLPO vs TLPLDC (2:1) in 60 patients. Both TLPLDC and TLPO inoculations will be monthly x3, followed by boosters at 6, 12, and 18 months. Primary endpoints will be disease free survival (DFS) at 24 months in the TLPLDC arm, and overall safety in the TLPO arm. We have completed enrollment in the phase IIb portion of the study. Clinical trial information: NCT02301611.

Bevacizumab biosimilar and reference bevacizumab in subjects with stage IIIB/IV non-squamous non-small cell lung cancer (STELLA): Design of a confirmatory, double-blind, randomized, controlled study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20731-e20731 ◽  
Author(s):  
Yaroslav V. Shparyk ◽  
Igor Bondarenko ◽  
Alexandra Paravisini ◽  
Amalia Florez ◽  
Camino Huerga ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Small Cell Lung Cancer ◽  
Disease Progression ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Stage Iiib ◽  
Small Cell Lung ◽  
Double Blind ◽  
To Receive

e20731 Background: MB02 is a bevacizumab biosimilar developed to stringent guidelines, including non-clinical and preclinical investigations and a clinical trial as first-line treatment in metastatic colorectal cancer (Romera A et al. Lancet Gastroenterol Hepatol 2018;3 (12): 845-855). A clinical trial (STELLA) has been initiated to confirm there are no clinically meaningful differences between MB02 and reference bevacizumab (Avastin) in terms of efficacy, safety, and immunogenicity (NCT03296163). Methods: STELLA study is a multinational, double-blind, randomized, parallel-group, equivalence study comparing the efficacy and safety of MB02 vs reference bevacizumab plus chemotherapy in subjects with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC). Subjects aged 18-80 years, with ECOG status ≤1 and histologically confirmed NSCLC not receiving curative intent surgery or systemic therapy for advanced disease are randomized (1:1) to receive: chemotherapy (paclitaxel 200 mg/m2 and carboplatin AUC6) and either MB02 or reference bevacizumab 15 mg/kg every 3 weeks for up to 6 cycles (unless disease progression or treatment intolerance). Randomization is stratified by sex, smoking status, disease diagnosis (newly/recurrent), and stage. After 6 cycles, subjects can continue to receive MB02/reference bevacizumab in monotherapy every 3 weeks (until disease progression, treatment intolerance, death, withdrawal or end of study). The primary objective is to compare the objective response rate (ORR) between arms by week 18 (independently assessed) measured by RECIST v1.1. Progression free survival and overall survival (at 18 and 52 weeks), safety and immunogenicity will be assessed as secondary objectives. A sample size of 600 subjects was assumed providing about 89% power to show equivalence of MB02 plus chemotherapy with reference bevacizumab plus chemotherapy on a primary endpoint of risk ratio based on ORR. To date, 596 subjects have been recruited from more than 15 countries worldwide (Europe, Asia, Latin-America, Africa and Middle-East). At their last meeting in September, 2018 the independent data safety monitoring board (DSMB) recommended that the study continue without change. Clinical trial information: NCT03296163.

Crenolanib versus midostaurin combined with induction and consolidation chemotherapy in newly diagnosed FLT3 mutated AML.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7068-TPS7068 ◽  
Author(s):  
Richard M. Stone ◽  
Eunice S. Wang ◽  
Aaron David Goldberg ◽  
Kendra Lynn Sweet ◽  
Amir Tahmasb Fathi ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Phase 1 ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
Primary Analysis ◽  
Phase 3 ◽  
Free Survival ◽  
Flt3 Inhibitor ◽  
Tki Treatment ◽  
To Receive

TPS7068 Background: Despite the approval of multi-targeted protein kinase inhibitor midostaurin for use in combination with chemotherapy which improves 5-year survival in newly diagnosed (NDx) acute myeloid leukemia (AML) associated with FLT3 mutations; the cumulative incidence of relapse in FLT3 mutant AML remains high, with progression often characterized by secondary FLT3-TKD mutations. Crenolanib is a potent pan- FLT3 inhibitor that has shown promising efficacy and tolerability in combination with chemotherapy in Phase 1/2 trials for AML patients with FLT3-ITD or - TKD mutations. This is the first globally initiated, randomized Phase 3 trial comparing the efficacy of two FLT3-TKIs, crenolanib and midostaurin, combined with intensive chemotherapy in NDx FLT3-mutated AML patients. Methods: This Phase 3, randomized, multi-center trial will be conducted at multiple sites worldwide, with a target enrollment of 510 subjects. Patient inclusion was modified to match the midostaurin RATIFY criteria to enroll NDx FLT3-mutated AML (18 – 60 yo), who are eligible for intensive chemotherapy; with the addition of any FLT3-ITD and/or -TKD mutations being eligible. All subjects will receive TKI treatment and will be randomized in a 1:1 ratio to receive either crenolanib (arm A) or the active-control, midostaurin (arm B). All patients will be treated with 7+3 (100 mg/m2 IV cytarabine; 90 mg/m2 IV daunorubicin) and can initiate treatment while awaiting FLT3 results prior to randomization. Consolidation could include chemotherapy (3000 mg/m2 IV HiDAC) for up to 4 cycles and/or Allo-HSCT, depending on patient condition. During induction and consolidation patients on arm A will take crenolanib (100 mg TID) from d9 until 72h prior to the next cycle, and patients on arm B will take midostaurin (50 mg BID) on d8 to d21 of each cycle. Following consolidation or HSCT, patients may receive up to 12 months of FLT3-TKI maintenance. Maintenance efficacy will be evaluated over time using single-cell sequencing to assess MRD. Primary endpoint is event-free survival. Interim analyses will occur at approximately 178 and 267 events, and primary analysis at 356 events. Enrollment is underway as of January 31, 2019. Clinical trial information: NCT03258931.

Maximum tumor dimension and tumor volume as prognostic factors in patients with newly diagnosed localized Ewing sarcoma (ES)- a report from the Children’s Oncology Group (COG).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11529-11529
Author(s):  
Leo Mascarenhas ◽  
Allen Buxton ◽  
Steven G. DuBois ◽  
Dian Wang ◽  
Nadia N. Laack ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Prognostic Factors ◽  
Tumor Size ◽  
Tumor Volume ◽  
Cox Model ◽  
Rank Test ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Increased Risk ◽  
Significant Difference

11529 Background: Maximum tumor dimension > 8 cm. and large tumor volume have been reported to be adverse prognostic factors in patients with ES but have not been prospectively evaluated in the context of a phase 3 clinical trial with interval compressed chemotherapy. Methods: COG AEWS1031 (NCT01231906) was a randomized phase 3 clinical trial comparing interval compressed chemotherapy regimens in patients with newly diagnosed localized ES of bone and soft tissue. A correlative objective of AEWS1031 was to evaluate tumor size and volume as prognostic factors. Institution-reported dimensions of the primary tumor from baseline imaging were prospectively collected. For inclusion in this analysis, patients had to have at least 1 tumor dimension reported for tumor size analyses and dimensions in 3 axes for tumor volume analyses. Maximum dimension was dichotomized as less than vs. > / = 8cm. Tumor volume was dichotomized as less than vs. > / = 200 mL. Event-free (EFS) and overall survival (OS) from enrollment were calculated using Kaplan-Meier methods and compared between groups using a two-sided log-rank test. Hazard ratios (HR) and confidence intervals (CI) were calculated using the Cox model. Results: The 5-year EFS and OS of the 629 eligible patients was 78% (95% CI: 75-81%) and 87% (95% CI: 84-90%) respectively and there was no significant difference in both EFS and OS between the randomized interval compressed chemotherapy arms of AEWS1031. 590 of 629 (94%) patients were evaluable for maximum tumor dimension and 307 (52%) had tumors > / = 8 cm. Patients with tumors > / = 8 cm were at significantly increased risk for EFS events (p = 0.016) with estimated 5-year EFS of 73.7% (95% CI: 68.1 vs.78.4%) vs. 82.9% (95% CI 77.7-87.1%) for patients with tumors < 8 cm [HR: 1.53 (1.08-2.17)]. For tumor volume, 586 of 629 patients (93%) were evaluable and 180 (31%) had tumors > / = 200 mL. Patients with tumor volume > / = 200 mL were at significantly increased risk for EFS events (p = 0.003) with estimated 5-year EFS of 70% (95% CI: 62.3-76.4%) vs. 81.6% (95% CI: 77.2-85.2%) for patients with tumors < 200 mL [HR: 1.69 (1.2-2.39)]. Conclusions: Maximum tumor dimension and tumor volume as defined are both prognostic in patients with newly diagnosed localized ES treated with interval compressed chemotherapy. Clinical trial information: NCT01231906 .

scholarly journals Estimand Framework in AML Based on a Randomized, Placebo-Controlled, Phase 3 Study Investigating the Effect of Adding Midostaurin to Standard Chemotherapy in Patients with Newly Diagnosed AML without a FLT3 Mutation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5196-5196 ◽  
Author(s):  
Bourras-Rezki Bengoudifa ◽  
Hans Weber ◽  
Insa Gathmann ◽  
Albert Hoenekopp ◽  
Noah Berkowitz
Keyword(s):  
Induction Treatment ◽  
Newly Diagnosed ◽  
Standard Chemotherapy ◽  
Phase 3 ◽  
Scientific Question ◽  
Treatment Policy ◽  
Flt3 Mutation ◽  
Induction Failure ◽  
Definition Of ◽  
To Receive

Abstract In the ongoing randomized, placebo-controlled, phase 3 study in patients with newly diagnosed FLT3-mutation-negative acute myeloid leukemia (AML; NCT03512197) investigating the effect of adding midostaurin to standard chemotherapy, event-free survival (EFS) is the primary endpoint. EFS is a standard endpoint in clinical studies in AML. In a recent FDA submission, EFS was confirmed by an advisory committee to be clinically meaningful in AML (https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM570800.pdf. Accessed August 1, 2018). With the release of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E9 draft addendum, we describe EFS in the estimand framework to address the scientific question of interest and illustrate the power of this concept to transparently define the relevant population, the variable of interest, and the management of relevant incidents that can occur in a clinical trial ("intercurrent events"). The objective is to determine the benefit of adding midostaurin to the whole standard chemotherapy sequence, consisting of induction, consolidation therapy, hematopoietic stem cell transplant (HSCT; if applicable), and postconsolidation therapy, in patients with newly diagnosed AML without a FLT3 mutation. The main interest is the interventional effect of the whole treatment sequence and not the contribution of an individual part of it. The study population includes all randomized patients following the treatment policy approach. Patients can be randomized only if there is confirmation from the central laboratory that there is no FLT3 mutation. EFS is a composite endpoint defined as the time from randomization until death, relapse, or induction failure. Induction failure is defined as no achievement of remission until end of the induction period. The definition of induction failure also includes instances in which HSCT is conducted as salvage therapy in nonresponding patients. Per convention, the EFS event date of induction failure is set to the randomization date. The option to receive HSCT can be an outcome of the treatment. Therefore, clinical benefit is assessed regardless of whether patients received HSCT. This treatment policy approach mandates collection of disease assessments after HSCT has been completed. In the same consideration, the option to receive consolidation and postconsolidation treatment is also an outcome of the induction treatment as only patients achieving remission with induction qualify to continue with consolidation and postconsolidation treatment. As such, the benefit is assessed regardless of treatment duration. The analysis plan defines a supportive estimand to assess the treatment effect of midostaurin, excluding potential benefit from HSCT. Another supportive estimand assesses the effect of discontinuation of induction treatment due to toxicities. This approach addresses a hypothetical scenario in which patients did not receive HSCT, for instance, to estimate the midostaurin-only effect. However, the outcome of the treatment is not limited to the direct effect of an experimental compound but also includes which new treatment option the compound allows for the patients (eg, HSCT). The estimand framework is an efficient tool to ensure consistency between the scientific question and the definition of the study objectives. It ensures transparency in unfavorable yet unavoidable situations in clinical trials ("intercurrent events"). It facilitates communication within the clinical team and with health authorities. The outcome of studies that are following the estimand framework can be interpreted in a consistent manner. Disclosures Bengoudifa: Novartis: Employment. Weber:Novartis: Employment. Gathmann:Novartis: Employment. Hoenekopp:Novartis: Employment. Berkowitz:Novartis: Employment.

Sign in / Sign up

Export Citation Format

Share Document