- Anastasios Stathis (Bellinzona, Switzerland)
- Stefan S. Bielack (Stuttgart, Germany)
1065O - Interim evaluation of a targeted radiotherapeutic, CLR 131, in relapsed/refractory diffuse large B-cell lymphoma patients (R/R DLBCL) (ID 5797)
- Jarrod Longcor (Florham Park, United States of America)
Abstract
Background
Forty to fifty percent of newly diagnosed DLBCL patients will relapse and another 10% will be refractory to initial therapy. Despite the introduction of new therapies, outcomes for patients with R/R DLBCL remain poor with no improvement in progression free survival (PFS), overall survival (OS) or response rates (ORR). Patients receiving 1 additional line of treatment have an OS of ∼13 months post relapse and for those requiring 3rd line treatment or more, only 10% survive for 12 months. CLR 131 is a novel therapeutic being evaluated in R/R DLBCL. CLR 131 leverages a novel delivery mechanism that takes advantage of a metabolic shift in tumor cells to allow the targeted delivery of I-131 directly into tumour cells.
Methods
A multi-center study is being conducted to evaluate the safety and efficacy of CLR 131 in patients with R/R DLBCL. An interim assessment was conducted to determine cohort expansion and continued enrollment of up to 40 additional patients. The criteria for expansion was a minimum 20% of patients experience clinical benefit (CBR) or better. Patients in this assessment received a single 25mCi/m2 30-minute infusion of the targeted radiotherapeutic CLR 131 on day 0. Patients were then followed until disease progression. The primary endpoint is CBR. Secondary endpoints included ORR, PFS and OS.
Results
Six R/R DLBCL patients having received an average of 3 prior lines of therapy received a single infusion of CLR 131. Overall 3/6 patients achieved CBR, 1 patient experienced a complete response (CR) with a total reduction in tumor volume of greater than 99% and continues to be a CR at nearly 8 months post dosing. One patient with cutaneous R/R DLBCL achieved a partial response (PR) with a 56% reduction in total tumor volume and 1 achieved stable disease. The average duration of response was ∼5 months and continues to be monitored. PFS and OS have not been reached at the time of submission.
Conclusions
In this interim evaluation of CLR 131 in R/R DLBCL patients, significant and durable responses were exhibited, including a 33% ORR, 15% CR and 50% CBR. Patients experienced durable responses (assessment continues). Larger, prospective trials are needed to elucidate optimal patient and dosing schedule of CLR 131 in these patients.
Clinical trial identification
NCT02952508.
Legal entity responsible for the study
Cellectar Biosciences, Inc.
Funding
National Institutes of Health, National Cancer Institute.
Disclosure
J. Longcor: Full / Part-time employment: Cellectar Biosciences, Inc. K. Oliver: Full / Part-time employment: Cellectar Biosciences Inc. J. Friend: Full / Part-time employment, Formerly: Cellectar Biosciences Inc. All other authors have declared no conflicts of interest.
1066O - Polo-like kinase 1 (PLK1) inhibitor, onvansertib, in combination with low-dose cytarabine or decitabine in patients with relapsed/refractory acute myeloid leukaemia in phase Ib (ID 2411)
- Amer Zeidan (New Haven, United States of America)
Abstract
Background
Polo-like Kinase 1 (PLK1) is a serine/threonine kinase and master regulator of G2/M cell-cycle progression. Inhibition of PLK1 causes mitotic arrest and cell death. Onvansertib is an orally active, highly selective PLK1 inhibitor with demonstrated safety and tolerability (phase 1, solid tumors) and demonstrates activity in preclinical AML models as a single agent and in combination with cytarabine. Previous studies indicate the phosphorylation status of TCTP (pTCTP), a direct substrate for phosphorylation by PLK1, is a biomarker for PLK1 inhibition by onvansertib.
Methods
R/R AML patients are treated with onvansertib for 5 days in combination with LDAC or decitabine within 21 to 28-day cycle. Dose escalation is 50% increments with dose limiting toxicity (DLT) evaluated at cycle 1 end. For correlative studies, blood samples were collected on day 1 before (0h) and 3h after treatment and % pTCTP (pTCTP/TCTP) was quantified. Positive target engagement was defined as ≥ 50% decrease in pTCTP/TCTP in 0h vs 3h post-dosing. RNA transcriptome analysis of circulating blasts followed by gene set enrichment analysis (GSEA) was compared between patients with target engagement (TE) vs no target engagement (NTE) pre- and post-dosing (t = 0, 3, 24h).
Results
As of April 1, 2019, 24 pts have completed 1 cycle and in both 1b arms with onvansertib dose escalated from 12, 18, 27, 40 to ongoing 60mg/m2. No DLTs in either arm to-date. For decitabine arm (n = 12), 2 CR’s and 1 CRi observed from 6 evaluable pts in the two highest doses (27 and 40 mg/m2). For LDAC arm, 1 CR observed from 3 evaluable pts in highest dose (40 mg/m2). For pTCTP status, 9 out of the 22 evaluable patients (41%) showed a decrease of ≥ 50% in % pTCTP at 3h post-dose with 5 of 9 having ≥50% decrease in BM blasts; TE was observed in all CR/CRi’s from both arms. GSEA analysis of TE vs NTE indicated an existing upregulation of MYC targets in TE pre-dose which decreased within TE patients 3h/24h post-dosing.
Conclusions
Dose escalation phase of study to-date demonstrates safety, tolerability and anti-leukaemic activity at higher doses that is significantly correlated with pTCTP biomarker status.
Clinical trial identification
NCT03303339.
Legal entity responsible for the study
Trovagene, Inc.
Funding
Trovagene Oncology.
Disclosure
M. Erlander: Full / Part-time employment: Trovagene. All other authors have declared no conflicts of interest.
Invited Discussant 1065O and 1066O (ID 6775)
- Anastasios Stathis (Bellinzona, Switzerland)
LBA64 - Bevacizumab for children with relapsed & refractory high-risk neuroblastoma (RR-HRNB): Results of the BEACON-neuroblastoma randomized phase II trial - A European ITCC-SIOPEN trial (ID 4267)
- Lucas Moreno (Barcelona, Spain)
Abstract
Background
BEACON-Neuroblastoma is a randomized phase II trial to assess the activity of backbone chemotherapy regimens for children with RR-HRNB and to determine if inhibiting angiogenesis with bevacizumab adds to the activity of this chemotherapy.
Methods
Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomized in a factorial design to: temozolomide (T) versus irinotecan-temozolomide (IT) or topotecan-temozolomide (TTo), with or without bevacizumab (Bev). The Bev randomization (Bev versus no-Bev) had two parts: Part 1 had a 2-stage Minimax Jung design with overall response (OR) as primary endpoint. Part 1 success criterion was ≥4 more responses in Bev arm compared to no-Bev. Protocol was amended to incorporate Part 2 (40 additional patients), including progression-free survival (PFS) as co-primary endpoint. OR was defined as complete or partial response (CR, PR) by RECIST (INRC for patients without measurable disease). OR and toxicity data for the Bev randomization is reported.
Results
For Part 1 (n = 106), 17 of 52 pts on Bev had responses [33%] and 8 of 54 pts on no-Bev had responses [15%]. The trial success criterion for the primary endpoint of ORR was met. Including Part 2 (total n = 154), 21 of 77 patients on Bev (7CR, 14PR) and 13 of 77 patients on no-Bev (1CR, 12PR) had responses. Response data was not available for 6 patients; 13 patients not assessable for response (discontinued before first assessment) were considered to be non-responders. OR rate [with 90% CI] was 27% [18-35%] for patients on Bev and 17% [10-24%] for patients on no-Bev. In subgroup analysis, there was no interaction between T, IT and TTo and treatment with/without Bev (heterogeneity test, p = 0.8). 86% Bev and 58% no-Bev patients had grade ≥3 toxicities as per CTCAE v4.0; the most common grade ≥3 toxicities associated with Bev were platelet count decrease and anemia.
Conclusions
Bev reached the Phase II success criterion for OR within Part 1 of the trial when added to temozolomide-based chemotherapy in RR-HRNB. The toxicity profile for Bev is acceptable. Longer follow-up is needed before assessing whether it impacts PFS or overall survival.
Clinical trial identification
NCT02308527; EudraCT: 2012-000072-42.
Legal entity responsible for the study
University of Birmingham.
Funding
Roche.
Disclosure
L. Moreno: Honoraria (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Mundipharma; Licensing / Royalties, I am member of Siopen Executive Committee, Siopen receives royalties for the sales of dinutuximab beta: Eusa Pharma. D. Valteau-Couanet: Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties, Member of Siopen Executive Committee, SIOPEN receives royalties for the sales of dinutuximab beta: Eusa Pharma; Research grant / Funding (institution): Ophelia; Travel / Accommodation / Expenses: Jazz Pharma. K. Nysom: Advisory / Consultancy: Bayer. N. Gerber: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Novartis. R. Ladenstein: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Royalties to the institution for dinutuximab beta: Apeiron; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Royalties to the institution for dinutuximab beta: Eusa Pharma; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. A.D. Pearson: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Genentech. All other authors have declared no conflicts of interest.
1067O - The influence of TDM on achieving busulfan target exposure and related determinants, in both children and adults who underwent an allogeneic hematopoietic cell transplantation (ID 3030)
- Jill Boss (Harderwijk, Netherlands)
Abstract
Background
Busulfan is widely used as conditioning in allogeneic haematopoietic cell transplantation (allo-HCT) and has a narrow therapeutic range (80-100 mg*hr/L). Primary objective was to examine the effect of therapeutic drug monitoring (TDM) on attaining busulfan target exposure in children and adults undergoing allo-HCT. Secondarily, we studied potential predictors for within-person variability in busulfan clearance.
Methods
All children and adults who underwent allo-HCT with intravenous busulfan were prospectively included (July 2011 – July 2016, UMC Utrecht, NL). Busulfan was administered once daily on four consecutive days and drug levels were measured on days 1 and 4. Cumulative exposure (cAUC) and clearance were estimated using a population model. cAUCs were compared between (1) without TDM (hypothetical, e.g. four times AUC-day1), (2) actual TDM (fixed clearance over time), and (3) TDM with an adapted PK model (taking into account age and temporal changes in busulfan clearance). Potential determinants of clearance alterations were modeled using linear regression.
Results
In the total patient population (n = 239), substantially more patients attained their busulfan target (76.2%) with TDM (adapted PK model) as compared to when no TDM would have been performed (49.8%, rate ratio 1.53, 95% confidence interval 1.21-1.93). Moreover, TDM resulted into a significantly lower variation in cAUC (-41%, p < 0.001). Age (p < 0.001) and use of paracetamol (p = 0.025) and anticonvulsants (p = 0.044) were identified as independent predictors for decline in busulfan clearance over time.
Conclusions
TDM is of added value in preventing severe under and over exposure of busulfan in patients undergoing allo-HCT. We strongly advocate the use of PK model aided TDM anticipating a decrease in busulfan clearance. This particularly applies to adults and individuals taking paracetamol or anticonvulsants, given the more pronounced decline in busulfan clearance observed in this subset of patients.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant LBA64 and 1067O (ID 6776)
- Stefan S. Bielack (Stuttgart, Germany)