- Email: [email protected]
refractory acute myeloid leukaemia in phase Ib
Annals of Oncology 30 (Supplement 5): v435–v448, 2019 doi:10.1093/annonc/mdz251
HAEMATOLOGICAL MALIGNANCIES Interim evaluation of a targeted radiotherapeutic, CLR 131, in relapsed/refractory diffuse large B-cell lymphoma patients (R/R DLBCL)
J. Longcor1, K. Oliver1, J. Friend1, N. Callandar1 Clinical, Cellectar Biosciences, Inc, Florham Park, NJ, USA, 3Medicine, University of Wisconsin Madison, Madison, WI, USA
1
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.
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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
A. Zeidan1, P. Becker2, P. Patel3, G. Schiller4, M.L. Tsai5, T. Lin6, E. Wang7, M. Erlander8, J. Cortes9 1 Hematology, Yale University Hospital, New Haven, CT, USA, 2Hematology, Seattle Cancer Care Alliance, Seattle, WA, USA, 3Hematology, UT Southwestern, Dallas, TX, USA, 4 Division of Hematology-Oncology, David Geffen School of Medicine, Los Angeles, CA, USA, 5Minnesota Oncology, Minneapolis Clinic, Minneapolis, MN, USA, 6Hematology, University of Kansas Cancer Center, Kansas City, KS, USA, 7Hematology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA, 8Research & Development, Trovagene, San Diego, CA, USA, 9Hematology, MD Anderson Cancer Center, Houston, TX, USA 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 postdosing (t ¼ 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 ¼ 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.
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The influence of TDM on achieving busulfan target exposure and related determinants, in both children and adults who underwent an allogeneic hematopoietic cell transplantation
J. Boss1, J. Langenhorst2, A. Lalmohamed2, P. van der Linden3, J.J. Boelens4, E. Van Maarseveen2 1 Clinical Pharmacy, St. Jansdal Ziekenhuis, Harderwijk, Netherlands, 2Clinical Pharmacy, UMC Utrecht, Utrecht, Netherlands, 3Clinical Pharmacy, Tergooi Ziekenhuis, Hilversum, Netherlands, 4Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, USA 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 ¼ 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 ¼ 0.025) and anticonvulsants (p ¼ 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.
C European Society for Medical Oncology 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V
All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz251.001/5577770 by North-West University user on 26 October 2019
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HAEMATOLOGICAL MALIGNANCIES Interim evaluation of a targeted radiotherapeutic, CLR 131, in relapsed/refractory diffuse large B-cell lymphoma patients (R/R DLBCL)
J. Longcor1, K. Oliver1, J. Friend1, N. Callandar1 Clinical, Cellectar Biosciences, Inc, Florham Park, NJ, USA, 3Medicine, University of Wisconsin Madison, Madison, WI, USA
1
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.
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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
A. Zeidan1, P. Becker2, P. Patel3, G. Schiller4, M.L. Tsai5, T. Lin6, E. Wang7, M. Erlander8, J. Cortes9 1 Hematology, Yale University Hospital, New Haven, CT, USA, 2Hematology, Seattle Cancer Care Alliance, Seattle, WA, USA, 3Hematology, UT Southwestern, Dallas, TX, USA, 4 Division of Hematology-Oncology, David Geffen School of Medicine, Los Angeles, CA, USA, 5Minnesota Oncology, Minneapolis Clinic, Minneapolis, MN, USA, 6Hematology, University of Kansas Cancer Center, Kansas City, KS, USA, 7Hematology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA, 8Research & Development, Trovagene, San Diego, CA, USA, 9Hematology, MD Anderson Cancer Center, Houston, TX, USA 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 postdosing (t ¼ 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 ¼ 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.
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The influence of TDM on achieving busulfan target exposure and related determinants, in both children and adults who underwent an allogeneic hematopoietic cell transplantation
J. Boss1, J. Langenhorst2, A. Lalmohamed2, P. van der Linden3, J.J. Boelens4, E. Van Maarseveen2 1 Clinical Pharmacy, St. Jansdal Ziekenhuis, Harderwijk, Netherlands, 2Clinical Pharmacy, UMC Utrecht, Utrecht, Netherlands, 3Clinical Pharmacy, Tergooi Ziekenhuis, Hilversum, Netherlands, 4Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, USA 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 ¼ 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 ¼ 0.025) and anticonvulsants (p ¼ 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.
C European Society for Medical Oncology 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V
All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz251.001/5577770 by North-West University user on 26 October 2019
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