Effectiveness of Darbepoetin alfa Administered Every 3 Weeks on Clinical Outcomes in Patients with Hematologic Malignancies and Chemotherapy-Induced Anemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3767-3767 ◽  
Author(s):  
Ralph Vincent Boccia ◽  
Peter T. Silberstein ◽  
Simon Tchekmedyian ◽  
Dianne Tomita ◽  
Greg Rossi ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Darbepoetin Alfa ◽  
Hematologic Malignancy ◽  
Hematologic Malignancies ◽  
Target Range ◽  
Tumor Type ◽  
Open Label ◽  
Serious Adverse Events ◽  
The Mean ◽  
Tumor Types

Abstract Patients (pts) with cancer receiving chemotherapy commonly have chemotherapy-induced anemia (CIA), often resulting in reduced quality of life. The primary objective of this analysis was to summarize the effectiveness of darbepoetin alfa (DA) administered at 300mcg every 3 weeks (Q3W), in achieving and maintaining a hemoglobin (Hb) target range of 11–13g/dL in pts with hematologic malignancies and CIA, versus pts with solid tumors and CIA. Data for all 1493 pts enrolled in this multicenter, open-label, 16-week study who received at least one dose of DA are included in this exploratory analysis stratified by tumor type. Pts ≥18 years of age receiving multicycle chemotherapy and with Hb <11g/dL were eligible for this study. Hb-based endpoints were adjusted for red blood cell transfusions and analyzed with and without imputing missing Hb values. Pt-reported outcomes were assessed using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scale. Most pts were white (79%), 61% were female, and the median age was 64 years (range, 19 to 97). At baseline (BL), 31% of pts had Hb <10g/dL and 61% had Hb ≥10g/dL; the mean (SD) was 10.1 (0.7)g/dL. Hematologic malignancy (14%) was the third most common tumor type after breast (29%) and gastrointestinal (24%); 45% of the hematologic malignancies were non-Hodgkin’s lymphoma (NHL) pts. Hb, transfusion, and FACT-F endpoints are shown in the table. A slightly lower percent of NHL pts achieved the Hb target range recommended by current guidelines (11–13g/dL), compared to pts with other hematologic malignancies or with solid tumors. Similar proportions of pts with hematologic malignancies or solid tumors maintained Hb within the target range. The proportion of pts receiving RBC transfusions from week 5 to the end of study (EOS) was similar for pts with hematologic malignancies and for pts with solid tumors. Improvements in FACT-F scores were seen in all groups, although the mean change was lower in NHL pts compared with other tumor types. Serious adverse events were as expected for this patient population. DA Q3W appears to be effective in achieving and maintaining Hb between 11 to 13g/dL in pts with CIA and hematologic malignancies. Since chemotherapy is often administered Q3W, synchronizing DA treatment with pts’ chemotherapy schedules may simplify the treatment of CIA in these pts. Hematologic - NHL N=98 Hematologic - non-NHL N=118 Solid N=1277 All Tumor Types N=1493 *For pts who achieved target. **For pts available at day 29. K-M=Kaplan Meier. CL=confidence limits Mean (95%CL) BL Hb (g/dL) 10.1 (9.9, 10.2) 10.0 (9.8, 10.1) 10.1 (10.1, 10.2) 10.1 (10.1, 10.2) Pts who achieved ≥ Hb 11g/dL. Crude % (95% CL) 74 (66, 83) 82 (75, 89) 79 (77, 81) 79 (77, 81) Proportion of pts maintaining Hb between 11 and 13g/dL after achieving target - n (%)* 51 (70) 68 (70) 739 (73) 858 (73) Time to target Hb (weeks). K-M Median (95% CL) 7 (6, 8) 6 (4, 7) 4 (4, 5) 4 (4, 5) Transfusions from week 5 to EOS. Crude % (95% CL)** 21 (13, 30) 20 (13, 27) 18 (16, 20) 18 (16, 20) Mean change in FACT-F from BL to week 16 (95% CL) 2.8 (−0.9, 6.5) 5.2 (1.8, 8.6) 4.8 (3.9, 5.7) 4.7 (3.9, 5.6)

BET inhibitor molibresib for the treatment of advanced solid tumors: Final results from an open-label phase I/II study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3618-3618 ◽  
Author(s):  
Sophie Cousin ◽  
Jean-Yves Blay ◽  
Irene Braña Garcia ◽  
Johann S. De Bono ◽  
Christophe Le Tourneau ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Treatment Discontinuation ◽  
Tolerability Profile ◽  
Repeat Dose ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Total Cohort ◽  
Tumor Types

3618 Background: Molibresib is an orally available, small molecule bromodomain and extra-terminal domain (BET) protein inhibitor under investigation for treatment of advanced solid tumors. Methods: This was an open-label, single- and repeat-dose, 2-part, Phase 1/2 study including patients (aged ≥16 years) with advanced solid tumors. Part 1: patients received different oral doses of molibresib (2–100mg QD; amorphous free-base formulation) to determine recommended Phase 2 dose. Part 2 (expansion cohort): patients with various tumor types received the bioequivalent besylate formulation (75mg) to explore clinical activity at recommended dose. Safety and efficacy (response rate [RR] based on RECIST 1.1 criteria, progression-free survival [PFS], and overall survival [OS]) were evaluated for the total cohort (patients from Part 1 and 2). Safety, pharmacokinetic, pharmacodynamic, and efficacy per tumor type were evaluated in Part 2. Results: Part 1 only data have previously been reported. Overall, 196 patients were included in the total cohort (1 patient in Part 1 was counted twice). In the all treated population, 195 patients (median age 58 years; 46% male) received ≥1 dose of molibresib (Part 1: n = 93; Part 2: n = 102). Adverse events (AEs) were experienced by 193/196 (98%) patients; 180/196 (92%) had a treatment-related AE (TRAE). AEs led to permanent treatment discontinuation in 38/196 (19%) patients. Of different tumor types in Part 2, NUT carcinoma (NC) had the lowest frequency of TRAEs (10/12 [83%]) and AEs leading to permanent treatment discontinuation (1/12 [8%]). In total cohort, 3/31 NC patients and 1/35 with castration-resistant prostate cancer (CRPC) achieved a confirmed partial response. A further 67/196 (34%) achieved stable disease (SD). In Part 2, RR in 12 NC patients was 8% (CI: 0.2–38.5); 50% had SD and median PFS was 4.8 months with median OS of 5.0 months. In CRPC patients, RR was 4% (CI: 0.1–21.9); 22% had SD; median PFS was 8.0 months with median OS of 9.1 months. Plasma concentrations for molibresib and active metabolites were similar between different tumor types. Gene expression analysis from pre- and post-dose biopsy samples collected from 10 mCRPC patients showed transcriptional downregulation of Myc target genes upon treatment with molibresib. Conclusions: Molibresib demonstrated a manageable safety and tolerability profile with single agent activity observed in selected patients with NC and CRPC. Clinical trial information: NCT01587703 .

scholarly journals ETV6-NTRK3 is Associated With Trisomy 8 and Sensitive to TRK Inhibitor in Hematologic Malignancy: Case Report of a Refractory AML and Review of the Literature

2021 ◽  
Author(s):  
Ling Zhang ◽  
Lijun Wen ◽  
Zheng Wang ◽  
Zhao Zeng ◽  
Yi Xu ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Hematologic Malignancy ◽  
Low Frequency ◽  
Chromosomal Translocation ◽  
Fusion Transcript ◽  
Hematologic Malignancies ◽  
Tumor Type ◽  
Trisomy 8 ◽  
Genetic Features ◽  
Genetic Aberration

Abstract Background: The ETV6-NTRK3 fusion transcript has been found to recurrently identified in both solid tumors and leukemias. It has attracted a lot of interest for the clinical targeted therapy and genetic features in ETV6-NTRK3 positive solid tumors. While the t(12;15)(p13;q25)/ETV6-NTRK3 is a rare genetic aberration in hematologic malignancies at a low frequency of ≤1%. An accumulation of reported cases would be needed to discuss clinical and cytogenetic characteristics of the important entity. Therefore, it is useful to report every case for clinical implication of prognosis or therapy. Case presentation: We report the case of a previously healthy 30-year-old female, who was diagnosed as acute myeloid leukemia (AML) and presented with chemoresistance and short survival. The patient was treated with four cycles of chemotherapy but failed to achieve remission. Then the patient underwent a salvage haploidentical stem cell transplantation. Unfortunately, she worsened within 1 month and died of the refractory leukemia 35 days after transplantation. ETV6-NTRK3 rearrangement was revealed by RNA sequencing but the chromosomal translocation t(12;15)(p13;q25) was cryptic by conventional karyotype analysis. We review the literature and find that the ETV6-NTRK3 fusion transcript is associated with cryptic karyotype, trisomy 8, aggressive and poor prognosis in hematologic malignancy. The clinical and laboratory characteristics of ETV6-NTRK3 positive hematologic malignancies are different from those of solid tumors. Nevertheless, tropomyosin receptor kinase (TRK) inhibitor has powerful anti-tumor activity in patients with TRK fusion–driven cancers, regardless of the tumor type. Conclusions: We demonstrated that TRK inhibitor larotrectinib is an effective treatment on the primary bone marrow (BM) cells derived from the patient described here with ETV6-NTRK3 positive AML. Our report stresses the importance of screening for ETV6-NTRK3 fusion transcript in newly diagnosed leukemias and clinical treatment of TRK inhibitor in hematologic malignancies.

scholarly journals Molidustat for the treatment of renal anaemia in patients with non-dialysis-dependent chronic kidney disease: design and rationale of two phase III studies

BMJ Open ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. e026704 ◽  
Author(s):  
Hiroyasu Yamamoto ◽  
Megumi Taguchi ◽  
Yoshimi Matsuda ◽  
Kazuma Iekushi ◽  
Takashi Yamada ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Darbepoetin Alfa ◽  
Phase Iii ◽  
Target Range ◽  
Renal Anaemia ◽  
Current Standard ◽  
Open Label ◽  
Link Type ◽  
The Mean

IntroductionAnaemia is a common complication of chronic kidney disease (CKD). Owing to the limitations of erythropoiesis-stimulating agents (ESAs), the current standard of care, there is a need to develop new therapies. Hypoxia-inducible factor prolyl-hydroxylase (HIF-PH) inhibitors might be a promising new treatment option. Molidustat is an oral HIF-PH inhibitor that stimulates the endogenous, predominantly renal, production of erythropoietin and was generally well tolerated in phase IIb clinical trials. Here, we report the design and rationale of two studies from the molidustat phase III programme: MolIdustat once dailY improves renal Anaemia By Inducing erythropoietin (MIYABI).Methods and analysisMIYABI Non-Dialysis-Correction (ND-C) and MIYABI Non-Dialysis-Maintenance (ND-M) are randomised, open-label, parallel-group, multicentre studies that aim to demonstrate the efficacy of molidustat treatment compared with darbepoetin alfa in patients with anaemia and non-dialysis-dependent CKD. The secondary objectives are to assess the safety, pharmacokinetics and pharmacodynamics of molidustat treatment. MIYABI ND-C will recruit patients currently untreated with ESAs, whereas patients treated with an ESA will enter MIYABI ND-M. Each study will recruit 150 patients who will be randomised in a 1:1 ratio to receive either molidustat or darbepoetin alfa for 52 weeks, with efficacy evaluated during weeks 30–36. Study drug doses will be titrated regularly using an interactive voice/web response system with the aim of maintaining the patients’ haemoglobin (Hb) levels between ≥110 and <130 g/L. The primary objective will be achieved if, in molidustat-treated patients, the mean Hb level remains within the target range during the evaluation period, and if the change in the mean Hb level at evaluation time points from baseline is non-inferior to darbepoetin alfa.Ethics and disseminationThe protocols were approved by ethics committees at all participating sites. These studies will be conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. Results arising from these studies will be published in peer-reviewed journal(s).Trial registration numbersNCT03350321; Pre-results,NCT03350347; Pre-results.

A randomized open-label study of darbepoetin alfa administered every 3 weeks with or without parenteral iron in anemic subjects with nonmyeloid malignancies receiving chemotherapy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8612-8612 ◽  
Author(s):  
A. Vandebroek ◽  
B. Gaede ◽  
S. Altintas ◽  
K. Smith ◽  
B. Yao ◽  
...  
Keyword(s):  
Adverse Events ◽  
Darbepoetin Alfa ◽  
Interim Analysis ◽  
Oral Iron ◽  
Tumor Type ◽  
Open Label ◽  
Serious Adverse Events ◽  
Efficacy Analysis ◽  
Iron Administration ◽  
Iv Iron

8612 Background: Patients (pts) with cancer receiving chemotherapy often have chemotherapy-induced anemia (CIA) and reduced quality of life. Darbepoetin alfa (DA) is an erythropoiesis-stimulating agent (ESA) that can effectively treat CIA when administered once every 3 weeks (Q3W). In patients with CIA, limited data in the literature suggest that administration of intravenous (IV) iron with ESA therapy may increase clinical response. Methods: This randomized, multicenter, open-label, 16-week study evaluated the safety and efficacy of DA 500 mcg administered Q3W using the SureClick injection device in pts with CIA (Hb < 11 g/dL) who received either IV iron or standard practice for iron administration (oral iron or no iron). The dose of IV iron was 200 mcg administered either Q3W with DA Q3W or, if required, as 2 doses (200 mcg total) within a 3-week period. Pts who received ≥ 1 dose of DA and who completed the 16-week study period by October 19, 2005 are included in this interim analysis (planned sample size = 400 pts). Accrual will have finished by conference time. Randomization was stratified by tumor type and baseline (BL) Hb (< 10 or ≥ 10 g/dL). The incidence of adverse events and serious adverse events, in particular embolic/thrombotic events, was summarized. Efficacy endpoints were estimated using the crude % of pts (95% CI). Hb values within 28 days of a transfusion were not included in any efficacy analysis. Results: Of the 114 pts included in this interim analysis, 65% were women, 99% were Caucasian, the mean (SD) age was 60 years (12), and 26% had lung or gynecological tumors; study endpoints are shown in the table. Conclusions: Based on the interim results, the safety profile for pts receiving DA 500 mcg Q3W with IV iron appears to be comparable to pts receiving DA 500 mcg Q3W with oral iron or no iron. The % pts who achieved the target Hb (≥ 11 g/dL) appeared higher, and the % pts who required transfusions appeared lower, in the group receiving IV iron. [Table: see text] [Table: see text]

MO539HEMATOLOGIC EFFICACY OF VADADUSTAT FOR ANEMIA IN PATIENTS WITH KIDNEY FAILURE ON DIALYSIS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Wolfgang Winkelmayer ◽  
James A Tumlin ◽  
Steven Fishbane ◽  
Youssef Farag ◽  
Dennis Vargo ◽  
...  
Keyword(s):  
Darbepoetin Alfa ◽  
Reticulocyte Count ◽  
Hypoxia Inducible Factor ◽  
The United States ◽  
Target Range ◽  
Cardiovascular Safety ◽  
Open Label ◽  
Phase 3 ◽  
Evaluation Period ◽  
Safety Outcome

Abstract Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase being developed for treatment of anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two of the four phase 3, randomized, open-label, sponsor-blind trials (the INNO2VATE trials) in adult patients with dialysis-dependent (DD) CKD and anemia, where vadadustat met prespecified noninferiority criteria compared with darbepoetin alfa with respect to cardiovascular safety and correction/maintenance of hemoglobin (Hb) target concentrations. Method The mean screening Hb range for the incident DD-CKD trial (NCT02865850) was 8.0-11.0 g/dL; for the prevalent DD-CKD trial (NCT02892149), it was 8.0-11.0 g/dL in the United States (US) and 9.0-12.0 g/dL for non-US. Patients in the incident and prevalent DD-CKD trials had initiated dialysis within &lt;16 weeks with limited or no prior ESA exposure and &gt;12 weeks with established ESA treatment prior to screening, respectively. Vadadustat starting dose was 300 mg/day for all patients, whereas initial darbepoetin alfa dose depended on each patient’s prior dose or product label. Both vadadustat and darbepoetin alfa doses were titrated according to prespecified dosing algorithms to achieve target Hb concentrations (US: 10-11 g/dL; non-US: 10-12 g/dL) during the primary evaluation period (PEP; weeks 24-36) and the secondary evaluation period (SEP; weeks 40-52). Herein, we present topline results from PEP and SEP endpoints, as well as other, more detailed hematologic erythrocyte parameters. Results A total of 3923 patients (369 with incident DD-CKD and 3554 with prevalent DD-CKD) were randomized 1:1 to vadadustat or darbepoetin alfa. Vadadustat was noninferior to darbepoetin alfa in achieving target-range Hb concentrations (primary efficacy endpoint) among patients who were new to, or established on, dialysis. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 43.6% versus 56.9% and 39.8% versus 41.0% in the incident trial and 49.2% versus 53.2% and 44.3% versus 50.9% in the prevalent dialysis trial. The proportion of patients who achieved an Hb increase &gt;1.0 g/dL from baseline to week 52 was assessed only for the incident trial and was 84.0% (95% CI: 77.8%, 89.0%) for vadadustat versus 89.9% (95% CI: 84.7%, 93.8%) for darbepoetin alfa. Hematologic erythrocyte parameters at time points within the PEP and SEP are presented in Table 1. In the incident trial, reticulocyte count was slightly increased from baseline at 28 and 52 weeks for vadadustat, whereas for darbepoetin alfa, reticulocyte count was slightly decreased or unchanged in both trials. Erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb showed increases by week 52 for both groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of anemia associated with CKD in adults in both incident dialysis and prevalent dialysis settings.

scholarly journals Effect of Patiromer in Hyperkalemic Patients Taking and Not Taking RAAS Inhibitors

2018 ◽  
Vol 23 (6) ◽  
pp. 524-531 ◽  
Author(s):  
Robert A. Kloner ◽  
Coleman Gross ◽  
Jinwei Yuan ◽  
Ansgar Conrad ◽  
Pablo E. Pergola
Keyword(s):  
Adverse Events ◽  
Serum Potassium ◽  
Common Adverse Event ◽  
Open Label ◽  
Serious Adverse Events ◽  
End Point ◽  
The Mean ◽  
Baseline Characteristics ◽  
Raas Inhibitors ◽  
Post Hoc

Introduction: Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin–angiotensin–aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi. Methods: Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi. Results: Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was −0.67 (0.08) mEq/L in patients taking RAASi and −0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer. Conclusions: Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.

Antitumor activity of dostarlimab in patients with mismatch repair-deficient/microsatellite instability–high tumors: A combined analysis of two cohorts in the GARNET study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2564-2564
Author(s):  
Dominique Berton ◽  
Susana N. Banerjee ◽  
Giuseppe Curigliano ◽  
Sara Cresta ◽  
Hendrik-Tobias Arkenau ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Low Grade ◽  
Open Label ◽  
Tumor Types

2564 Background: Dostarlimab is an investigational, humanized programmed death 1 (PD-1) receptor monoclonal antibody that blocks interaction with the PD-1 ligands, PD-L1 and PD-L2. GARNET (NCT02715284) is a phase 1 study assessing the antitumor activity and safety of dostarlimab monotherapy in patients with solid tumors. Methods: This multicenter, open-label, single-arm study is being conducted in 2 parts: dose escalation and expansion. Here we report on the 2 expansion cohorts that enrolled mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) patients. Cohort A1 enrolled patients with advanced or recurrent dMMR/MSI-H endometrial cancer (EC), and cohort F enrolled patients with advanced or recurrent dMMR/MSI-H or POLε-hypermutated non-EC solid tumors, mainly gastrointestinal (GI) tumors (99 [93.4%] had GI tumors, including 69 [65.1%] with colorectal cancer). Patients received 500 mg IV of dostarlimab every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks until disease progression or discontinuation. The primary endpoints were objective response rate (ORR) and duration of response (DOR) by RECIST v1.1. Here we report ORR and DOR, by individual cohort and as an overall population, in patients with dMMR tumors identified by immunohistochemistry testing. Results: For this interim analysis, an efficacy analysis was performed for the patients who had baseline measurable disease and ≥6 months of follow-up in the study (N = 209). The ORR was 41.6% (95% CI, 34.9%–48.6%) for the combined A1+F dMMR cohorts (Table). Responses were durable, and median DOR has not been reached in either cohort (median follow-up: cohort A1, 16.3 months; cohort F, 12.4 months). A total of 267 patients were included in the safety population (all patients who received ≥1 dose; cohort A1, N = 126; cohort F, N = 141). Treatment-related adverse events (TRAEs) were consistent across tumor types. Overall, the most frequently reported any-grade TRAEs were asthenia (13.9%), diarrhea (13.5%), and fatigue (11.2%). The most common grade ≥3 TRAEs were anemia (2.2%), lipase increased (1.9%), alanine aminotransferase increased (1.1%), and diarrhea (1.1%). No deaths were attributed to dostarlimab. Conclusions: Dostarlimab demonstrated durable antitumor activity in patients with dMMR solid tumors, with consistent antitumor activity seen across endometrial and nonendometrial tumor types. The safety profile was manageable, with no new safety signals detected. Most TRAEs were low grade and were similar across cohorts. Clinical trial information: NCT02715284. [Table: see text]

PLANETTE: A modular phase IIa multicenter open-label study evaluating the ATR inhibitor ceralasertib (AZD6738) in ATM mutant advanced solid tumors.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS189-TPS189
Author(s):  
Wassim Abida ◽  
Elkhan Sanay ◽  
Natalia Lukashchuk ◽  
Andrew Pierce ◽  
Wessel de Graaf ◽  
...  
Keyword(s):  
Dna Damage ◽  
Solid Tumors ◽  
Ataxia Telangiectasia ◽  
Synthetic Lethality ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Minor Response ◽  
Open Label Study ◽  
Label Study ◽  
Tumor Types

TPS189 Background: Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) are kinases that orchestrate cellular responses to DNA damage. ATM is primarily activated by DNA double strand breaks, and ATR is recruited to regions of single stranded DNA that arise due to collapsed or stalled replication forks. Although ATM and ATR are activated by distinct pathways, their downstream targets and effects partially overlap to activate cell cycle checkpoints and DNA damage repair. Ceralasertib is a potent, oral, selective inhibitor of ATR. Pre-clinical studies have consistently demonstrated synthetic lethality of ATR inhibitors, including ceralasertib, in ATM-deficient models across multiple tumor types (Kwok et al 2017, Min et al 2017, Lloyd et al 2020, Hustedt et al 2019). Early clinical evidence of efficacy is from a phase I study of ceralasertib in combination with olaparib in relapsed, refractory cancer (NCT02576444). Amongst 5 participants with a range of solid tumors harboring deleterious ATM mutations, there was 1 complete response, 3 stable diseases (1 with minor response 20-30%) and 1 patient with disease progression. Two participants had clinical benefit ongoing for more than 12 months (Eder et al 2019). ATM deficiency may be detected through genomic testing for loss-of-function alterations in the gene, or through immunohistochemical methods to detect loss of protein expression. Genomic alterations in ATM occur across multiple solid tumor types, including approximately 4% of advanced prostate cancers. Methods: PLANETTE (clinicaltrials.gov identifier (NCT 04564027) is a modular phase 2a multicenter open-label study investigating DNA-damage response agents in patients with advanced cancers that harbor molecular alterations. Module 1 will study the ATR inhibitor ceralasertib in tumors with deleterious or suspected deleterious mutations in ATM. Patients will be identified at cancer centers which routinely perform molecular profiling to detect ATM mutations. Central confirmation of ATM mutation by NGS and ATM IHC testing will be conducted retrospectively. Cohort A will enroll ~25 patients with advanced solid tumors (except NSCLC and prostate cancer), cohort B will include ~27 patients with metastatic CRPC who have previously progressed on a novel hormonal agent. The primary endpoints are investigator assessed ORR in Cohort A and composite response that includes radiographic, PSA, and CTC response per PCWG criteria in Cohort B. Secondary endpoints include duration of response, and progression free survival. Pharmacodynamic and other biomarkers will be explored. Enrolment is planned to start in November 2020. Clinical trial information: 04564027.

NE-180, a Novel glycoPEGylated Erythropoietin Demonstrates Dose-Dependent Activity in a Phase 1 Single Dose, Dose Escalating Study in Normal Human Volunteers (NHV).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1149-1149
Author(s):  
Bruce A. Wallin ◽  
Denise Ramjit ◽  
Michael Seiberling ◽  
David Zopf
Keyword(s):  
Adverse Events ◽  
Animal Studies ◽  
Phase 1 ◽  
Stopping Rules ◽  
Open Label ◽  
Serious Adverse Events ◽  
Maximal Increase ◽  
The Mean ◽  
Dose Dependent

Abstract NE-180 is a glycoPEGylated recombinant human erythropoietin that binds to and activates the erythropoietin (EPO) receptor. It has demonstrated in vitro activities comparable to EPO and an extended serum half-life in animal studies. This may allow less frequent dosing in patients being treated with chronic anemia. METHODS: A single center, open-label study of NE-180, administered as single escalating doses given by the SC or IV route, was conducted to assess the safety, tolerability, PK and PD. Subjects (male or female NHV) were planned to be assigned to one of 4 dose groups, 10 subjects per dose with 5 SC and 5 IV subjects per group: 0.5, 1.5, 3, or 4.5 mg/kg. Each dose group was planned to be initiated in an ascending, sequential fashion unless or until stopping rules were met. RESULTS: 25 NHV (16 females) were enrolled in the first two dose cohorts and have completed 56 day follow-up. The 1.5 mg/kg IV cohort met the protocol-specified Hb rate of rise stopping rule (change in Hb greater than 1 g/dL during any 14 day period). Injections were generally well tolerated with no discontinuations for adverse events or serious adverse events. Reticulocyte increases were dose proportional. Average reticulocyte count at baseline was 1.0±0.3%. The maximal increase occurred at day 7. The mean change from baseline for the 0.5 and 1.5 mg/kg SC group was: 0.9±0.4% and 2.2±0.9%, respectively. The mean change from baseline for the 0.5 and 1.5 mg/kg IV group was: 1.7±0.8% and 2.3±0.8%, respectively. PK data will be presented. CONCLUSIONS: Single doses up to 1.5 mg/kg of NE-180 administered to NHV were generally well tolerated and demonstrated potent dose-dependent erythropoietic activity.

Myeloablative Conditioning with Clofarabine and Busulfan X 4 (CloBu4) Is Well Tolerated, Facilitates Secure Engraftment, and Exhibits Significant Anti-Tumor Activity against Non-Remission Hematologic Malignancies Including AML.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2150-2150 ◽  
Author(s):  
Shin Mineishi ◽  
John Magenau ◽  
Attaphol Pawarode ◽  
Timothy Buck ◽  
Dawn Jones ◽  
...  
Keyword(s):  
Hematologic Malignancy ◽  
Blast Crisis ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Single Daily Dose ◽  
Disease Assessment ◽  
Mixed Chimerism ◽  
Target Range ◽  
Daily Dose ◽  
Anti Tumor Activity

Abstract Background: The combination of fludarabine with a myeloablative dose of busulfan (FluBu4) has been shown to be well tolerated with reduced toxicity compared to other myeloablative regimens. Clofarabine is a second generation purine antimetabolite with potent anti-leukemia properties. We replaced fludarabine with clofarabine in a phase I/ II trial of Clofarabine-Busulfan x 4 (CloBu4) in an attempt to develop a pre-transplant conditioning regimen suitable for pts with refractory, non-remission hematologic malignancies at the time of transplant. Methods: All pts had a hematologic malignancy not in remission at the time of transplant. Busulfan was administered as a single daily dose of 3.2 mg/kg IV x 4d (days -5 to -2) and clofarabine as a single daily dose of 20, 30 or 40 mg/m2 IV x 5d (days -6 to -2) with the specific dose per pt determined by the Time to Event-Continuous Reassessment Method (TITE-CRM). All pts received dexamethasone 12 mg IV on the days of clofarabine to avoid capillary leak syndrome. GVHD prophylaxis was tacrolimus/MMF in19 pts and tacrolimus/methotrexate in 1. Results: To date, 20 pts are evaluable for toxicity, 19 for engraftment, and 16 for response. Diseases were AML (including 2 myeloid blast crisis of CML) (n=13), ALL (n=2), CLL (n=2), NHL (n=2), and multiple myeloma (n=1). Six pts had received previous stem cell transplantation (SCT), 2 auto SCT (range between SCT 295-1066 d) and 4 allo (range 75–1002 d). The clofarabine dose levels were: 20 mg/m2 (n=6), 30 mg/m2 (n=13) and 40 mg/ m2 (n=1). The median age of patients was 51 years (range 13–68). Donors were siblings (n=8) or unrelated volunteers (n=12). All 19 evaluable pts engrafted at a mean of 11 days for both neutrophils and platelets. Busulfan kinetics were evaluated in 14 patients with an average steady state level of 803 ng/ml (605–1132). Dose increase was required in 2 cases and decrease in 2 cases to maintain target range of 600–900 ng/ml. One pt who developed hypersensitivity to clofarabine with fever and joint pain after the first dose, received an additional 20 mg of dexamethasone with subsequent doses and finished all five doses of clofarabine. Other grade 3–4 toxicities attributable to the conditioning regimen include transient liver enzyme abnormalities (8/20), hypoxia (5/20), hypertension (2/20), seizure (1/20), and ascites (2/20). Neither case of ascites had elevated bilirubin, but one case showed pathologic findings compatible with veno-occlusive disease on liver biopsy. Both of these pts had pre-existing conditions including pretransplant liver damage (1) and enlarged spleen before SCT due to preceding myelofibrosis (1). Acute GVHD developed in 2/20 and proved fatal in one case. Peripheral blood CD3+ cell chimerism was evaluable in 10 pts on day 30; 1 pt had 100% donor CD3+ cells, whereas 9 pts had in mixed chimerism (&lt;5% to 29% recipient cells). By day 100, 5/10 pts achieved complete donor type chimerism, and 5 still had mixed chimerism (&lt;5% to 20% recipient cells). Four pts were too early for disease assessment; 11/16 pts were in CR at day 30, including 9/11 pts with AML. The 10 months OS is 80% (82% for AML) with a median follow-up of 6 months. Conclusion: Clofarabine is well tolerated when given with full dose busulfan in this group of very high risk pts. All pts engrafted rapidly, and this combination shows promising anti-tumor activity in pts with relapsed/refractory diseases. The trial continues to accrue pts and updated results will be presented at the meeting. Figure Figure

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