Umbralisib (TGR-1202) is a novel next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) isoform p110δ (PI3Kδ), which is structurally distinct from other PI3Kδ inhibitors and shows improved ...isoform selectivity. Umbralisib also uniquely inhibits casein kinase-1ε, a major regulator of protein translation. The aim of this first-in-human phase 1 study was to establish the safety and preliminary activity profile of umbralisib in patients with haematological malignancies.
We did an open-label, phase 1, dose-escalation study at seven clinics in the USA. We recruited patients aged at least 18 years with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, B-cell and T-cell non-Hodgkin lymphoma, or Hodgkin's lymphoma, who had received one or more previous lines of therapy, with measurable and assessable disease, and adequate organ system function. Patients self-administered an umbralisib oral tablet once per day in 28-day cycles, with dose escalation done in a traditional 3 + 3 design to establish safety and determine the maximum tolerated dose. In initial cohorts, patients took umbralisib in a fasting state at a starting dose of 50 mg, increasing to 100, 200, 400, 800, 1200, and 1800 mg until the maximum tolerated dose was reached, or the maximal dose cohort was accrued without a dose-limiting toxicity. Subsequent cohorts self-administered a micronised formulation of umbralisib tablet in a fed state at an initial dose of 200 mg, increased in increments to 400, 800, 1200, and 1800 mg until the maximum tolerated dose or the maximal dose level was accrued. In August, 2014, all patients still on study were transitioned to 800 mg of the micronised formulation and dosing of the initial formulation was discontinued. The primary endpoints of the study were investigator-assessed safety in all treated patients (the safety population), the maximum tolerated dose, and the pharmacokinetics of umbralisib. Secondary endpoints included preliminary assessments of anti-cancer activity (objective responses and duration of response). Follow-up stopped for a patient once they discontinued therapy. This study has been completed and is registered with ClinicalTrials.gov, number NCT01767766.
Between Jan 17, 2013, and Jan 14, 2016, we enrolled and treated 90 patients with umbralisib. The median duration of treatment and follow-up was 4·7 cycles (IQR 2·0–14·0) or 133 days (IQR 55–335). The most common treatment-emergent adverse events irrespective of causality were diarrhoea (in 39 43% of 90 patients), nausea (38 42%), and fatigue (28 31%). The most common grade 3 or 4 adverse events were neutropenia (in 12 13% patients), anaemia (eight 9%) and thrombocytopenia (six 7%). Serious adverse events considered at least possibly related to umbralisib occurred in seven patients: pneumonia in three (3%) patients, lung infection in one (1%), febrile neutropenia in one (1%), and colitis in two (2%), one of whom also had febrile neutropenia. The maximum tolerated dose was 1200 mg of the micronised formulation, with 800 mg of this formulation selected as the recommended phase 2 dose. Both cases of colitis occurred at above the recommended phase 2 dose. 33 (37%) of the 90 patients enrolled had an objective response to treatment with umbralisib.
Umbralisib was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory haematological malignancies. The safety profile of umbralisib in this phase 1 study was distinct from that of other PI3Kδ inhibitors, with fewer occurrences of autoimmune-like toxicities such as colitis. These findings warrant further evaluation of this agent in this setting.
TG Therapeutics.
The purpose of this study was to assess the safety and efficacy of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Patients with multiple ...myeloma who had relapsed after at least one prior treatment were eligible to participate. In the dose escalation part of the study a standard 3+3 design was used to determine the maximum tolerated dose of four planned dose levels of the combination of carfilzomib and panobinostat. Panobinostat was administered on days 1, 3, 5, 15, 17, and 19. Carfilzomib was administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Treatment was continued until progression or intolerable toxicity. Forty-four patients were accrued into the trial, 13 in the phase I part and 31 in the phase II part of the study. The median age of the patients was 66 years and the median number of prior therapies was five. The expansion dose was established as 30 mg panobinostat, 20/45 mg/m(2) carfilzomib. The overall response rate was 67% for all patients, 67% for patients refractory to prior proteasome inhibitor treatment and 75% for patients refractory to prior immune modulating drug treatment. At a median follow up of 17 months, median progression-free survival was 7.7 months, median time to progression was 7.7 months, and median overall survival had not been reached. The regimen was well tolerated, although there were several panobinostat dose reductions. In conclusion, the combination of panobinostat and carfilzomib is feasible and effective in patients with relapsed/refractory multiple myeloma. (Trial registered at ClinicalTrials.gov: NCT01496118).
Summary
Hypomethylating agents (HMAs) are standard of care for higher‐risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose ...their response. Pracinostat is a pan‐histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single‐agent HMA treatment. The goal was to estimate the clinical improvement rate complete remission (CR), marrow CR, partial response (PR) and haematological improvement. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single‐agent HMAs. Forty‐five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.
Lessons Learned
Ofatumumab infusion reactions can be diminished by escalating the dose rate in individual patients in sequential infusions.
Background
Ofatumumab (OFA) is a fully humanized, anti‐CD20 ...antibody approved for use in chronic lymphocytic leukemia (CLL). The recommended administration requires long infusion times. We evaluated an accelerated infusion regimen of 2 hours.
Methods
The first dose of OFA (300 mg) was given on week 1 day 1 starting at 3.6 mg/hour and doubling every 30 minutes until a rate of 240 mg/hour was reached. If tolerated, the second dose (1,000 mg) was given on week 1 day 3 starting at 50 mg/hour and doubling every 30 minutes until a rate of 800 mg/hour was reached. If tolerated, the third dose (2,000 mg) was given on week 2 day 1 at 800 mg/hour over the first 30 minutes and, if tolerated, at 1,068 mg/hour over the next 90 minutes (goal infusion time: 120 minutes). Subsequent OFA infusions were administered weekly in the same manner for 8 weeks, and then monthly for 4 months.
Results
Thirty‐four patients were treated. Most infusion‐related reactions occurred during the first and second infusion. Eighty‐seven percent (87%) of patients finished the third infusion within 15 minutes of the planned 2 hours and only one had an infusion reaction.
Conclusion
Using this stepped‐up dosing regimen, a rapid infusion of OFA is safe and well tolerated.
经验总结
• 通过逐步升高个体患者每次输注的剂量速率可降低Ofatumumab的输注反应。
摘要
背景. Ofatumumab（OFA）是被批准用于治疗慢性淋巴细胞白血病（CLL）的完全人源化抗CD20抗体。推荐的给药量所需的输注时间较长。研究对2小时的加速输注方案进行了评估。
方法. 在第1周第1天给予第一剂OFA（300mg）, 起始输注速率为3.6 mg/小时, 每30分钟翻一倍, 直到输注速率达到240 mg/小时。如果可耐受, 则在第1周第3天给予第二剂药物（1 000 mg）, 起始输注速率为50 mg/小时, 每30分钟翻一倍, 直到输注速率达到800 mg/小时。如果可耐受, 在第2周第1天给予第三剂药物（2 000 mg）, 输注的前30分钟内速率为800 mg/小时, 如果仍能耐受, 则在接下来的90分钟内以1 068 mg/小时的速率给药（目标输注时间：120分钟）。随后以相同的方式每周进行OFA输注给药, 持续8周, 然后每月以相同的方式给药, 持续4个月。
结果. 34名患者接受治疗。大多数输注相关反应在首次或第二次输注时出现。87%的患者在15分钟内完成了原计划持续2小时的第三次输注, 仅1名患者出现输注反应。
结论. 使用这种加速给药方案快速输注OFA是安全和可良好耐受的。
To assess the activity of vinorelbine in women with recurrent or resistant epithelial ovarian cancer following treatment with platinum and paclitaxel in terms of survival rate at 6 months, objective ...response rate (in the subset of patients with bidimensionally measurable disease), and health-related quality of life.
Seventy-nine evaluable patients with progressive ovarian cancer following platinum and taxane therapy received vinorelbine 30 mg/m
2 days 1 and 8 of a 21-day treatment cycle.
Six-month survival rate for the entire group was 65% (95% CI: 54–75%) and median survival was 10.1 months (95% CI: 7.7–13.6 months). In the 71 women with measurable disease, 0 complete and 2 partial responses were observed (RR = 3%) (95% CI: 0.3–10%). Patients reported substantial symptom-related distress at baseline, which persisted, but did not worsen, during treatment. Patients also had impaired physical functioning at baseline and this continued to decline during treatment.
The 6-month survival rate achieved with salvage vinorelbine is comparable to the results obtained with other salvage therapies in patients with relapsed ovarian cancer. During the initial 10 weeks of treatment, vinorelbine did not appear to be effective in alleviating the symptom-related distress or progressive impairment of physical functioning associated with this disease.
Background: Proteasome inhibitors (PI) such as bortezomib (BTZ) and carfilzomib (CFZ) have improved the treatment (tx) of MM; however, resistance invariably develops and MM remains an incurable ...disease. Changes in histone modification are commonly found in human cancers including MM, and several histone deacetylase inhibitors (HDACi) are in clinical development. Panobinostat (PAN) is an oral pan-HDACi which has shown synergy with PIs through inhibition of the proteasome and aggresome pathways. It was recently approved by the FDA in combination with BTZ and dexamethasone based on the results of the PANORAMA1 study demonstrating efficacy, but significant G3 diarrhea (Lancet Oncol 2014;15:1195-206). We have previously reported the combination of CFZ and PAN in pts with relapsed and relapsed/refractory MM with encouraging results (Haematologica 2015;100:670-6). The maximum tolerated dose (MTD) of CFZ and PAN was never reached and we extended our original study to investigate higher dose levels. Here we present a comparison of the initial dose expansion (DL 4) and the subsequent dose expansion (DL 6).
Methods: Ps with MM who had relapsed after ≥ 1 prior tx were enrolled. PAN was administered orally on days 1, 3, 5, 15, 17, 19 of each 28-day cycle. CFZ was administered IV over 30 min on days 1, 2, 8, 9, 15, and 16. In the initial dose escalation portion of the study a standard 3+3 design was used to determine the maximum tolerated dose (MTD) of an initial 4 planned dose levels of the combination of CFZ and PAN. The 4 dose levels tested were DL 1 (20 mg PAN and 20/27 mg/m2 CFZ); DL 2 (20 mg PAN and 20/36 mg/m2 CFZ); DL 3 (20 mg PAN and 20/45 mg/m2 CFZ), and DL 4 (30 mg PAN and 20/45 mg/m2 CFZ). MTD was not reached and the maximum planned dose DL 4 was expanded. We then revised the study in order to escalate to DL 5 (30 mg PAN plus 20/56 mg/m2 CFZ). Due to numerous PAN dose reductions resulting in a delivered PAN dose closer to 20 mg, we explored DL 6 (PAN 20 mg and CFZ 20/56 mg/m2). Tx continued until PD or intolerable toxicity. The primary efficacy endpoint was the overall response rate (ORR) (≥ PR). Secondary end points were time to progression (TTP), progression-free survival (PFS) and overall survival (OS), calculated using Kaplan-Meier methods. AEs were assessed according to CTCAE Version 4 and responses were assessed using IMWG criteria (plus MRs as per the EBMT criteria).
Results: 80 pts were enrolled (50% male, median age 65 (range 41-91), 58% poor risk, and median of 4.5 prior therapies (1-9)). Prior PI or IMiD exposure and refractory status for all pts and expansion cohorts are shown in Table 1. 34 pts were in the 1st dose expansion (DL 4) and 33 in the 2nd (DL6). 13 (16%) pts remain on active tx overall, 6% of pts on DL 4 and 30% of pts on DL6. The most common all grade toxicities were thrombocytopenia (73%), nausea (69%), diarrhea (64%), and fatigue (51%). There were no significant differences in types or grades of toxicities between the 2 expansion cohorts except for decreased all grade diarrhea favoring DL 6 (71% v 49%). There was 1 tx related death due to heart failure in a pt with a prior history of hypertension and hyperlipidemia. The ORR was 75% (32% ≥ VGPR, 43% PR) for all pts, 72% (37% ≥ VGPR, 34% PR) for DL4 and 84% (34% ≥ VGPR, 50% PR) for DL 6 pts. With a median follow up (FU) of 14.5 mos for all pts, median PFS and TTP were 13.5 and 18.7 mos, respectively. Median OS was not reached. DL4 pts had a median FU of 24.3 mos, median PFS of 17.8 mo, median TTP of 19.5 mo, and median OS of 28.2 mo. The PFS and OS data of DL 6 pts is immature.
Conclusions: The PAN/CFZ combination is effective with an acceptable safety profile in this heavily pretreated and highly refractory population. The results of this study compare favorably with the results of the PANORAMA-1 study in both efficacy and toxicity. An increase in CFZ from 45 to 56 mg/m2 did not appear to increase cardiopulmonary toxicity while a decrease in PAN from 30 to 20 mg appeared to have decreased the incidence of diarrhea. Both expansion dose levels tested were highly efficacious and well tolerated. Further evaluation of this combination in this schedule is warranted.
Table 1DL 4 (n=34)DL 6 (n=33)All Pts (n=80)Median # prior therapies, (range)5 (1-9)4 (1-9)4.5 (1-9)Prior PIs33 (97%)33 (100%)79 (99%)Prior IMiDs31 (91%)26 (79%)69 (86%)Refractory to prior PIs15 (44%)19 (58%)37 (46%)Refractory to prior IMiDs17 (50%)16 (48%)42 (53%)Refractory to both prior IMiDs and PIs8 (24%)8 (24%)20 (25%)Refractory to Last Therapy23 (68%)27 (81%)57 (71%)
Berdeja:Acetylon: Research Funding; MEI: Research Funding; Array: Research Funding; Onyx: Research Funding; Takeda: Research Funding; Curis: Research Funding; Janssen: Research Funding; Celgene: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novartis: Research Funding. Gregory:Novartis: Speakers Bureau. Hart:Onyx: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mace:Spectrum Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Pfizer: Speakers Bureau. Flinn:Celgene Corporation: Research Funding.
Hepatic complications are a major cause of illness and death after bone marrow transplantation.
To confirm the results of a pilot study that indicated that ursodiol prophylaxis could reduce the ...incidence of veno-occlusive disease of the liver.
Randomized, double-blind, placebo-controlled study.
Tertiary care teaching hospital.
67 consecutive patients undergoing transplantation with allogeneic bone marrow (donated by a relative) in whom busulfan plus cyclophosphamide was used as the preparative regimen and cyclosporine plus methotrexate was used to prevent graft-versus-host disease.
Before the preparative regimen was started, patients were randomly assigned to receive ursodiol, 300 mg twice daily (or 300 mg in the morning and 600 mg in the evening if body weight was > 90 kg), or placebo.
Patients were prospectively evaluated for the clinical diagnosis of veno-occlusive disease, the occurrence of acute graft-versus-host disease, and survival.
The incidence of veno-occlusive disease was 40% (13 of 32 patients) in placebo recipients and 15% (5 of 34 patients) in ursodiol recipients (P = 0.03). Assignment to placebo was the only pretransplantation characteristic that predicted the development of veno-occlusive disease. The most significant predictor of 100-day mortality was the diagnosis of veno-occlusive disease. The difference in actuarial risk for hematologic relapse in patients with chronic myelogenous leukemia and nonhepatic toxicities between the two groups was not statistically significant (13% in the ursodiol group and 20% in the placebo group; P > 0.2).
Ursodiol prophylaxis seemed to decrease the incidence of hepatic complications after allogeneic bone marrow transplantation in patients who received a preparative regimen with busulfan plus cyclophosphamide.
Acute graft-versus-host disease (aGVHD) is partly mediated through activated T cells, and these cells are known to express the high-affinity receptor for interleukin 2 (IL-2R). Denileukin diftitox is ...composed of human IL-2 and diphtheria toxin that is cytotoxic to activated lymphocytes expressing the high-affinity IL-2R. We describe the results of a phase II study of denileukin diftitox in 22 patients with steroid-resistant aGVHD. Twenty patients were treated at dose level 1 (4.5 μg/kg daily on days 1–5 and then weekly on study days 8, 15, 22, and 29), and 2 patients were treated at dose level 2 (9.0 μg/kg delivered on the same schedule). Dose level 2 was associated with grade 3/4 renal and hepatic toxicity and vascular leak syndrome, and no further patients were treated at this level. Dose level 1 was generally well tolerated. The response of aGVHD was assessed at study days 36 and 100. Nine patients (41%) responded, all with a complete response at study day 36, and 6 patients (27%) responded at study day 100 (4 complete responses and 2 partial responses). Denileukin diftitox has promising activity in steroid-resistant aGVHD, and further study is warranted.
cGVHD exhibits both autoimmune and fibrotic features across multiple organ systems. KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor.
KD025-208 enrolled 3 ...cohorts (C1: 200 mg QD, C2: 200 mg BID, and C3: 400 mg QD) of cGVHD patients (pts) after 1-3 prior lines of therapy. Treatment was until progression or toxicity. Primary endpoint is overall response rate (ORR) per 2014 NIH response criteria. Additional endpoints include Duration of Response (DOR), corticosteroid (CS) dose reductions, Failure Free Survival (FFS) and Lee Symptom Scale (LSS) score.
17, 16, and 21 pts enrolled in C1, C2, and C3. As of 8Mar19, median duration of follow up was 112, 97 and 64 weeks (wks) respectively. Median age was 52 yrs, median time from cGVHD diagnosis was 20 mos, and median prior lines of therapy was 2. Median duration of treatment was 37, 33, and 39 wks, respectively. 14 pts remained on KD025. Reasons for discontinuation: cGVHD progression (18), voluntary withdrawal (7), relapse of underlying disease (5), investigator decision (5), AE (3), and death (2).
ORR 95% CI was 65% 38, 85 in C1, 69% 41, 89 in C2, and 62% 38, 82 in C3, 65% 51, 77 across all 3 cohorts. Responses were achieved across key subgroups with ORRs of 62% (24/39) in pts with ≥2 prior lines of therapy, 70% (19/27) in pts with ≥4 organs involved and 60% (25/42) in pts with severe cGVHD, and 65% (22/34) in pts refractory to their previous line. CRs were observed in all affected organs except lung; PRs were observed in lung.
Median Time to Response was 8.14 wks (IQR 8-12); 4/35 responses occurred after 24 wks.
Responses were durable with a Kaplan-Meier median DOR of 34 wks across all cohorts. 57% of responders sustained a response for ≥20 wks. FFS at 6, 12 and 24 mos was 76%, 47% and 33% respectively. Overall survival was 94%, 91% and 83%.
Baseline median CS dose was 0.21 mg/kg/day (prednisone eq). During treatment, median CS dose was reduced by 50%. 20% pts discontinued CS.
52% of pts reported a ≥7-point reduction in LSS with median time to improvement 9 wks.
AEs were consistent with those expected in cGVHD pts receiving CS. Common AEs were URI 35%, diarrhea 31%, nausea 31%, fatigue 30%, dyspnea 28%, increased LFTs 24%, and peripheral edema 22%. 63% had a Grade ≥3 AE, the most common was dyspnea, 13%. <10% pts experienced Grade 3 anemia, neutropenia, or thrombocytopenia. SAEs, reported in 43%, were not related to KD025. SAEs in >2% were dyspnea (7%), lung infection (6%), hypoxia (4%) and flu-like illness (4%). Three pts discontinued KD025 due to possibly related AEs (C1: diarrhea, headache; C3: fatigue). 3 pts died on study (C3: relapse of leukemia; lung infection; cardiac arrest), all considered unrelated to KD025.
Durable and clinically meaningful responses have been seen across all 3 cohorts. KD025 was well tolerated, with sustained responses and encouraging FFS in patients with advanced cGVHD.
cGVHD is characterized by an imbalance between effector and regulatory arms of the immune system that results in over production of IL-17 and IL-21. A reduction in the regulatory T (Treg) cells ...limits the ability of the immune system to re-calibrate this pro-inflammatory environment. KD025 is an oral Rho kinase 2 (ROCK2) selective inhibitor. In vitro data demonstrate KD025 modulates immune homeostasis by shifting the Th17/Treg balance towards Treg.
3 cohorts (C1: 200 mg QD, C2: 200 mg BID, and C3: 400 mg QD) of patients (pts) with cGVHD after 1-3 prior lines of systemic therapy were treated in 28-Day cycles until disease progression. The primary endpoint is overall response rate (ORR) (partial/complete response) per 2014 NIH criteria. Additional endpoints include duration of response (DOR), corticosteroid (CS) dose reductions, Lee Symptom Scale (LSS) score and PD.
Blood samples were collected at Cycle 1 Day 1 (C1D1), C2D1, C4D1 and C6D25, and shipped at ambient temperature. PBMC were isolated and kept frozen until analysis. Intracellular expression of IL-17A and FOXP3 was determined by flow cytometry.
Data as of 6-June-2018 for C1 and C2 are included; C3 data will be available 4Q18. 17 and 16 pts were enrolled in C1 and C2 with median age 52 years, time from cGVHD diagnosis to KD025 treatment of 19 months, and 3 prior regimens. Median duration of treatment was37 (C1) and 33 (C2) weeks. KD025 demonstrated ORR of 65% in C1 and 63% in C2. Responses were rapid (76% at first assessment at 8 weeks) and durable (≥20 weeks) in 82% (C1) and 50% (C2) of responders. Median CS dose was reduced 44% (C1) and 26% (C2). 76% and 56% of pts achieved CS dose reductions. 5/33 (15%) pts discontinued CS. 65% (C1) and 50% (C2) achieved a meaningful improvement (≥7 point reduction) in the LSS score. Common AEs were increased LFTs 42%, URI 33%, anemia 27%, nausea 24%, diarrhea 24% and fatigue 21%. Grade 3+ LFT increases were reported for 6 (18%) pts. 2 pts discontinued treatment due to AEs possibly related to KD025 (headache, diarrhea). SAEs were reported for 11/33 pts, none considered related to KD025. There was no apparent increased risk of infection. Exploratory PD analyses revealed an early increase in the percentage of CD4+ Treg cells by C2D1 with a simultaneous decrease in Th17 cells. The percentage of CD4+ Tregs continued to increase, and the Th17 cells continued to decrease through C6D25.
KD025 achieved responses with little toxicity. Responses are clinically meaningful with durability, reductions in CS doses and improvement in LSS score. PD data indicate KD025 may restore the Th17/Treg balance.
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