Trial Of Bortezomib Research Articles

Abstract CT120: Phase 1 trial of bortezomib and clofarabine combination in adults with refractory solid tumors

Abstract Background/Rationale: The combination of the proteosome inhibitor bortezomib (B) and purine analog clofarabine (C) induced synergy in the NCI-ALMANAC screen of FDA-approved cancer drug combinations; preclinical xenograft studies confirmed this activity and suggested a combination mechanism of action involving greater-than-additive effects on markers of DNA damage response (DDR) and pyroptotic cell death. We conducted a phase 1 clinical trial (NCT02211755) to assess the safety of the B and C combination in patients (pts) with solid tumors and myelodysplastic syndrome (MDS), and to determine the effect of the combination on biomarkers of cell death and DDR. Due to limited MDS pt accrual, this cohort was terminated early, and MDS pt data are not included here.Objectives: The primary objective was to assess safety and maximum tolerated dose (MTD) of B and C in pts with solid tumors and MDS. Secondary objectives were to assess pharmacodynamic (PD) effects using validated assays for cell death and DDR in tumor biopsy tissue and circulating tumor cells (CTCs).Design: The dose escalation followed a 3+3 design, enrolling at least 1 pt from each group (solid tumor and MDS) per dose level until hematologic dose-limiting toxicity (DLT) was observed. Adverse events (AEs) were graded using CTCAE v4.0. Ten planned dose levels (DL) included C ranging from 1 to 10 mg/m2 on D2-5 of cycle 1 and D1-5 from cycle 2 on and B from 0.8 to 1.5 mg/m2 on D1 and D4 of 21-day cycles. Response was assessed by RECIST 1.1 every 2 cycles. Biopsies were performed on the expansion cohort pre-dose, 2-4 hours after C on C1D1, and C2D4; CTCs were collected pre-dose, C1D2, day 1 of subsequent cycles, and at progression.Results: We enrolled 25 pts with advanced solid tumors (15 male, 10 female). Median age was 62 years (range 30-81). DLT occurred in 4 pts (at DL3 [1 pt], DL5 [2], and DL4 [1]) and included Grade 4 neutropenia (3), Grade 3-4 thrombocytopenia (3), and Grade 3 anemia (1). There were no Grade 5 AEs. DL4 (B 1.3 mg/m2 D1 and 4, C 1.5 mg/m2 D1-5, 21-day cycles) was the MTD. Twenty-one pts were evaluable for response; the best response was stable disease (SD) for 10 pts (47.6%). Median duration of response for pts achieving SD was 3.5 months (range 2-7). Of note, 3 out of the 10 colorectal cancer (CRC) pts had SD > 4 months. Four pts with CRC have been enrolled in an expansion cohort for biomarker evaluation; induction of pyroptosis has been measured in a limited number of paired biopsies collected to date. Conclusions: Despite preclinical evidence of synergy, the human equivalent of the efficacious preclinical combination dose could not be achieved clinically, which may account for the lack of antitumor response. Prolonged SD was observed in 3 pts with CRC. PD analyses, including of CTCs and additional cell death biomarkers, are ongoing. Funded by NCI Contract No. HHSN261201500003I. Citation Format: Andre L. De Souza, Naoko Takebe, Alice P. Chen, James H. Doroshow, Ralph E. Parchment, Apurva K. Srivastava, Lawrence Rubistein, Deborah Wilsker, Brandon L. Miller, Murielle Hogu, Geraldine O`Sullivan Coney, Shivaani Kummar, Jeevan Govindharajulu, Robert Meehan, William G. Herrick, Angie Dull, Donna Ketchum, Shaowei Li, Jiuping Ji, Richard Piekarz. Phase 1 trial of bortezomib and clofarabine combination in adults with refractory solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT120.

Bortezomib Is Effective in the Treatment of T Lymphoblastic Leukaemia by Inducing DNA Damage, WEE1 Downregulation, and Mitotic Catastrophe.

T lymphoblastic leukemia (T-ALL) is an aggressive haematolymphoid malignancy comprising 15% of acute lymphoblastic leukemia (ALL). Although its prognosis has improved with intensive chemotherapy, the relapse/refractory disease still carries a dismal prognosis. Thus, there is an urgent need to develop novel therapy for T-ALL. Bortezomib, a 26S proteasome inhibitor, is licensed to treat plasma cell myeloma and mantle cell lymphoma. Due to its favorable side effect profile, it is a novel agent of research interest in the treatment of ALL. Despite an increasing number of clinical trials of bortezomib in T-ALL, its detailed mechanistic study in terms of DNA damage, cell cycle, and mitotic catastrophe remains elusive. Moreover, WEE1, a protein kinase overexpressed in ALL and involved in cell-cycle regulation, has been known to be a novel therapeutic target in many cancers. But the role of bortezomib in modulating WEE1 expression in ALL still remains elusive. In this study, we demonstrate the therapeutic efficacy of bortezomib on T-ALL primary samples and cell lines. Our findings reveal that bortezomib treatment induces DNA damage and downregulates WEE1, leading to G2-M cell-cycle progression with damaged DNA. This abnormal mitotic entry induced by bortezomib leads to mitotic catastrophe in T-ALL. In conclusion, our findings dissect the mechanism of action of bortezomib and provide further insights into the use of bortezomib to treat T-ALL. Our findings suggest the possibility of novel combination therapy using proteasome inhibitors together with DNA-damaging agents in the future, which may fill the research gaps and unmet clinical needs in treating ALL.

Isotonic design for phase I cancer clinical trials with late-onset toxicities

ABSTRACT This article addresses the problem of identifying the maximum tolerated dose (MTD) in Phase I dose-finding clinical trials with late-onset toxicities. The main design challenge is how best to adaptively allocate study participants to tolerable doses when the evaluation window for the toxicity endpoint is long relative to the accrual rate of new participants. We propose a new design framework based on order-restricted statistical inference that addresses this challenge in sequential dose assignments. We illustrate the proposed method on real data from a Phase I trial of bortezomib in lymphoma patients and apply it to a Phase I trial of radiotherapy in prostate cancer patients. We conduct extensive simulation studies to compare our design’s operating characteristics to existing published methods. Overall, our proposed design demonstrates good performance relative to existing methods in allocating participants at and around the MTD during the study and accurately recommending the MTD at the study conclusion.

Pancreatitis as a Potential Trigger for Severe Accelerated Cardiac Allograft Vasculopathy Early Post Heart Transplant: A Case Report

We present a case of severe accelerated cardiac allograft vasculopathy (CAV), an infrequent finding usually related to dismal prognosis, in a heart recipient with recurrent episodes of acute pancreatitis. A 38-year-old male was transplanted owing to advanced heart failure related to nonischemic dilated cardiomyopathy. On the fifth day after transplantation, a nonbiliary acute ischemic pancreatitis occurred. Recurrent relapses ensued within the following year requiring hospital readmissions for both supportive and pain management. The patient developed graft dysfunction by the 18th month post-transplant with severe multivessel CAV. A trial of bortezomib and percutaneous coronary interventions with drug-eluting stents at coronary arteries were attempted but the patient died suddenly, before the scheduled staged percutaneous coronary intervention for the coronary total occlusion was performed. The causal mechanisms of aggressive accelerated CAV are unclear, but it is suggested that important inflammatory and/or humoral responses may play a pivotal role in this life-threatening disease pathogenesis. Increased levels of biomarkers have been linked to advanced CAV, as well as pancreatitis pathogenesis, related to cytokine activation with remarkable systemic inflammatory response. Some of those inflammatory mediators have been reported as central in both pancreatitis and CAV, more specifically interleukin-6. A pro-inflammatory state due to recurrent acute pancreatitis early after transplantation may have contributed to severely accelerated CAV development in the presented case. Comprehensive evaluation of risk factors may assist in close surveillance and targeted therapies in the management of this challenging post-heart transplant scenario.

Rational drug combination design in patient-derived avatars reveals effective inhibition of hepatocellular carcinoma with proteasome and CDK inhibitors

BackgroundHepatocellular carcinoma (HCC) remains difficult to treat due to limited effective treatment options. While the proteasome inhibitor bortezomib has shown promising preclinical activity in HCC, clinical trials of bortezomib showed no advantage over the standard-of-care treatment sorafenib, highlighting the need for more clinically relevant therapeutic strategies. Here, we propose that rational drug combination design and validation in patient-derived HCC avatar models such as patient-derived xenografts (PDXs) and organoids can improve proteasome inhibitor-based therapeutic efficacy and clinical potential.MethodsHCC PDXs and the corresponding PDX-derived organoids (PDXOs) were generated from primary patient samples for drug screening and efficacy studies. To identify effective proteasome inhibitor-based drug combinations, we applied a hybrid experimental-computational approach, Quadratic Phenotypic Optimization Platform (QPOP) on a pool of nine drugs comprising proteasome inhibitors, kinase inhibitors and chemotherapy agents. QPOP utilizes small experimental drug response datasets to accurately identify globally optimal drug combinations.ResultsPreliminary drug screening highlighted the increased susceptibility of HCC PDXOs towards proteasome inhibitors. Through QPOP, the combination of second-generation proteasome inhibitor ixazomib (Ixa) and CDK inhibitor dinaciclib (Dina) was identified to be effective against HCC. In vitro and in vivo studies demonstrated the synergistic pro-apoptotic and anti-proliferative activity of Ixa + Dina against HCC PDXs and PDXOs. Furthermore, Ixa + Dina outperformed sorafenib in mitigating tumor formation in mice. Mechanistically, increased activation of JNK signaling mediates the combined anti-tumor effects of Ixa + Dina in HCC tumor cells.ConclusionsRational drug combination design in patient-derived avatars highlights the therapeutic potential of proteasome and CDK inhibitors and represents a feasible approach towards developing more clinically relevant treatment strategies for HCC.

Randomized phase II trial of bortezomib, lenalidomide, dexamthasone with/without elotuzumab for newly diagnosed, high risk multiple myeloma (SWOG-1211).

8054 Background: The introduction of immunomodulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT) has improved outcomes for patients with multiple myeloma (MM), but those with high risk MM (HRMM) have a poor long-term prognosis. Herein we provide survival outcomes on the first randomized trial in newly diagnosed HRMM, S1211, to follow-up on the previously reported progression-free survival (PFS) (NCT01668719, Usmani SZ et al, Lancet Haem 2021). Methods: S1211 is a randomized phase II trial comparing 8 cycles of lenalidomide, bortezomib and dexamethasone (RVd) induction followed by dose-attenuated RVd maintenance until disease progression with or without elotuzumab (RVd-Elo). Stem cell collection was allowed, but ASCT was deferred until progression. HRMM was defined by one of the following: gene expression profiling high-risk (GEPhi), t(14;16), t(14;20), del(17p), amplification 1q21, primary plasma cell leukemia (pPCL), or elevated serum LDH (> 2X ULN). Median PFS was the primary endpoint, using a one-sided stratified log-rank test at a one-sided significance level of 0.1. Secondary endpoints included overall response rate (ORR), adverse events (AE), serious adverse events (SAE) and OS. Response was assessed using the IMWG 2009 criteria. Results: S1211 enrolled 103 evaluable patients, RVd n=54, RVd-Elo n=49. 74% had ISS II/III, 48% amp1q21, 38% del(17p), 11% t(14;16), 9% GEPhi, 7% pPCL, 5% t(14;20) and 4% elevated LDH (17% >1 feature). With median follow-up of 72 months (mos.), no difference in median PFS was observed [RVd-Elo=29 mos., RVd= 34 mos., HR = 1.11 (80% CI=0.82, 1.49, p=0.66]. No difference in OS was observed [RVd-Elo = median not reached (NR), RVd= 68 mos., HR = 0.85 (80% CI: 0.59, 1.23), p-value = 0.58]. 76% pts had >Grade 3 AEs, no differences in the safety profile were observed. Amongst patients with gain/amp 1q21, median PFS was [RVd-Elo=31 mos., RVd= 37 mos., HR = 1.48 (80% CI= 0.95, 2.31), p=0.25], median OS was [RVd-Elo = 61 mos., RVd= 68 mos., HR = 1.23 (80% CI: 0.72, 2.10), p-value = 0.63]. In patients with del(17p), median PFS was RVd-Elo=41 mos., RVd= 30 mos.[HR = 0.98 (80% CI= 0.60, 1.58), p=0.95], median OS RVd-Elo = NR, RVd= 72 mos., [HR = 0.77 (80% CI: 0.40, 1.48), p-value = 0.61]. Conclusions: In the first randomized HRMM study reported to date, the addition of Elo to RVd induction and maintenance did not improve PFS and OS with a median follow-up of 6 years. Although the median PFS for Del17p subgroup on RVd-Elo arm is higher than RVd, it did not achieve statistical significance. The PFS and OS observed for gain/amp 1q21 and del17p in the RVd control arm may serve as important benchmarks for future enrichment design HRMM clinical trials. The PFS and OS in both arms of the study exceeded the original statistical assumptions and support the role for PI/IMiD combination induction/maintenance therapy for this population. Clinical trial information: NCT01668719.

Primary analysis of the randomized phase II trial of bortezomib, lenalidomide, dexamthasone with/without elotuzumab for newly diagnosed, high-risk multiple myeloma (SWOG-1211).

8507 Background: The introduction of immunomodulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT) has improved outcomes for patients with multiple myeloma (MM), but those with high risk MM (HRMM) have a poor long-term prognosis. To date, no trials have addressed optimal treatment for these patients. Methods: S1211 is a randomized phase II trial (NCT01668719) comparing 8 cycles of lenalidomide, bortezomib and dexamethasone (RVd) induction followed by dose-attenuated RVd maintenance until disease progression with or without elotuzumab. Stem cell collection was allowed, but ASCT was deferred until progression. HRMM was defined by one of the following: gene expression profiling high-risk (GEPhi), t(14; 16), t(14; 20), del(17p) or amplification 1q21, primary plasma cell leukemia (pPCL) and elevated serum LDH (> 2X ULN). Median progression-free survival (PFS) was the primary end-point, using a one-sided stratified log-rank test at a one-sided significance level of 0.1. Secondary endpoints included overall response rate (ORR), adverse events (AE), serious adverse events (SAE) and OS. Response was assessed using the IMWG 2009 criteria. Results: S1211 enrolled 103 evaluable patients, RVd n = 54, RVd-Elo n = 49. 75% had ISS II/III, 47% amp1q21, 38% del17p, 12% t(14; 16), 9% GEPhi, 7% pPCL, 5% t(14; 20) and 4% elevated serum LDH (18.5% > 1 feature). With median follow-up of 53 months (mos.), no difference in median PFS was observed [RVd-Elo = 31 mos., RVd = 34 mos.,HR = 0.968 (80% CI = 0.697-1.344), p = 0.449]. No difference in OS was observed [RVd-Elo = 68 mos, RVd = not reached, HR = 1.279 (80% CI: 0.819, 2.000), p-value = 0.478]. 72% pts had > Grade 3 AEs, no differences in the safety profile were observed except >Grade 3 infections (RVd 8%, RVd-Elo 16%), >Grade 3 sensory neuropathy (RVd 8%, RVd-Elo 13%). Conclusions: In the first randomized HRMM study reported to date, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. However, the PFS and OS seen in both arms of the study exceeded the original statistical assumptions and support the role for PI/IMiD combination maintenance therapy for this patient population. The S1211 data will serve as an important benchmark for future HRMM clinical trials. Clinical trial information: NCT01668719 .

LIGHTNING STRIKES TWICE? ALVEOLAR HEMORRHAGE AND SINUS NODE DYSFUNCTION REQUIRING PACEMAKER AFTER INITIATING BORTEZOMIB FOR MULTIPLE MYELOMA

SESSION TITLE: Medical Student/Resident Pulmonary Manifestations of Systemic Disease 3 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Bortezomib is a proteasome inhibitor used in the treatment of multiple myeloma. Neuropathy, constipation, and edema are common side effects. Cardiotoxicity causing dysrhythmia and pacemaker placement have occurred, yet controversy exists regarding the risk of adverse cardiac events based on recent data. To date only 18 cases of alveolar hemorrhage (AH) associated with bortezomib have been described; symptoms occur after a median of four doses and respond to glucocorticoids. CASE PRESENTATION: DB is an 82 year old previously healthy male who presented with fatigue and arm pain admitted for a pathologic humerus fracture, acute renal failure and anemia. Bone marrow biopsy (48% k-restricted plasma cells via morphology, IgA K/L ratio of 345) confirmed the diagnosis of multiple myeloma. The patient received dexamethasone and 2.6mg of bortezomib on D1 and D4. Lenalidomide was held due to NSAID-induced nephropathy. The patient initially experienced distal neuropathy and extremity edema but was discharged and scheduled for outpatient therapy. At home, DB had a syncopal episode secondary to orthostasis and was admitted to the hospital where he received his third dose of bortezomib on D8 per protocol. A chest film ordered for worsening cough revealed right lower lobe infiltrates and bilateral pleural effusions. DB then developed sinus node dysfunction with multiple syncopal episodes requiring a pacemaker. On D26, he developed worsening hypoxia with increased effusions and ground glass opacities on CT imaging. He had preserved ejection fraction and normal IVC collapsibility on echocardiogram. Cefepime, vancomycin, sulfamethoxazole-trimethoprim, and prednisone yielded no improvements. Fat pad biopsy was negative for amyloid. Bronchial lavage was not done due to concern for inability to extubate post-procedure. Worsening renal function precluded CTA for pulmonary embolism. On D33 he was intubated due to respiratory failure. A BAL revealed three progressively bloody aliquots suggestive of AH and the patient was treated with 1g IV solumedrol for three days. Repeat BAL on D39 revealed markedly less bloody aliquots, suggestive of improvement and he was extubated on D48. DISCUSSION: Similar to previously cases, we demonstrate AH after three doses of bortezomib, bilateral infiltrates and effusions, lavage-proven hemorrhage and response to steroids. Unlike others, our case appears to be the first Caucasian male and the oldest known patient to experience this toxicity. Our case has an additional complexity of sinus node dysfunction after induction of bortezomib suggesting an even more rare potential toxicity of bortezomib. CONCLUSIONS: This may represent the first case of concomitant AH and sinus node dysfunction associated with bortezomib and highlights the importance of early recognition and rapid initiation of high dose glucocorticoid therapy. Reference #1: Sugita, Y., et al (2018). Early-Onset Severe Diffuse Alveolar Hemorrhage after Bortezomib Administration Suggestive of Pulmonary Involvement of Myeloma Cells. Reference #2: Diwadkar, Sachin, et al. “Bortezomib-Induced Complete Heart Block and Myocardial Scar: The Potential Role of Cardiac Biomarkers in Monitoring Cardiotoxicity.” Case Reports in Cardiology, vol. 2016, 2016, pp. 1–5., https://doi.org/10.1155/2016/3456287. Reference #3: Laubach, Jacob P., et al. “A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.” British Journal of Haematology, vol. 178, no. 4, Mar. 2017, pp. 547–560., https://doi.org/10.1111/bjh.14708. DISCLOSURES: No relevant relationships by Patrick Bagley, source=Web Response No relevant relationships by Alexander Dew, source=Web Response

Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation

BackgroundMantle cell lymphoma (MCL) is an aggressive and incurable lymphoma. Standard of care for younger patients with MCL is induction chemotherapy followed by autologous stem cell transplantation (auto-HCT). Rituximab maintenance after auto-HCT has been shown to improve progression-free survival (PFS) and overall survival (OS) in MCL. Bortezomib maintenance therapy has also been shown to be tolerable and feasible in this setting. However, the combination of bortezomib and rituximab as maintenance therapy post-auto-HCT has not been studied.MethodsWe conducted a multicenter, phase II trial of bortezomib given in combination with rituximab as maintenance in MCL patients after consolidative auto-HCT. Enrolled patients (n = 23) received bortezomib 1.3 mg/m2 subcutaneously weekly for 4 weeks every 3 months (up to 24 months) and rituximab 375 mg/m2 intravenously weekly for 4 weeks every 6 months (up to 24 months) for a total duration of 2 years. The primary study endpoint was disease-free survival (DFS).ResultsWith a median follow-up of 35.9 months, the 2-year DFS probability was 90.2% (95% CI 66–97), and 2-year OS was 94.7% (95% CI 68–99). The most frequent grade 3/4 toxic events were neutropenia (in 74% of patients) and lymphopenia (in 35%). The incidence of peripheral neuropathy was 48% for grade 1, 9% for grade 2, and 0% for grade 3/4. We also examined the role of quantitative cyclin D1 (CCND1) mRNA in monitoring minimal residual disease.ConclusionCombined bortezomib and rituximab as maintenance therapy in MCL patients following auto-HCT is an active and well-tolerated regimen.Trial registrationClinicalTrials.govNCT01267812, registered Dec 29, 2010.

A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-cell Lymphoma

BackgroundThe proteasome inhibitor bortezomib has demonstrated marked preclinical activity when combined with the histone deacetylase inhibitor vorinostat in leukemia, multiple myeloma, and mantle cell lymphoma (MCL) cells. The present study evaluated the efficacy and safety of the combination in patients with relapsed or refractory MCL and diffuse large B-cell lymphoma (DLBCL). Patients and MethodsThe present multicenter, nonrandomized phase II trial used a Simon 2-stage design with 3 cohorts: cohort A, MCL with no previous bortezomib (including untreated MCL); cohort B, MCL with previous bortezomib; and cohort C, relapsed or refractory DLBCL with no previous bortezomib. Vorinostat (400 mg) was administered orally on days 1 to 5 and 8 to 12 before bortezomib (1.3 mg/m2), which was administered intravenously on days 1, 4, 8, and 11 of each 21-day cycle. ResultsFor the 65 treated patients (22 in cohort A, 4 in cohort B, and 39 in cohort C), the overall response rate was 31.8%, 0%, and 7.7%, respectively. The median progression-free survival was 7.6 months for cohort A and 1.8 months for cohort C. In cohort A, 7 patients had a partial response (PRs), 5 had stable disease (SD), 7 had progressive disease (PD), 1 was not assessed, and 2 were not evaluable. In cohort B, 2 had SD and 2 had PD. In cohort C, 3 had a PR, 8 had SD, 23 had PD, and 5 were not assessed. Baseline NF-κB activation, measured as nuclear RelA by immunohistochemistry, did not correlate with clinical response. ConclusionThe combination of bortezomib and vorinostat is safe and has modest activity in MCL and limited activity in DLBCL.

Phase 2 trial of bortezomib in combination with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with bortezomib, rituximab, methotrexate, and cytarabine for untreated mantle cell lymphoma

Although the outcomes of patients with mantle cell lymphoma (MCL) have improved, there is still no cure. Bortezomib has a 33% response rate in relapsed/refractory MCL and has shown additive and/or synergistic effects in preclinical trials with known effective agents. This is a report of a prospective phase 2 trial of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD)/rituximab, high-dose methotrexate, and high-dose cytarabine (BzR-MA) for 95 patients with newly diagnosed MCL. The overall and complete response rates were 100% and 82%, respectively. Hematologic toxicity was high but expected and did not lead to an increased incidence of neutropenic fever or dose reductions in comparison with a similar reported regimen without bortezomib. After a median follow-up of 44 months, the median overall survival had not been reached, and the time to treatment failure (TTF) was 55 months, which is not different from that of historical controls. BzR-hyperCVAD/BzR-MA at the dose and schedule studied produced high rates of response and a TTF similar to that of historical reports without bortezomib. Cancer 2018;124:2561-9. © 2018 American Cancer Society.

A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection.

Late antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Uncontrolled studies have suggested efficacy of the proteasome inhibitor bortezomib, but no systematic trial has been undertaken to support its use in ABMR. In this randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial), we investigated whether two cycles of bortezomib (each cycle: 1.3 mg/m2 intravenously on days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor-specific antibody (DSA)-positive ABMR. Forty-four DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years; pretransplant DSA documented in 19 recipients), who were identified on cross-sectional screening of 741 patients, were randomly assigned to receive bortezomib (n=21) or placebo (n=23). The 0.5-ml/min per 1.73 m2 per year (95% confidence interval, -4.8 to 5.8) difference detected between bortezomib and placebo in eGFR slope (primary end point) was not significant (P=0.86). We detected no significant differences between bortezomib- and placebo-treated groups in median measured GFR at 24 months (33 versus 42 ml/min per 1.73 m2; P=0.31), 2-year graft survival (81% versus 96%; P=0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes in 24-month follow-up biopsy specimens. Bortezomib, however, associated with gastrointestinal and hematologic toxicity. In conclusion, our trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. Our results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR.

Using Delayed Toxicities to Re-evaluate Tolerability in Phase 2 Trials: A Case Example using Bortezomib

ABSTRACTIn advanced stage patients enrolled in dose-finding trials, it is difficult to assess delayed toxicities because frequently patients discontinue after one or two cycles of treatment. Patients enrolled in phase 2 trials are typically followed longer to assess efficacy. Thus, their data may be useful for evaluating long-term tolerability. We illustrate this using as example two phase 2 bortezomib trials (total N = 172) conducted by SWOG. While treatment-related severe toxicity rates based on cycle 1 were acceptable (23% and 31%), they were notably higher over extended administration (37% and 70%). This additional information should be considered when designing subsequent trials.

A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.

This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3-4·0% in studies in relapsed/refractory MM and 1·2-4·7% in previously untreated MM (2·0-7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3-5·9% grade ≥2; 0·6-4·1% grade ≥3), IHD (1·2-2·9% all grades; 0·4-2·7% grade ≥3) and cardiac death (0-1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.

Long-term follow-up of exceptional responders on the phase II trial of weekly bortezomib and rituximab in untreated and relapsed patients with waldenstrom's macroglobulinemia.

8065Background: This follow-up study aimed to update the progression-free survival (PFS) and identify responder subgroups in the phase II trial of Bortezomib and Rituximab in patients with Waldenst...

Bortezomib for the treatment of multiple myeloma.

Multiple myeloma is a malignancy of plasma cells accounting for approximately 1% of cancers and 12% of haematological malignancies. The first-in-class proteasome inhibitor, bortezomib, is commonly used to treat newly diagnosed as well as relapsed/refractory myeloma, either as single agent or combined with other therapies. We conducted a systematic review and meta-analysis to assess the effects of bortezomib on overall survival (OS), progression-free survival (PFS), response rate (RR), health-related quality of life (HRQoL), adverse events (AEs) and treatment-related death (TRD). We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE (till 27 January 2016) as well as conference proceedings and clinical trial registries for randomised controlled trials (RCTs). We included randomised controlled trials (RCTs) that compared i) bortezomib versus no bortezomib with the same background therapy in each arm; ii) bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s) and iii) bortezomib dose comparisons and comparisons of different treatment administrations and schedules. Two review authors independently extracted outcomes data and assessed risk of bias. We extracted hazard ratios (HR) and their confidence intervals for OS and PFS and odds ratios (OR) for response rates, AEs and TRD. We contacted trial authors to provide summary statistics if missing. We estimated Logrank statistics which were not available. We extracted HRQoL data, where available. We screened a total of 3667 records, identifying 16 relevant RCTs involving 5626 patients and included 12 trials in the meta-analyses. All trials were randomised and open-label studies. Two trials were published in abstract form and therefore we were unable to assess potential risk of bias in full.There is moderate-quality evidence that bortezomib prolongs OS (four studies, 1586 patients; Peto OR 0.77, 95% CI 0.65 to 0.92) and PFS (five studies, 1855 patients; Peto OR 0.65, 95% CI 0.57 to 0.74) from analysing trials of bortezomib versus no bortezomib with the same background therapy in each arm.There is high-quality evidence that bortezomib prolongs OS (five studies, 2532 patients; Peto OR 0.76, 95% CI 0.67 to 0.88) but low-quality evidence for PFS (four studies, 2489 patients; Peto OR 0.67, 95% CI 0.61 to 0.75) from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s).Four trials (N = 716) examined different doses, methods of administrations and treatment schedules and were reviewed qualitatively only.We identified four trials in the meta-analysis that measured time to progression (TTP) and were able to extract and analyse PFS data for three of the studies, while in the case of one study, we included TTP data as PFS data were not available. We therefore did not analyse TTP separately in this review.Patients treated with bortezomib have increased risk of thrombocytopenia, neutropenia, gastro-intestinal toxicities, peripheral neuropathy, infection and fatigue with the quality of evidence highly variable. There is high-quality evidence for increased risk of cardiac disorders from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or versus other agents. The risk of TRD in either comparison group analysed is uncertain due to the low quality of the evidence.Only four trials analysed HRQoL and the data could not be meta-analysed.Subgroup analyses by disease setting revealed improvements in all outcomes, whereas for therapy setting, an improved benefit for bortezomib was observed in all outcomes and subgroups except for OS following consolidation therapy. This meta-analysis found that myeloma patients receiving bortezomib benefited in terms of OS, PFS and response rate compared to those who did not receive bortezomib. This benefit was observed in trials of bortezomib versus no bortezomib with the same background therapy and in trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s). Further evaluation of newer proteasome inhibitors is required to ascertain whether these agents offer an improved risk-benefit profile, while more studies of HRQoL are also required.

IntReALL HR and the benefits of adaptive design

Survival of children with acute lymphoblastic leukemia (ALL) has improved considerably over the past few decades, but relapsed ALL remains difficult to treat, particularly in those whose relapse puts them in a high risk (HR) group. Little progress has been made during the last two decades in the HR group despite several new drugs being investigated. The International BFM Study Group consists of experts from 20 European countries who have combined to ensure enough patients to carry out clinical trials and advance the treatment of HR relapsed ALL paediatric patients. Even though the previous 2 new treatments have not been beneficial, these clinicians are keen to give patients new treatments that look promising and are reticent to recruit them into a trial where there is only a 50% chance of being randomised to the new treatment. Hence the design chosen for IntReALL-HR is a covariate adaptive response adaptive (CARA) randomised controlled trial of bortezomib plus standard treatment versus standard treatment alone in children with relapsed ALL in the HR group. Patients are randomised with higher probability to the treatment that is currently “best”, thereby gaining the benefits of randomisation, while satisfying the clinicians in assigning more patients to the better treatment and being a benefit to the patients who have a high chance of obtaining the best treatment at the point of their diagnosis with relapse. All countries have agreed to take part in the trial.

Phase II trial of bortezomib in KRAS G12D mutant lung cancers.

e19002 Background: KRAS mutations are the most common oncogenic drivers in lung cancers without any approved targeted therapy. Preclinical evidence suggests that KRAS mutations are highly dependent...

Phase I Trial of Bortezomib and Everolimus in Relapsed/Refractory Non-Hodgkin Lymphoma

INTRODUCTION: Non-Hodgkin lymphomas (NHL) are characterized by dysregulation of pathways controlling cell proliferation and apoptosis. Proteosome inhibitors and mTOR inhibitors target these pathways and have single-agent activity in NHL, though their safety and efficacy when used in combination requires further study. We conducted a prospective, phase I dose-escalation study to determine the safety, efficacy and maximum tolerated dose (MTD) of everolimus in combination with bortezomib in patients (pts) with relapsed/refractory NHL.METHODS: Eligibility criteria included: (1) relapsed or relapsed/refractory NHL with no limit on prior therapy; (2) measurable disease by standard radiographic findings (or monoclonal protein assessment for pts with lymphoplasmacytic lymphoma (LPL)); (3) ECOG PS ≤ 2 and adequate organ function. Hematologic parameters initially include platelets > 100,000 but subsequent amendments permitted >75,000. Dose levels for bortezomib were 0.7, 1, or 1.3 mg/m2 given either IV or SC on d1, 4, 8, and 11 every 21 days. Everolimus was given orally 5 mg every other day (qod) or daily (qd), or 10 mg qd. Dose levels were increased using a standard 3 x 3 design (see table). Pts were assessed for response after every 2 cycles and maintained on treatment continuously until disease progression, death, intolerance to treatment or patient choice.RESULTS: 28 pts were enrolled from July 2008 to June 2014. The median age was 65 (range, 40–86) years and 20/28 (61%) were male. Diagnoses included: follicular lymphoma (FL, 9), mantle cell lymphoma, (MCL, 5), diffuse large B-cell lymphoma (5), small lymphocytic lymphoma (SLL, 2), T-cell lymphoma, NOS (1), nodal marginal zone lymphoma (2), anaplastic large cell lymphoma (1), LPL (1), and splenic marginal zone lymphoma (SMZL, 1). Median number of prior therapies was 3 (range, 1-5) with no pts previously receiving bortezomib. Median number of cycles of therapy on study was 3 (range, 1-41). Hematologic toxicities included anemia (36 grade I/II, 6 grade III), neutropenia (10 grade I/II, 2 grade III), and lymphopenia (14 grade I/II, 3 grade III). Thrombocytopenia (44 grade I/II, 6 grade III) was the AE most commonly leading to treatment interruptions. Non-hematologic grade III toxicities included: cardiac (n=1), fatigue (n=1), skin infection (n = 1), low testosterone (n = 1), pneumonia (n=1), LFT elevation (n=4), hyperglycemia (n=1), hypercalcemia (n=1), electrolyte abnormalities (n=2), muscle weakness (n=1), syncope (n=1), herniated disc (n=1), flu-like symptoms (n=1). There were two grade IV toxicities: hyperkalemia (n=1) and secondary malignancy (n=1). Escalation of everolimus to 10 mg qd with bortezomib 1.3 mg/m^2 on d1, 4, 8 and 11 (dose level 5) resulted in dose-limiting thrombocytopenia requiring protocol amendment to declare the MTD to be dose level 4: 5 mg everolimus qd with 1.3 mg/m2 bortezomib d1, 4, 8, and 11 every 21 days. Of 24 response-evaluable pts there was 1 complete response in an MCL patient and 3 partial responses (2 MCL, 1 FL) for an overall response rate of 17%. There were 9 pts with stable disease (5 FL, 1 MCL, 1 SLL and 1 SMZL) and 11 pts had progressive disease. All but one patient have discontinued treatment. Reasons for discontinuation included disease progression (15), adverse event (10) or patient choice (2).CONCLUSIONS: The combination of everolimus and bortezomib results in dose limiting thrombocytopenia at maximal single agent doses. Everolimus at 5 mg qd can be safely combined with standard dose bortezomib (1.3 mg/m2 d1, 4, 8 and 11 q 21d). This combination has modest clinical activity in heavily pre-treated aggressive and follicular NHL. Notable responses were found in 3 of 5 MCL patients, warranting further investigation of this combination for mantle cell lymphoma. Abstract 4482. Table:Dose levels, toxicities, treatment length and responses of relapsed/refractory NHL patients treated with bortezomib + everolimusDose levelNEverolimus(mg)Bortezomib1(mg/m2)Grade III/IV Adverse EventsMean # CyclesResponseHematologicNon-Hematologic135 qod0.702242 PR, 1 SD235 qod1.02331 PR, 1 SD, 1 PD375 qd1.041052 SD, 3 PD, 2NE465 qd1.35751 SD, 3 PD, 2NE25910 qd1.35291 CR, 3 SD, 4 PD, 1 NEAbbreviations: CR, complete response; PR, partial response, PD, progressive disease; NE, not-evaluableNotes: (1). Bortezomib at indicated dose on d1, 4, 8, 11 q21 days, (2) patient still on treatment DisclosuresHill:Novartis: Research Funding; Millenium: Research Funding. Off Label Use: Bortezomib and everolimus are both off-label for the treatment of most NHL.. Smith:Novaartis: Research Funding; Millenium: Research Funding.

A Phase II Trial of Bortezomib Added to Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients with Previously Untreated Indolent Non-Hodgkin’s Lymphoma

Background: Bortezomib-containing combination chemotherapy regimens are effective in non-Hodgkin’s lymphoma (NHL), although there are limited data on toxicity in the front-line setting for indolent NHL when combined with reduced-dose vincristine-containing chemotherapy. Our group (Sinha et al, Cancer 2012) reported outcomes from a phase I study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (VR-CHOP) and found a maximum tolerated dose (MTD) of bortezomib (V) of 1.6mg/m2 with vincristine capped at 1.5 mg with an overall response rate (ORR) of 100%. Herein we report the results of our phase II study of this regimen.Patients and Methods: Eligible patients had untreated indolent NHL (small lymphocytic lymphoma [SLL], marginal zone lymphoma [MZL], or follicular lymphoma [FL] grades 1-3) meeting standard criteria for treatment or with FL international prognostic index (FLIPI) ≥3. Patients received V administered at a dose of 1.6mg/m2 on days 1 and 8 as well as rituximab (R) 375mg/m2, cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, and vincristine 1.4mg/m2 (capped at 1.5mg/dose) on day 1 and prednisone 100mg on days 1-5 of a 21-day cycle. Patients received at least 6 cycles and up to 8 cycles of therapy at the discretion of the treating physician. Patients who achieved a complete response (CR) after induction were assigned to receive maintenance R 375mg/m2 every 12 weeks for 2 years while patients with a partial response (PR) or stable disease received R 375mg/m2 along with V 1.6mg/m2 (VR), both administered weekly for 4 weeks every 6 months for up to 2 years. Response was assessed by Cheson 1999 criteria, and toxicity assessed by CTCAE version 3.0. One FL patient discontinued study therapy after cycle 2 when a central pathology review revised the diagnosis to diffuse large B-cell lymphoma. This patient was not included in the efficacy analysis but is included in the safety reports. CR rate and ORR were determined at the conclusion of induction therapy, and progression-free survival (PFS) and overall survival (OS) were evaluated by the Kaplan-Meier method from the date of study entry.Results: Thirty patients received at least 1 treatment of VR-CHOP, including 16 males and 14 females. The median age was 58 (range: 31-71), and histologies included MZL (n=5), SLL (n=4), and FL (Grade 1, n=7; Grade 2, n=12; Grade 3, n=2). FLIPI score for patients with FL were 1 (n=2), 2 (n=4), 3 (n=12), and 4 (n=3). Twenty-nine were evaluable for response, including 19 patients with CR and 10 patients with PR at the conclusion of induction therapy (CR rate of 66%; ORR of 100%). For 20 evaluable patients with FL, the CR rate was 75%. Twenty-five patients proceeded with maintenance therapy, including 6 patients who received VR and 19 patients who received R alone. Three patients with PR to induction converted to CR after maintenance with VR. Four patients received no maintenance due to refusal/lost to follow-up (n=2), toxicity (n=1), and progression (n=1). Three patients with PR received only R due to neuropathy. Four patients have relapsed or progressed on therapy, including 1 patient prior to starting maintenance, 2 patients during VR maintenance, and 1 patient who achieved a PR but was receiving R maintenance. One additional patient progressed after completing R maintenance. With a median follow-up of 39 months, 3-year PFS rate is 85.8%, and the 3-year OS rate is 96.4% (Figure). Grade ≥3 peripheral neuropathy was noted in 2 patients (7%), while grade 1-2 neuropathy occurred in 17 patients (57%). Grade 3-4 hematologic toxicities included neutropenia (n=14, 47%), thrombocytopenia (n=3, 10%), anemia (n=1, 3%), and febrile neutropenia (n=1, 3%). Eight patients experienced additional grade 3 non-hematologic toxicities, including the following which occurred in more than 1 patient: vomiting (n=3, 10%), abdominal pain (n=2, 7%), fatigue (n=2, 7%), hyperglycemia (n=2, 7%), hypokalemia (n=2, 7%), and nausea (n=2, 7%).Conclusion: VR-CHOP is highly efficacious in the front-line setting for management of patients with untreated indolent NHL, and toxicities are expected and manageable. Incidence of grade 3 peripheral neuropathy is low with incorporation of a decreased dose of vincristine, and the PFS compares favorably with previously reported outcomes in FL and indolent NHL for R-CHOP, R-Bendamustine, and R-CHOP plus maintenance R. [Display omitted] DisclosuresCohen:Janssen: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Off Label Use: Bortezomib is not currently approved for follicular lymphoma, marginal zone lymphoma, or small lymphocytic lymphoma and is being evaluated in combination with a standard induction regimen.. Kaufman:Millennium: Consultancy; Janssen: Consultancy. Nastoupil:TG Therapeutics: Research Funding; Celgene: Honoraria; Genentech: Honoraria; Janssen: Research Funding. Lechowicz:Millennium: Consultancy. Lonial:Millennium, Celgene, Novartis, BMS, Onyx: Consultancy, Research Funding. Flowers:Gilead, Spectrum, Millennium, Janssen: Research Funding; Celgene, Prescription Solutions, Seattle Genetics, Millennium (unpaid), Genentech (unpaid) : Consultancy.