Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of ...pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2. PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions CRs, 5 complete remission with incomplete peripheral count recovery, 7 partial remissions PRs), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.
•RP2D of PEV 20 mg/m2 in PEV/AZA combo did not alter toxicity profile of AZA; dose-limiting toxicities were transiently elevated AST/ALT.•In treatment-naive older AML patients, the intent-to-treat ORR was 50%.
Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or ...their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Conversion from MRD− to MRD+ or from MRD+ to MRD− status during ixazomib or placebo maintenance modulates the risk of disease progression.•Ixazomib prolonged progression-free survival in patients ...who were MRD+ before maintenance and at a 14-month landmark analysis.
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Measurable residual disease (MRD) evaluation may help to guide treatment duration in multiple myeloma (MM). Paradoxically, limited longitudinal data exist on MRD during maintenance. We investigated the prognostic value of MRD dynamics in 1280 transplant-eligible and -ineligible patients from the TOURMALINE-MM3 and -MM4 randomized placebo-controlled phase 3 studies of 2-year ixazomib maintenance. MRD status at randomization showed independent prognostic value (median progression-free survival PFS, 38.6 vs 15.6 months in MRD− vs MRD+ patients; HR, 0.47). However, MRD dynamics during maintenance provided more detailed risk stratification. A 14-month landmark analysis showed prolonged PFS in patients converting from MRD+ to MRD− status vs those with persistent MRD+ status (76.8% vs 27.6% 2-year PFS rates). Prolonged PFS was observed in patients with sustained MRD− status vs those converting from MRD− to MRD+ status (75.0% vs 34.2% 2-year PFS rates). Similar results were observed at a 28-month landmark analysis. Ixazomib maintenance vs placebo improved PFS in patients who were MRD+ at randomization (median, 18.8 vs 11.6 months; HR, 0.65) or at the 14-month landmark (median, 16.8 vs 10.6 months; HR, 0.65); no difference was observed in patients who were MRD−. This is the largest MM population undergoing yearly MRD evaluation during maintenance reported to date. We demonstrate the limited prognostic value of a single–time point MRD evaluation, because MRD dynamics over time substantially impact PFS risk. These findings support MRD− status as a relevant end point during maintenance and confirm the increased progression risk in patients converting to MRD+ from MRD− status. These trials were registered at www.clinicaltrials.gov as #NCT02181413 and #NCT02312258.
Measurable residual disease (MRD) status after initial therapy for multiple myeloma is a proven surrogate for progression-free survival (PFS), but its value during maintenance is uncertain. Paiva et al report that serial monitoring of MRD during maintenance treatment captures dynamic conversion between MRD-negative and -positive states and robustly anticipates PFS. This shows the feasibility of longer term MRD monitoring and provides a rationale for trials that investigate intervention prior to frank relapse or shortening of maintenance for those who remain MRD negative.
Estimating progression-free survival (PFS) and overall survival (OS) superiority during clinical trials of multiple myeloma (MM) has become increasingly challenging as novel therapeutics have ...improved patient outcomes. Thus, it is imperative to identify earlier endpoint surrogates that are predictive of long-term clinical benefit to expedite development of more effective therapies. Minimal residual disease (MRD)-negativity is a common intermediate endpoint that has shown prognostic value for clinical benefit in trials of patients with multiple myeloma (MM). This meta-analysis was based on the FDA guidance for considerations for a meta-analysis of MRD as a clinical endpoint and evaluates MRD-negativity as an early endpoint reasonably likely to predict long-term clinical benefit. Eligible studies were phase 2 or 3 randomized controlled clinical trials measuring MRD negativity as an endpoint in patients with MM, with follow-up of ≥6 months following an a priori defined time point of 12±3 months post-randomization. Eight newly diagnosed MM-(NDMM)-studies evaluating 4,907 patients were included. Trial-level associations between MRD-negativity and PFS were R2WLSiv (95% CI) 0.67 (0.43-0.91) and R2copula 0.84 (0.64->0.99) at the 12-month timepoint. The individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 4.02 (95% CI: 2.57-5.46). For relapse/refractory MM-(RRMM), there were four studies included, and the individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 7.67 (4.24-11.10). A clinical trial demonstrating a treatment effect on MRD is reasonably likely to eventually demonstrate a treatment effect on PFS, suggesting that MRD may be an early clinical endpoint reasonably likely to predict clinical benefit in MM, that may be used to support accelerated approval and thereby expedite the availability of new drugs to patients with MM.
Summary
Purpose
This phase Ib study (NCT01862328) evaluated the maximum tolerated dose (MTD), safety, and efficacy of pevonedistat in combination with standard-of-care chemotherapies in patients with ...solid tumors.
Methods
Patients received pevonedistat with docetaxel (arm 1,
n
= 22), carboplatin plus paclitaxel (arm 2,
n
= 26), or gemcitabine (arm 3,
n
= 10) in 21-days (arms 1 and 2) or 28-days (arm 3) cycles. A lead-in cohort (arm 2a,
n
= 6) determined the arm 2 carboplatin dose. Dose escalation proceeded via continual modified reassessment.
Results
Pevonedistat MTD was 25 mg/m
2
(arm 1) or 20 mg/m
2
(arm 2); arm 3 was discontinued due to poor tolerability. Fifteen (23%) patients experienced dose-limiting toxicities during cycle 1 (grade ≥3 liver enzyme elevations, febrile neutropenia, and thrombocytopenia), managed with dose holds or reductions. Drug-related adverse events (AEs) occurred in 95% of patients. Most common AEs included fatigue (56%) and nausea (50%). One drug-related death occurred in arm 3 (febrile neutropenia). Pevonedistat exposure increased when co-administered with carboplatin plus paclitaxel; no obvious changes were observed when co-administered with docetaxel or gemcitabine. Among 54 response-evaluable patients, two had complete responses (arm 2) and 10 had partial responses (three in arm 1, one in arm 2a, six in arm 2); overall response rates were 16% (arm 1) and 35% (arm 2). High ERCC1 expression correlated with clinical benefit in arm 2.
Conclusion
Pevonedistat with docetaxel or with carboplatin plus paclitaxel was tolerable without cumulative toxicity. Sustained clinical responses were observed in pretreated patients receiving pevonedistat with carboplatin and paclitaxel.
ClinicalTrials.gov
identifier: NCT01862328.
Some cytogenetic abnormalities (CAs) are associated with poorer prognosis in multiple myeloma (MM); proteasome inhibitors appear to benefit patients with high-risk CAs. We evaluated 2247 MM patients ...from the TOURMALINE-MM1/-MM2/-MM3/-MM4 trials to assess the PFS benefit of ixazomib plus lenalidomide-dexamethasone (Rd) vs placebo-Rd (TOURMALINE-MM1/-MM2) or ixazomib vs placebo (TOURMALINE-MM3/-MM4) in specific high-risk CAs. After a pooled median follow-up of 25.6 months, the hazard ratio (HR) for PFS with ixazomib- vs placebo-based therapy for high-risk patients was 0.74 (95% confidence interval CI: 0.59-0.93; median PFS mPFS 17.8 vs 13.2 months), and 0.70 (95% CI: 0.62-0.80; mPFS 26.3 vs 17.6 months) for complementary standard-risk patients. The HR for expanded high-risk patients was 0.75 (95% CI: 0.64-0.87; mPFS 18.1 vs 14.1 months), and 0.71 (95% CI: 0.59-0.85; mPFS 36.1 vs 21.4 months) for complementary standard-risk patients. The HR for PFS with ixazomib- vs placebo-based therapy was 0.68 in patients with t(4;14) (95% CI: 0.48-0.96; mPFS 22.4 vs 13.2 months), and 0.77 for patients with amp1q21 (95% CI: 0.63-0.93; mPFS 18.8 vs 14.5 months). A PFS benefit was demonstrated with ixazomib- vs placebo-based therapy regardless of cytogenetic status, with greatest benefit observed in patients with t(4;14) and amp1q21.
Objectives
Evaluating potential relationships between progression‐free survival (PFS) and tumor gene expression patterns and mutational status was an exploratory objective of the phase 3 ...TOURMALINE‐MM1 study (NCT01564537) of ixazomib‐lenalidomide‐dexamethasone (IRd) vs placebo‐Rd in 722 patients with relapsed/refractory multiple myeloma (MM).
Methods
We utilized gene expression and mutation data from screening bone marrow aspirates to identify tumors with non‐canonical nuclear factor‐κB (NF‐κB) signaling pathway activation.
Results
DNA/RNA sequencing data were available for 339 (47.0%)/399 (55.2%) patients; 49/339 (14.5%) patients had non‐canonical NF‐κB pathway gene mutations (tumor‐necrosis‐factor receptor‐associated factor 2, 3 TRAF2, TRAF3, baculoviral‐inhibitor‐of‐apoptosis repeat‐containing 2/3 BIRC2/3), and PFS was significantly longer with IRd vs placebo‐Rd in these patients (hazard ratio HR 0.23). In patients with lower TRAF3 expression (median not reached vs 11 months, HR 0.47) and higher NF‐κB‐inducing kinase (NIK) expression (median not reached vs 14 months, HR 0.45), both associated with non‐canonical NF‐κB pathway activation, PFS was significantly longer with IRd vs placebo‐Rd. TRAF3 expression was decreased in patients harboring t(4;14) and 1q21 amplification, suggesting increased non‐canonical NF‐κB pathway activation.
Conclusions
Adding ixazomib to Rd provides clinical benefit in MM tumors with increased non‐canonical NF‐κB pathway activity. This is a potential mechanism for activity in 1q21 amplified high‐risk tumors.
Constitutive activation of tyrosine kinases, such as the BCR/ABL fusion associated with t(9;22)(q34;q22), is a hallmark of chronic myeloid leukemia (CML) syndromes in humans. Expression of BCR/ABL is ...both necessary and sufficient to cause a chronic myeloproliferative syndrome in murine bone marrow transplantation models, and absolutely depends on kinase activity. Progression of CML to acute leukemia (blast crisis) in humans has been associated with acquisition of secondary chromosomal translocations, including the t(7;11)(p15;p15) resulting in the NUP98/HOXA9 fusion protein. We demonstrate that BCR/ABL cooperates with NUP98/HOXA9 to cause blast crisis in a murine model. The phenotype depends both on expression of BCR/ABL and NUP98/HOXA9, but tumors retain sensitivity to the ABL inhibitor STI571 in vitro and in vivo. This paradigm is applicable to other constitutively activated tyrosine kinases such as TEL/PDGFβR. These experiments document cooperative effects between constitutively activated tyrosine kinases, which confer proliferative and survival properties to hematopoietic cells, with mutations that impair differentiation, such as the NUP98/HOXA9, giving rise to the acute myeloid leukemia (AML) phenotype. Furthermore, these data indicate that despite acquisition of additional mutations, CML blast crisis cells retain their dependence on BCR/ABL for proliferation and survival.
The
pim-1 oncogene is regulated by hematopoietic cytokine receptors, encodes a serine/threonine protein kinase, and cooperates with c-
myc in lymphoid cell transformation. Using a yeast two-hybrid ...screen, we found that Pim-1 protein binds to p100, a transcriptional coactivator that interacts with the c-Myb transcription factor. Pim-1 phosphorylated p100 in vitro, formed a stable complex with p100 in animal cells, and functioned downstream of Ras to stimulate c-Myb transcriptional activity in a p100-dependent manner. Thus, Pim-1 and p100 appear to be components of a novel signal transduction pathway affecting c-Myb activity, linking all three to the cytokine-regulated control of hematopoietic cell growth, differentiation, and apoptosis.
Background: Clinical responses to hypomethylating agents (HMA) occur in the minority of patients with myelodysplastic syndromes (MDS) and related disorders and require months of treatment. Robust ...biomarkers of HMA response would have great clinical utility but remain elusive. Combinations of HMA and novel agents may improve response rates and latency and be associated with distinct biomarkers. Predictive baseline DNA methylation (DNAm) profiles have yet to be identified in MDS, although responders show more global hypomethylation after response occurs. DNAm changes shortly after treatment may add predictive power as they reflect additional factors including effective cellular exposure and the rate of DNAm recovery between treatment cycles. To determine if DNAm profiling at baseline and early during treatment can improve our ability to predict response, we examined targeted DNAm profiles in samples from patients with higher-risk MDS (HR-MDS), chronic myelomonocytic leukemia (CMML), and low-blast count acute myeloid leukemia (LB-AML), previously untreated with HMA who were enrolled in the Pevonedistat-2001 (P-2001) Phase 2 study of azacitidine (AZA) with or without pevonedistat (PEV).
Methods: Targeted DNAm was quantified using bisulfite padlock probes (BSPP) at ~141,000 unique regions known to contain differentially methylated CpG sites. BSPP sequencing was performed on 130 genetically and clinically annotated bone marrow mononuclear cell DNA samples collected at screening and Cycle 2 Day 22±3 (C2D22). Data from 15 samples were removed due to low CpG coverage resulting in 115 samples with >10X coverage of 322,387 CpGs each. There were 27 patients with paired samples, 30 with screening only, and 31 with C2D22 only (Table 1, Figure 1A). Responses for HR-MDS and CMML were categorized according to the IWG-2006 modified criteria and for LB-AML according to the IWG-2003 criteria. Differentially methylated CpGs were identified using the R package ’DSS’ v2.35.0. Non-negative matrix factorization-based unsupervised clustering was performed using the Onco-GPS method within the Python ’ccal’ package. Statistical analyses were carried out using R version 3.6.2.
Results: Differential DNAm analysis between screening and C2D22 for the 27 paired samples shows global demethylation after treatment in nearly all cases but is more pronounced in responders (mean change in global DNAm: response = -5.5%; non-response = -2.0%; t-test p < 0.001). There was no significant difference in demethylation between AZA and AZA+PEV treated groups (AZA: -5.3%; AZA+PEV: -4.1%; t-test p = 0.32). Patients who attained a complete response (CR) in the AZA+PEV arm tended to have more demethylated CpGs than those with a CR in the AZA arm (Figure 1B. Mean number of demethylated CpGs in complete responders: AZA = 16,459; AZA+PEV = 24,731; t-test p = 0.396). In general, responding patients strictly defined by CR or partial response had steeper declines in mean DNAm levels (Figure 1C) than patients with other types of responses, but did not show an association between demethylation and time to response (TTR). Unsupervised clustering of the top 3% most variably methylated CpGs using Onco-GPS did not identify clusters associated with response at screening, but did resolve a cluster highly enriched for responders assessed at C2D22 (Figure 1D. Cluster B, Fisher’s exact test p = 0.011; odds-ratio 95% CI = 1.52-Inf). Analysis of the CpG sites that define Cluster B and creation of a formalized statistical predictor of response based on DNAm patterns is ongoing.
Conclusions: DNAm patterns early in the course of HMA treatment correlate with eventual response, with CRs associated with the greatest degree of demethylation. Responders are more likely to have greater demethylation that may reflect greater effective AZA exposure or slower remethylation dynamics. Addition of PEV may intensify site-specific demethylation in responders and increase the proportion of responding patients. With a median TTR of 3-4 months in the P-2001 study, depth of demethylation at the C2D22 timepoint may help predict eventual response. Strategies to augment demethylation with adjunctive agents or HMA dose escalation in patients with early inadequate demethylation should be investigated. Ongoing work will incorporate mutation status and focus on refining DNAm signatures that can predict eventual response.
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Luger:Arcturus Therapeutics: Current Employment. Zhao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Fram:Takeda, Bristol Myers, Gilead, Pfizer, Baxter, Teva: Current equity holder in publicly-traded company; BeyondSpring Pharmaceuticals Inc.: Consultancy; Takeda Pharmaceuticals Intl. Co.: Current Employment; Vertex Pharmaceuticals: Patents & Royalties: No Royalties; Patent 10/728,114 (Vertex Pharmaceuticals). Dash:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment, Other: Stockholder. Bejar:Forty-Seven/Gilead: Honoraria; Genoptix/NeoGenomics: Honoraria; Daiichi-Sankyo: Honoraria; Takeda: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Astex/Otsuka: Honoraria; AbbVie/Genentech: Honoraria; Aptose Biosciences: Current Employment.
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