Upgrading Of Response Research Articles

Durable responses in patients with genitourinary cancers following immune checkpoint therapy rechallenge after moderate-to-severe immune-related adverse events

BackgroundImmune checkpoint therapy (ICT) prolongs survival in subsets of patients with cancer but can also trigger immune-related adverse events (irAEs) requiring treatment discontinuation. Recent studies have investigated safety of ICT...

Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Response Adapted Induction Treatment Improves Outcomes for Myeloma Patients; Results of the Phase III Myeloma XI Study

Response Adapted Induction Treatment Improves Outcomes for Myeloma Patients; Results of the Phase III Myeloma XI Study

Sequential Immunomodulatory Drug (IMiD) and Proteosome Inhibitor Therapy Improves Response Rates in Newly Diagnosed Multiple Myeloma: Preliminary Results From the Myeloma XI Trial

AbstractAbstract 335 BackgroundInduction treatment for myeloma has focused on improving response rates and many centres have evaluated and used triplets of therapy based on either IMiD or proteosome inhibitor drugs. Other strategies rely on combining the two classes of novel agents and excellent response rates have been obtained. An alternative approach to this, which moves some way towards personalised therapy, is to use sequential combinations of the two classes of novel agents dependent on the response achieved. The aim of this approach is to maximise responses and, by so doing, improve survival. MethodsIn order to test this concept, we have carried out a trial, Myeloma XI, which compared responses to cyclophosphamide, thalidomide and dexamethasone (CTD) with cyclophosphamide, lenalidomide and dexamethasone (CRD). Following the randomised use of either of these triplets, given to maximum response, patients achieving no response (NC or PD) received further therapy with a triplet composed of cyclophosphamide, bortezomib and dexamethasone (CVD). In order to test if a bortezomib combination could improve the response of maximally treated patients, those with a suboptimal response (MR or PR) were randomised to either no further therapy or to CVD. For patients achieving ≥ VGPR no further induction was given. Younger fitter patients went on to receive HDM plus ASCT whereas older less fit patients did not. All patients were eligible for a maintenance randomisation to no maintenance, lenalidomide or lenalidomide/vorinostat maintenance. For patients receiving CVD, treatment was continued to a maximum of 8 cycles, with response being assessed using IMWG criteria after each cycle and therapy continued to maximum response or intolerance. Here we present the response rates for patients who have received CVD. ResultsAt the time of this initial analysis 1424 patients have been randomised overall; 790 in the intensive pathway and 634 in the non-intensive pathway. Across both pathways, of the refractory patients with no response to induction treatment, an upgrade in response from NC or PD to ≥MR was seen after CVD treatment in 58% of patients, with 31% going on to achieve a VGPR or CR. In the other group of patients, those with a suboptimal response to induction treatment and randomised to receive CVD, 45% went on to achieve VGPR or CR. These patients reduced their paraprotein value by a mean of 74% from the start of CVD suggesting that the improvement in response is significant and not the result of patients marginally crossing the boundaries of response criteria. It seems that even in a group of maximally treated patients that response rates can be increased further by the use of a proteosome inhibitor drug.In the MRC Myeloma IX study the response rates at a similar time point for those treated with similar thalidomide based induction were PD/NC 7.1%, MR/PR 41.8%, VGPR/CR 37.5%. Assuming at least the same response rates in the current study then we calculate that it would be possible to get approximately 45% extra patients from MR/PR and 31% from PD/NC to ≥VGPR, equating to an approximate 21% increase in the ≥VGPR rate to 59% of the total patients. ConclusionsWe have demonstrated an improvement in response with the addition of a bortezomib based regimen in the group of patients who had a suboptimal response following induction chemotherapy with an IMiD based regimen. Particularly encouraging is the excellent rate of achievement of CR/VGPR in patients with no initial response to treatment. We anticipate that together this will significantly improve the percentage of patients achieving ≥VGPR, approximating 60% of all patients following induction, a response rate that should improve further following ASCT. Further follow up is required to know whether or not this will translate into an improvement in OS or PFS, however from previous studies we would expect this to be the case. Disclosures:Pawlyn:Celgene: Unrestricted educational grant Other. Off Label Use: Lenalidomide and vorinostat as maintenence therapy. Davies:Celgene: Honoraria, Speakers Bureau, Unrestricted educational grant, Unrestricted educational grant Other; Ortho Biotech: Honoraria, Speakers Bureau. Gregory:Celgene: Unrestricted educational grant Other. Szubert:Celgene: Unrestricted educational grant Other. Bell:Celgene: Unrestricted educational grant Other. Ouzman:Celgene: Unrestricted educational grant Other. Drayson:Celgene: Unrestricted educational grant Other. Owen:Celgene: Unrestricted educational grant Other. Jackson:Celgene: Honoraria, Unrestricted educational grant Other. Russell:Celgene: Unrestricted educational grant Other. Morgan:Ortho Biotech: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau, Unrestricted educational grant, Unrestricted educational grant Other.

Enhancing the value of horizon scanning through collaborative review

AbstractThere is an increased appreciation of the need for horizon scanning: the identification and assessment of issues that could be serious in the future but have currently attracted little attention. However, a process is lacking to identify appropriate responses by policy makers and practitioners. We thus suggest a process and trial its applicability. Twelve environmental conservation organizations assessed each of 15 previously identified horizon scanning issues for their impact upon their organization and the urgency with which they should consider the issue. They also identified triggers that would result in changes in their scoring of the likely urgency and impact of the issues. This process enables organizations to identify priority issues, identify issues they can ignore until there are further developments, benchmark priorities across organizations and identify cross-organizational priorities that warrant further attention, so providing an agenda for collation of evidence, research and policy development. In this trial the review of responses by other organizations resulted in the upgrading of response by a substantial proportion of organizations for eight of the 15 issues examined. We suggest this approach, with the novel components of collaborative assessment and identification of triggers, could be adopted widely, both within conservation organizations and across a wider range of policy issues.

Thalidomide Maintenance Significantly Improves Progression-Free Survival (PFS) and Overall Survival (OS) of Myeloma Patients When Effective Relapse Treatments Are Used: MRC Myeloma IX Results

AbstractAbstract 623 Background:Although a meta-analysis has suggested that a consistent PFS benefit is seen with maintenance thalidomide therapy in multiple myeloma (MM) patients, the impact on OS remains unclear (Hicks LK, et al. Cancer Treat Rev 2008;34:442-452). This could be due to a lack of effect, differing biological subgroups in relatively small studies with short follow-up, or lack of effective relapse treatment. Aims:The study was set up to evaluate the effect of thalidomide maintenance therapy in newly diagnosed MM patients aged ≥ 18 years with OS and PFS as end points, and to examine differential effects in fluorescence in situ hybridization (FISH) identified molecular subgroups. Methods:Following induction treatment in an intensive pathway for younger fitter patients and a non-intensive pathway for the remaining patients, eligible patients were randomized to open-label thalidomide maintenance until progression (50 mg/day escalating to 100 mg/day after 4 weeks assuming good tolerance) or no maintenance. Patients of all ages were included in the randomization. FISH was performed using standard approaches. Adverse FISH groups were defined as any of t(4;14), t(14;16), t(14;20), 1q+, 17p−, or 1p32− (in the intensive pathway only); the remainder were defined as favorable. Results:Overall, 820 patients were eligible of which 818 were evaluable. Median patient age was 65 years (range, 31−89). Median follow-up from maintenance was 38 months (range 12−66 months). Median time on maintenance was 7 months (range 0−50 months). Maintenance thalidomide significantly improved PFS, with a difference between the curves of 13% (95% confidence interval [CI] 6%−20%) established by 24 months and maintained till the current maximum follow-up at 66 months (hazard ration [HR] 1.36; 95% CI 1.15−1.61; logrank P < 0.001). However, in the initial analysis there was no apparent impact on OS (P = 0.40). These findings were consistent regardless of prior intensive or non-intensive induction treatment. At 66 months follow-up, a PFS benefit was seen in the favorable FISH group (P = 0.004) with no effect on OS (P = 0.6). In the adverse FISH group there was no effect on PFS (P = 0.48) and a negative effect on OS (P = 0.009). Subsequently, we evaluated the effect of relapse treatment on outcomes and used this data in a mathematical model to determine if OS benefit would have accrued from the prolonged PFS if all patients had received effective treatment at relapse. A total of 523 patients have progressed to date and of these, 47% received thalidomide as initial relapse treatment (either as a single agent or in combination), 30% received novel agents (either bortezomib or lenalidomide), and 27% received alkylating agents or steroids. Median survival after progression was significantly worse in patients who received thalidomide maintenance than those who did not (P < 0.005); this could, at least partly, be attributed to patients who received thalidomide at progression. In those patients, the median OS after progression was significantly greater in the no maintenance group versus the thalidomide maintenance group (P = 0.004). Among patients treated with novel agents at progression, prior thalidomide maintenance therapy had no impact on OS and these patients were effectively salvaged. The mathematical model employed to examine the effect of effective salvage therapy at progression suggested that a significant survival benefit of 5.5% at 3-years in favor of thalidomide maintenance would have accrued if all patients had received effective therapy at progression (HR 0.77; 95% CI 0.60–0.99; P = 0.04). Next, we examined whether continuous thalidomide therapy was associated with a consolidation or maintenance effect. Upgrading of response with thalidomide maintenance was not common. Importantly, there was no difference in response over time between maintenance therapy and no maintenance. In contrast to what has been reported previously, these findings suggest a maintenance effect. Conclusions:Maintenance thalidomide significantly improves PFS and if effective relapse treatment is available this translates into an OS advantage. The median duration of maintenance thalidomide therapy of 7 months in the present study was short. The clinical impact of maintenance would be improved if patients could remain on therapy for longer, suggesting that the use of other agents such as lenalidomide, with better tolerability profiles, may produce better results. Disclosures:Off Label Use: THALOMID (thalidomide) in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma. Davies:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ortho Biotech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees.

Evaluation of Nitrification Kinetics for a 2.0 MGD IFAS Process Demonstration

The James River Treatment Plant (JRTP) operated a 2 MGD Integrated Fixed Film Activated Sludge (IFAS) demonstration process from November 2007 to April 2009 to explore IFAS performance and investigate IFAS technology as an option for a full scale plant upgrade in response to stricter nutrient discharge limits in the James River Basin. During the study, nitrification kinetics for both ammonia and nitrite oxidizing bacteria and plastic biofilm carrier biomass content were monitored on a near-weekly basis comparing the IFAS media, the IFAS process mixed liquor, and mixed liquor from the full-scale activated sludge process. Carrier biomass content is variable with respect to temperature and process SRT and relates to the localization of nitrification activity in the IFAS basin. Similar to trends observed for carrier biomass content (Regmi, 2008), ammonia oxidizing bacteria (AOB) and nitrite oxidizing bacteria (NOB) activity also shifted from the fixed film to the suspended phase as water temperatures increased and vice versa as the temperature decreased. The data suggest that AOB activity occurs on the surface of the biofilm carriers, while NOB activity remains deeper in the biofilm. During the highest temperatures observed in the IFAS tank, AOB activity on the media contributed as little as 30% of the total nitrification activity in the basin, and after temperatures dropped below 20 °C, AOB activity in the fixed film phase made up 75% of the total activity in the IFAS basin. During the warmest period of the summer, the media still retained more than 60% of the total NOB activity, and more than 90% of the total NOB activity during the period of coldest water temperature. This trend also points out that some AOB and NOB activity remained in the mixed liquor, even during the coldest periods. The retention of nitrification activity in the

Vorinostat Plus Bortezomib for the Treatment of Relapsed/Refractory Multiple Myeloma: Early Clinical Experience

Bortezomib, a proteasome inhibitor, is extremely effective for the treatment of multiple myeloma (MM). However, nearly all patients will eventually become refractory to bortezomib. Vorinostat is a potent inhibitor of histone deacetylase enzymes, and has been shown to affect growth of various cell lines, including MM, in a variety of in vitro non-clinical studies. Furthermore, the combination of bortezomib and vorinostat has demonstrated synergy in several in vitro and murine models. Subsequently, 2 multicenter, open-label, Phase I clinical trials have been conducted to investigate the combination of vorinostat with bortezomib in patients with MM. In the first trial, 34 patients with relapsed/refractory MM were enrolled. Patients received escalating doses of vorinostat (200 mg bid or 300–400 mg daily for 14 days) and bortezomib (0.7, 0.9, 1.1, or 1.3 mg/m2 on days 1, 4, 8, and 11); cycles were repeated every 21 days for ≤8 cycles or until progressive disease (PD) or intolerable toxicity. In the event of PD, oral dexamethasone (20 mg on days 1–4 and 17–20) could be added to the bortezomib plus vorinostat combination. The highest dose level of vorinostat was 400 mg daily for 14 days and bortezomib 1.3 mg/m2. The maximum tolerated dose (MTD) was not determined because ≥2 dose-limiting toxicities (DLTs) did not occur at any dose level. The most common drug-related adverse events were nausea (61.8%), diarrhea (58.8%), thrombocytopenia (50%), and vomiting (50%). Two patients experienced a DLT; grade 3 transient AST elevation was experienced by 1 patient receiving 400 mg vorinostat daily and 0.9 mg/m2 bortezomib, and grade 4 thrombocytopenia was experienced by 1 patient receiving 400 mg vorinostat daily and 1.3 mg/m2 bortezomib. Among 34 evaluable patients, the best response to vorinostat plus bortezomib was a partial response (PR) in 9 (26%) patients, minimal response (MR) in 7 (21%) patients, and stable disease (SD) in 18 (53%) patients. Mean duration of SD was 89 days, range 9–369 days. Of the 13 evaluable patients who had previously been treated with bortezomib, 5 achieved a PR, 1 had a MR, and 7 had SD. The effect of adding dexamethasone will also be analyzed and presented. The second trial enrolled 23 patients who received vorinostat (100–500 mg on days 4–11) and bortezomib (1–1.3 mg/m2 on days 1, 4, 8, and 11). Dexamethasone was added at cycle 2 for 6 patients who achieved less than a PR, and at cycle 4 for 5 patients with PD and at cycle 6 for 2 patients with PD. There was no upgrade in response for any patients who received additional dexamethasone. Two patients in the vorinostat 500 mg group experienced DLT (fatigue and prolonged QTc); MTD was identified as vorinostat 400 mg plus bortezomib 1.3 mg/m2. The main toxicities in this trial were hematologic (anemia, neutropenia, and thrombocytopenia). Twenty-one patients were evaluable for response (2 achieved very good PR, 7 PR, 10 SD, 2 progressive PD). Of the 9 patients who were refractory to bortezomib, 3 had PR, 4 had SD, 1 had PD, and 1 was non-evaluable. Co-administration of bortezomib did not alter the pharmacokinetics of vorinostat. In conclusion, these data suggest that the combination of vorinostat plus bortezomib is active for treatment of MM, even among some patients with prior exposure to bortezomib.

Phase I Trial of Suberoylanilide Hydroxamic Acid (SAHA) + Bortezomib (Bort) in Relapsed Multiple Myeloma (MM) Patients (pts).

SAHA, vorinostat, an oral, histone deacetylase inhibitor, affects cell growth by modifying the transcription of cellular proteins such as histones, transcription factors, ubiqutin E3 ligases and stress response proteins (e.g. HSP90). In vitro, SAHA showed synergistic cytotoxicity with the proteasome inhibitor Bort in MM cells by disrupting aggregates of the ubiquitin conjugated aggresomes. The aims of the study were to determine the MTD, pharmacokinetics (PK) and pharmacodynamic (PD) effects and activity of SAHA plus Bort in pts with relapsed/refractory MM. Twenty-one Pts have been treated. Median age was 55 yrs (range 38–79). Median time from MM diagnosis to study entry was 5.3 yrs (range: 1.5–15 yrs). Isotypes included IgG (n=10), IgA (n=5), light chain (n=4), and nonsecretory (n=2). Twelve Pts had complex karyotype. Median number of prior regimens was 6 (range 3–10); including tandem SCT (n=11), one SCT (n=8), thalidomide (n=21) and lenalidomide (n=14). Nineteen pts had received a median of 2 (range: 1–5) Bort-based prior regimens, 14 Pts had PD to last Bort therapy. 19 pts had PD to last therapy, with a median of 20 days (15–39) between last therapy and study entry. Only 2 patients were in first relapse on thalidomide maintenance. Five 3-Pt cohorts were evaluated at various dose levels as outlined in the table below.The MTD of SAHA in cycle 1 was 400 mg daily, as 2 DLTs, grade 4 prolonged QT interval and grade 4-fatigue occurred in the 500 mg daily cohort. Several grade 3–4 toxicities were observed after cycle 2, including myelo-suppression requiring transfusional support and growth factors. Non-hematological toxicities grade 2 and higher included fatigue (n=5), diarrhea (n=3), atrial fibrillation (n=1), shingles (n=1), pneumonia (n=2, bacterial and RSV). In 16 pts evaluable for response, there was 1 nCR and 7 PR (overall response rate of 50%), 6 pts had stable disease and 3 had PD. At last follow up, three pts remain in remission off therapy for 3–5 months, 9 had PD and 5 have died. Dexamethasone was added 4 pts in cycle 2; with no upgrade in response. The PK of SAHA after a single oral dose were linear from 100–500 mg with mean AUC (0.7 + 0.45 to 4.4+ 0.07), Cmax (0.3 + 0.14 to 1.2 + 0.06) and Tmax (1.3 + 0.4 to 2.3 + 2.5). Ten pts had CD-138+ cells isolated from bone marrow on day 1 [median, 1.8 × 106, range: 0.2–42.6] and on day 11 of the first cycle [median, 0.9 × 106: range: 0.4–5.4] for PD studies. The MTD for SAHA plus Bort was 400 mg daily × 8 days plus1.3 mg/ m2 days 1, 4, 8 and 11. SAHA administration after Bort does not affect PK. The regimen showed promising responses in Bort-refractory pts and should be evaluated in a phase II trial.Study schedule/responseCohortBort (mg/m2)SAHA (mg)No. PtsNo CyclesResponse11.0100 bid35, 7, 5SD, SD, SD21.3100 bid35, 6, 3SD, PR, PD31.3200 bid38, 3, 8VGPR, SD, PR41.3400 daily35, 3, 3SD, PD, PR51.3500 daily37, 1, 1PR, NE, NEMTD1.3400 daily6*4, 3, 2, “1, 1, 1”PR, PR, PR, “too early for evaluation”Bort days 1, 4, 8, 11 of 21-day cycle + SAHA days 4–11. Pts received 8 cycles. Dexamethasone was added for nonresponders, cycle 2. * Of 10 pts to be treated at MTD. PR, partial response; NE, not evaluable; SD/PD, stable/progressive disease.