Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent ...melphalan (Sanchez et al., Leuk Res 35(3):373–379,
2011
). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1–16) and two prior bortezomib-containing regimens (range, 0–9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.
e13602
Background: Terminations of oncology clinical trials are an unavoidable potential outcome when novel anti-cancer therapeutics are evaluated, yet are a significant burden on cancer patients, ...institutions, regulators and the industry as a whole. Overall, approximately 1 in 5 trials are terminated – the four main reasons are poor enrollment (PE), business decisions, lack of efficacy, and toxicity. The objective of our study is to describe trends in trial terminations. Methods: We searched Citeline® Trialtrove database for oncology, phase 1-3, industry sponsored trials, started 1Jan2000-31Dec2019 listed as completed or terminated. Data collection was performed in Jan2022. For analysis purposes, they were grouped based on start year into four 5-year periods: I-2000-2004, II-2005-2009, III-2010-2014, IV-2015-2019. Undetermined phase, phase 4 and non-oncology trials were excluded. Parameters collected: phase, reason for termination (more than one could be listed), sponsor (academic involvement; Top20 pharma as determined by Scrip 100 annually). Results: A total of 21,125 trials met search criteria, of which 4,596 (22%) were indicated as terminated. Termination rate increased from period I to II (17% to 24%) and remained at a steady 22% in periods III, IV. When evaluating the rate of termination according to phase, over periods I-II-III-IV we observed an increase in the rate of termination of phase 1/2 trials - 10%, 17%, 19% and 20% respectively. Across other phases, the change in termination rates was similar to change in their proportional representation per period. In terms of reason for termination, PE remained a major reason overall, 1275 trials (28%) were terminated due to poor enrollment with a low rate of 13% in period I, followed by 37%, 29%, 21% in periods II, III, IV. Of the trials that were terminated due to PE, 51% had academic, and 73% had Top20 involvement. This is a higher representation that their respective involvement in trials. Conclusions: According to the results of our analysis, the proportion of oncology industry-sponsored terminated trials remained high over the last 20 years, with early phases (1, 1/2 & 2) being the most affected. PE accounted for almost 1/3 of the overall terminations, with a possible trend of decrease. In terms sponsor type, there appeared to be a higher number of trials terminated due to PE with Top20, and with academic involvement, compared to their representation in the overall numbers. It is yet to be determined whether innovation in oncology early phase drug development, such as biomarker driven trials and seamless phase transitions will impact termination rates. Further analysis is ongoing focusing on early phase oncology trials.Table: see text
Abstract only Introduction: We recently demonstrated the combined prognostic value of two simple non-invasive parameters obtained from treadmill exercise testing in patients with HFrEF, the ...hemodynamic gain index (HGI) and peak rate-pressure product (pRPP). However, their prognostic value is yet to be validated in patients with undifferentiated HF syndrome. Hypothesis: Both HGI and pRPP predict all-cause mortality in patients with chronic HF. Methods: We identified 126,356 consecutive patients undergoing treadmill exercise testing for HF symptom evaluation between 1/1991-2/2015. Patients with a confirmed diagnosis of HF were included. HGI was calculated from (SBPpeak x HRpeak) - (SBPrest x HRrest)/(SBPrest x HRrest), and pRPP was calculated from SBPpeak x HRpeak. Hazard ratios per doubling of HGI and pRPP for all-cause mortality were estimated using multivariable Cox regression models with adjustment for traditional cardiovascular risk factors and exercise testing parameters (chronotropic reserve index, METs, abnormal heart rate recovery, and total exercise time). Optimal cut-off for HGI and pRPP were determined by the Youden’s index. Kaplan-Meier plots with log-rank test across patients with low or high HGI and pRPP were used. Results: There were 5,940 patients with symptomatic HF diagnosis included in the analysis (mean age 56.2±12.4 years, 68.1% male, 46.5% with CAD, 55.8% with beta-blocker use). During the median follow up of 7.1 years, 2,222 (37.4%) patients died. Higher both HGI and pRPP were associated with a lower risk of mortality (hazard ratio 0.85 0.81-0.90 and 0.72 0.62-0.84, respectively, all P <0.001). Optimal cut-off values for HGI and peak RPP were 1.06 and 18,966, respectively. Figure 1 shows Kaplan-Meier plots across patients with low and high HGI and pRPP (log-rank P <0.001). Conclusions: Both HGI and pRPP are predictors of mortality in patients with chronic HF and can be used for prognostication and referral for advanced HF therapy evaluation.
Abstract only
9100
Background: Viagenpumatucel-L (HS-110) is an allogeneic cell therapy derived from a human lung adenocarcinoma cell line incorporating multiple cancer testis antigens and ...transfected with a gp96-Ig fusion protein. Methods: We report interim results of cohort A (previously treated pts who had not received a checkpoint inhibitor CPI) and cohort B (pts who progressed after CPI treatment) in an ongoing phase 2 trial evaluating HS-110 plus nivolumab (NIVO) in advanced NSCLC pts (NCT02439450). Pts received HS-110 (1×10
7
cells) intradermally QW for 18 wk and NIVO Q2W until tumor progression. Stratified analyses were performed by injection site reaction (ISR), yes (+) or no (–); baseline blood tumor mutational burden (bTMB), bTMB-L (<10 mutations/ megabase mut/Mb) or bTMB-H (≥10 mut/Mb) by FoundationACT test; and baseline PD-L1 expression, – (<1%) or + (≥1%). Results: As shown in the Table, median progression-free survival (PFS) in cohort A (n=47) was 1.8 mo (95% CI 1.8-7.8) and median overall survival (OS) was 24.6 mo (95% CI 11.7-36.0) after a median follow-up (MFU) of 19.5 mo. We observed significantly longer PFS and OS in ISR+ pts (hazard ratio HR 0.43, p=0.01; HR 0.23, p<0.001) and longer OS in PD-L1+ pts (HR 0.25, p=0.02). In cohort B (n=68), median PFS was 2.8 mo (1.8-3.9) and median OS was 11.9 mo (9.7-16.3) after a MFU of 11.9 mo. We observed significantly longer OS in ISR+ pts (HR 0.48, p=0.03) and a trend toward extended OS in bTMB-L pts (HR 0.58, p=0.20). HS-110 TEAEs were reported in 21 (44.7%) pts in cohort A and 18 (26.5%) pts in cohort B. TEAEs in >5% of pts included fatigue, maculopapular rash, nausea, diarrhea, and pruritus. Few HS-110–related TEAEs led to discontinuation of treatment cohort A, 5 (10.6%); cohort B, 3 (4.4%), and no serious AEs were considered related to HS-110. Conclusions: HS-110 was well tolerated when administered in combination with NIVO. In previously treated pts with advanced NSCLC, we observed (1) significantly longer PFS and OS in ISR+ pts in both CPI naïve and CPI progressor cohorts; (2) significantly longer OS in PD-L1+ patients in the CPI naïve cohort; and (3) a trend of improved OS in bTMB-L pts in the CPI progressor cohort. Further clinical evaluation of HS-110 is warranted in both CPI naïve and CPI progressor NSCLC patients. Clinical trial information: NCT02439450. Table: see text
Abstract only
Introduction:
In the randomized VALOR-HCM study of symptomatic patients with obstructive hypertrophic cardiomyopathy (oHCM), mavacamten reduced the need for septal reduction therapy at ...16 weeks. Because mavacamten is a cardiac myosin inhibitor that may improve ventricular compliance, this sub-study hypothesized that mavacamten would favorably impact diastolic function.
Methods:
Symptomatic patients on maximally-tolerated medical therapy referred for septal reduction therapy were randomized 1:1 to mavacamten or placebo. Echocardiographic assessment was performed by an independent, blinded core laboratory. Diastolic grade was determined according to ASE guidelines. Between-group comparisons were made from baseline to week 16.
Results:
Among 112 enrolled patients, baseline left atrial volume index (LAVi) was similar (Table). At 16 weeks, mavacamten treatment resulted in a significant reduction in LAVi (-5.2 vs -0.5 with placebo,
p
= .003). Similarly, although lateral E/e’ and septal E/e’ were comparable at baseline, patients treated with mavacamten demonstrated a significant reduction at week 16 (lateral E/e’: -3.5 vs 0.7,
p
<0.001; septal E/e’: -3.3 vs 0.7,
p
< 0.001)(Table). Patients treated with mavacamten were also more likely to improve their diastolic dysfunction grade (31.4% vs 12.8%,
p
= 0.032) (Figure).
Conclusions:
After only 16 weeks of therapy, in a highly symptomatic oHCM population with echocardiographic-guided drug titration, mavacamten improved measures of diastolic function.
Abstract only
Introduction:
In the randomized VALOR-HCM study of symptomatic patients with obstructive hypertrophic cardiomyopathy (oHCM), mavacamten reduced the need for septal reduction therapy at ...16 weeks. The current sub-study sought to assess the impact of mavacamten on systolic anterior motion (SAM) of the mitral valve and associated mitral regurgitation (MR).
Methods:
Patients on maximally-tolerated medical therapy referred for septal reduction therapy were randomized 1:1 to mavacamten or placebo. Echocardiographic assessment was performed by an independent, blinded core laboratory. SAM was assessed as none, mild (anterior leaflet >/= 1 cm from the septum), moderate (anterior leaflets <1cm from the septum), and severe (anterior leaflet in contact with septum). MR was assessed according to ASE guidelines.
Results:
Among 112 enrolled patients, 23.2% (n=27) had at least moderate (2+) MR. Most (92.9%, n=104) had at least moderate resting SAM, of whom 55.4% (n = 62) had severe SAM. At 16 weeks, 53.7% of patients treated with mavacamten had at least one level improvement in resting SAM compared to 21.6% of patients treated with placebo (
p
= 0.001), and 35.2% had at least a two level improvement in SAM compared with 11.8% of placebo patients (
p
= 0.007)(Figure 1A). Similarly, patients treated with mavacamten had an improvement of -36.0
+
28.8 mmHg in resting left ventricular outflow tract gradient at week 16 compared to -1.5
+
26.5 mmHg with placebo (<0.001). At week 16, 48.1% of patients treated with mavacamten had at least a one grade improvement in MR, and 23.1% had at least a two grade improvement compared to 12.2% and 6.1% of patients treated with placebo (
p
<0.001 and 0.025, respectively)(Figure 1B).
Conclusions:
In highly symptomatic patients with oHCM, treatment with mavacamten reduced resting SAM with an improvement in associated MR.
Abstract only
101
Background: Viagenpumatucel-L (HS-110) is an allogeneic cellular vaccine derived from a human lung adenocarcinoma (AD) cell line transfected with the gp96-Ig fusion protein. DURGA ...is a multi-cohort study evaluating the combination of HS-110 and immune checkpoint blockers (ICBs) in patients with advanced NSCLC. Here we report the initial two cohorts with the combination of HS-110 and nivolumab. Methods: Patients (pts) with previously treated NSCLC received 1 X 10
7
HS-110 cells weekly for the first 18 weeks and nivolumab 3 mg/kg or 240 mg every 2 weeks until intolerable toxicity or tumor progression. Tissue was tested at baseline for PD-L1 expression (≥ 1% or < 1%) and tumor infiltrating lymphocytes (TILs). TIL high was defined by more than 10% CD8+ lymphocytes in the tumor stroma. Pts in cohort A had never received, and pts in cohort B had received, prior ICBs. The primary objectives were safety and objective response rates (ORR). Results: As of the August 2018 data cut-off, there were 43 pts enrolled into cohort A (40 AD and 3 squamous cell carcinoma SCC) and 18 pts in cohort B (15 AD and 3 SCC). In cohort A, 14 pts (32.6%) were TIL high, 13 (30.2%) TIL low and 16 (37.2%) TIL unknown. ORR, disease control rate (DCR), median progression-free survival (PFS) and 1 year PFS were 18.6%, 48.8%, 1.9 months and 23.9% respectively in cohort A, with median follow up of 432 days. ORR, DCR, and PFS were 22%, 50% and 2.2 months respectively in cohort B, with median follow up of 43 days. The median overall survival (mOS) was not reached in either cohort. In cohort A, TIL low at baseline was associated with increased mOS compared to TIL high (not reached vs 13.8 months, hazard ratio HR 0.23, 95% CI 0.068-0.81, p = 0.04). There were no differences in mOS according to PD-L1 status in cohort A (p = 0.82). 57 (93%) pts experienced at least one adverse event (AE), of which 39 (64%) were grade 1 or 2. The most common AEs were fatigue (31%), cough and diarrhea (19.7% each). There were 2 grade 5 AEs (3.3%) caused by pulmonary embolism and tumor progression, neither considered to be treatment related. Conclusions: The combination of HS-110 and nivolumab is safe with encouraging preliminary efficacy data. The study is ongoing and additional populations are being explored. Clinical trial information: NCT02439450.
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