Model-based analysis to support dose selection of pevonedistat (PEV) combined with azacitidine (AZA) in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7042-7042
Author(s):  
Xiaofei Zhou ◽  
Diane R. Mould ◽  
Dan Zhao ◽  
Mikkael A. Sekeres ◽  
Lionel Adès ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Phase 1 ◽  
Performance Status ◽  
Disease Type ◽  
International Prognostic Scoring System ◽  
Population Pharmacokinetic ◽  
Starting Dose ◽  
Grade 3 ◽  
The Impact ◽  
Dose Reductions

7042 Background: PEV+AZA has been studied in higher-risk MDS/CMML and AML, with encouraging efficacy and an acceptable safety profile without added myelosuppression. This pooled analysis was performed to evaluate the impact of PEV exposure on safety and efficacy. Methods: Data from three studies (NCT01814826, NCT02782468 and NCT02610777) were used in the PEV exposure–safety analyses, including ≥ grade 3 neutropenia (NEU3), febrile neutropenia (FN), ≥ grade 3 thrombocytopenia, ≥ grade 3 alanine aminotransferase elevation, ≥ grade 3 aspartate aminotransferase elevation and ≥ grade 3 treatment-emergent adverse event (TEAE3), in pts with higher-risk MDS/CMML and AML who received PEV+AZA. Data from NCT02610777 were used for exposure–efficacy analyses, including overall survival (OS), event-free survival (EFS), complete response (CR) and CR+partial response (PR), in pts with higher-risk MDS/CMML who received PEV+AZA. The exposure metrics for individual pts were derived from a previously developed population pharmacokinetic model with pooled data from eight phase 1/2 studies. PEV exposure–safety relationships for the toxicity endpoints, exposure–CR and exposure–CR+PR, were estimated by logistic regression. Age, sex, race, baseline Eastern Cooperate Oncology Group (ECOG) Performance Status score and disease type were evaluated as covariates. Cox proportional-hazards models were used to evaluate the PEV exposure–survival for higher-risk MDS/CMML, with age, sex, baseline ECOG PS score, Revised International Prognostic Scoring System score (IPSS-R) and disease type as potential covariates. Results: In total, 135 pts (median age, 74 years; male, 64%; Caucasian, 82%) and 41 pts (median age, 74 years; male, 76%; Caucasian, 90%; median IPSS-R, 5.5) were included in PEV exposure–safety and exposure–efficacy analyses, respectively. PEV exposure was significantly related to the incidence of NEU3 ( p = 0.003), FN ( p = 0.02) and TEAE3 ( p = 0.02), supporting PEV dose reductions for pts with treatment-related toxicities. Relationships between PEV exposures and CR, CR+PR, EFS or OS indicated consistent clinical benefit across ranges of PEV exposure following a starting dose of 20 mg/m2. Conclusions: The association between exposure and safety supports PEV dose reductions for pts with treatment-related toxicities. The exposure–efficacy analyses indicated consistent clinical benefit across ranges of PEV exposure following a starting dose of 20 mg/m2. These results support a favorable benefit–risk profile of the 20 mg/m2 PEV dose on days 1, 3 and 5 in combination with AZA 75 mg/m2 for 7 days in 28-day cycles. Clinical trial information: NCT01814826 , NCT02782468 , NCT02610777.

A phase 1 study of weekly, divided dose perifosine in patients (pts) with non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13063-13063 ◽  
Author(s):  
I. C. Henderson ◽  
D. R. Spigel ◽  
J. J. Nemunaitis ◽  
D. A. Richards ◽  
J. E. Liebmann ◽  
...  
Keyword(s):  
Phase 1 ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Weekly Schedule ◽  
Ecog Performance Status ◽  
Phase 2 Trial ◽  
Starting Dose ◽  
Grade 3 ◽  
Nsclc Patients

13063 Background: Perifosine (P) is known to modulate signal transduction pathways, including Akt which is frequently constitutively activated in NSCLC. The half life of P is ∼100 hours and GI toxicities are dose limiting. Studies of a single dose weekly regimen found that the maximum tolerated dose (MTD) was 800 mg. This study was undertaken to see if a higher MTD could be reached using divided doses in NSCLC patients. Methods: Twenty NSCLC patients (pts) were given P, 300 mg, at intervals of 4–6 hours with no more than 4 doses in a 24 hour period. The starting dose was 900 mg and this was escalated by 300 mg/week in subsequent pts to an MTD of 1800 mg. Results: The median age of pts was 62 (range 39–79); 9 were male and median ECOG performance status was 1 (range 0–1). Nineteen pts had received prior chemotherapy (median 2 regimens) and 18 prior radiotherapy. Three pts were entered at each dose and the cohort expanded to 6 pts if 1 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during the first week of therapy. A dose level was toxic if 2 or more pts experienced a DLT. The median time on study was 8 weeks (range 2–28). Seventy-seven percent of pts had no dose reduction (85% of those on 900 mg, 95% on 1200, 72% on 1500, and 78% on 1800 mg). In cohort 1, one pt died within a week without toxicity from P and 1 pt experienced grade 3 nausea, so this cohort was expanded. The other pts in the cohort had no toxicity. In cohort 4 one pt. took 300 mg daily for 6 days and was considered inevaluable. In cohort 3, grade 3/4 toxicity was not observed until after day 28 in 3 pts. Fifteen pts were evaluable for response; 1 had an unconfirmed partial response and 2 had stable disease. Conclusions: This study demonstrated that higher doses of P can be administered on a weekly schedule with divided doses. Weekly doses of 900 and 1200 mg lead to almost no toxicity in most pts. This study has been expanded to a phase 2 trial with direct comparison of weekly and daily doses. The grade 3/4 toxicities for each cohort are given in the table below. [Table: see text] [Table: see text]

FOLFIRINOX for advanced pancreatic cancer: The Princess Margaret experience.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 417-417 ◽  
Author(s):  
Muralidharan Chllamma ◽  
Natalie Cook ◽  
Kazim Giby ◽  
Anna Dodd ◽  
Lisa Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Performance Status ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Pancreatic Head ◽  
Validated Questionnaire ◽  
Significant Difference ◽  
Starting Dose ◽  
Grade 3 ◽  
Dose Reductions

417 Background: The FOLFIRINOX regimen has been shown to significantly increase both overall (OS) and progression free (PFS) survival in metastatic pancreas cancer (MPC), albeit with an increase in adverse events (AEs). It is not known whether initial dose reductions compromise FOLFIRINOX efficacy and there are limited data regarding treatment of locally advanced pancreatic cancer (LAPC). Methods: We conducted a retrospective review of patients (pts) treated with FOLFIRINOX for MPC or LAPC at Princess Margaret Cancer Centre, and began treatment between Dec 2011 and April 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications. Results: 102 pts were identified; 66 MPC and 36 LAPC. Median age was 65 years. 72% of pts had pancreatic head tumors. At baseline 95% of pts had an ECOG performance status of 0 or 1; 95% had bilirubin < 1.5 ULN and 45% had a biliary stent. 68% of pts initiated treatment with a dose reduction (93% reduction or omission of bolus 5FU, 88% reduction in Irinotecan, 68% reduction in Oxaliplatin and 66% reduction in infusional 5FU). Median number of cycles was 6 (1-31); 25% of pts received <4 cycles. Median OS in metastatic pts was 12.9 months (mo) and 23 mo in LAPC; Median PFS was 8.7 mo (metastatic) and 11.1 mo in LAPC. There was no significant difference in PFS (10.9 vs. 10.3 mo; p=0.60) or OS (11.1 vs. 14.0 mo; p=0.19) between the full starting dose and reduced starting dose groups respectively. Partial response or stable disease was achieved in 57% of pts; 11% of the LAPC pts had a surgical resection. Grade 3/4 hematologic AEs were observed in 43% of pts (febrile neutropenia in 6%). Only 13% of pts received G-CSF support. Grade 3/4 non-hematologic AEs were observed in 28% of pts, including vomiting (19%), nausea (16%) and diarrhea (16%). 18% of pts had a treatment related hospitalization (5% neutropenic sepsis, 13% GI toxicity/dehydration.) There was one treatment related death. Pt wellbeing (scored on a validated questionnaire) significantly improved from baseline to cycle 4 (p=0.002). Conclusions: Modest dose reductions do not appear to compromise efficacy of FOLFIRINOX. Our median PFS, OS and AEs are comparable to other studies using FOLFIRINOX in both LAPC and metastatic disease.

First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from CheckMate 9LA.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9000-9000
Author(s):  
Martin Reck ◽  
Tudor-Eliade Ciuleanu ◽  
Manuel Cobo ◽  
Michael Schenker ◽  
Bogdan Zurawski ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Performance Status ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Expression Level ◽  
First Line ◽  
Ecog Performance Status ◽  
Grade 3

9000 Background: In the randomized phase 3 CheckMate 9LA trial (NCT03215706), first-line NIVO + IPI combined with 2 cycles of chemo significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs chemo alone (4 cycles). Clinical benefit was observed regardless of programmed death ligand 1 (PD-L1) expression level and histology. Here we report data with 2 years’ minimum follow-up from this study. Methods: Adult patients (pts) with stage IV / recurrent NSCLC, ECOG performance status ≤ 1, and no known sensitizing EGFR/ALK alterations were stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous) and were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles; n = 361) or chemo alone (4 cycles; n = 358). Pts with non-squamous NSCLC in the chemo-alone arm could receive pemetrexed maintenance. The primary endpoint was OS. Secondary endpoints included PFS and ORR by blinded independent central review, and efficacy by different PD-L1 levels. Safety was exploratory. Results: At a minimum follow-up of 24.4 months for OS (database lock: Feb 18, 2021), pts treated with NIVO + IPI + chemo continued to derive OS benefit vs chemo, with a median OS of 15.8 months vs 11.0 months, respectively (HR, 0.72 [95% CI, 0.61–0.86]); 2-year OS rates were 38% vs 26%. Median PFS with NIVO + IPI + chemo vs chemo was 6.7 months vs 5.3 months (HR, 0.67 [95% CI, 0.56–0.79]); 8% and 37% of pts who had disease progression received subsequent immunotherapy, respectively. ORR was 38% with NIVO + IPI + chemo vs 25% with chemo. Similar clinical benefit with NIVO + IPI + chemo vs chemo was observed in all randomized pts and across the majority of subgroups, including by PD-L1 expression level (Table) or histology. Any grade and grade 3–4 treatment-related adverse events were reported in 92% and 48% of pts in the NIVO + IPI + chemo arm vs 88% and 38% in the chemo arm, respectively. Conclusion: With 2 years’ minimum follow-up, first-line NIVO + IPI + chemo demonstrated durable survival and benefit versus chemo in pts with advanced NSCLC; no new safety signals were identified. Clinical trial information: NCT03215706. [Table: see text]

Association of statins and nivolumab activity in patients with metastatic renal cell carcinoma (mRCC): Results from the phase II nivoren—GETUG AFU 26 trial.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 359-359
Author(s):  
Emeline Colomba ◽  
Ronan Flippot ◽  
Cécile Dalban ◽  
Sylvie Negrier ◽  
Christine Chevreau ◽  
...  
Keyword(s):  
Phase Ii ◽  
Immune Modulation ◽  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Population Based ◽  
Metabolic Reprogramming ◽  
Oncogenic Signaling ◽  
Grade 3 ◽  
The Impact

359 Background: Statins are HMG-CoA inhibitors that regulate several mechanisms involved in tumor growth, including mitochondrial metabolism, activation of oncogenic signaling pathways, and immune modulation. Population-based studies showed that statin intake may be negatively associated with RCC onset. The impact of statins on response to immunotherapy in mRCC is unknown. Herein we study the association between statin administration and outcomes in patients with mRCC treated with nivolumab in the NIVOREN-GETUG AFU 26 phase II trial (NCT03013335). Methods: Patients with mRCC who failed previous VEGFR inhibitors were included. We assessed nivolumab activity, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to statin intake at baseline. Toxicity was assessed using CTCAE v4.0. Results: Overall,133 patients were treated with statins at baseline among 702 evaluable for concomitant therapies (19%). Among them, median age was 68 (49-90), 84% were male, 85% had a performance status ≥ 80%, 42% were overweight and 20% obese. Patients treated with statins had mostly good (23%) or intermediate (58%) IMDC risk, 64% had grade 3 or 4 tumors, and nivolumab was given in a third line setting or more in 55%. Median follow-up was 23.9 months (95%CI 23.0-24.5) in the overall cohort. The ORR was 26% in patients treated with statins, PFS 5.0 months (CI95% 3.0 – 5.5), OS 27.9 months (CI95% 19.4-30.3). Outcomes of patients with or without statins did not differ significantly. Similar rates of grade 3-5 TRAE were reported in patients with (20%) or without (18%) statin intake. Conclusions: This is the first study to evaluate statin intake and outcomes with nivolumab in patients with mRCC. Despite numerically higher ORR, statins were not significantly associated with improved outcomes. These data require other analyzes considering other factors such as BMI and other comorbidities. Further studies may help better understand the interplay between immunity and metabolic reprogramming in RCC.

Toxicity, response, and survival in older adults with metastatic melanoma treated with checkpoint inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9544-9544
Author(s):  
Nienke A De Glas ◽  
Esther Bastiaannet ◽  
Frederiek van den Bos ◽  
Simon Mooijaart ◽  
Astrid Aplonia Maria Van Der Veldt ◽  
...  
Keyword(s):  
Older Adults ◽  
Overall Survival ◽  
Metastatic Melanoma ◽  
Older Patients ◽  
Regression Models ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Toxicity Response ◽  
Grade 3 ◽  
The Impact

9544 Background: Checkpoint inhibitors have strongly improved survival of patients with metastatic melanoma. Trials suggest no differences in outcomes between older and younger patients, but only relatively young patients with a good performance status were included in these trials. The aim of this study was to describe treatment patterns and outcomes of older adults with metastatic melanoma, and to identify predictors of outcome. Methods: We included all patients aged ≥65 years with metastatic melanoma between 2013 and 2020 from the Dutch Melanoma Treatment registry (DMTR), in which detailed information on patients, treatments and outcomes is available. We assessed predictors of grade ≥3 toxicity and 6-months response using logistic regression models, and melanoma-specific and overall survival using Cox regression models. Additionally, we described reasons for hospital admissions and treatment discontinuation. Results: A total of 2216 patients were included. Grade ≥3 toxicity did not increase with age, comorbidity or WHO performance status, in patients treated with monotherapy (anti-PD1 or ipilimumab) or combination treatment. However, patients aged ≥75 were admitted more frequently and discontinued treatment due to toxicity more often. Six months-response rates were similar to previous randomized trials (40.3% and 43.6% in patients aged 65-75 and ≥75 respectively for anti-PD1 treatment) and were not affected by age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity, but age, comorbidity and WHO performance status were associated with overall survival in multivariate analyses. Conclusions: Toxicity, response and melanoma-specific survival were not associated with age or comorbidity status. Treatment with immunotherapy should therefore not be omitted solely based on age or comorbidity. However, the impact of grade I-II toxicity in older patients deserves further study as older patients discontinue treatment more frequently and receive less treatment cycles.[Table: see text]

scholarly journals Toxicity management of regorafenib in patients with gastro-intestinal stromal tumour (GIST) in a tertiary cancer centre

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Florence Chamberlain ◽  
Sheima Farag ◽  
Constance Williams-Sharkey ◽  
Cecilia Collingwood ◽  
Lucia Chen ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Progression Free Survival ◽  
Individual Risk ◽  
Duration Of Treatment ◽  
Ecog Performance Status ◽  
Third Line ◽  
Grade 3 ◽  
Dose Reductions

Abstract Background Regorafenib is a multi-kinase inhibitor approved as third line treatment for metastatic GIST. Dose limiting toxicities are frequently seen and many patients require dose reductions. This study aimed to evaluate regorafenib toxicities and their management in a real-world GIST population. Methods Retrospective review of a prospectively maintained database identified 50 patients with GIST treated with regorafenib at our centre between March 2013 and September 2018. Results Median progression free survival (PFS) was 7.7 months [interquartile range (IQR) 2.8–14.4 months]. Median overall survival (OS) from start of regorafenib to death or last follow up was 15.7 months (IQR 9.2–28.4 months). Baseline median Eastern Cooperative Oncology Group (ECOG) performance status on starting regorafenib was 1. The main reason for discontinuing regorafenib was progressive disease (PD) (31/50 [62%]) rather than toxicity (10/50 [20%]). Grade 3–4 adverse events (AEs) were seen in 23/50 (46%) patients; palmar-plantar erythrodysesthesia (PPE) was most frequently seen (9/50 (18%)). Two patients died whilst on treatment with regorafenib from multi-organ failure secondary to sepsis (4%). Dose reductions were required in 19/50 patients (38%) and 8/50 (16%) patients started regorafenib at a lower dose band than the recommended dose (160 mg) due to comorbidities or concern over a higher individual risk of toxicity. Conclusion Although PD was the main reason for discontinuing treatment, toxicity management and dosing of regorafenib remains critical. Median duration of treatment was longer compared to previous studies suggesting a durable clinical benefit with regorafenib with rigorous toxicity management.

European Post-Approval Safety Study (PASS) of Relapsed/Refractory Multiple Myeloma (RRMM): Safety, Including SPM, in a Large Cohort of Patients Treated with Lenalidomide, Thalidomide, and Bortezomib

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3331-3331
Author(s):  
Barbara Gamberi ◽  
Miguel Hernandez ◽  
Christian Berthou ◽  
Eleni Tholouli ◽  
Elena Zamagni ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Performance Status ◽  
Treatment Discontinuation ◽  
Second Primary ◽  
Advisory Committees ◽  
Grade 3 ◽  
Noninterventional Study ◽  
Dose Reductions

Abstract Background: EU PASS is an observational, noninterventional study designed to investigate the safety of lenalidomide (LEN) and other agents in the treatment of RRMM in a real-world setting. Aims:To assess the incidence of adverse events (AEs) of special interest, including neutropenia, thrombocytopenia, venous thromboembolism (VTE), peripheral neuropathy (PN), and second primary malignancies (SPMs) in RRMM patients (pts) treated with LEN and other antimyeloma therapies according to current clinical practice. Methods: Pts with RRMM who were commencing LEN treatment were enrolled at the investigator's discretion into a LEN cohort (LEN + dexamethasone, the approved combination for the treatment of RRMM); pts who received ≥ 1 prior therapy and were commencing a non-LEN-based therapy were enrolled into a background cohort (all other treatments, including novel agents). Thromboprophylaxis was per local standard practice. AEs were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (version 3). SPMs were defined using Medical Dictionary for Regulatory Activities (MedDRA) terms under the category Neoplasms SOC. Following protocol amendment in 2011, assessments for SPMs were to be conducted up to 36 mos after treatment discontinuation. Results: As of June 2016, 3632 pts across 269 institutions in 17 European countries were included in the safety population. Of those, 59.2% received LEN (n = 2151), 32.7% received bortezomib (BORT; n = 1188), 3.8% received thalidomide (THAL; n = 137), and 4.3% received other therapies (n = 156). The majority of pts had discontinued from treatment (97.9%; n = 3556); of the 2.1% (n = 76) ongoing pts, 66 are treated with LEN, 6 with BORT, 0 with THAL, and 4 with other substances. Baseline characteristics were similar across the cohorts. Median age was 70 yrs (range, 25-95 yrs) and 54.0% were male. Of 2985 pts with available ECOG data, 2865 (96.0%) had good performance status (ECOG score 0-2), and the remaining 4.0% had an ECOG score of 3/4. The median number of prior therapies was 1 (range, 1-6) but was higher in the LEN cohort (2; range, 1-6) than in the BORT (1; range, 1-6) and THAL (1; range, 1-5) cohorts; the proportion of pts with only 1 prior treatment was also lower in the LEN cohort (44.3%), whereas BORT was 70.8% and THAL 56.2%. Overall, 50.7% of pts (n = 1842) had grade 3/4 AEs. Grade 3/4 neutropenia occurred in 17.1%, 3.5%, and 4.4% of pts in the LEN, BORT, and THAL cohorts, respectively, and grade 3/4 thrombocytopenia in 9.2%, 7.3%, and 3.6%. The incidence rate of SPM was 3.63 per 100 pt-yrs, with 3.18 per 100 pt-yrs in the LEN cohort, 5.23 per 100 pt-yrs in the BORT cohort, 2.73 per 100 pt-yrs in THAL, and 6.48 per 100 pt-yrs in others. AEs of interest of all grades are listed in Table 1. The median duration on study treatment was 6.6 mos (range, 0.1-81.6 mos) for LEN, 4.1 mos (range, 0-63.6 mos) for BORT, and 4.6 mos (range, 0.2-36.9 mos) for THAL. Treatment discontinuation rate due to AEs was similar in each cohort (22.1% in the LEN, 20.0% in the BORT, and 21.2% in the THAL cohorts). In the LEN cohort, dose reductions occurred in 38.1% of pts, with a median time to first dose reduction due to AEs of 12.4 weeks. Treatment-emergent adverse events leading to dose reductions were similar across cohorts, with 23.7% in the LEN cohort, 21.4% in the BORT cohort, and 17.5% in the THAL cohort. Conclusions: Results of this noninterventional study in RRMM show that AEs were similar across cohorts except for higher rates of neutropenia and lower rates of PN with LEN compared with THAL or BORT. Higher rates of neutropenia did not translate into increased febrile neutropenia. Infections, independent from neutrophil counts, occurred in all cohorts, but few pts developed serious infections such as pneumonia. VTEs as well as myocardial infarctions were low throughout all cohorts. The occurrence of SPMs was generally low and comparable between cohorts. LEN was generally well tolerated. Disclosures Tholouli: Johnson and Johnson: Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria; MSD: Speakers Bureau; Giles: Speakers Bureau. Hájek:Janssen: Honoraria; Takeda: Consultancy; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Frost Andersen:Celgene: Research Funding. Waage:Amgen: Speakers Bureau; Celgene: Consultancy, Honoraria; Novartis, Amgen, Celgene: Membership on an entity's Board of Directors or advisory committees. Crotty:BMS, Takeda, Novartis, Janssen, Roche: Honoraria. Kueenburg:Celgene International Sarl: Consultancy, Honoraria. Di Micco:Celgene: Employment. Bacon:Celgene: Employment, Equity Ownership.

A phase 1 study of daily oral perifosine (P) with every 3-week paclitaxel (T)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13134-13134 ◽  
Author(s):  
T. F. Goggins ◽  
J. J. Nemunaitis ◽  
R. Shiffman ◽  
R. Birch ◽  
D. H. Berdeaux ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Performance Status ◽  
Single Agent ◽  
State Level ◽  
Hematologic Toxicity ◽  
Ecog Performance Status ◽  
Full Dose ◽  
Phase Ii Studies ◽  
Grade 3

13134 Background: Perifosine is a novel alkylphospholipid that has been shown to affect multiple signal transduction pathways including Akt, MAPK and JNK (Kondapaka, Mol. Canc. Ther 2: 1093–1103. 2003). Treatment with a taxane initially activates Akt, and persistent activation increases resistance to the drug (Vanderweele, Mol. Canc. Ther. 3: 1605–13, 2004). Methods: Twelve patients (pts) were enrolled on this study. T was given at a dose of 175 mg/m2 on day 8 (after 7 days of perifosine) of a 21 day cycle; this was to obtain a steady state level of P at the tumor before exposure to T. The intent of the protocol was to determine if full dose P could be delivered with 50 mg of perifosine given orally 1, 2 or 3 times a day on days 1–14 of each cycle. Results: Disease sites included lung 3, thyroid 3, breast 1, esophagus 1 and other 4, Median age was 66 (range 45 - 83); 6 pts were male and median ECOG performance status was 1 (range 0–2). All pts had received prior chemotherapy (median 2 regimens); 3 had prior treatment with a taxane. Three pts were entered at each dose level and the cohort expanded to 6 pts if 2 or more pts experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose level was toxic if 4 or more pts experienced a DLT during cycle 1. A total of 30 cycles and a median of 2 cycles (range 1–11) per patient were delivered. There were no grade 3/4 hematologic toxicities. Full dose T was given in all treatment cycles. P dose reductions were required in 6% of cycles (50 mg - 7%, 100 mg - 0%, 150 mg - 7%). One patient missed one dose due to nausea and one pt was stopped due to diarrhea. The grade 3 toxicities for each cohort are given in the table below. The elevated glucose value was 321. Nine pts were evaluable for response; two pts with thyroid cancer had stable disease by the RECIST criteria for 9 and 10+ months. Conclusions: In this study the usual single agent doses of P (150 mg daily) & T (175 mg/m2 q 3 weeks) were given together without increasing the toxicities that would be expected from using each drug alone. Phase II studies are warranted to define activity of the combination. [Table: see text] [Table: see text]

Effect of lenalidomide (LEN) on biochemical responses and clinical benefit (CB) as a single agent in chemotherapy-naive castration-resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 128-128 ◽  
Author(s):  
Chadi Nabhan ◽  
Anand Patel ◽  
Dana Villines ◽  
Kathy Tolzien ◽  
Susan K. Kelby ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Benefit ◽  
Single Agent ◽  
Complete Response ◽  
Median Number ◽  
Castration Resistant Prostate Cancer ◽  
Serious Adverse Events ◽  
Biochemical Responses ◽  
Grade 3 ◽  
Dose Reductions

128 Background: LEN has anti-angiogenesis and immunomodulatory properties making it ideal to investigate in CRPC. We report on a phase II study investigating LEN in chemotherapy-naïve CRPC patients (pts) Methods: Eligible pts received LEN at 25 mg daily on days 1 – 21 every 28-days until progression. Daily aspirin or coumadin were required. Responses were assessed every 2 cycles. Toxicity was assessed every cycle. Primary end point: The CB of LEN [Sum of complete response (CR), partial response (PR) and stable disease (SD)]. Secondary end points: Toxicity, time to radiographic and PSA progression (TTP and TTP-PSA), time to next treatment (TTNT), overall survival (OS), and LEN’s impact on quality of life (QOL). Results: 31 pts were enrolled; 27 response-evaluable (1 withdrew consent, 3 off per choice after adverse events). Median age is 74 (range 58-89) with 24 (77%) having Gleason ≥ 7 disease. Median PSA is 66 (2.1-918.6). Six pts (19%) had liver/lung involvement. Fourteen pts (51%) showed biochemical response with 4 (15%) having >50% PSA drop. TTP-PSA is 4 months (2-11). No radiographic responses seen but 17 pts had SD for a median of 4 months (2-16) (CB=55%). Median number of LEN cycles was 3 (2-15). With a median follow-up of 18 months (5-38), 17 patients (55%) remain alive; median OS of 18 months. Grade 3/4 hematologic toxicities were most common (neutropenia 41%, leukopenia 12%, anemia 9%, thrombocytopenia 9%). Other grade 3/4 toxicities: venothromboembolism, atrial fibrillation, and dehydration (6% each). Serious adverse events (SAEs) were witnessed in 10 pts (32%) with only 1 (3%, rash) definitely related to LEN. Others were not related or possibly related. Of 27 pts, 7 (26%) had a dose reduction and 2 (7%) required two dose reductions. Dose reductions occurred after cycle 3. QOL scales suggested no adverse impact. Median TTNT is 2 months (9 pts received chemotherapy, 10 pts went onto studies, 3 pts received hormonal therapies, 4 pts received radiation, 3 pts had no therapy yet, and 2 pts remain on LEN). Conclusions: LEN is active as monotherapy in CRPC. Biochemical responses are witnessed and clinical benefit is observed. Myelosuppression is the most common toxicity.

Clinical outcomes and safety in men ≥ 75 and < 75 years with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide in the phase 3 PREVAIL trial.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 200-200 ◽  
Author(s):  
Julie Nicole Graff ◽  
Giulia Baciarello ◽  
Andrew J. Armstrong ◽  
Celestia S. Higano ◽  
Peter Iversen ◽  
...  
Keyword(s):  
Performance Status ◽  
Specific Antigen ◽  
Age Groups ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Phase 3 ◽  
Ecog Performance Status ◽  
Grade 3 ◽  
Treatment Safety ◽  
The Impact

200 Background: In the phase 3 PREVAIL trial, enzalutamide (ENZA), an androgen receptor inhibitor, improved overall survival (OS) and radiographic progression-free survival (rPFS) relative to placebo (PBO) in chemotherapy-naïve men with mCRPC. Methods: PREVAIL randomized 1,717 patients (pts) with asymptomatic or minimally symptomatic chemotherapy-naïve mCRPC 1:1 to ENZA 160 mg daily or PBO. Coprimary endpoints were OS and rPFS. This prespecified analysis evaluated the impact of age (≥ 75 vs < 75 years) on efficacy and safety. Results: In PREVAIL, 609 (35%) pts were aged ≥ 75 years. This older subset had several poorer baseline prognostics relative to those aged < 75 years: worse ECOG performance status (ECOG 1: 45.0% vs 24.7%), higher prostate-specific antigen (PSA; 73.3 vs 37.3 ng/mL) and more cardiovascular disease (26.9% vs 16.5%). In both older and younger pts, ENZA improved OS, rPFS and time to PSA progression (Table). Pts aged ≥ 75 years in both the ENZA and PBO groups combined had a higher rate of grade ≥ 3 adverse events (46% vs 37% in younger pts) and among enzalutamide-treated men more older pts reported falls (any grade; ENZA 19% and PBO 8%) than younger pts (ENZA 7% and PBO 4%). Fewer pts ≥ 75 years received subsequent antineoplastic therapies. Conclusions: In PREVAIL, efficacy outcomes in elderly (≥ 75 years) and younger (< 75 years) pts with chemotherapy-naïve mCRPC were comparable and pts consistently benefited from ENZA treatment. Safety with ENZA was similar in both age groups, although older pts reported a higher incidence of falls and received fewer subsequent antineoplastic therapies. Clinical trial information: NCT01212991. [Table: see text]

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