Effects of pazopanib (PAZ) and sunitinib (SUN) dose modification on safety and efficacy in patients with metastatic renal cell carcinoma (mRCC) from COMPARZ.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4574-4574 ◽  
Author(s):  
Georg A. Bjarnason ◽  
Christian K. Kollmannsberger ◽  
Qasim Ahmad ◽  
Luca Dezzani ◽  
Mohamed Elmeliegy ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Drug Exposure ◽  
Progression Free Survival ◽  
Comparable Efficacy ◽  
Therapeutic Drug ◽  
Open Label ◽  
Safety And Efficacy ◽  
Dose Modification ◽  
Dose Modifications ◽  
Dose Reductions

4574 Background: COMPARZ was a randomized, controlled, open-label, phase 3 trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of life profiles for PAZ in patients (pts) with mRCC (NEJM 2013;369:722). We evaluated the relationship between dosing, safety, and efficacy in PAZ- and SUN-treated pts who did or did not undergo dose reduction or interruption resulting from adverse events (AEs) and other reasons. Methods: The AEs and median progression-free survival (mPFS) of PAZ and SUN were evaluated for pts with no, any, 1, and ≥2 dose reductions or dose interruptions lasting ≥7 days. Results: Similar percentages of pts in the PAZ and SUN groups had a dose interruption (44% vs 49%, respectively) or reduction (44% and 51%, respectively). The incidence of AEs in pts from the PAZ and SUN groups with dose modifications was higher compared to those with no dose modifications. Longer mPFS was observed in pts with dose modification (Table). Pts treated with PAZ or SUN with no dose reductions had mPFS of 7.3 months (mos) and 5.5 mos, respectively, whereas pts with any dose reduction had mPFS of 12.5 mos and 13.8 mos, respectively. Similarly, pts treated with PAZ or SUN with no dose interruptions lasting ≥7 days had mPFS of 8.2 mos and 5.6 mos, respectively, whereas those with any dose interruption lasting ≥7 days had mPFS of 12.6 mos and 13.8 mos, respectively. Pts with 2 or more dose interruptions or reductions had mPFS > 16 mos with both SUN and PAZ. Conclusions: Consistent with previous data for SUN, the current analyses showed longer mPFS with PAZ and SUN when dose modification is required to manage toxicity, suggesting that pts are not disadvantaged by such dose reductions or interruptions. Pts not requiring dose modification may have sub-optimal therapeutic drug exposure. Clinical trial information: NCT00720941. [Table: see text]

Impact of bevacizumab dose reduction on clinical outcomes for patients treated on the Eastern Cooperative Oncology Group’s Study E3200

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3538-3538 ◽  
Author(s):  
B. J. Giantonio ◽  
P. J. Catalano ◽  
P. J. O’Dwyer ◽  
N. J. Meropol ◽  
A. B. Benson
Keyword(s):  
Dose Reduction ◽  
Progression Free Survival ◽  
Free Survival ◽  
Hazard Ratios ◽  
Previously Treated ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Colorectal Cancer Patients ◽  
Dose Modifications ◽  
Dose Reductions

3538 Background: E3200 demonstrated improved survival (OS) for previously treated metastatic colorectal cancer patients who received second-line therapy with bevacizumab (10 mg/kg) in combination with FOLFOX4. Dose reductions of bevacizumab to 5 mg/kg were allowed for: hypertension, bleeding and thrombosis of ≤ grade 2; proteinuria of > 2 grams/24 that resolved to <0.5 grams/24hrs; liver function abnormalities ≥ grade 3 that resolved to ≤ grade 1. Methods: Data on dose modifications of bevacizumab were obtained from a post-study survey of participating institutions for all participants. Median OS and progression-free survival (PFS) were determined based upon a dose reduction any time during treatment. Hazard ratios (HR) for OS and PFS were stratified by number of cycles (1–5, 6–10, 11+) to adjust for the time-varying nature of dose reductions. Results: Surveys were received on 84% of E3200 patients treated with bevacizumab. Dose reductions of bevacizumab were performed in 134 of 240 (55.8%) patients treated with FOLFOX + bevacizumab (Arm A) and 77 of 205 (37.6%) patients treated with bevacizumab alone (Arm C). The average number of cycles of bevacizumab administered at a dose reduction for Arm A is 42% and for Arm C is 52%. Conclusions: OS and PFS on E3200 were not compromised for patients who underwent dose reductions of bevacizumab. [Table: see text] [Table: see text]

Safety and efficacy of AMG 386 in combination with sunitinib in patients with metastatic renal cell carcinoma (mRCC) in an open-label multicenter phase II study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4606-4606 ◽  
Author(s):  
Michael B. Atkins ◽  
Alain Ravaud ◽  
Gwenaelle Gravis ◽  
Kazimierz Drosik ◽  
Tomasz Demkow ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Angiogenesis Inhibitors ◽  
Risk Scores ◽  
Open Label ◽  
Safety And Efficacy ◽  
Kaplan Meier ◽  
Amg 386 ◽  
Hand Foot Syndrome ◽  
Grade 3 ◽  
Dose Modifications

4606 Background: AMG 386, an investigational peptide-Fc fusion protein, inhibits angiogenesis by disrupting the angiopoietin/Tie2 axis. We evaluated the safety and efficacy of AMG 386 plus sunitinib in patients (pts) with mRCC. Methods: Adults with mRCC who were naïve to angiogenesis inhibitors were sequentially enrolled to 2 cohorts: sunitinib 50 mg PO QD (4 wks on, 2 wks off) plus AMG 386 at 10 mg/kg (A) or 15 mg/kg (B) IV QW. Primary endpoints: adverse events (AEs), dose interruptions/reductions due to AEs in the first 12 wks of treatment; secondary endpoints included: progression-free survival (PFS) and response rate (ORR). Results: 85 pts received ≥1 dose of study medication (A/B, n=43/42). In A/B, 88%/76% were male and 30%/36% were age ≥65; MSKCC risk scores were low (40%/36%) or intermediate (60%/62%). For A/B: median follow-up time was 19.6/12.0 mos; AMG 386 discontinuations due to AEs were 16%/29%; and grade ≥3 treatment-related AEs occurred in 72%/74% with virtually all attributed to sunitinib. Grade 3 AEs occurring with >5% frequency were hypertension, hand foot syndrome, asthenia, fatigue, elevated lipase, diarrhea, mucositis, vomiting, thrombocytopenia, and neutropenia, with no distinction between dose levels. The percentage of pts with sunitinib dose interruptions within the first 12 wks (A/B, 58%/57%) met the prespecified criteria. One pt in B had fatal acute pulmonary edema. No pt developed anti-AMG 386 antibodies. The Kaplan-Meier estimate (95% CI) of PFS was 13.9 (10.4, 19.2) mos in A; PFS in B is not yet mature with only 21% of pts having disease progression. ORR (95% CI) was 58% (42, 73) in A including 1 CR, and 59% (42, 74) in B. Conclusions: In pts with mRCC, AMG 386 at 10 and 15 mg/kg combined with sunitinib appeared to be tolerable. Reported sunitinib dose modifications for the observation period were within the prespecified range. Efficacy results suggest potential benefit for the addition of AMG 386 to sunitinib.

scholarly journals Dose Modifications of Ribociclib and Endocrine Therapy for Treatment of ER+ HER2- metastatic Breast Cancer 

2021 ◽  
Author(s):  
Kristoffer Bøss Kristensen ◽  
Ida Marie Nedergaard Thomsen ◽  
Tobias Berg ◽  
Annette R. Kodahl ◽  
Anders B. Jensen
Keyword(s):  
Breast Cancer ◽  
Dose Reduction ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Lymph Node Involvement ◽  
Treatment Information ◽  
Estrogen Receptor Positive ◽  
Node Involvement ◽  
Dose Modifications ◽  
Dose Reductions

Abstract Purpose: Treatment for estrogen receptor positive (ER+), human epidermal receptor 2 negative (HER2-) metastatic breast cancer (MBC) has improved with the approval of CDK 4/6 inhibitors. Clinical trials with the CDK4/6 inhibitor ribociclib, suggest that between 35% to 57.5% of the patients experience a dose reduction during treatment. Information on the possible consequences of dose reduction concerning efficacy is needed. Methods: A retrospective cohort study on patients with ER+ HER2- MBC from three Danish oncology departments. Data on tolerability and progression-free survival were collected from electronic health records. Results: 128 patients with ER+ HER2- MBC who initiated ribociclib treatment between 1st January 2018 to 31st March 2020 were included in our analysis. Of these patients, 48.4% required one or more dose reductions. Overall median PFS was 19.2 months (CI-95%: 14.3-NR). Patients with one or more dose reductions did not have decreased median PFS (19.2 months, CI-95%: 14.3-NR compared to 12.2 months, CI-95%: 7.3-NR. p=0.078). Frequency of adverse events were as previously reported, with grade III and IV neutropenia occurring in 45.3% and 7% of patients, respectively. Patients treated with fulvestrant versus an aromatase inhibitor and patients with lymph node involvement at baseline had lower odds of requiring dose reduction (ORa = 0.30, CI-95%: 0.18-0.89 & ORa = 0.41, CI-95%: 0.12-0.73, respectively). Conclusion: Our results indicate that dose reduction of ribociclib is safe and do not compromise the efficacy of the treatment. Furthermore, the study supports translation of results from the MONALEESA trials to patients treated in real-world clinical settings.

scholarly journals 349 Tolerability of tivozanib vs. sorafenib in elderly and/or immunotherapy-pretreated patients with metastatic renal cell cancer (mRCC) in TIVO-3

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A376-A376
Author(s):  
Vijay Kasturi ◽  
Bernard Escudier ◽  
Brian Rini ◽  
Sumanta Pal ◽  
David McDermott ◽  
...  
Keyword(s):  
Renal Cell ◽  
Drug Exposure ◽  
Cell Cancer ◽  
Age Groups ◽  
Progression Free Survival ◽  
List Type ◽  
Class Effect ◽  
Open Label ◽  
Grade 3 ◽  
Dose Reductions

BackgroundThe TIVO-3 trial demonstrated improved progression-free survival (PFS) with TIVO when compared to sorafenib (SOR; 5.6 mo. vs 3.9 mo., respectively; HR 0.73) and better tolerability with reduced need for dose interruptions (p = 0.0164), dose reductions (p = 0.0147), and discontinuations< sup >1</sup >. As the majority of patients diagnosed with mRCC in the US are >65 years, with the largest recent increase in incidence among those ≥75, and front-line treatment now standardly includes immunotherapy (IO), tolerability of new therapies for relapsed or refractory (R/R) mRCC must be acceptable in the elderly and/or IO pretreated populationMethodsData was analyzed to identify relationships between tolerability and advanced age or IO pretreatment. In addition to measures of drug exposure, any grade ≥3 treatment related adverse events (TRAEs) and VEFGR TKI class effect grade ≥3 TRAEs are reported by age (<65, 65–74, ≥75) and prior IO (yes, no)ResultsOf the 343 patients treated on study, 120 (35%) were between age 65 and 75 and 34 (10%) were over 75. Patients received 1.5-2x more cycles of TIVO compared to SOR and fewer overall grade ≥3 TRAEs in all age groups and irrespective of prior IO. Differences in VEGFR TKI class effect TRAEs seen in the total population were retained across most subgroups (table 1). Among patients 75 and over, there were almost half the rate of the dose reductions or discontinuations with TIVO compared to SOR. Prior IO was associated with less asthenia overall, more HTN with TIVO, and more rash but less diarrhea with SORAbstract 349 Table 1Drug exposure, dose modifications, and TRAEs in TIVO-3 by age and prior IOConclusionsTolerability benefits with TIVO compared to SOR in mRCC are retained in elderly patients and those previously treated with IO. This finding, paired with consistently improved PFS in these subpopulations (age >65: HR 0.59, prior IO: HR 0.55), suggests TIVO is a safe and effective option in the context of the current R/R mRCC treatment paradigmTrial RegistrationClinicalTrialsgov Identifier: NCT02627963ReferenceRini B, Pal S, Escudier B, Atkins M, Hutson T, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol 2020;21:95–104Ethics ApprovalThis trial was approved by the institutional review board or ethics committee at every centre and complied with Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws. All patients provided written informed consent before any trial procedure. The trial protocol including the relevant centres is provided in the appendix of the reference 1

scholarly journals Safety and efficacy of panitumumab in combination with trifluridine/tipiracil for pre-treated patients with unresectable, metastatic colorectal cancer with wild-type RAS: The phase 1/2 APOLLON study

2021 ◽  
Author(s):  
Takeshi Kato ◽  
Yoshinori Kagawa ◽  
Yasutoshi Kuboki ◽  
Makio Gamoh ◽  
Yoshito Komatsu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Therapeutic Option ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Wild Type ◽  
Open Label ◽  
Safety And Efficacy ◽  
Multicentre Phase

Abstract Background We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. Methods APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. Results Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8–45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5–6.5), 14.1 months (95% CI 12.2–19.3), 37.0% (95% CI 24.3–51.3), 81.5% (95% CI 68.6–90.8), and 5.8 months (95% CI 4.29–6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. Conclusion Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

scholarly journals Oral vinorelbine and cisplatin as first-line therapy for advanced squamous NSCLC patients: a prospective randomized international phase II study (NAVoTrial 03)

2021 ◽  
Vol 13 ◽  
pp. 175883592110229
Author(s):  
Francesco Grossi ◽  
Piotr Jaśkiewicz ◽  
Marion Ferreira ◽  
Grzegorz Czyżewicz ◽  
Dariusz Kowalski ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Current Knowledge ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Comparable Efficacy ◽  
Open Label ◽  
Oral Vinorelbine ◽  
First Line Therapy ◽  
Nsclc Patients

Objective: The study investigated the efficacy and safety of oral vinorelbine-cisplatin (OV-CDDP) and gemcitabine-cisplatin (GEM-CDDP) in patients with squamous non-small cell lung cancer (sq-NSCLC). Patients and methods: This was an open-label, prospective, multicenter, international phase II study that enrolled untreated patients with advanced sq-NSCLC. Patients were randomized to receive 3-week cycles of either 60–80 mg/m2 OV days 1 and 8 in combination with 80 mg/m2 CDDP day 1 (arm A) or 1250 mg/m2 GEM days 1 and 8 in combination with 75 mg/m2 CDDP day 1 (arm B). After four cycles, patients without disease progression continued maintenance dose of OV or GEM until progression or unacceptable toxicity. The primary objective was disease control rate (DCR). Secondary objectives included progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), safety, and quality of life (QoL). Results: A total of 114 patients with sq-NSCLC were randomized, and 113 were treated (57 in arm A and 56 in arm B). DCR was high in both arms: 73.7% (95%CI: 62.4–100.0) in arm A and 75.0% (95%CI: 63.7–100.0) in arm B. Median PFS and TTF were similar in arm A and B 4.2 and 2.8 months, and 4.3 and 3.1 months, respectively. Even though the difference was not significant, the OS was 10.2 for arm A and 8.4 months for arm B. The safety profiles were consistent with the current knowledge of adverse events. QoL results revealed an improvement in patients under OV treatment. Conclusion: The OV-CDDP combination showed comparable efficacy to GEM-CDDP with acceptable safety profile and enhanced patients’ QoL. Trial registration: The study was registered under EudraCT number 2012-003531-40.

Relationship Between Lenalidomide Dose Modification and Duration Of Treatment In Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2944-2944
Author(s):  
Kathy Lang ◽  
Gary Binder ◽  
Iris Lin ◽  
Dejan Milentijevic ◽  
Huan Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Reduction ◽  
Research Funding ◽  
Duration Of Treatment ◽  
Employment Equity ◽  
Medical Claims ◽  
Dose Modification ◽  
Equity Ownership ◽  
Dose Change ◽  
Dose Reductions

Abstract Introduction A number of studies have shown clinical benefits for multiple myeloma (MM) patients who continue to stay on therapy with lenalidomide (LEN), including progression-free survival (PFS) and overall survival (OS) (Palumbo A, et al. NEJM. 2013, McCarthy P, et al. NEJM. 2013, Boccadoro. JCO. 2013). Dose modification is one factor used by physicians to achieve sustained duration of treatment (DOT), particularly to manage toxicities and/or pursue a continuous therapy regimen; in a clinical trial of LEN in newly diagnosed MM (NDMM) patients (pts) followed-up for a median of 30 mos, 42% of pts experienced a dose reduction (Palumbo A, et al. NEJM. 2012). This analysis evaluated whether there is supporting evidence, in a real-world setting, for physicians using LEN dose modification to achieve a longer time on therapy. Objective Medical claims analysis was performed to evaluate the relationship between lenalidomide (LEN), dose modification and DOT among patients with NDMM. Methods A retrospective cohort analysis was conducted using a claims database from a large US payer, covering approximately 14 million commercially insured and Medicare advantage members. Patients with at least two outpatient or one inpatient medical claims associated with a diagnosis of MM (ICD-9-CM code: 203.0x) between Jan 1, 2008 and Oct 31, 2012 were extracted from the database. Index date was defined as the date of the first diagnosis of MM. A minimum of 12 months pre-index and 6 months post-index enrollment with no MM treatment was required to define the NDMM patient population. To avoid DOT limitations imposed by fixed-length induction therapy, only pts without claims for stem cell transplant (SCT) were evaluated. DOT was compared among the group treated with LEN who had dose modification (increase or decrease in number of mg per day) relative to the group with no dose modification. Results Among the 236 pts meeting the inclusion criteria, 69 (29%) pts had LEN dose reductions, 15 (6%) had dose increases, and 152 (64%) had no dose change. DOT in pts without a dose change was 7.33 months ± 7.62 (mean ± SD), while pts who had a dose reduction had significantly longer DOT of 14.63 months ± 10.47 (p<0.01). Of the 69 pts with dose reductions, DOT before dose reduction was 5.18 months ± 4.82 compared with 9.46 months ± 10.26 after dose reduction (p<0.01, paired). The subset of pts who were still on LEN therapy at the end of the data window (N=27) showed a similar association between dose reduction and DOT, with DOT of 20.29 months ± 11.62 and 11.99 months ± 9.29 in dose reduction and non-dose reduction subgroups (p<0.01), respectively. Conclusion NDMM pts who had dose reductions of LEN had twice the duration of therapy compared with pts without dose reductions. This analysis suggests that dose modification of MM treatment may be an effective tool to help pts achieve the benefits associated with longer time on therapy. Future clinical studies are needed to determine the best approaches to dose adjustment to improve disease control. Disclosures: Lang: Celgene: Research Funding. Off Label Use: Lenalidomide is a thalidomide analog indicated for the treatment of multiple myeloma, in combination with dexamethasone, in patients who have received at least one prior therapy. Binder:Celgene: Employment, Equity Ownership. Lin:Celgene: Research Funding. Milentijevic:Celgene: Consultancy. Huang:Celgene: Research Funding. Nagarwala:Celgene: Employment, Equity Ownership. Harwin:Celgene: Honoraria.

Randomized phase II study of the safety and efficacy of a human anti-αv integrin monoclonal antibody (CNTO 95) alone and in combination with dacarbazine in patients with stage IV metastatic melanoma: 12-month results

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9029-9029
Author(s):  
C. Loquai ◽  
A. Pavlick ◽  
D. Lawson ◽  
R. Gutzmer ◽  
J. Richards ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Research And Development ◽  
Metastatic Melanoma ◽  
Single Agent ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Complete Response ◽  
Open Label ◽  
Safety And Efficacy ◽  
To Receive

9029 Objectives: Evaluate the safety and efficacy of CNTO 95, a human anti-αv integrin monoclonal antibody, when administered alone or in combination with dacarbazine (DTIC). Methods: Patients with Stage IV metastatic melanoma were randomized 1:1:1:1 to receive 5 or 10mg/kg CNTO 95 alone, or DTIC (1000mg/m2) + either 10mg/kg CNTO 95 or placebo administered intravenously once every 3 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity. DTIC arms were blinded; single-agent arms were open-label. The primary endpoint was progression free survival (PFS); secondary endpoints included partial response (PR), complete response (CR), stable disease (SD) and overall survival (OS). Major safety endpoints included the incidence of adverse events (AEs) and serious AEs (SAEs). Results: Patients were randomized to receive 5mg/kg CNTO 95 (n=32), 10mg/kg CNTO 95 (n=33), CNTO 95+DTIC (n=32), or placebo+DTIC (n=32). Baseline demographics were similar across groups. The median PFS for CNTO 95+DTIC was 75 days, placebo+DTIC was 54 days and both CNTO 95 alone arms were 42 days. Six patients achieved PR (2–10mg/kg CNTO 95, 1-CNTO 95+DTIC, 3-placebo+DTIC); one patient achieved CR (CNTO 95+DTIC). A higher proportion (43.3%) of patients achieved SD ≥ 12 wks in the CNTO 95+DTIC group compared with the other 3 groups (<20.0%). The median survival was 11.0 months for the patients in the CNTO 95+DTIC arm, 9.8 months and 14.9 months for the 5mg/kg and 10mg/kg arms, and 8.0 months for those in the DTIC control arm. The most common AEs were headache, nausea, fatigue, pyrexia, vomiting and transient uveitic reactions. Three patients (1–5mg/kg, 2-CNTO 95+DTIC) discontinued treatment due to AEs. A higher proportion of patients experienced SAEs in the placebo+DTIC group (29.0%) than in the 5mg/kg (12.9%), 10mg/kg (16.2%) or CNTO 95+DTIC (18.8%) groups. Conclusions: CNTO 95 alone or combined with DTIC was generally well tolerated. In patients with Stage IV metastatic melanoma, a trend toward improvement in PFS, OS and disease control was demonstrated with CNTO 95+DTIC. Centocor, Centocor Research and Development, Inc. Centocor Research and Development, Inc. Johnson & Johnson Centocor Research and Development, Inc. No significant financial relationships to disclose.

Long-term safety and efficacy of pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in relapsed and refractory multiple myeloma (RRMM) patients enrolled in the MM-002 phase II trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8588-8588 ◽  
Author(s):  
David Samuel DiCapua Siegel ◽  
Paul Gerard Guy Richardson ◽  
Ravi Vij ◽  
Craig C. Hofmeister ◽  
Rachid C. Baz ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Response Duration ◽  
Median Number ◽  
Open Label ◽  
Safety And Efficacy ◽  
Vein Thrombosis ◽  
Intent To Treat

8588 Background: MM-002 is a randomized, open-label, multicenter phase II trial evaluating the safety and efficacy of POM with or without LoDEX in advanced RRMM pts. Methods: Pts who had received ≥ 2 prior therapies, including lenalidomide (LEN) and bortezomib (BORT), and were refractory to their last treatment were randomized to POM+LoDEX (POM 4 mg/day, days 1–21 of a 28-day cycle; LoDEX 40 mg/week) or POM alone. End points included progression-free survival (PFS), response rate (according to EBMT criteria and investigator assessment), response duration, overall survival (OS), and safety. The efficacy outcomes are based on the intent-to-treat population (POM+LoDEX, n = 113; POM, n = 108). Results: The median number of prior therapies in each group was 5 (range 1–13). In the POM+LoDEX arm, 30 (27%) pts had high-risk cytogenetics, including del(17p13) and/or t(4p16/14q32). The overall response rate (≥ partial response) was 34% and 15% with POM+LoDEX and POM, respectively, with a median duration of 8.3 (95% CI: 5.8–10.1) and 8.8 (95% CI: 5.5–11.4) mos, respectively. At least minimal response was observed in 45% and 31% of pts, respectively. Median PFS was 4.6 (95% CI: 3.6–5.5) and 2.6 (95% CI: 1.9–2.8) mos with POM+LoDEX and POM, respectively, with a median follow-up of 16.0 and 12.2 mos. Median OS was 16.5 (95% CI: 12.4–18.5) and 13.6 (95% CI: 9.6–18.1) mos, respectively. The most common treatment emergent Gr 3/4 adverse events (AEs) reported in the safety population (n = 219) were neutropenia (44%), anemia (23%), thrombocytopenia (21%), and pneumonia (18%); there were no reports of Gr 3/4 peripheral neuropathy. The incidence of deep-vein thrombosis was low (2%). AEs were managed through dose reductions or interruptions, and supportive care with G-CSF (52%), RBC transfusions (47%), and platelet transfusions (17%). Discontinuations due to AEs were 10%. Conclusions: POM with or without LoDEX is clinically effective and generally well tolerated in RRMM pts who have received multiple prior treatments, including LEN and BORT. AEs were predictable and manageable. Updated data will be presented at the meeting. Clinical trial information: NCT00833833.

scholarly journals Combined BRAF (Dabrafenib) and MEK Inhibition (Trametinib) in Patients With BRAFV600-Mutant Melanoma Experiencing Progression With Single-Agent BRAF Inhibitor

2014 ◽  
Vol 32 (33) ◽  
pp. 3697-3704 ◽  
Author(s):  
Douglas B. Johnson ◽  
Keith T. Flaherty ◽  
Jeffrey S. Weber ◽  
Jeffrey R. Infante ◽  
Kevin B. Kim ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Rapid Progression ◽  
Open Label ◽  
Safety And Efficacy ◽  
Mek Inhibition ◽  
Part C ◽  
Inhibitor Treatment

Purpose Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAFV600-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. Patients and Methods In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). Results In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). Conclusion Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor–resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

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