Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma.

2011 ◽  
Vol 29 (18_suppl) ◽  
pp. LBA5-LBA5 ◽  
Author(s):  
J. D. Wolchok ◽  
L. Thomas ◽  
I. N. Bondarenko ◽  
S. O'Day ◽  
J. S. Weber ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Randomized Study ◽  
Survival Rates ◽  
Standard Of Care ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
Prior Therapy ◽  
Treatment Naïve ◽  
Ecog Ps

LBA5 Background: IPI monotherapy (3mg/kg) improved overall survival (OS) in a phase III study of previously treated, unresectable or metastatic melanoma. Current study in 1st line metastatic melanoma evaluates combination of DTIC (a global standard of care) plus IPI. Methods: In this double-blind phase 3 study, patients (pts) with metastatic melanoma, ECOG PS 0/1, and no prior therapy for advanced disease, were randomized 1:1 to IPI (10 mg/kg) + DTIC (850 mg/m2) or placebo + DTIC (850 mg/m2) at Wks 1, 4, 7, 10 followed by DTIC q3 wks through Wk 22 (induction). Eligible pts received IPI or placebo q12 wks as maintenance. Primary endpoint was OS; 2-sided log-rank test was performed, stratified by baseline M stage and ECOG PS. Results: Of 502 pts, 56% had M1c disease, 40% elevated LDH, and 26% adjuvant therapy. 37% in IPI + DTIC and 65% in DTIC alone arms received 4 induction doses. A significant improvement in OS (HR=0.72; P=0.0009) and higher estimated 1, 2 and 3 yr survival rates were seen with IPI + DTIC (Table). 56% in IPI +DTIC (n=247) and 27% in DTIC alone (n=251) arms had grade 3/4 adverse events (AEs, regardless of attribution), including: elevated ALT (22% vs 1%); diarrhea (4% vs 0%); rash (1% vs 0%). No intestinal perforations or hypophysitis were noted. There were no drug-related deaths in IPI + DTIC and one in DTIC alone arm [gastrointestinal (GI) hemorrhage]. Conclusions: IPI (10mg/kg) + DTIC significantly improved OS in 1st line metastatic melanoma vs DTIC alone; durable survival and objective responses were noted in some pts after follow-up for up to 4yrs. Type of AEs was consistent with prior IPI studies; however, frequencies of some AEs differed with a higher transaminitis and lower diarrhea/colitis/ GI perforation rates than expected. No drug-related deaths were noted in IPI arm. OS benefit of IPI is confirmed in treatment-naive metastatic melanoma. [Table: see text]

A single-arm, open-label, U.S. expanded access study of vemurafenib in patients with metastatic melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8567-8567
Author(s):  
Lynn Mara Schuchter ◽  
Lawrence E. Flaherty ◽  
Omid Hamid ◽  
Gerald P. Linette ◽  
Sigrun Hallmeyer ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Response Rate ◽  
Phase Iii ◽  
Open Label ◽  
Expanded Access ◽  
Treatment Naïve ◽  
Phase Iii Study ◽  
Prior Systemic Therapy ◽  
Ecog Ps

8567 Background: Vemurafenib (vem) has been FDA approved for the treatment of unresectable or metastatic BRAFV600E mutated melanoma since August 2011 based on results of a randomized phase III study (treatment-naive) and a single arm phase II study (previously treated). We report results of an expanded access study that allowed appropriate patients (pts) to receive vem until the drug was approved. Methods: Eligible pts had metastatic melanoma with a BRAFV600E mutation as detected by the cobas 4800 BRAFV600 Mutation Test. Enrolled pts received oral vem 960 mg b.i.d. Adverse events (AEs) were evaluated for vem-related toxicities; tumor responses were assessed using RECIST 1.1. Results: 29 US sites screened 745 pts and enrolled 374 from December 2010 until October 2011. The following results are based on a median follow up time and treatment duration of 2 months. At baseline, mean age of pts was 54 y with 22% of pts ≥65 y; 75% had stage M1c disease; 29% had received radiotherapy for brain metastases. 19% of pts were ECOG PS 2 or 3; 71% of pts had prior systemic therapy for metastatic melanoma (21% 1 regimen; 50% ≥2 regimens). 50 pts had prior adjuvant treatment. At data cut-off, 243 pts had sufficient follow-up time for tumor assessment. In this group, the unconfirmed overall response rate was 52% (95% CI, 46 to 59). The median time to response was 1.8 months. Based on 240 pts with available ECOG PS status at time of analysis, response rate was 53% for pts with ECOG PS 0 or 1 (n=209), and 45% for pts with ECOG PS 2 or 3 (n=31). 370 pts were evaluable for safety analysis. The most common vem-related AEs were rash (36%), arthralgia (33%) and fatigue (21%) with the majority (~90%) of grade 1 or 2. 25 vem-related serious AEs were reported in 5.4% of pts with a slightly higher rate of pts with ECOG PS 2 or 3 (8.7%) compared to ECOG PS 0 or 1 (4.7%). 18% of pts missed at least one dose and 11% of pts required dose reduction of at least one level due to AEs. Conclusions: This expanded access study, with its limited follow-up time, confirms the established rapid and high tumor response rate with vem. No new safety signals were detected. Compared to the overall population, pts with an ECOG PS 2 or 3 demonstrated a similar benefit.

ENGOT-OV44/FIRST study: A randomized, double-blind, adaptive, phase III study of platinum-based therapy with dostarlimab (TSR-042) + niraparib versus standard-of-care (SOC) platinum-based therapy as first-line treatment of stage 3/4 non-mucinous epithelial ovarian cancer (OC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5600-TPS5600 ◽  
Author(s):  
Anne-Claire Hardy-Bessard ◽  
Kathleen N. Moore ◽  
Mansoor Raza Mirza ◽  
Bernard Asselain ◽  
Andres Redondo ◽  
...  
Keyword(s):  
Residual Disease ◽  
Survival Rates ◽  
Standard Of Care ◽  
Figo Stage ◽  
Primary Objective ◽  
Phase Iii ◽  
Clinical Activity ◽  
Double Blind ◽  
The Us ◽  
Phase Iii Study

TPS5600 Background: Despite surgery and SOC therapy (paclitaxel and carboplatin ± bevacizumab[bev]), 5-year survival rates remain low for patients (pts) with FIGO stage 3/4 OC. Niraparib (ZEJULA) is the first selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved in the US and Europe for maintenance treatment in pts with recurrent OC regardless of BRCAmut status. Preclinical data suggest synergy with PARPi + anti-PD-1 blockade. Niraparib + pembrolizumab has shown clinical efficacy in pts with platinum-resistant or secondary refractory OC regardless of biomarker status. Dostarlimab is an anti–PD-1 humanized monoclonal with clinical activity as monotherapy in early phase trials. The primary objective of the currently enrolling FIRST trial is to compare PFS (per RECIST v1.1) in pts treated with SOC + dostarlimab + niraparib to SOC. Methods: Eligible pts (up to 912) are FIGO stage 3 (with residual disease, CC0 high risk, or planned neoadjuvant therapy) or stage 4, non-mucinous epithelial OC and ECOG score < 2. After 1 cycle of SOC, pts are stratified by concurrent bev use, BRCAmut/HRR status, and disease burden then randomized as 1:1:2 to 1 of 3 arms (Table). An innovative feature of ENGOT-OV44/FIRST (NCT03602859; EUDRACT 2018-000413-20) is the pre-planned adaptive study design to adapt the control arm to the evolving SOCs in OC, allowing pts in the control arm to receive up to date SOC. These adaptations will occur when practice-changing data are released. Following publication of SOLO1 results, BRCAmut pts will only be randomized to arm 2 or 3 to ensure they receive niraparib. Further adaptations may be incorporated as new data become available, leading to stop randomization in arm 1 or 2 of pts based on their biomarker status. Clinical trial information: NCT03602859. [Table: see text]

KEYNOTE-177: Randomized phase III study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair-deficient or microsatellite instability-high metastatic colorectal carcinoma.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS815-TPS815 ◽  
Author(s):  
Luis A. Diaz ◽  
Dung T. Le ◽  
Takayuki Yoshino ◽  
Thierry Andre ◽  
Johanna C. Bendell ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Standard Of Care ◽  
Phase Iii ◽  
Open Label ◽  
Eligibility Criteria ◽  
Prior Therapy ◽  
Open Label Phase ◽  
Ecog Ps ◽  
To Receive

TPS815 Background: A subset of colorectal carcinomas (CRCs) are characterized by mismatch repair (MMR) deficiency resulting in microsatellite instability (MSI). MSI-high tumors contain high levels of lymphocyte infiltrates and express the PD-1 immune checkpoint receptor and its ligand, PD-L1. In the phase 2 KEYNOTE-016 study, the anti–PD-1 antibody pembrolizumab demonstrated antitumor activity against MMR-deficient tumors in patients with treatment-refractory metastatic CRC. KEYNOTE-177 (ClinicalTrials.gov, NCT02563002) is an international, randomized, open-label, phase 3 study of pembrolizumab versus standard-of-care (SOC) chemotherapy in first-line MMR-deficient or MSI-high metastatic CRC. Methods: Key eligibility criteria include age ≥18 years, confirmed MSI-high or MMR-deficient metastatic CRC, ECOG PS 0-1, no active autoimmune disease or brain metastases, and no prior therapy for metastatic disease. ~270 patients will be randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 weeks or investigator's choice of SOC chemotherapy (mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab, chosen before randomization). Treatment is to continue until progressive disease (PD), unacceptable toxicity, patient/investigator decision, or completion of 35 cycles (pembrolizumab only). Response is to be assessed every 9 weeks per RECIST v1.1 by central imaging vendor review and per RECIST adapted for immunotherapy response patterns. Eligible patients may continue pembrolizumab beyond initial RECIST-defined progression. Patients in the SOC arm who have PD and meet crossover criteria may be eligible to receive pembrolizumab for up to 17 treatment cycles. AEs are to be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Patients are to be followed up for survival every 9 weeks. The primary end point is PFS per RECIST v1.1; key secondary end points include OS and ORR. Enrollment in KEYNOTE-177 is ongoing. Clinical trial information: NCT02563002.

An open-label extension study to evaluate safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5110-5110 ◽  
Author(s):  
R. E. Hawkins ◽  
S. J. Hong ◽  
A. Ulys ◽  
J. Rolski ◽  
B. Hong ◽  
...  
Keyword(s):  
Angiogenesis Inhibitor ◽  
Phase Iii ◽  
Chemistry Laboratory ◽  
Extension Study ◽  
Symptom Improvement ◽  
Hair Color ◽  
Double Blind ◽  
Treatment Naïve ◽  
Phase Iii Study ◽  
Ecog Ps

5110 Background: The efficacy and safety of pazopanib (paz), a multikinase angiogenesis inhibitor, was evaluated in a randomized, double-blind placebo-controlled phase III study (VEG105192), in treatment-naïve and cytokine-pretreated patients (pts) with advanced RCC. Pts with progressive disease (PD) on placebo had the option to receive paz 800 mg QD via an extension study (VEG107769). Methods: Pts with ECOG PS ≤ 2, adequate organ function and no other systemic anticancer treatment since PD on VEG105192 were eligible. The primary endpoint was safety. Secondary endpoints included response rate (RR) per RECIST and progression-free survival (PFS). RR was described along with 95% confidence intervals (CIs). PFS was summarized descriptively using Kaplan-Meier estimates for the median, quartiles and PFS rates at 6, 12, and 18 mo along with approximate 95% CIs. Results: 70 placebo pts were enrolled (+ 1 paz pt as an exemption due to symptom improvement). 34 pts (48%) were treatment-naïve and 37 (52%) were cytokine pretreated (at baseline in VEG105192). Median age was 59 y (25–80); baseline ECOG PS 0 (32%), 1 (52%), and 2 (14%). Median time from randomization to placebo in VEG105192 to start of paz treatment on VEG107769 was 6.4 mo (1–18 mo). At VEG107769 clinical cut-off (May 08), 21 (30%) pts had died, 40 (56%) pts had discontinued paz, and 31 (44%) pts were still on paz. Median exposure to paz was 5.7 mo. Most pts died or discontinued paz due to PD. The majority of adverse events (AEs) were Gr 1/2. Gr 3/4 AEs were experienced by 21%/7% of pts. The most common AEs were hypertension (46%; 4% Gr 3/4), hair color changes (39%; 0% Gr 3/4), diarrhea (38%; 1% Gr 3/4), anorexia (24%; 1% Gr 3/4), and nausea (24%; 0% Gr 3/4). Two pts had fatal AEs: sudden death and gastrointestinal hemorrhage. The most common Gr 3 chemistry laboratory abnormalities were hyponatremia (7%) and elevated ALT (7%) and AST (6%); no Gr 4. RR was 32.4% (95% CI: 21.5, 43.3); median PFS was 8.3 mo (95% CI: 6.1, 11.4 mo). Conclusions: Patients with advanced RCC who developed PD on placebo in a phase III study subsequently achieved clinical benefit from paz treatment in this extension study. These findings support the continued evaluation of paz in advanced RCC. [Table: see text]

ARCHER: Dacomitinib (D; PF-00299804) versus erlotinib (E) for advanced (adv) non-small cell lung cancer (NSCLC)—A randomized double-blind phase III study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS7615-TPS7615 ◽  
Author(s):  
Michael J. Boyer ◽  
Pasi A. Janne ◽  
Tony Mok ◽  
Kenneth John O'Byrne ◽  
Luis G. Paz-Ares ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kras Mutation ◽  
Objective Response ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
Mutation Status ◽  
Log Rank Test ◽  
Ecog Ps ◽  
Kras Mutation Status

TPS7615 Background: D is a highly selective irreversible small molecule inhibitor of all catalytically active members of the HER (human epidermal growth factor receptor) family of tyrosine kinases. In a randomized phase II trial in patients (pts) who had received 1–2 prior systemic therapy regimens for adv NSCLC, D demonstrated significantly longer progression-free survival (PFS) vs. E in the overall population (12.4 vs. 8.3 weeks; HR=0.66, P=0.012), with benefit consistent across several clinical and molecular subgroups. Median PFS in the KRAS wild-type (WT) subgroup was 16.1 vs. 8.3 weeks for D and E, respectively (HR=0.55, P=0.006). Methods: Based on phase II data, a randomized, double-blinded phase III clinical trial (ARCHER; NCT01360554) was designed to compare the efficacy of D with E in two co-primary populations of pts with adv NSCLC: (a) all enrolled pts with adv NSCLC, and (b) pts with KRAS WT NSCLC. Pts with locally adv/metastatic pathologically confirmed NSCLC, radiologically measurable disease, 1 or 2 prior chemotherapy regimens, ECOG PS 0–2, and tissue available for molecular analysis will be randomized to receive D 45 mg or E 150 mg orally once daily. As of Jan 31, 2012, 117 of a planned 800 pts have been enrolled. The primary endpoint is PFS. Secondary endpoints include overall survival, objective response rate, duration of response, safety and tolerability, and pt-reported outcomes of health-related quality of life and disease-/treatment-related symptoms. Study design provides 90% and 80% power to detect ≥33% and ≥45% improvement in PFS in all pts receiving D vs. E, and in pts with KRAS W T NSCLC, respectively, and HR ≤0.75 and ≤0.69 using a 1-sided stratified log-rank test at a significance level of 0.015 and 0.01, respectively. The final primary analysis stratified log-rank test will include ECOG PS, KRAS mutation status and EGFR mutation status as stratification factors. The sample sizes above will also allow the assessment of OS in the co‑primary populations with adequate power. Post-hoc analyses will be performed to explore EGFR, HER family, and KRAS mutation status, as well as other tumor-derived biomarkers collected from all pts in this trial.

SUNSHINE: Randomized double-blind phase II trial of vitamin D supplementation in patients with previously untreated metastatic colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3506-3506 ◽  
Author(s):  
Kimmie Ng ◽  
Halla Sayed Nimeiri ◽  
Nadine Jackson McCleary ◽  
Thomas Adam Abrams ◽  
Matthew B. Yurgelun ◽  
...  
Keyword(s):  
Vitamin D ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Vitamin D3 ◽  
Controlled Trial ◽  
Vitamin D Supplementation ◽  
Phase Iii ◽  
Double Blind ◽  
Prior Therapy ◽  
Ecog Ps

3506 Background: In prospective observational studies of mCRC patients, higher plasma levels of 25-hydroxyvitamin D have been associated with improved progression-free (PFS) and overall survival (OS), but the role of vitamin D supplementation in the treatment of mCRC is unknown. Methods: SUNSHINE was a multi-center double-blind phase II randomized controlled trial in previously untreated mCRC patients. Patients were eligible if they had histologically confirmed mCRC, no prior therapy for metastatic disease, ECOG PS 0-1, and were not taking vitamin D >2,000 IU/day x 1 year. All subjects received standard treatment with mFOLFOX6 + bevacizumab with 1:1 randomization to concurrent: HiVitD (vitamin D3 po 8,000 IU/d x 2 wks as loading dose followed by 4,000 IU/d) or LowVitD (standard vitamin D3 400 IU/d) until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was PFS, with the sample size designed to provide 80% power to detect a HR of 0.66 for PFS at a 1-sided alpha=0.2. Results: From April 2012 to November 2016, 139 patients were randomized. Median age was 54 yrs (range 24-82), 57% were male, 77% were white, and 7% had received prior adjuvant chemo. Baseline characteristics were balanced between arms except ECOG PS = 0 was 42% vs. 60% in HiVitD vs. LowVitD. Median follow-up was 16.1 mos (range 0-45.9) and median compliance with VitD capsules was 98%. Patients randomized to HiVitD experienced longer PFS than those receiving LowVitD (median PFS, 12.4 vs. 10.7 mos, respectively; log rank P=0.03). After multivariate adjustment for prognostic variables, HR was 0.66 (95% CI, 0.45-0.99, 2-sided P=0.04). Comparing HiVitD vs LowVitD, RR was 58% vs. 63% ( P=0.54) and disease control rate was 100% vs. 94% ( P=0.05). The most common grade 3-4 toxicities were as expected for FOLFOX-bevacizumab, and none were related to vitamin D. Currently, 14 patients are still actively receiving treatment, and OS data are not yet mature. Conclusion: SUNSHINE met its prespecified primary endpoint, with patients randomized to HiVitD experiencing longer PFS compared to those randomized to LowVitD. A larger confirmatory phase III randomized trial appears warranted. Clinical trial information: NCT01516216.

scholarly journals Vosaroxin in relapsed/refractory acute myeloid leukemia: efficacy and safety in the context of the current treatment landscape

2017 ◽  
Vol 8 (6) ◽  
pp. 185-195 ◽  
Author(s):  
Valeriy Sedov ◽  
Robert K. Stuart
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Standard Of Care ◽  
Initial Response ◽  
Current Treatment ◽  
Phase Iii ◽  
Double Blind ◽  
Poor Outcomes ◽  
Acute Myeloid

Treatment for acute myeloid leukemia (AML) generally consists of a combination of cytarabine and an anthracycline. Although induction therapy leads to complete remission (CR) for most patients, refractoriness to chemotherapy or relapse after initial response is associated with poor outcomes. The 1-year survival rates after first relapse have been reported at 29%, declining to 11% at 5 years. Prognosis is particularly poor among older patients whose higher prevalence of unfavorable cytogenetics and high frequency of comorbidities diminish their ability to tolerate intensive chemotherapy. There is no standard of care for relapsed/refractory (R/R) AML, and no new therapies have shown consistently superior outcomes in this setting in over two decades. Vosaroxin is an anticancer quinolone derivative (AQD) that was evaluated in combination with cytarabine for the treatment of R/R AML in the randomized, double-blind, placebo-controlled, phase III VALOR study ( n = 711). Compared with placebo/cytarabine, the vosaroxin/cytarabine regimen demonstrated favorable CR rates and survival in patients ⩾60 years of age, with toxicities similar to other AML regimens. Here we review outcomes of recent studies of commonly used chemotherapy regimens for the treatment of R/R AML and evaluate the results of the VALOR trial in the context of the current treatment landscape.

Radium-223 chloride (Ra-223) impact on skeletal-related events (SREs) and ECOG performance status (PS) in patients with castration-resistant prostate cancer (CRPC) with bone metastases: Interim results of a phase III trial (ALSYMPCA).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4551-4551 ◽  
Author(s):  
A. Oliver Sartor ◽  
Daniel Heinrich ◽  
Joe M. O'Sullivan ◽  
Sophie D. Fossa ◽  
Ales Chodacki ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Performance Status ◽  
Standard Of Care ◽  
High Energy ◽  
Alpha Particles ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Radium 223 ◽  
Ecog Ps

4551 Background: Ra-223, a 1st-in-class alpha-pharmaceutical, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) v placebo (pbo) plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint was OS; secondary endpoints included SREs and ECOG PS. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to 6 injections of Ra‑223 (50 kBq/kg IV) q4 wks or matching pbo and stratified by prior docetaxel use, baseline ALP level, and current bisphosphonate use. Results: 921 pts were randomized from 6/2008-2/2011. In a planned interim analysis (n = 809), Ra-223 significantly improved OS v pbo (median OS 14.0 v 11.2 mo, respectively; two-sided P = .00185; HR = .695; 95% CI, .552-.875).SREs were lower in the Ra-223 v pbo group, and time to 1st SRE was significantly delayed (median time to SRE 13.6 mo v 8.4 mo, respectively; P = .00046; HR = .610; 95% CI, .461-.807). The proportion of pts with ECOG PS deterioration (≥ 2 points) was less in Ra-223 v pbo group at Wk 12 and Wk 24 (4%, 15/389 v 9%, 16/180 and 7%, 16/236 v 12%, 10/83, respectively). Time to ECOG PS deterioration (≥ 2 points) was significantly delayed by Ra-223 v pbo (P = .003; HR = .62; 95% CI, .46-.85). Conclusions: Ra-233 significantly delayed time to 1st SRE and SRE components, notably SCC. Fewer pts in the Ra-223 group had ECOG PS deterioration. Ra-223 improves OS with excellent safety and may provide a new standard of care for CRPC pts with bone mets. [Table: see text]

LUME-Colon 1: A double-blind, randomized phase III study of nintedanib plus best supportive care (BSC) versus placebo plus BSC in patients with colorectal cancer (CRC) refractory to standard therapies.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS794-TPS794 ◽  
Author(s):  
Heinz-Josef Lenz ◽  
Josep Tabernero ◽  
Takayuki Yoshino ◽  
Zohra Oum'Hamed ◽  
Soetkin Vlassak ◽  
...  
Keyword(s):  
Safety Profile ◽  
Predictive Biomarkers ◽  
Best Supportive Care ◽  
Resistance Mechanisms ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
Related Quality ◽  
Angiogenic Effect ◽  
Ecog Ps

TPS794 Background: Clinical studies with anti-VEGF agents, such as regorafenib (R), demonstrate that angiogenesis is critical to CRC tumor growth and metastasis. R has provided proof of principle in patients with refractory CRC, but is associated with a specific safety profile; there is a need for an effective alternative treatment with a different safety profile. Nintedanib (N) is a triple angiokinase inhibitor of VEGF, PDGF, and FGF signaling that has shown clinical benefit and a manageable safety profile in trials in several tumor types, including NSCLC, ovarian cancer, and renal cell carcinoma. In a recent Phase I study of N in CRC, one patient had a confirmed partial response, and a clinically relevant anti-angiogenic effect was observed in 67% of patients. These findings and a manageable safety profile provide a rationale to examine N in refractory CRC. The objective of this study (NCT02149108; 1199.52) is to evaluate the efficacy and safety of N in patients with refractory CRC after failure with standard chemotherapy and biologic agents. Methods: 764 patients worldwide (≥18 years of age, ECOG-PS 0–1, and histologically/cytologically confirmed CRC adenocarcinoma unamenable to surgery and/or radiotherapy) will be randomized 1:1 to receive either N (200 mg bid) + BSC or placebo (bid) + BSC in 21-day courses until disease progression or undue toxicity. The study is powered to distinguish a clinically meaningful effect in the co-primary endpoints PFS and OS. Secondary endpoints are objective tumor response and disease control. Patients will be stratified at randomization based on previous R treatment (yes vs. no), time from onset of metastatic disease to randomization (<24 months vs. ≥24 months), and region. PFS and OS will be evaluated by the log-rank test to determine the effect of N independently at the two-sided alpha level of 0.05. Other assessments include frequency and severity of adverse events and changes in laboratory parameters to measure safety; health-related quality of life; and biomarker analyses that will focus on exploring predictive biomarkers and drug resistance mechanisms. Results are expected in 2016. Clinical trial information: NCT02149108.

Alectinib versus crizotinib in treatment-naive advanced ALK-positive non-small cell lung cancer (NSCLC): Primary results of the global phase III ALEX study.

2017 ◽  
Vol 35 (18_suppl) ◽  
pp. LBA9008-LBA9008 ◽  
Author(s):  
Alice Tsang Shaw ◽  
Solange Peters ◽  
Tony Mok ◽  
Shirish M. Gadgeel ◽  
Jin Seok Ahn ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Primary Data ◽  
Open Label ◽  
Risk Of Progression ◽  
Treatment Naïve ◽  
Secondary Endpoints ◽  
Ecog Ps

LBA9008 Background: Alectinib, a TKI targeting ALK, has shown robust efficacy in crizotinib-naïve/resistant ALK+ NSCLC. J-ALEX showed superiority of alectinib 300mg BID vs crizotinib in Japanese pts with crizotinib-naïve ALK+ NSCLC (progression-free survival [PFS] HR 0.34, p<0.0001). We report primary results from the ALEX study of first-line alectinib 600mg BID vs crizotinib in advanced ALK+ NSCLC (NCT02075840). Methods: This open-label randomized multicenter phase III study enrolled pts with stage IIIB/IV ALK+ NSCLC, determined by central IHC testing. Eligible pts had ECOG PS 0–2 and no prior systemic therapy for advanced NSCLC. Pts with asymptomatic CNS metastases were allowed. Pts (n=303) were randomized 1:1 to receive alectinib 600mg or crizotinib 250mg BID. Primary endpoint: Investigator (Inv)-assessed PFS (RECIST v1.1), with systematic CNS imaging in all pts. Secondary endpoints included independent review committee (IRC)-assessed PFS, IRC-assessed time to CNS progression (TTP), objective response rate (ORR), overall survival (OS) and safety. Results: At the primary data cut-off (9 Feb 2017), alectinib demonstrated statistically significant superiority vs crizotinib, reducing risk of progression/death by 53% (HR 0.47, 95% CI 0.34–0.65, p<0.0001); alectinib median PFS was not reached (95% CI 17.7–NE) vs crizotinib 11.1 months (95% CI 9.1–13.1). Key secondary endpoints showed superiority for alectinib vs crizotinib, respectively: IRC PFS, HR 0.50 (95% CI 0.36–0.70; p<0.0001); median PFS 25.7 months (95% CI 19.9–NE) vs 10.4 months (95% CI 7.7–14.6); CNS TTP, cause-specific HR of CNS progression 0.16 (95% CI 0.10–0.28; p<0.0001); ORR (Inv) 83% (95% CI 76–89) vs 76% (95% CI 68–82), p=0.09; OS, based on 25% events, HR 0.76 (95% CI 0.48–1.20; p=0.24). Grade 3/4 AEs were less frequent with alectinib, 41%, vs 50% with crizotinib; fatal AEs occurred in 3% vs 5%, respectively. Rates of AEs leading to discontinuation, dose reduction and interruption were lower with alectinib. Conclusions: Alectinib showed superior efficacy and favorable tolerability compared with crizotinib. ALEX results support alectinib as a new standard of care for treatment-naïve ALK+ NSCLC. Funding: F. Hoffmann-La Roche Clinical trial information: NCT02075840.

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