Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial.

2014 ◽  
Vol 32 (18_suppl) ◽  
pp. LBA7008-LBA7008 ◽  
Author(s):  
John C. Byrd ◽  
Jennifer R. Brown ◽  
Susan Mary O'Brien ◽  
Jacqueline Claudia Barrientos ◽  
Neil E. Kay ◽  
...  
Keyword(s):  
Treatment Options ◽  
Randomized Study ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Drug Discontinuation ◽  
Purine Analog ◽  
Independent Review ◽  
Secondary Endpoints

LBA7008 Background: Treatment options for CLL/ SLL patients (pts) who fail chemoimmunotherapy are limited. We report interim results from a phase III randomized study of ibrutinib (ibr), a first in class covalent BTK inhibitor, vs ofatumumab (ofa) in R/R CLL/SLL. The Data Monitoring Committee recommended this analysis be considered final, based on meeting the primary and a key secondary endpoint. Methods: R/R CLL/SLL pts who failed ≥1 therapy received 420 mg oral ibr daily until progression or IV ofa 300/2000mg for 12 doses. Primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). Secondary endpoints included overall survival (OS), IRC assessed overall response rate (ORR) and safety. Results: Of 391 pts enrolled (median age 67 years; 40% ≥70 years; 57% Rai stage III/IV disease; 30% del 17p), 195 were randomized to ibr and 196 to ofa. Ibr pts had median 3 prior therapies vs 2 for ofa. Median follow-up was 9.4 months (m). Ibr significantly lengthened PFS (median not reached vs 8.1 m; HR 0.215, CI 0.146–0.317, p<0.0001; 78.5% risk reduction), and significantly improved OS (median not reached; HR 0.434, CI 0.238–0.789, p=0.0049) compared with ofa. ORR was 42.6 vs 4.1% (p<0.0001) and ORR+PR with lymphocytosis was 62.6 vs 4.1% for ibr vs ofa. Similar effects were seen in del17p and purine analog refractory subsets. In each arm 2 pts had confirmed Richter’s transformation. Most frequent adverse events (AE) for ibr vs ofa were diarrhea (47.7 vs 17.8%) fatigue (27.7 vs 29.8%), and nausea (26.2 vs 18.3%). Atrial fibrillation was more frequent with ibr (5.1 vs 0.5%). Major hemorrhages were reported in 1.0 vs 1.6% for ibr vs ofa. Drug discontinuation due to AE was 4.1 vs 3.6% for ibr vs ofa. 86% of ibr pts were continuing treatment. 57 pts randomized to ofa with confirmed PD had initiated ibr at cross-over. Conclusions: Compared with ofa, ibr significantly improved PFS, OS and ORR in pts with R/R CLL/SLL. The safety profile was comparable with that previously reported (Byrd NEJM 2013). These results support ibr as a beneficial therapy for R/R CLL patients irrespective of del 17p or purine analog refractory disease. Clinical trial information: NCT01578707.

SELECT: Randomized phase III study of docetaxel (D) or pemetrexed (P) with or without cetuximab (C) in recurrent or progressive non-small cell lung cancer (NSCLC) after platinum-based therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7502-7502 ◽  
Author(s):  
Edward S. Kim ◽  
Marcus A. Neubauer ◽  
Allen Lee Cohn ◽  
Lee Steven Schwartzberg ◽  
Lawrence E. Garbo ◽  
...  
Keyword(s):  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Staining Intensity ◽  
Primary Objective ◽  
Phase Iii ◽  
Open Label ◽  
Duration Of Response ◽  
Independent Review ◽  
Secondary Endpoints

7502 Background: SELECT investigated whether the addition of C to standard chemotherapy improved progression-free survival (PFS) in patients (pts) with recurrent or progressive NSCLC after failure of platinum-based therapy. Methods: SELECT was a multicenter, open label, randomized phase III trial. Per investigator choice, pts received either P (500 mg/m2) or D (75 mg/m2) on day 1 and then were randomized within each group to chemotherapy plus C (400/250 mg/m2) (initial/weekly) or chemotherapy alone. Therapy was given for up to six 3-week cycles; pts randomized to C continued weekly monotherapy until disease progression or unacceptable toxicity. The primary objective was PFS for PC vs. P as determined by an Independent Review Committee (IRC). Secondary endpoints included overall survival (OS), objective response rate (ORR) and duration of response (DOR) by IRC, and safety. Preplanned subgroup analyses for epidermal growth factor receptor (EGFR) staining intensity by immunohistochemistry and histology were performed. Results for PC vs. P only are presented. Results: Between Jan 2005 and Feb 2010, 938 total pts were randomized. Baseline demographics were comparable between PC (n=301) and P (n=304): median age 64 years; male 60%; Caucasian 88%; KPS 80-100/60-70 84%/16%; squamous/non-squamous 24%/76%. Median PFS (months) PC: 2.89 and P: 2.76 (hazard ratio [HR] =1.03 [95% confidence interval (CI)=0.87-1.21]; p=0.76). Median OS (months) PC: 6.93 and P: 7.79 (HR=1.01 [95% CI=0.86-1.20]; p=0.86). ORR PC: 6.6% and P: 4.3% (odds ratio =1.59 [95% CI=0.78-3.26]; p=0.20). Median DOR (months) PC: 4.17 and P: 6.93 (HR=1.58 [95% CI=0.74-3.36]; p=0.24). There were no statistical differences in efficacy based on histology or EGFR staining intensity. More drug-related AEs/SAEs were observed in the PC arm, with differences mainly attributable to skin toxicities, GI (diarrhea/stomatitis), and hypomagnesemia. Conclusions: The addition of C to P did not improve efficacy in this pt population. Further biomarker analyses are planned. The safety profiles for C and P were consistent with existing data and no new safety signals were observed.

A phase III randomized study of nivolumab plus ipilimumab versus nivolumab for previously treated patients with stage IV squamous cell lung cancer and no matching biomarker (Lung-MAP Sub-Study S1400I, NCT02785952).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9014-9014 ◽  
Author(s):  
Lyudmila Bazhenova ◽  
Mary Weber Redman ◽  
Scott N. Gettinger ◽  
Fred R. Hirsch ◽  
Philip C. Mack ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Randomized Study ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Grade 5 ◽  
Secondary Endpoints ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

9014 Background: Lung-MAP is a master protocol for patients (pts) with stage IV previously treated SqNSCLC. S1400I enrolled pts who were not eligible for a biomarker-matched sub-study. Methods: S1400I is phase III randomized trial for immunotherapy-naïve patients with ECOG 0-1 not selected by PD-L1 expression. Pts were assigned 1:1 to nivolumab and ipilimumab (N+I) vs nivolumab (N). N was given at 3 mg/kg q 2w, I was given at 1 mg/kg q 6w. The primary endpoint was overall survival (OS). Secondary endpoints: investigator-assessed progression-free survival (IA-PFS), response by RECIST 1.1, and toxicity. Results: From December 18, 2015 to April 23, 2018, 275 pts enrolled and 252 determined eligible (125 N+I and 127 N). The study was closed for futility at an interim analysis. Baseline characteristics were similar across arms. mOS was 10.0 m (8.0-12.8) and 11.0 m (8.2-13.5) for N+I and N. HR 0.97 (0.71-1.31), p 0.82. mPFS was 3.8 m (2.3-4.2) and 2.9 m (1.8-3.9) for N+I and N. HR 0.84 (0.64-1.09), p 0.19. Outcomes based on PD-L1 and TBM subsets are shown in table. Response rates were 18% (12-25%) and 17% (11-24%) for N+ I and N. Median follow up for patients still alive was 17.4 m. Grade ≥3 treatment-related AEs occurred in 48(39%) of pts on N+I vs 38(31%) on N. irAE reported in 39% of pts on N+I and 34% of patients on N. Drug-related AEs led to discontinuation in 25% and 16% of pts on N+I and N. There were 5 grade 5 AE in N+I arm and 1 in N arm. Conclusions: S1400I failed to show improvement in outcomes with N+I. Study was closed for futility at interim analysis. Toxicities were not different between two arms. Clinical trial information: 02785952. [Table: see text]

Effect of adding ublituximab to ibrutinib on PFS, ORR, and MRD negativity in previously treated high-risk chronic lymphocytic leukemia: Final results of the GENUINE phase III study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8022-8022 ◽  
Author(s):  
Jeff P. Sharman ◽  
Danielle M. Brander ◽  
Anthony R. Mato ◽  
Nilanjan Ghosh ◽  
Stephen J. Schuster ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
First Year ◽  
Bulky Disease ◽  
Depth Of Response ◽  
Independent Review ◽  
Secondary Endpoints ◽  
Anti Cd20

8022 Background: The BTK inhibitor ibrutinib (IB) has advanced the treatment for patients (pts) with CLL, however, among pts with high-risk CLL, disease control with IB is less durable. Ublituximab (UTX) is a glycoengineered mAb with enhanced ADCC. The GENUINE study evaluated the addition of UTX to IB vs. IB alone in high-risk rel/ref CLL. With a median follow up now 3.5+ yrs, we present the final results. Methods: Eligible pts having rel/ref CLL with centrally confirmed del17p, del11q, and/or a TP53 mutation, were randomized 1:1 to IB (420 mg QD) alone or with UTX (900 mg on D1, 8, 15 of Cy 1, D1 of Cy 2-6, and Q3 Cy thereafter). No limit on # of prior Tx; prior IB excluded. Primary endpoint was overall response rate (ORR) by iwCLL 2008 (excludes PR-L); secondary endpoints were CR rate, peripheral blood MRD negativity (analyzed centrally), PFS, and safety. Response was by blinded independent review. Results: 117 pts were treated (59 in UTX + IB arm; 58 in IB arm). Med age was 66 yrs and med # of prior Tx was 1 (range 1-5) for each arm. Baseline features were relatively balanced including ECOG, gender, and med time since diagnosis (6+ yrs). 17p del was greater in the IB arm (50% vs 44%); bulky disease was greater in UTX + IB arm (47% vs 28%); IGHV-unmut was 83% for both arms. At data-cutoff of Sep 1, 2019, AEs were comparable between the arms, except infusion reactions (UTX + IB: All G 53% / G 3/4 3%) and neutropenia (All G 36% vs 21%, G 3/4 19% vs. 12%) which were higher for UTX + IB. At a med follow up of 42 mos, all efficacy endpoints were in favor of UTX + IB (see Table). Conclusions: In contrast to prior studies adding rituximab to IB, GENUINE is the first randomized trial to demonstrate a PFS benefit with the addition of an anti-CD20 to IB. Increasing depth of response (CR rate, MRD-neg) post first year of Tx supports maintenance therapy with UTX. Clinical trial information: NCT02301156 . [Table: see text]

Flavopiridol (Alvocidib) Induces Durable Responses in Relapsed Chronic Lymphocytic Leukemia (CLL) Patients with High-Risk Cytogenetic Abnormalities

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 46-46 ◽  
Author(s):  
Thomas S. Lin ◽  
Nyla A. Heerema ◽  
Gerard Lozanski ◽  
Beth Fischer ◽  
Kristie A. Blum ◽  
...  
Keyword(s):  
High Risk ◽  
Response Rate ◽  
Phase 1 ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Purine Analog ◽  
Reduced Intensity

Abstract Background: Relapsed CLL patients (pts) with high-risk cytogenetic features have limited treatment options. Flavopiridol induces p53-independent apoptosis of CLL cells in vitro. We previously demonstrated that a pharmacokinetically (PK) derived dosing schedule administering flavopiridol by 30-min IV bolus (IVB) followed by 4-hr continuous IV infusion (CIVI) achieves the necessary serum concentration to induce apoptosis and is clinically active in pts with relapsed, genetically high-risk CLL. Study Design and Treatment: We report response and median progression free survival (PFS) results for 117 pts with relapsed CLL (n=107) or small lymphocytic lymphoma (n=10) treated on successive phase 1–2 studies of this PK-derived schedule. Pts received flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses every 6 weeks (n=79), or weekly for 3 doses every 4 weeks with pegfilgrastim support (n=38), for up to 6 cycles. Twenty pts received 30 mg/m2 IVB + 30 mg/m2 CIVI, and 3 pts received 40 mg/ m2 IVB + 40 mg/m2 CIVI. The remaining pts received 30 mg/m2 IVB + 30 mg/m2 CIVI for the first 1 or 5 dose(s) followed by dose escalation to 30 mg/m2 IVB + 50 mg/m2 CIVI beginning with dose 2 or dose 6 if severe tumor lysis was not observed. Pt Characteristics: Eighty pts were male (68%), median age was 60 years (range, 36–84), and 22 pts were age 70 or older (19%). Median number of prior therapies was 4 (range, 1–14); 116 pts had received prior purine analog therapy, and 85 pts (73%) were refractory to (n=82) or intolerant of purine analog (n=3). Ninety-three pts were Rai stage III/IV (79%), and 85 pts had bulky lymph nodes □ 5 cm (73%). Response Assessment: All 117 pts were evaluated for response by NCI 1996 Working Group criteria. Overall response rate (ORR) was 48%, including 52 partial responses (PR), 3 nodular PR (nPR), and 1 complete response (CR). Seven responders were taken to reduced intensity allogeneic stem cell transplants (SCT) and were censored. Median PFS of the 49 other responders was 10 months. Ten pts remain in remission with a median PFS of 12 months (range, 7–22.5). Six responders relapsed and received repeat flavopiridol therapy; 5 pts responded (4 PR, 1 CR) with a median PFS of 12.5 months. Forty-one of 85 pts (48%) with bulky adenopathy; 23 of 53 pts (43%) with a complex karyotype; 20 of 40 pts (50%) with del(17p13), resulting in loss of p53; and 29 of 49 pts (59%) with del(11q22), resulting in loss of the ATM tumor suppressor gene; responded to therapy. Median PFS was 10–12 months in all cytogenetic groups. Conclusions: Flavopiridol achieves durable responses in heavily treated, relapsed CLL pts with bulky adenopathy and poor-risk cytogenetic features. Flavopiridol allows pts who are not SCT candidates to achieve sufficient reduction of their disease to undergo reduced intensity allogeneic SCT. Pts who respond to flavopiridol and subsequently relapse may respond to repeat therapy. Based on these promising results, a phase 2 registration study is ongoing. All Patients Complex del(17p13) del(11q22) N 117 53 40 49 Response rate 48% 43% 50% 59% Median PFS 10.0 months 10.0 months 12.0 months 10.7 months

ALPINE: Phase III zanubrutinib (BGB-3111) versus ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7572-TPS7572 ◽  
Author(s):  
Peter Hillmen ◽  
Jennifer R. Brown ◽  
John C. Byrd ◽  
Barbara Eichhorst ◽  
Nicole Lamanna ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Complete Response ◽  
Geographic Region ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Open Label ◽  
Duration Of Response ◽  
Treatment Naïve ◽  
Independent Review ◽  
Ecog Ps

TPS7572 Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib, an investigational inhibitor of BTK, was specifically engineered to optimize selectivity, half-life and solubility in an effort to decrease toxicities and better penetrate tumor tissue. Early clinical data suggested that zanubrutinib treatment in patients with treatment-naïve (TN; n = 16) or R/R (n = 50) CLL/SLL induced deep responses: 94% overall response rate (ORR), including 6% and 2% complete response rates in TN and R/R CLL/SLL, respectively (ICML 2017). This study is designed to evaluate whether zanubrutinib monotherapy exhibits non-inferior and potentially superior efficacy based on the ORR vs ibrutinib monotherapy in patients with R/R CLL/SLL. Methods: This ongoing phase 3, randomized, open-label, global study (NCT03734016, BGB-3111-305) is comparing the efficacy and safety of zanubrutinib vs ibrutinib in adult patients with R/R CLL/SLL. Approximately 400 patients will be randomized, 1:1 to each arm and stratified by age (< 65 vs ≥ 65 years), refractory status (yes vs no), geographic region, and del(17p)/ TP53 mutation status (present vs absent). Key inclusion criteria include R/R CLL/SLL requiring treatment per iwCLL criteria, ECOG PS 0-2, and adequate hematologic function. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL and per 2014 Lugano Classification for patients with SLL. The study is powered to test the non-inferiority and superiority of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, safety, duration of response, and overall survival. Recruitment is ongoing. Clinical trial information: NCT03734016.

Fludarabine and Cyclophosphamide Produces a Higher Complete Response Rate and More Durable Remissions than Fludarabine in Patients with Previously Untreated CLL: Intergroup Trial E2997.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 475-475 ◽  
Author(s):  
Ian W. Flinn ◽  
Elizabeth Kumm ◽  
Michael R. Grever ◽  
Donna Neuberg ◽  
Gordon W. Dewald ◽  
...  
Keyword(s):  
Performance Status ◽  
Randomized Study ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
Complete Response ◽  
Phase Iii ◽  
Data Monitoring ◽  
P Value ◽  
Fisher Exact Test ◽  
Monitoring Committee

Abstract The combination of fludarabine and cyclophosphamide (FC) has been noted to produce a high complete response rates in previously untreated patients with CLL. However, it may be accompanied by increased toxicity. To further evaluate its efficacy and toxicity, a phase III randomized study of FC versus Fludarabine (F) was conducted in patients with previously untreated CLL. The study, which was open to accrual from December 23, 1999 to March 19, 2004, closed with 278 patients enrolled, 141 on the FC arm and 137 on the F arm. Four patients declined to receive protocol treatment, including one who was later found to be ineligible. Five additional patients were also deemed ineligible. All patients with data are included in this analysis (intent to treat). Patients on the FC arm received C 600 mg/m2 iv day 1 and F 20 mg/m2 iv days 1 through 5, followed by filgrastim 5 mg/kg SC starting approximately day 8. Patients randomized to the F arm received F 25 mg/m2 iv days 1 through 5. In April 2004, the ECOG Data Monitoring Committee conducted a planned review at 76% information, and determined that the null hypothesis of no difference in CR rates could be rejected. The Data Monitoring Committee gave permission for the submission of abstracts to ASH. The median age of patients was 62 years (34–86), and the median performance status was 1 (0 to 2). As is expected in CLL, 70% of patients were male (194) and 30% were female (83). At study entry, 56% of cases were Rai stages, 0,1 or 2, while 44% were in stage 3 or 4. 57% of patients received the maximum of 6 cycles of therapy. Toxicity data is available on 127 CF and 125 F patients. There were two deaths due to infection with grade 3 or 4 neutropenia (one in each arm). In the CF arm, 17% of patients suffered grade 4 or higher non-hematologic toxicities, while in the F alone arm, 13% had higher grade toxicities (p= 0.48). Additionally, 17% of patients in the FC arm suffered infections versus 11% in the F alone arm (p= 0.21). Response data was available on 246 of the 278 patients. In the FC arm (125 cases), 28 patients achieved CR (22.4%), 60 patients achieved PR (48.0%) for a total of 88 objective responses (70.0%). In contrast, on the F alone arm (121 cases), there were 7 CRs (5.8%), 53 PRs (43.8%) for a total of 60 objective responses (49.6%). The Fisher exact test for the difference in CR rates gives a p-value of 0.0002, while the test for difference in OR rate was 0.001. Currently, 235 patients are alive and 42 have died. Among the 229 patients with information on time to progression, 131 are alive without progression, 78 have progression, and 20 have died without progression. 58 of the 78 with progressive disease remain alive. The preliminary estimates of the median progression free survival time are 41.0 months for the FC arm, and 17.7 months for the F alone arm ( p &lt;0.001). It is noteworthy that the CR rate of F alone is similar to that reported by the GCLLSG (Eichhorst #243 ASH 2003). In summary, FC is a highly effective and tolerable regimen that produces more durable remissions than F in patients with previously untreated CLL.

Comparison of Cladribine Plus Cyclophosphamide With Fludarabine Plus Cyclophosphamide As First-Line Therapy for Chronic Lymphocytic Leukemia: A Phase III Randomized Study by the Polish Adult Leukemia Group (PALG-CLL3 Study)

2010 ◽  
Vol 28 (11) ◽  
pp. 1863-1869 ◽  
Author(s):  
Tadeusz Robak ◽  
Krzysztof Jamroziak ◽  
Joanna Gora-Tybor ◽  
Beata Stella-Holowiecka ◽  
Lech Konopka ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Deletion ◽  
Randomized Study ◽  
Nucleoside Analogs ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Tp53 Gene ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
First Line

Purpose Little is known about comparison of the activity of different purine nucleoside analogs in chronic lymphocytic leukemia (CLL). We conducted a randomized phase III trial to compare efficacy and safety of cladribine and fludarabine, each combined with cyclophosphamide, in previously untreated progressive CLL. Patients and Methods Patients received cladribine at 0.12 mg/kg combined with cyclophosphamide at 250 mg/m2 for 3 days intravenously (CC regimen) or fludarabine at 25 mg/m2 combined with cyclophosphamide at 250 mg/m2 for 3 days intravenously (FC regimen), every 28 days for up to six cycles. The primary end point was complete response (CR) rate. Secondary end points included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicity. Results Of 423 randomly assigned patients (211 to CC and 212 to FC), 395 were evaluated in the final analysis. The CR and ORR reached 47% and 88% in the CC arm and 46% and 82% in the FC arm (P = .25 and P = .11, respectively). The median PFS was 2.34 years with CC and 2.27 years with FC (P = .51). OS and grade 3/4 treatment-related toxicity were also comparable. Moreover, we did not observe any significant differences in CC and FC efficacy across different patient prognostic subgroups that included patients with 17p13 (TP53 gene) deletion who had poor survival in both study arms. Conclusion Cladribine and fludarabine in combination with cyclophosphamide are equally effective and safe first-line regimens for progressive CLL. Both combinations have unsatisfactory activity in patients with 17p13 (TP53 gene) deletion.

METRIC phase III study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAFV600E/K mutant advanced or metastatic melanoma (MM).

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA8509-LBA8509 ◽  
Author(s):  
Caroline Robert ◽  
Keith T. Flaherty ◽  
Peter Hersey ◽  
Paul D. Nathan ◽  
Claus Garbe ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Mek Inhibitor ◽  
Phase Iii ◽  
Rank Test ◽  
Brafv600e Mutation ◽  
Independent Review ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Grade 3 ◽  
To Receive

LBA8509 Background: Dacarbazine (D) and paclitaxel (P) have been used to treat MM pts with limited effect. The MM treatment landscape has recently changed with the approval of vemurafenib and ipilimumab in 2011, but secondary malignancies or other toxicities are of concerns. T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. In a PhII trial (NCT01037127), pts with BRAFV600E mutation MM had median PFS of 5.3 mos. This PhIII trial (NCT01245062) was conducted in pts with BRAFV600E/K mutant advanced or MM. Methods: Pts were randomized 2:1 to T (2mg QD) or C (D or P). Pts were stratified by baseline LDH level and prior C; pts in the C arm were allowed to crossover to receive T after confirmation of PD. Primary endpoint was PFS in pts with BRAFV600E mutation-positive MM and no prior brain mets; secondary endpoints were OS, ORR and safety in primary and ITT. PFS and OS were compared using a stratified log-rank test. The study was designed with ≥99% power and one-sided α = 0.025 to detect 57% reduction in the risk of PD or death in pts treated with T vs C. Results: Between Dec 2010 and Jul 2011, 322 pts were randomized to T (n=214) or C (n=108); 273 pts were BRAFV600E mutation-positive with no prior brain mets. HR for primary population for PFS by investigator was 0.44 (95% CI 0.31–0.64; p<0.0001) in favor of T with a median PFS of 4.8 mo vs 1.4 mo with C. PFS benefit in favor of T was observed in ITT; this was confirmed by an independent review. The confirmed ORR was 24% with T and 7% with C. HR for interim OS was 0.53 (95% CI 0.30–0.94; p=0.0181), in favor of T in primary population. OS benefit was consistent in ITT pop despite 51 pts crossover from C to T. The most frequent AEs with T were skin rash, diarrhea, edema, hypertension, fatigue. Known MEKi class effects were observed, e.g. chorioretinopathy (<1%) and decreased ejection fraction (7%). Grade 3 AEs in T arm were hypertenstion (12%) and rash (7%). Conclusions: T is the first in class MEKi associated with a significant improvement of PFS and OS compared to C in pts with BRAFV600E/K mutant MM.

Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate (AA) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA4518-LBA4518 ◽  
Author(s):  
Charles J. Ryan ◽  
Matthew Raymond Smith ◽  
Johann Sebastian De Bono ◽  
Arturo Molina ◽  
Christopher Logothetis ◽  
...  
Keyword(s):  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Primary Objective ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Strong Trend ◽  
Secondary Endpoints ◽  
Grade 3

LBA4518 Background: AA is an androgen biosynthesis inhibitor that inhibits CYP17 and improves overall survival (OS) in post-docetaxel mCRPC. The primary objective of COU-AA-302 was to compare clinical benefit of AA + prednisone (P) vs placebo (PL) + P in chemo-naive, asymptomatic/mildly symptomatic mCRPC pts. Methods: 1088 pts (151 centers; 12 countries) were randomized 1:1 to AA (1 g) + P (5 mg BID) or PL + P. Co-primary endpoints: radiographic progression-free survival (rPFS) and OS. Median times estimated using K-M method including LR statistic for inference. The Lan-DeMets α-spending function was used for OS. Results:The Independent Data Monitoring Committee concluded that the OS, rPFS and secondary endpoints (Table) all favored the AA arm and unanimously recommended unblinding the study and crossing pts from PL to AA at IA (43% of total events). Median follow up = 22.2 mos. Grade 3/4 AEs (AA + P, PL + P) (%): hypertension 3.9 vs 3.0; hypokalemia 2.4 vs 1.9; ALT↑ 5.4 vs 0.7; AST↑ 3.0 vs 0.9. Conclusions:AA + P produced a statistically significant improvement in rPFS and a strong trend for increased OS at this IA. AA resulted in clinically and statistically significant effects on all secondary endpoints. IA results confirmed the acceptable tolerability/safety profile of AA. This is the first randomized trial to demonstrate both OS and rPFS benefits in chemo-naive mCRPC and that inhibition of persistent extragonadal androgen synthesis significantly delays initiation of cytotoxic chemo. While median OS (AA arm) has not been reached, median PL arm OS (27.2 mos) is the longest measured in any phase III mCRPC study. [Table: see text]

Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. LBA385-LBA385 ◽  
Author(s):  
Axel Grothey ◽  
Alberto F. Sobrero ◽  
Salvatore Siena ◽  
Alfredo Falcone ◽  
Marc Ychou ◽  
...  
Keyword(s):  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
Multicenter Trial ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Correct Trial ◽  
Double Blind ◽  
Multikinase Inhibitor ◽  
Secondary Endpoints ◽  
Grade 3

LBA385 Background: Regorafenib (BAY 73-4506) is an oral multikinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases. The phase III CORRECT trial was conducted to evaluate efficacy and safety of regorafenib in pts with mCRC who had progressed after all approved standard therapies. Methods: Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive regorafenib (160 mg od po, 3 weeks on/1 week off) plus BSC, or placebo (PL) plus BSC. Pts continued on treatment until progression, death, or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), safety, and quality of life. Results: From May 2010 to March 2011, 760 pts were randomized (regorafenib: 505; PL: 255). Baseline characteristics were balanced between two arms. Preliminary results are available from a pre-planned formal interim analysis. The estimated hazard ratio (HR) for OS was 0.773 (95% CI: 0.635, 0.941; 1-sided p=0.0051). Median OS was 6.4 mos (95% CI: 5.9, 7.3) for regorafenib and 5.0 mos (95% CI: 4.4, 5.8) for PL. The estimated HR for PFS was 0.493 (95% CI: 0.418, 0.581; 1-sided p < 0.000001). Median PFS was 1.9 mos (95% CI: 1.88, 2.17) for regorafenib and 1.7 mos (95% CI: 1.68, 1.74) for PL. ORR was 1.6% for regorafenib and 0.4% for PL. DCR was 44% for regorafenib and 15% for PL (p < 0.000001). Since the prespecified OS efficacy boundary was crossed (nominal α: 0.0093), the Data Monitoring Committee recommended to unblind the study and pts on PL were allowed to cross over to regorafenib. The most frequent grade 3+ AEs in the regorafenib arm were hand-foot skin reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension (7%). Updated results will be presented. Conclusions: Statistically significant benefit in OS and PFS was observed for regorafenib over PL in pts with mCRC who have failed all approved standard therapies. No new or unexpected safety signal was found.

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