scholarly journals The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, Phase III study in patients with myelofibrosis

2013 ◽  
Vol 161 (4) ◽  
pp. 508-516 ◽  
Author(s):  
Srdan Verstovsek ◽  
Ruben A. Mesa ◽  
Jason Gotlib ◽  
Richard S. Levy ◽  
Vikas Gupta ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Phase Iii ◽  
Phase Iii Study ◽  
Patient Subgroups

Improved survival outcomes in clinically relevant patient subgroups from COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel-based chemotherapy.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 4-4 ◽  
Author(s):  
H. I. Scher ◽  
C. Logothetis ◽  
A. Molina ◽  
O. B. Goodman ◽  
C. N. Sternberg ◽  
...  
Keyword(s):  
Abiraterone Acetate ◽  
Phase Iii ◽  
Double Blind Study ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Androgen Synthesis ◽  
Phase Iii Study ◽  
Study Population ◽  
Grade 3 ◽  
Patient Subgroups

4 Background: AA is a selective androgen biosynthesis inhibitor that blocks the action of CYP17. Preclinical and early clinical studies suggest that AA potently inhibits persistent androgen synthesis from adrenal and intratumoral sources, thus suppressing an important growth stimulus for mCRPC. Methods: COU-AA-301 ( NCT00638690 ) is an international, randomized, double blind study of AA (1,000 mg + P 5 mg po BID) vs placebo + P administered to men with mCRPC progressing after docetaxel-based chemo. OS is the primary endpoint. Patients treated with previous ketoconazole or > 2 prior chemo regimens were excluded. Results: Data are drawn from a planned, stratified interim analysis, unblinded in August 2010, based on significant OS improvement in the AA + P treatment group compared to the placebo + P group [median OS 14.8 vs.10.9 months; HR = 0.646 (0.54-0.77), P < 0.0001]. A subgroup analysis for OS is presented in the table. Mineralocorticoid- related AEs were more common in the AA arm vs placebo: fluid retention 30.5% vs 22.3%, hypokalemia 17.1% vs 8.4%; but grade 3/4 hypokalemia (3.8% vs 0.8%), and grade 3/4 hypertension (1.3% vs 0.3%) were infrequent. LFT abnormalities were observed in 10.4% AA vs 8.1% placebo; and cardiac disorders were observed in 13.3% AA vs 10.4% placebo. Conclusions: AA significantly prolongs OS in patients with mCRPC who have progressed after docetaxel-based chemo. AA's favorable treatment effect on OS, observed across multiple patient subgroups (HR range 0.59 – 0.74 vs placebo + P), was consistent with the survival benefit for the overall study population. [Table: see text] [Table: see text]

DETECT III: A multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus lapatinib in patients (pts) with initially HER2-negative metastatic breast cancer but with HER2-positive circulating tumor cells (CTC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS1146-TPS1146
Author(s):  
Carsten Hagenbeck ◽  
Carola Anna Melcher ◽  
Johann Wolfgang Janni ◽  
Andreas Schneeweiss ◽  
Peter A. Fasching ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Targeted Therapy ◽  
Clinical Benefit ◽  
Standard Treatment ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Her2 Status ◽  
Her2 Positive ◽  
Phase Iii Study

TPS1146 Background: HER2 status may change over the course of disease in breast cancer pts. Approx. 20-30% of pts with initially HER2-negative breast cancer have HER2-positive metastasis (Zidan et al. 2005; Tewes et al. 2009). Determining HER2 status on CTC is one option to re-evaluate HER2 status at the time metastasis is diagnosed. Currently it is unclear if HER2-targeted therapy based on the assessment of HER2 status of CTC reveals a clinical benefit. Methods: This is a randomized, open-label, two arm phase III study to investigate the clinical efficacy of lapatinib, as a HER2-targeted therapy in initially HER2-negative metastatic breast cancer pts with HER2-positive CTC at the time of distant disease. As only half of the pts with HER2-negative metastatic breast cancer show CTC-positivity and of those approx. 32% will exhibit HER2-positive CTC (Fehm et al. 2010), screening of about 1420 pts is required to enroll 228 pts. Main inclusion criteria: metastatic breast cancer with HER2-negative primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences, evidence of ≥1 HER2-positive CTC and ≥1 measurable metastatic lesion according to RECIST. Eligible pts will be randomized 1:1 to receive standard treatment vs. standard treatment plus lapatinib. Standard chemo- or endocrine therapy must be approved in combination with lapatinib or been investigated in prior clinical trials. Primary endpoint is progression free survival. Secondary endpoints include overall response rate, clinical benefit rate, overall survival and dynamic of CTC. The DETECT III trial is one of the first trials where treatment is based on phenotypic characteristics of CTC. If this trial succeeds in proving efficacy of lapatinib in pts with initially HER2-negative metastatic breast cancer but HER2-positive CTC, this will establish a new strategy in the treatment of metastatic breast cancer.

Phase III study of lapatinib (L) plus trastuzumab (T) and aromatase inhibitor (AI) vs T+AI vs L+AI in postmenopausal women (PMW) with HER2+, HR+ metastatic breast cancer (MBC): ALTERNATIVE.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1004-1004 ◽  
Author(s):  
William John Gradishar ◽  
Roberto Hegg ◽  
Seock-Ah Im ◽  
In Hae Park ◽  
Sergei Tjulandin ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Clinical Benefit ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
To Receive ◽  
Clinical Trial Information

1004 Background: Combination ofHER2-targeted therapy+AI improved clinical benefit in patients (pts) with HER2+, HR+ MBC vs AI alone in two previous trials, median progression free survival (mPFS) 4.8 vs 2.4 mo (TAnDEM), and 8.2 vs 3.0 mo (EGF30008). Dual HER2 blockade enhances clinical benefit vs single HER2 blockade. This study evaluated the safety and efficacy of dual vs single HER2 blockade (L+T vs T/L)+AI in HER2+, HR+ MBC progressing on (neo)adjuvant/first-line T+chemotherapy (CT). HER2 and HR status were assessed for eligibility at local lab. Methods: PMW were randomized 1:1:1 to receive T (8mg/kg followed by 6mg/kg IV Q3W)+L (1000mg/d)+AI or T+AI or L (1500mg/d)+AI. AI was per investigator’s choice. Pts were excluded if they were intended for CT. The primary endpoint was to assess superiority of PFS with L+T vs T. Secondary endpoints included PFS (L vs T), overall survival (OS), overall response rate (ORR), and safety. Results: 369 pts were enrolled; current analysis included 355 pts (data cutoff, March 11, 2016); L+T (n = 120), T (n = 117) or L (n = 118). Final PFS data were analyzed after 137 events. Baseline characteristics were balanced across all treatment (tx) arms. The primary endpoint was met; superior PFS was observed with L+T vs T (mPFS, 11 vs 5.7 mo; HR = 0.62, 95% CI [0.45, 0.88], P= 0.0064). This benefit of L+T was consistent in key subgroups. mPFS with L vs T was 8.3 vs 5.7 mo (HR = 0.71, 95% CI [0.51, 0.98], P= 0.0361). ORR with L+T, T, and L was 32%, 14%, and 19% respectively. OS data are immature. Most common adverse events (AEs) with L+T, T and L (≥15%, any arm) were diarrhea (69%, 9%, 51%), rash (36%, 2%, 28%), nausea (22%, 9%, 22%), and paronychia (30%, 0, 15%). Hepatic abnormalities of > 3 ULN ALT/AST levels were noted in 4%, 6%, and 16% respectively. Incidence of tx-related SAEs was 5%, 2%, and 4% and on-tx deaths was 3%, 4%, and 5%, respectively. Conclusions: Dual HER2 blockade with L+T+AI showed superior PFS benefit vs T+AI, in pts with HER2+, HR+ MBC. Incidence of AEs was increased with L+T. This combination can potentially offer an effective CT-sparing tx option in subgroup of HER2+, HR+ pts without aggressive disease and who are not candidates for CT. Clinical trial information: 2010-019577-16.

scholarly journals Reimbursement recommendations for cancer drugs supported by phase II evidence in Canada

2020 ◽  
Vol 27 (5) ◽  
Author(s):  
Y.Y.R. Li ◽  
H. Mai ◽  
M.E. Trudeau ◽  
N. Mittmann ◽  
K. Chiasson ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Multivariable Analysis ◽  
Unmet Need ◽  
Phase Iii ◽  
Expert Review ◽  
Phase Iii Study ◽  
Patient Values ◽  
Background Phase ◽  
Positive Recommendation

Background Phase ii data are increasingly being used as primary evidence for public reimbursement for oncologic drugs. We compared the frequency of reimbursement recommendations for phase ii and phase iii submissions and assessed for variables associated with a positive or conditional recommendation. Methods We identified submissions made to the pan-Canadian Oncology Drug Review’s Expert Review Commit­tee (perc), of the Canadian Agency for Drugs and Technologies in Health, July 2011 to July 2019, that were supported only by phase ii data. We identified variables within the perc’s deliberative framework, including clinical and eco­nomic factors, associated with the final reimbursement recommendation. We conducted a multivariable analysis with logistic regression for these variables: feasibility of phase iii study, hematologic indication, and unmet need. Results We identified 139 submissions with a perc final recommendation. In 27 instances (19%), the submission had only phase ii evidence, and a positive recommendation was issued for 63% of them (the positive recommendation rate was 82% for submissions with phase iii evidence). Clinical benefit (p < 0.001), unmet need (p = 0.047), and patient alignment (p = 0.015) were associated with a positive recommendation. If a future phase iii study was deemed feasible for submissions with only phase ii evidence, then in univariable (p = 0.040) and multivariable analysis (p = 0.024), the perc was less likely to recommend reimbursement (odds ratio: 0.132). Conclusions Although more than half the oncologic submissions with phase ii data were recommended for pub­lic reimbursement, compared with submissions having phase iii data, they were less likely to be recommended. A positive or conditional recommendation was more likely if clinical benefit and alignment with patient values was demonstrated. The perc was less likely to recommend reimbursement for submissions with phase ii evidence if a phase iii trial was deemed possible.

Gemcitabine in Combination With Oxaliplatin Compared With Gemcitabine Alone in Locally Advanced or Metastatic Pancreatic Cancer: Results of a GERCOR and GISCAD Phase III Trial

2005 ◽  
Vol 23 (15) ◽  
pp. 3509-3516 ◽  
Author(s):  
C. Louvet ◽  
R. Labianca ◽  
P. Hammel ◽  
G. Lledo ◽  
M.G. Zampino ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Benefit ◽  
Performance Status ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Iii Study ◽  
Grade 3

Purpose Gemcitabine (Gem) is the standard treatment for advanced pancreatic cancer. Given the promising phase II results obtained with the Gem-oxaliplatin (GemOx) combination, we conducted a phase III study comparing GemOx with Gem alone in advanced pancreatic cancer. Patients and Methods Patients with advanced pancreatic cancer were stratified according to center, performance status, and type of disease (locally advanced v metastatic) and randomly assigned to either GemOx (gemcitabine 1 g/m2 as a 100-minute infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour infusion on day 2 every 2 weeks) or Gem (gemcitabine 1 g/m2 as a weekly 30-minute infusion). Results Three hundred twenty-six patients were enrolled; 313 were eligible, and 157 and 156 were allocated to the GemOx and Gem arms, respectively. GemOx was superior to Gem in terms of response rate (26.8% v 17.3%, respectively; P = .04), progression-free survival (5.8 v 3.7 months, respectively; P = .04), and clinical benefit (38.2% v 26.9%, respectively; P = .03). Median overall survival (OS) for GemOx and Gem was 9.0 and 7.1 months, respectively (P = .13). GemOx was well tolerated overall, although a higher incidence of National Cancer Institute Common Toxicity Criteria grade 3 and 4 toxicity per patient was observed for platelets (14.0% for GemOx v 3.2% for Gem), vomiting (8.9% for GemOx v 3.2% for Gem), and neurosensory symptoms (19.1% for GemOx v 0% for Gem). Conclusion These results confirm the efficacy and safety of GemOx, but this study failed to demonstrate a statistically significant advantage in terms of OS compared with Gem. Because GemOx is the first combined treatment to be superior to Gem alone in terms of clinical benefit, this promising regimen deserves further development.

Reimbursement recommendations for cancer drugs supported by phase II evidence in Canada.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14133-e14133
Author(s):  
Regina Li ◽  
Helen Mai ◽  
Kaitlyn Chiasson ◽  
Maureen E. Trudeau ◽  
Kelvin K. Chan ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Multivariable Analysis ◽  
Unmet Need ◽  
Current Treatment ◽  
Phase Iii ◽  
Treatment Standards ◽  
Exact Test ◽  
Phase Iii Study ◽  
Positive Recommendation

e14133 Background: Historically, pharmaceutical companies submitted phase III evidence for consideration of public reimbursement; however, phase II data is being more commonly used as primary evidence. Whether submissions with phase II data lead to similar rates of positive reimbursement recommendations as phase III data has not been comprehensively investigated. We compared frequency of reimbursement recommendations between phase II and phase III submissions for oncologic drugs and assessed for factors associated with a positive or conditional recommendation. Methods: We identified all submissions with phase II data from the CADTH pCODR’s expert review committee (pERC) recommendations from July 2011 to July 2019. We identified fourteen binary variables relating to clinical benefit, patient-based values, economic impact, and adoption feasibility. We used Fisher’s exact test to characterize associations between all variables and the final recommendation. We conducted multivariable analysis with logistic regression for three variables: feasibility of phase III study, hematologic indication, and unmet need. Results: We identified 139 submissions with a pERC final recommendation. Twenty-seven (19%) submissions were supported by phase II evidence, with 63% having a positive recommendation in comparison to 82% among submissions with phase III evidence. Clinical benefit (p < 0.001), gap in current treatment standards (p = 0.047), and patient alignment (p = 0.015) were associated with a positive recommendation, whereas the future feasibility of conducting a phase III study was associated with a negative recommendation (p = 0.040). No significant association was found between the recommendation and factors related to cost effectiveness or adoption feasibility. In multivariable analysis, only feasibility of a phase III study was significantly associated with a negative recommendation (p = 0.024, OR = 0.132). Conclusions: Oncologic submissions with phase II data were less likely to be recommended for public reimbursement than phase III studies. Positive or conditional recommendation was more likely if they demonstrated clinical benefit and aligned with patient values. pERC was less likely to recommend a submission with phase II if a phase III trial was either possible or already initiated.

No Significant Clinical Benefit of First Line Therapy with Fludarabine (F) in Comparison to Chlorambucil (Clb) in Elderly Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Phase III Study of the German CLL Study Group (GCLLSG).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 629-629 ◽  
Author(s):  
Barbara F. Eichhorst ◽  
Raymonde Busch ◽  
Martina Stauch ◽  
Manuela Bergmann ◽  
Matthias Ritgen ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Clinical Benefit ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Free Survival ◽  
Significant Clinical Benefit ◽  
First Line Therapy ◽  
Line Therapy ◽  
Phase Iii Study

Abstract Introduction: Treatment regimens based on purine analogues as F have become standard in first line therapy of younger or physically fit CLL pts. In these pts purine analogue-based regimens resulted in higher response rates and prolongation of progression free survival (PFS). Because it is not clear if elderly or physically non-fit pts benefit from more intense first line strategies as well, Clb is still widely used in first line therapy of elderly CLL pts. The GCLLSG initiated a phase III study (CLL5 protocol) to evaluate the effect of F versus (vs.) Clb in first line therapy of elderly patients with advanced CLL. Patients: 206 pts (F 101; Clb 105), older than 64 years, were enrolled between July 1999 and September 2004. 13 pts had to be excluded due to violation of exclusion/inclusion criteria. 15% of the pts were in Binet stage A, 47% in stage B, and 38% in stage C. The median pt age was 70 years (range 64 to 80). Pts were randomized to receive either F 25mg/mi.v. d1–5 q 28 days for 6 courses or Clb 0,4mg/kg ideal bodyweight (BW) (dose escalation up to 0.8mg/kg) q15d for up to 12 months. The mean number of administered courses was 4.9 in the F arm, the median duration of Clb treatment was 6.5 months (median dose 0.5 mg/kg). Results: After a median observation time of 41,5 months (mo) (range 1–89 mo) 165 pts (F 78; Clb 87) were evaluable for response and 184 (F 88; Clb 96) for progression free survival (PFS). In spite of a significantly higher complete remission rate (CRR) and overall response rate (ORR) in the F arm (CRR8% vs. 0%; p=0.008; ORR86% vs. 59%; p<0.001) no difference in the PFS was assessed (median PFS time 18.7 mo for F vs. 17.8 mo for Clb; p=0.72). Moreover, 46% of F treated pts in comparison to 34% Clb treated pts died so far, but overall survival (OS) curves showed no significant difference (median OS 45.9 mo vs. 63.6 mo, p=0.21). Analyzing PFS and OS separately for pts <70 years and ≥70 years no difference between both arms was assessed as well. Impaired creatinine clearance did not have any effect on PFS and OS as well as gender. Pts in the Clb arm received rescue treatment more frequently than F recipients (62% vs. 39%). Pts initially treated with Clb received for first relapse treatment Clb in 20%, F in 43%, F-based combinations in 17% and in 20% others. ORR to 2nd line F was 53% (10 of 19). Pts initially treated with F received in 26% each F-based combinations and CHOP regimen. Retreatment with F was administered in 12%, while 2 pts only received Clb. Conclusion: This long-term follow-up analysis shows that elderly pts have no significant clinical benefit from first line therapy with F in comparison to Clb. Though higher CRR and ORR F failed to show any benefit in terms of PFS and OS. A possible explanation for this phenomenon is the longer treatment period with Clb, that might prevent earlier relapses. Moreover, in case of relapse F treated pts received either no treatment at all or more intense regimen in comparison to Clb. In conclusion, Clb and F are similar potent first-line treatment options for elderly CLL pts.

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