A phase II trial assessing pazopanib (paz) as third-line therapy for metastatic renal cell carcinoma (mRCC): Clinical outcome and temporal analysis of molecular profile.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4571-4571
Author(s):  
Sumanta Kumar Pal ◽  
Dewan Md Sakib Hossain ◽  
Qifang Zhang ◽  
Chan Gao ◽  
Paul Henry Frankel ◽  
...  
Keyword(s):  
Type I Error ◽  
Temporal Analysis ◽  
Phase Iii ◽  
Molecular Profile ◽  
Vegf Receptor ◽  
Type I ◽  
Prior Therapy ◽  
Best Response ◽  
Treatment Naïve ◽  
Line Setting

4571 Background: Paz, an oral vascular endothelial growth factor (VEGF) receptor inhibitor, was assessed in a phase III study conducted in patients (pts) with mRCC who were cytokine-refractory or treatment-naïve (Sternberg et al J Clin Oncol 2010). Clinical outcomes with paz have been associated with a molecular profile (Tran et al Lancet Oncol 2012). The activity of paz in the 3rd-line setting and temporal changes in molecular profile during paz therapy are poorly understood. Methods: Eligibility was limited to pts with 2 prior lines of therapy (including at least 1 VEGF-directed therapy), ECOG PS 0-2, and clear cell histology. Pts received paz 800 mg/daily on a 28d cycle, and were assessed for response by RECIST 1.1 every 2 cycles. A Simon MinMax 2-stage design was employed, with 80% power of declaring an encouraging overall response rate (ORR) of 23% (type I error=10%). Molecular profiles were assessed on a Luminex platform using the Human Cytokine 30-plex Cytokine Immunoassay (Invitrogen) at baseline, 6 mos and 12 mos. Results: 28 pts (20M, 8F) were enrolled, with a median age of 63 (range, 45-86). All patients received at least 2 lines of prior therapy, and 6 pts (21%) had received 2 prior lines of VEGF-directed therapy. In the pre-specified intent-to-treat analysis, 12/28 pts (43%) had a confirmed response (1 CR, 11 PR), with 1 additional unconfirmed PR. 8 pts (29%) had SD as a best response. Median PFS for the cohort was 17.4 mos (95% CI 14.7-NR). No grade 4 treatment-related toxicities were observed. The most common grade 3 toxicities were hypertension (46%) and proteinuria (14%). At baseline, IL-6 was marginally lower in patients who achieved PR/CR (responders) as compared to those who did not (non-responders; P=0.06). Amongst patients still on therapy at 6 months and 12 months, responders had lower levels of HGF, IL-2R, IL-6, IL-8, and VEGF (P<0.05 for each) at both time intervals. Conclusions: Paz demonstrated an ORR of 43%, representing the highest ORR observed to date in a 3rd-line trial in mRCC. At 6 and 12 months, differences in molecular profile emerged between responders and non-responders, potentially underscoring mechanisms of drug resistance. Clinical trial information: NCT01157091.

Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: E1608.

2013 ◽  
Vol 31 (18_suppl) ◽  
pp. CRA9007-CRA9007 ◽  
Author(s):  
F. Stephen Hodi ◽  
Sandra J. Lee ◽  
David F. McDermott ◽  
Uma N. M. Rao ◽  
Lisa H. Butterfield ◽  
...  
Keyword(s):  
Cell Activation ◽  
Type I Error ◽  
Tumor Vaccine ◽  
Multiorgan Failure ◽  
Performance Status ◽  
Colonic Perforation ◽  
Phase Iii ◽  
Type I ◽  
Dendritic Cell Activation ◽  
Prior Therapy

CRA9007 Background: CTLA-4 blockade and GM secreting tumor vaccine combinations demonstrate therapeutic synergy in multiple preclinical models. GM has activity in prostate and ovarian carcinoma and is being evaluated in phase III adjuvant trials for melanoma and lymphoma. GM enhances dendritic cell activation and potentiates antitumor T and B cell responses. GM may induce regulatory immune responses. A key issue is whether systemic GM might synergize with CTLA-4 blockade. Methods: Eligibility: measureable disease, ≤1 prior therapy, no CNS mets, ECOG PS 0-1, > 4 wks prior therapy, adequate end organ function, no autoimmune disease, no prior CTLA-4 blockade/CD137 agonist. OS was primary endpoint. Pts randomized to Arm A Ipi 10 mg/kg q3 wks IV x 4 then q12 wks plus GM 250 μg SC days 1-14 of 21 day cycles vs. Arm B Ipi 10 mg/kg as in Arm A alone. Due to known inflammatory effects of treatments, pts were permitted to continue up to 100% increase in SPD and four new lesions in absence of declining performance status and discretion of treating physician. Drug supply, funding from Sanofi/Bristol-Myers Squibb. Results: 245 pts were enrolled. Arms were balanced for demographics. Median follow up 13.3 mos. RR Arm A 11.3 % (6.1, 18.6), Arm B 14.7% (8.6,22.8) (not significant;NS). PFS Arm A 3 mos (2.9,4.3), Arm B 3.2 mos (3,4) (NS). Median OS Arm A not reached, Arm B 12.6 mos (9.2,-). One year OS for Arm A was 67.9% (59%,76%), Arm B 51.2% (42.6%, 61.3%) (stratified log rank p1=0.016, p2=0.033). HR for mortality on Ipi + GM/Ipi=0.65. Per study design (overall one-sided type I error 0.10), OS interim analysis was conducted at 69% info time. O’Brien-Fleming boundary was crossed for OS. Toxicity assessed for all cases regardless of eligibility. Gr 3-5 AEs 45% Arm A, 57% Arm B (p2=0.078). Gr 5 AEs: Arm A colonic perforation (1), cardiac arrest (1); Arm B multiorgan failure (2), colonic perforation (2), hepatic failure (1), respiratory failure (2). Conclusions: Ipi plus GM significantly improves OS over Ipi alone. No significant differences in toxicity were observed. A trend toward improved tolerability is noted in the GM arm. Clinical trial information: NCT01134614.

TIVO-3: Tivozanib in patients with advanced renal cell carcinoma (aRCC) who have progressed after treatment with axitinib.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 278-278
Author(s):  
Brian I. Rini ◽  
Sumanta K. Pal ◽  
Bernard Escudier ◽  
Michael B. Atkins ◽  
Thomas E. Hutson ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Risk Category ◽  
Vegf Receptor ◽  
Free Survival ◽  
Prior Therapy ◽  
Third Line ◽  
Line Setting ◽  
Clinical Trial Information

278 Background: Tivozanib (T) is a potent and highly selective VEGF receptor (R) tyrosine kinase inhibitor in clinical development for RCC. Axitinib is also a potent and selective VEGF-R inhibitor now commonly part of front-line aRCC treatment. The activity of T after axitinib has not been previously defined. The activity of T after prior therapy types including axitinib is of clinical relevance. Methods: The pivotal TIVO-3 study enrolled subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI, stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective of the overall trial was to compare progression free survival (PFS) by blinded independent radiological review. Patients with prior axitinib received as monotherapy in the second or third line setting and other predefined subgroups were reviewed for outcome with T. Results: Patients treated with T after prior axitinib had a PFS of 5.5 months and an ORR of 13% compared to 3.7 months and 8% for patients treated with S. Other subgroups are presented in the table below. Clinical trial information: NCT02627963 . Conclusions: Tivozanib improved PFS vs. sorafenib in patients who have progressed after multiple VEGFR-TKIs, including patients with prior second or third line axitinib treatment. These results suggest differential activity from tivozanib and axitinib despite both being potent and selective VEGF-R inhibitors. [Table: see text]

Association of human endogenous retrovirus (hERV) expression with clinical efficacy of PD-1 blockade in metastatic clear cell renal cell carcinoma (mccRCC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4568-4568 ◽  
Author(s):  
Jean-Christophe Pignon ◽  
Opeyemi Jegede ◽  
Sachet A Shukla ◽  
David A. Braun ◽  
Christine Horak ◽  
...  
Keyword(s):  
Error Control ◽  
Type I Error ◽  
Endogenous Retrovirus ◽  
Phase Iii ◽  
Human Endogenous Retrovirus ◽  
Rank Test ◽  
Type I ◽  
Limit Of Quantification ◽  
Cell Renal Cell Carcinoma ◽  
Exact Test

4568 Background: hERV levels positively correlate with tumor immune infiltrate and were recently shown to be associated with clinical benefit to PD-1/PD-L1 blockade in two small cohorts of patients (pts) with mccRCC (Smith C.C. et al and Panda A. et al; 2018). We tested whether hERV levels correlate with efficacy of nivolumab in a prospective phase II study of pts with mccRCC (Checkmate 010). Methods: Reverse transcribed RNA extracted from 99 FFPE pretreatment tumors were analyzed by RT-qPCR to assess levels of pan- ERVE4, pan- ERV3.2, hERV4700 GAG or ENV, and the reference genes 18S and HPRT1. Normalized hERV levels were transformed as categorical value (high or low) using population quartiles as cutoffs. For each cutoff, samples with non-quantifiable hERV levels for which the limit of quantification was above the tested cutoff could not be categorized and were excluded from analysis. Log rank test was used to test the association of hERV levels with PFS/irPFS (RECISTv1.1/irRECIST) at each cutoff using Holm-Bonferroni correction for Type I error control; adjusted P-values are reported. Fisher’s exact test was then used to explore the association with ORR/irORR (RECISTv1.1/irRECIST). Results: Among the hERV studied, only hERV4700 ENV was significantly associated with PFS/irPFS. At the 25th percentile cutoff, 45 pts had high levels of hERV4700 ENV and 24 pts had low levels of hERV4700 ENV. Median PFS and irPFS were significantly longer in the high- hERV4700 ENV group [7.0 (95% CI: 2.2 - 10.2) and 8.5 (95% CI: 4.2 - 14.1) months, respectively] versus the low- hERV4700 ENV group [2.6 (95% CI: 1.4 - 5.4) and 2.9 (95% CI: 1.4 - 5.7) months, respectively] ( P = 0.010 for PFS and P = 0.028 for irPFS). At the same cutoff, ORR and irORR rates were significantly higher in the high- hERV4700 ENV group [35.6 (95% CI: 21.9 - 51.2) % for both ORR/irORR] versus the low- hERV4700 ENV group [12.5 (95% CI: 2.7 - 32.4) and 8.3 (95% CI: 1.0 - 27.0) %, respectively] ( P = 0.036 for ORR and P = 0.012 for irORR). Conclusions: hERV4700 ENV levels may predict outcome on nivolumab in mccRCC. Validation of our results and correlation of hERV levels with immune markers in a controlled phase III trial (CheckMate 025) is ongoing.

scholarly journals Rational Clinical Experiment: Assessing Prior Probability and Its Impact on the Success of Phase II Clinical Trials

2015 ◽  
Vol 33 (26) ◽  
pp. 2914-2919 ◽  
Author(s):  
Daniel M. Halperin ◽  
J. Jack Lee ◽  
Cecile Gonzales Dagohoy ◽  
James C. Yao
Keyword(s):  
Phase Ii ◽  
Prior Probability ◽  
Type I Error ◽  
Drug Approval ◽  
Phase Iii ◽  
Type I ◽  
Phase Ii Trials ◽  
Predictive Values ◽  
Phase Ii Studies ◽  
Therapeutic Decisions

Purpose Despite a robust clinical trial enterprise and encouraging phase II results, the vast minority of oncologic drugs in development receive regulatory approval. In addition, clinicians occasionally make therapeutic decisions based on phase II data. Therefore, clinicians, investigators, and regulatory agencies require improved understanding of the implications of positive phase II studies. We hypothesized that prior probability of eventual drug approval was significantly different across GI cancers, with substantial ramifications for the predictive value of phase II studies. Methods We conducted a systematic search of phase II studies conducted between 1999 and 2004 and compared studies against US Food and Drug Administration and National Cancer Institute databases of approved indications for drugs tested in those studies. Results In all, 317 phase II trials were identified and followed for a median of 12.5 years. Following completion of phase III studies, eventual new drug application approval rates varied from 0% (zero of 45) in pancreatic adenocarcinoma to 34.8% (24 of 69) for colon adenocarcinoma. The proportion of drugs eventually approved was correlated with the disease under study (P < .001). The median type I error for all published trials was 0.05, and the median type II error was 0.1, with minimal variation. By using the observed median type I error for each disease, phase II studies have positive predictive values ranging from less than 1% to 90%, depending on primary site of the cancer. Conclusion Phase II trials in different GI malignancies have distinct prior probabilities of drug approval, yielding quantitatively and qualitatively different predictive values with similar statistical designs. Incorporation of prior probability into trial design may allow for more effective design and interpretation of phase II studies.

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 trial of panitumumab in cetuximab refractory KRAS wild-type colorectal cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 428-428 ◽  
Author(s):  
R. C. Wadlow ◽  
A. F. Hezel ◽  
B. M. Wolpin ◽  
J. N. Allen ◽  
L. S. Blaszkowsky ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Type I Error ◽  
Human Monoclonal Antibody ◽  
Growth Factor Receptor ◽  
Chimeric Antibody ◽  
Type I ◽  
Wild Type ◽  
Third Line ◽  
Line Setting

428 Background: While FOLFOX or FOLFIRI with bevacizumab are the standard first-line regimens in the treatment of metastatic colorectal cancer, a role for epidermal growth factor receptor inhibitiion in KRAS wild-type colorectal cancer has been established in the second and third line setting. Cetuximab is a chimeric antibody that consists of approximately 30% murine protein, and panitumumab is a fully human monoclonal antibody. Correspondingly, the rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). Presently, cetuximab is typically used in combination with irinotecan in the second or third line setting, and panitumumab is occasionally substituted if hypersensitivity occurs. The value of panitumumab as a salvage agent in cetuximab-resistant colorectal cancer is unknown. Methods: Panitumumab (6 mg/kg every 14 days) was administered to patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab. Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate (RR). Twenty patients were enrolled in the first stage and, if at least one responded, 12 additional patients were to be enrolled in a second stage. This two-stage design tested the null hypothesis that the RR is less than or equal to 1% versus greater than or equal to 10% with a type I error of 3.6% and 80% power. Blood samples were collected at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies using the Biacore immunoassay. Results: 22 patients with ECOG PS 0-2 were treated for a median of two cycles. The best response was stable disease (45%) and the RR was 0%. There were a total of 266 toxicities reported, the majority of which were mild (n = 184, 69%) or moderate (n = 63, 24%) in severity. There were 19 grade 3 and 0 grade 4 toxicities. Median overall survival was 1.9 months. Immunologic data will be reported at the time of presentation. Conclusions: Panitumumab is not active as salvage therapy for patients with cetuximab-resistant, KRAS wild-type metastatic colorectal cancer. [Table: see text]

Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. LBA1-LBA1 ◽  
Author(s):  
Tomasz M. Beer ◽  
Andrew J. Armstrong ◽  
Cora N. Sternberg ◽  
Celestia S. Higano ◽  
Peter Iversen ◽  
...  
Keyword(s):  
Error Rate ◽  
Interim Analysis ◽  
Radiographic Progression ◽  
Type I Error ◽  
Data Monitoring Committee ◽  
Phase Iii ◽  
Type I ◽  
Risk Of Death ◽  
Type I Error Rate ◽  
Upper Limit

LBA1^ Background: Enzalutamide, an orally administered androgen receptor inhibitor, improved overall survival (OS) in men with mCRPC who had received prior docetaxel therapy (Scher et al, NEJM 367:13, 2012). This study examined whether enzalutamide could prolong OS and radiographic progression-free survival (rPFS) in asymptomatic or mildly symptomatic chemotherapy-naive men with mCRPC. Methods: In this randomized, double-blind, placebo-controlled, multinational phase 3 study (NCT01212991), chemotherapy-naive patients with mCRPC were stratified by site and randomized 1:1 to enzalutamide 160 mg/day or placebo. OS and rPFS were co-primary endpoints and analyzed for the intent-to-treat population. Planned sample size was 1,680 with 765 deaths to achieve 80% power to detect a target OS hazard ratio (HR) of 0.815 with a type I error rate of 0.049 and a single interim analysis at 516 (67%) deaths. The co-primary endpoint of rPFS had sufficient power to detect a target HR of 0.57 and a type I error rate of 0.001 with a minimum of 410 events. Results: A total of 1,717 men were randomized (1,715 treated) between September 2010 and September 2012. The interim analysis at 539 deaths showed a statistically significant benefit of enzalutamide over placebo with a 30% reduction in risk of death (OS: HR 0.70; 95% CI: 0.59-0.83; P< 0.0001) and an 81% reduction in risk of radiographic progression or death (rPFS: HR 0.19; 95% CI: 0.15-0.23; P< 0.0001). At the time of the analysis, 28% of enzalutamide patients and 35% of placebo patients had died. Estimated median OS was 32.4 months (mo) (95% CI, 31.5–upper limit not yet reached [NYR]) in the enzalutamide arm vs 30.2 mo (95% CI, 28–upper limit NYR) in the placebo arm. Median rPFS was NYR (95% CI: 13.8–upper limit NYR) in the enzalutamide arm vs 3.9 mo (95% CI: 3.7-5.4) in the placebo arm. Seizure events were reported in two patients. The Independent Data Monitoring Committee considered the benefit-risk ratio to favor enzalutamide and recommended stopping the study and crossing placebo patients to enzalutamide. Secondary endpoints and safety analysis will be presented. Conclusions: Treatment with enzalutamide significantly improves OS and rPFS in men with chemotherapy-naive mCRPC. Clinical trial information: NCT01212991.

A randomized, double-blind, multi-center phase III study evaluating paclitaxel with and without RAD001 in patients with gastric or esophagogastric junction carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4027-4027 ◽  
Author(s):  
Sylvie Lorenzen ◽  
Jorge Riera Knorrenschild ◽  
Claudia Pauligk ◽  
Thorsten Oliver Goetze ◽  
Susanna Hegewisch-Becker ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Esophagogastric Junction ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Double Blind ◽  
Prior Therapy ◽  
Intention To Treat ◽  
Significant Difference ◽  
Phase Iii Study ◽  
Line Setting

4027 Background: There is a need for effective treatments in the second- or further line setting in advanced gastric cancer, especially for new agents. In the current trial we evaluated paclitaxel with RAD001 (everolimus) in patients with gastric carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen. Methods: This is a randomized, double-blind, multi-center phase III study. Patients with gastric carcinoma or adenocarcinoma of the esophagogastric junction (EGJ) who have progressed after treatment with a fluoropyrimidine/platinum-containing regimen were randomly assigned to receive Paclitaxel (80 mg/m2) on day 1, 8 and 15 plus placebo (arm A) or RAD001 (10mg daily, arm B) d1-d28, repeated every 28 days as 2nd, 3rd or 4th line therapy. Primary end point was overall survival (OS), secondary endpoints were best overall response, disease control rate, progression free survival (PFS) and toxicity. Results: 300 patients (median age: 62 years; median lines prior therapy: 2; 47.7% of patients had prior taxane therapy) were randomly assigned (Arm A, 150, Arm B, 150). In the intention to treat population, there was no significant difference in median PFS (placebo, 2.07 vs. RAD001, 2.2 months, HR 0.88, p = 0.3) or median OS (placebo, 5.0 vs. RAD001, 6.1 months, HR 0.93, p = 0.54). For patients with prior taxane use, RAD001 improved PFS (placebo 1.8 vs. RAD001, 2.7 months, HR 0.69, p = 0.03) and OS (placebo 3.9 vs. RAD001, 5.8 months, HR 0.73, p = 0.07). Combination of paclitaxel and RAD001 was tolerable, but the RAD001 arm was associated with significantly more grade 3-5 mucositis (13.3% vs. 0.7%; p < 0.001). Conclusions: The addition of RAD001 to paclitaxel/RAD001 did not improve outcomes in pretreated metastatic gastric/EGJ cancer. Of note, activity was seen in the taxane pretreated group. Additional biomarker studies are planned to look for subgroups that may have a benefit. Clinical trial information: 2009-018092-14.

ABOUND.70+: Safety and efficacy of nab-paclitaxel/carboplatin (nab-P/C) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9059-9059 ◽  
Author(s):  
Corey J. Langer ◽  
Eric C. Anderson ◽  
Robert M. Jotte ◽  
Jonathan Wade Goldman ◽  
Daniel Ernest Haggstrom ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Type I Error ◽  
Locally Advanced ◽  
Dose Intensity ◽  
Median Number ◽  
Phase Iii ◽  
Type I ◽  
Weekly Dose ◽  
Safety And Efficacy ◽  
Grade 3

9059 Background: Treatment (tx) of elderly pts with NSCLC is challenging. nab-P/C demonstrated efficacy in a subset of pts with NSCLC ≥ 70 y in a phase III trial. ABOUND.70+ was designed to determine whether a 1-week break can further improve tolerability of nab-P/C in pts ≥ 70 y with NSCLC. Safety and efficacy were evaluated and are reported. Methods: Pts ≥ 70 y with tx-naive locally advanced/metastatic NSCLC were randomized (1:1) nab-P 100 mg/m2 d 1, 8, 15 + C AUC 6 d 1 q3w (Arm A) or the same nab-P/C dose q3w followed by a 1-week break (Arm B). Primary endpoint: percentage of pts with either grade ≥ 2 peripheral neuropathy (PN) or grade ≥ 3 myelosuppression AEs. Key secondary endpoints: PFS, ORR, OS, for which statistical analyses do not control for type I error ( Pvalues unadjusted). Results: At interim evaluation, the primary endpoint was similar across arms, resulting in early closure of enrollment. In Arms A and B, 71 and 72 pts were randomized; median age was 76 and 75 y, majority of pts were male (57.7% vs 55.6%) and had ECOG PS 1 (70.4% vs 72.2%). There were no differences in histology across tx arms. See table for primary endpoint data. Median number of tx cycles for Arms A and B was 4.0 and 5.5, median cumulative nab-P dose was 875.0 and 1287.5 mg/m2, and median weekly dose intensity was 62.0 and 54.1 mg/m2. nab-P dose modifications (Arms A and B): ≥ 1 dose reduction in 64.7% and 58.6%, ≥ 1 dose delay in 58.8% and 48.6%, and ≥ 1 missed dose in 80.9% and 72.9%, respectively. Median PFS (Arms A and B) 3.9 vs 7.0 mo (HR 0.49; 95% CI, 0.30 - 0.79; P = 0.003), confirmed ORR 23.9% vs 40.3% ( P = 0.037), and median OS 15.2 vs 16.2 mo (HR 0.76; 95% CI, 0.46 - 1.26; P= 0.292). Conclusions: Incidence of grade ≥ 2 PN or grade ≥ 3 myelosuppression AEs was similar between the 2 nab-P/C schedules in pts ≥ 70 y with advanced NSCLC. There appears to be a signal of improvement in PFS and ORR observed in Arm B, potentially due to increased tx exposure. NCT02151149 Clinical trial information: NCT02151149. [Table: see text]

scholarly journals Two Stage Designs for Phase III Trials

2020 ◽  
Author(s):  
Dean Follmann ◽  
Michael Proschan
Keyword(s):  
Type I Error ◽  
Surrogate Endpoint ◽  
Phase Iii ◽  
Type I ◽  
Two Stage ◽  
Early Evaluation ◽  
Phase Iii Trials ◽  
Fixed Power ◽  
Improved Performance ◽  
Stage 1

Phase III platform trials are increasingly used to evaluate a sequence of treatments for a specific disease. Traditional approaches to structure such trials tend to focus on the sequential questions rather than the performance of the entire enterprise. We consider two-stage trials where an early evaluation is used to determine whether to continue with an individual study. To evaluate performance, we use the ratio of expected wins (RW), that is, the expected number of reported efficacious treatments using a two-stage approach compared to that using standard phase III trials. We approximate the test statistics during the course of a single trial using Brownian Motion and determine the optimal stage 1 time and type I error rate to maximize RW for fixed power. At times, a surrogate or intermediate endpoint may provide a quicker read on potential efficacy than use of the primary endpoint at stage 1. We generalize our approach to the surrogate endpoint setting and show improved performance, provided a good quality and powerful surrogate is available. We apply our methods to the design of a platform trial to evaluate treatments for COVID-19 disease.

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