CTNI-40. EVALUATING FEASIBILITY AND EFFICIENCY OF PHASE II ADAPTIVE PLATFORM TRIAL DESIGNS BASED ON THE INDIVIDUALIZED SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGhT) EXPERIENCE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi68-vi69
Author(s):  
Rifaquat Rahman ◽  
Lorenzo Trippa ◽  
Eudocia Quant Lee ◽  
Isabel Arrillaga-Romany ◽  
Mehdi Touat ◽  
...  
Keyword(s):  
Phase Ii ◽  
Progression Free Survival ◽  
The United States ◽  
Experimental Therapy ◽  
Newly Diagnosed ◽  
Adaptive Randomization ◽  
Common Control ◽  
The Status ◽  
Trial Efficiency ◽  
Screening Trial

Abstract BACKGROUND The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial with Bayesian adaptive randomization and deep genomic profiling to more efficiently test experimental agents in newly diagnosed glioblastoma and to prioritize therapies for late-stage testing. METHODS In the ongoing INSIGhT trial, patients with newly diagnosed MGMT-unmethylated glioblastoma are randomized to the control arm or one of three experimental therapy arms (CC-115, abemaciclib, and neratinib). The control arm therapy is radiotherapy with concomitant and adjuvant temozolomide, and primary endpoint is overall survival. Randomization has been adapted based on Bayesian estimation of biomarker-specific probability of treatment impact on progression-free survival (PFS). All tumors undergo detailed molecular sequencing, and this is facilitated with the companion ALLELE protocol. To evaluate feasibility of this approach, we assessed the status of this ongoing trial. RESULTS Since INSIGhT was activated 4.3 years ago, it has expanded to include 12 sites across the United States. A total of 247 patients have been enrolled. Randomization probabilities have been repeatedly adjusted over time based upon early PFS results to alter the randomization ratio from standard 1:1:1:1 randomization. All three arms have completed accrual and efficacy estimates are available based upon comparison to the common control arm in context of relevant biomarkers. There are 87 patients alive and in follow-up, and there are ongoing plans to add additional arms to evaluate further treatments in the future. CONCLUSION The INSIGhT trial demonstrates that a multi-center Bayesian adaptive platform trial is a feasible and effective approach to help prioritize therapies and biomarkers for newly diagnosed GBM. The trial has maintained robust accrual, and the simultaneous testing of multiple agents, sharing a common control arm and adaptive randomization serve as features to increase trial efficiency relative to traditional clinical trial designs.

CTNI-05. PRELIMINARY RESULTS OF THE NERATINIB ARM IN THE INDIVIDUALIZED SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGHT): A PHASE II PLATFORM TRIAL USING BAYESIAN ADAPTIVE RANDOMIZATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi59-vi59
Author(s):  
Isabel Arrillaga-Romany ◽  
Lorenzo Trippa ◽  
Geffrey Fell ◽  
Eudocia Quant Lee ◽  
Rifaquat Rahman ◽  
...  
Keyword(s):  
Phase Ii ◽  
Progression Free Survival ◽  
Phase Iii ◽  
P Value ◽  
Newly Diagnosed ◽  
Logrank Test ◽  
Adaptive Randomization ◽  
Preliminary Results ◽  
Her2 Breast Cancer ◽  
Screening Trial

Abstract BACKGROUND EGFR is amplified in over 50% of glioblastoma and 20-30% have EGFRvIII mutations. Neratinib is a potent inhibitor of EGFR/HER2 approved for metastatic HER2+ breast cancer. To efficiently evaluate the potential impact of neratinib on overall survival (OS) in newly-diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, neratinib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and accelerate identification of novel therapies for phase III testing. Initial randomization was equal between neratinib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). We report preliminary results for the neratinib arm. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide or standard radiochemotherapy followed by adjuvant neratinib (240 mg daily). Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between neratinib efficacy and EGFR amplification was also investigated. RESULTS There were 144 patients (70 control; 74 neratinib). Neratinib was reasonably well-tolerated with no new toxicity signals identified. PFS was compared (HR 0.84; p=0.38, logrank test – not significant) between the neratinib (median 6.05 months) and control (median 5.82 months) arms. For patients EGFR pathway activation the PFS HR was 0.53 (p-value=0.03 – significant, median PFS: neratinib, 6.21 months, control, 5.26 months). However, there was no significant improvement in OS in EGFR amplified/mutated patients (HR 1.05; p-value 0.87) between neratinib (median 14.2) compared to the control arm (median 14.6). CONCLUSION Neratinib prolonged PFS in the EGFR positive subpopulation but there was no overall PFS benefit, or any OS improvement.

Evaluating the benefit of adaptive randomization in the CC-115 arm of the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A phase II randomized Bayesian adaptive platform trial in newly diagnosed MGMT unmethylated glioblastoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2006-2006
Author(s):  
Rifaquat Rahman ◽  
Lorenzo Trippa ◽  
Geoffrey Fell ◽  
Eudocia Quant Lee ◽  
Isabel Arrillaga-Romany ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Adaptive Randomization ◽  
Number Of Patients ◽  
Significant Difference ◽  
Enrollment Rates ◽  
Dependent Protein ◽  
The Impact ◽  
Screening Trial

2006 Background: Adaptive randomization adjusts enrollment rates based upon early trial results, which can allow for decreased enrollment for therapies less likely to meet the primary endpoint of a trial. CC-115, a CNS-penetrant, oral inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK), was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. As CC-115 was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio, we sought to investigate the impact of adaptive randomization in its testing. Methods: In INSIGhT, adults with newly diagnosed MGMT-unmethylated glioblastoma and available genomic data are adaptively randomized to an experimental arm or the control arm of standard radiotherapy with concurrent and adjuvant temozolomide. Patients randomized to CC-115 received it (10mg po BID) with radiotherapy and as adjuvant monotherapy, and a safety lead-in 3+3 design was used for this arm. By simulating the INSIGhT trial with standard uniform randomization, we estimated the reduction of enrollment rate and sample size of the CC-115 arm that was attributable to adaptive randomization. Results: Twelve patients were randomized to CC-115; 58% (n = 7) patients had possible treatment-related CTCAE grade > 3 toxicity. Compared to the control arm, there was no significant difference in progression-free survival (PFS, HR 0.66, 95% CI 0.32-1.36, p = 0.3) or overall survival (OS, HR 0.93, 95% CI 0.43-2.03, p = 0.8). Based on early PFS results, randomization probability to CC-115 decreased from 25% to 16%. At the time of the CC-115 arm closure, 14% of enrolled INSIGhT patients had been randomized to this arm. Compared to average expected enrollment by standard randomization, the use of adaptive randomization decreased the number of patients randomized to CC-115 by 50% (12 patients vs. 18 patients [95% CI 11-25 patients]). Conclusions: The INSIGhT trial, designed with adaptive randomization, facilitated more efficient testing of CC-115 and decreased the number of patients allocated to the CC-115 arm relative to a standard randomization design. Clinical trial information: NCT02977780.

Individualized screening trial of innovative glioblastoma therapy (INSIGhT).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2079-TPS2079 ◽  
Author(s):  
Brian Michael Alexander ◽  
Lorenzo Trippa ◽  
Sarah C. Gaffey ◽  
Isabel Arrillaga ◽  
Eudocia Quant Lee ◽  
...  
Keyword(s):  
Pik3ca Mutation ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Egfr Amplification ◽  
Common Control ◽  
Whole Exome ◽  
Screening Trial ◽  
Clinical Trial Information

TPS2079 Background: Patient with glioblastoma (GBM) with unmethylated MGMT promoters derive limited benefit from temozolomide (TMZ) and have dismal outcome. Prioritizing the numerous available therapies and biomarkers for late stage testing requires an efficient clinical testing platform. INSIGhT (NCT02977780) is a biomarker-based, Bayesian adaptively randomized, multi-arm phase II platform screening trial for patients with newly diagnosed GBM and unmethylated MGMT promoters. Methods: INSIGhT compares experimental arms to a common control of standard concurrent TMZ and radiation therapy (RT) followed by adjuvant TMZ. The primary endpoint is overall survival (OS). Patients with newly diagnosed, unmethylated GBM that are IDH R132H mutation negative, and with genomic data available or who consent to whole exome sequencing through the ALLELE companion study for biomarker grouping are eligible. Two experimental arms consist of concurrent RT/TMZ followed by adjuvant neratinib (EGFR, HER2, and HER4 inhibitor) or abemaciclib CDK 4/6 inhibitor), respectively, in place of TMZ. The other experimental arm is CC-115 (TORC1/2 and DNA PK inhibitor), which replaces TMZ in both the concurrent and adjuvant phases. Biomarker groups include: EGFR + patients with EGFR amplification/mutation; PI3K + patients with PIK3CA mutation/amplification, PIK3R1 mutation, AKT3amplification, PIK3C2B > 1 copy gain, or PTEN dual loss; CDK: + patients with wild-type RB1 and CDK4 amplification, CDK6 amplification, or CDKN2A > 1 copy loss. Given the lack of pretrial biomarker data and the anticipated overlap of the groups, randomization will initially be equal. As the trial progresses, randomization probabilities will be adapted based on the Bayesian estimation of the probability of treatment impact on progression-free survival (PFS). These randomization probabilities can vary among the biomarker groups so predictive biomarkers will be identified and utilized if present. Treatment arms may drop due to low probability of treatment impact on OS, and new arms may be added. Experimental arms are compared only with control and should be thought of as discrete experimental questions, with INSIGhT being open to new investigators with proposed therapeutic hypotheses. Clinical trial information: NCT02977780.

scholarly journals Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A Bayesian Adaptive Platform Trial to Develop Precision Medicines for Patients With Glioblastoma

2019 ◽  
pp. 1-13 ◽  
Author(s):  
Brian M. Alexander ◽  
Lorenzo Trippa ◽  
Sarah Gaffey ◽  
Isabel C. Arrillaga-Romany ◽  
Eudocia Q. Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
Biomarker Discovery ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Common Control ◽  
Low Probability ◽  
Trial Structure ◽  
Screening Trial ◽  
R132h Mutation

PURPOSE Adequately prioritizing the numerous therapies and biomarkers available in late-stage testing for patients with glioblastoma (GBM) requires an efficient clinical testing platform. We developed and implemented INSIGhT (Individualized Screening Trial of Innovative Glioblastoma Therapy) as a novel adaptive platform trial (APT) to develop precision medicine approaches in GBM. METHODS INSIGhT compares experimental arms with a common control of standard concurrent temozolomide and radiation therapy followed by adjuvant temozolomide. The primary end point is overall survival. Patients with newly diagnosed unmethylated GBM who are IDH R132H mutation negative and with genomic data available for biomarker grouping are eligible. At the initiation of INSIGhT, three experimental arms (neratinib, abemaciclib, and CC-115), each with a proposed genomic biomarker, are tested simultaneously. Initial randomization is equal across arms. As the trial progresses, randomization probabilities adapt on the basis of accumulating results using Bayesian estimation of the biomarker-specific probability of treatment impact on progression-free survival. Treatment arms may drop because of low probability of treatment impact on overall survival, and new arms may be added. Detailed information on the statistical model and randomization algorithm is provided to stimulate discussion on trial design choices more generally and provide an example for other investigators developing APTs. CONCLUSION INSIGhT (NCT02977780) is an ongoing novel biomarker-based, Bayesian APT for patients with newly diagnosed unmethylated GBM. Our goal is to dramatically shorten trial execution timelines while increasing scientific power of results and biomarker discovery using adaptive randomization. We anticipate that trial execution efficiency will also be improved by using the APT format, which allows for the collaborative addition of new experimental arms while retaining the overall trial structure.

Preliminary results of the abemaciclib arm in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A phase II platform trial using Bayesian adaptive randomization.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2014-2014
Author(s):  
Eudocia Quant Lee ◽  
Lorenzo Trippa ◽  
Geoffrey Fell ◽  
Rifaquat Rahman ◽  
Isabel Arrillaga-Romany ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Phase Iii ◽  
P Value ◽  
Cyclin D ◽  
Newly Diagnosed ◽  
Adaptive Randomization ◽  
Preliminary Results ◽  
Rb Pathway ◽  
Screening Trial

2014 Background: The cyclin D-CDK4/6-Rb pathway is activated in most glioblastomas. Abemaciclib is a potent CDK4/6 inhibitor with good brain penetration approved for HR+/HER2- breast cancer. In order to efficiently evaluate the potential impact of abemaciclib on overall survival (OS) in newly diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, abemaciclib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. Initial randomization was equal between abemaciclib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). Ineffective arms were discontinued and new arms added by protocol amendment. We report preliminary results for the abemaciclib arm which has completed accrual. Methods: Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide at standard doses or standard radiochemotherapy followed by adjuvant abemaciclib (150-200 mg orally BID). Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS which was assessed using the log-rank test estimated via the Kaplan Meier method using a type I error of 5%. The hazard ratio (HR) was estimated using a cox proportional hazards model. Association between abemaciclib efficacy and cyclin D-CDK4/6-Rb pathway genomic alterations was also investigated. Results: There were 142 patients (69 control; 73 treated with abemaciclib). Abemaciclib was generally well-tolerated with no new toxicity signals identified. PFS was significantly longer (HR 0.67; p = 0.03, logrank test) with abemaciclib (median 6.54 months) compared to the control arm (median 5.88 months). For patients with activation of the CDK4 pathway the PFS HR was 0.64 (p-value = 0.04). However, there was no significant improvement in overall survival (HR 0.9; p-value > 0.05) between abemaciclib (median 15.5) compared to the control arm (median 15.5). Conclusions: Abemaciclib was well-tolerated and prolonged PFS but there is no evidence of an overall survival improvement compared to standard radiochemotherapy. Clinical trial information: NCT02977780.

scholarly journals CTNI-12. PRELIMINARY RESULTS OF THE ABEMACICLIB ARM IN THE INDIVIDUALIZED SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGHT): A PHASE II PLATFORM TRIAL USING BAYESIAN ADAPTIVE RANDOMIZATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii44-ii44
Author(s):  
Patrick Wen ◽  
Lorenzo Trippa ◽  
Eudocia Lee ◽  
Geoffrey Fell ◽  
Rifaquat Rahman ◽  
...  
Keyword(s):  
Phase Ii ◽  
Survival Data ◽  
Phase Iii ◽  
Cyclin D ◽  
Newly Diagnosed ◽  
Adaptive Randomization ◽  
Preliminary Results ◽  
Her2 Breast Cancer ◽  
Rb Pathway ◽  
Screening Trial

Abstract BACKGROUND The cyclin D-CDK4/6-Rb pathway is activated in most glioblastomas. Abemaciclib is a potent CDK4/6 inhibitor with good brain penetration approved for ER/PR/HER2- breast cancer. In order to efficiently evaluate the potential impact of abemaciclib on overall survival (OS) in newly diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, abemaciclib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. Initial randomization was equal between abemaciclib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). Ineffective arms were discontinued and new arms added by protocol amendment. We report preliminary results for the abemaciclib arm which has completed accrual. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide at standard doses or standard radiochemotherapy followed by adjuvant abemaciclib (150–200 mg orally BID) without temozolomide. Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between abemaciclib efficacy and cyclin D-CDK4/6-Rb pathway genomic alterations was also investigated. RESULTS There were 123 patients (50 control; 73 treated with abemaciclib). Abemaciclib was generally well-tolerated with no new toxicity signals identified. PFS was significantly longer (p=0.03, logrank test) with abemaciclib (median 6.31 months 95% CI [5.29, 8.18]) compared to the control arm (5.16 months 95% CI [4.37, 6.28]). 28/50 control and 36/73 abemaciclib patients remain alive. CONCLUSION Preliminary analysis suggests that abemaciclib increases PFS compared to control. Updated toxicity, PFS and survival data and potential genomic biomarker associations will be presented.

A phase II study of short course FOLFOX chemotherapy with either nivolumab (Nivo) or Nivo plus radiation in the first line treatment of metastatic or unresectable gastroesophageal (GEA) cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS4157-TPS4157
Author(s):  
Rutika Mehta ◽  
Sarbajit Mukherjee ◽  
Kelsey Klute ◽  
Haeseong Park ◽  
Uqba Khan ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Patient Survival ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
The United States ◽  
Target Sample Size ◽  
Low Dose Radiotherapy ◽  
Short Course ◽  
Folfox Chemotherapy

TPS4157 Background: GEA remains incurable and novel therapies are needed. Studies have shown that cytotoxic chemotherapy can enhance antigenicity of tumors, leading to the recent practice changing studies that demonstrate checkpoint inhibition therapy combined with chemotherapy in PD-L1 overexpressing patients significantly improves patient survival (Keynote-590 and Checkmate-649). But long-term use can also subsequently dampen the immune response. Moreover, the stop-and-go strategy with chemotherapy can maintain patient survival while minimizing chemotherapy related side effects when compared to the traditional strategy of continuous chemotherapy. These observations prompted the inception of this trial with the hypothesis that a short course of FOFLOX therapy combined with immunotherapy will likely have similar activity to that of continuing FOFLOX until disease progression when combined with immunotherapy. We also will examine the hypothesis that low dose radiotherapy can further augment immunotherapy efficacy. Methods: This is a multicenter, randomized phase II study examining Nivo alone vs radiation therapy (RT) with Nivo in subjects who did not have disease progression with 3 months of FOLFOX + Nivo. Subjects with advanced unresectable or metastatic GEA cancer are eligible. All subjects will receive FOLFOX + Nivo therapy. Subjects who demonstrate at least stable disease, on their first imaging assessment at 2 months will receive 1 additional month of FOLFOX + Nivo, and then will be randomly assigned at a 1:1 ratio to receive either Nivo alone or Nivo + RT. After 4 mos of therapy, patients who remain on study will receive Nivo Q4WKly. The primary endpoint is to demonstrate that the addition of fractionated radiation to immunotherapy is associated with an improvement in the 12-month progression-free survival (PFS) proportion from 25% (i.e., historical control estimate; Nivo alone; Arm A) to approximately 50% (i.e., with the fractional radiation and Nivo; Arm B). A key secondary aim is to demonstrate that short course FOLFOX of 3 months + Nivo is similar in efficacy to continuing FOLFOX until disease progression. Another secondary aim of this study is to demonstrate safety of the combination of fractionated RT + Nivo. Target sample size is 74 patients. The study is now open at six sites across the United States. Clinical trial information: NCT04021108.

Full Dose Vincristine (V) Negatively Impacts Progression Free Survival in Newly Diagnosed or Relapsed/Refractory Multiple Myeloma Patients Treated with Pegylated Doxorubicin, Vincristine, Reduced-Dose Dexamethasone, and Thalidomide (DVd-T).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2570-2570
Author(s):  
R. Suppiah ◽  
E. Walker ◽  
K. Almhanna ◽  
S. Andresen ◽  
J. Reed ◽  
...  
Keyword(s):  
Phase Ii ◽  
Overall Response Rate ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Full Dose ◽  
Grade 3 ◽  
Positive Effect

Abstract Background: The activity of V in myeloma was first described in the 1970’s. Although Phase II data suggest that V demonstrates single agent activity, subsequent reports have questioned its role. Due to these conflicting results, we conducted a subanalysis investigating the effect of V dose in the phase II DVd-T regimen that we have previously reported (Agrawal et al ASH 2003). We evaluated the effects of V dose on progression free survival (PFS) and overall survival (OS) in newly diagnosed and relapsed/refractory patients treated with DVd-T. Patients and Methods: As previously reported, this Phase II study enrolled 102 patients with newly diagnosed or relapsed/refractory multiple myeloma with evidence of end organ damage. DVd-T was administered as previously reported. After best response, patients were maintained on prednisone 50mg every other day and the maximum tolerated dose of thalidomide until disease progression. For patients experiencing grade 1 neuropathy, V was reduced by 25%, and for grade 2, by 50%. Patients developing grade 3/4 neuropathy had V discontinued and thalidomide suspended until toxicity decreased by at least one grade. Univariate analyses were conducted to assess the effect of V dose reduction or elimination on PFS and OS. Multivariate analyses were performed to adjust for the impact of age, platelet count, stage, quality of response (CR or near CR versus SD or PR), and thalidomide dose. Results: Trial included 53 newly diagnosed and 49 relapsed/refractory patients. Median age was 62.9 years. 59% had stage 3 or 4 disease. 37% had abnormal cytogenetics. Median beta-2 microglobulin was 4.1. Overall response rate of 87% was seen in newly diagnosed patients (36% achieved CR; 13% near CR; 38% PR; 8% SD; 6% PD). In the relapsed/refractory patients, overall response rate of 87% was achieved (21% achieved CR; 26% near CR; 40% PR; 13% SD). Median follow up was 28.1 months. Median PFS for the newly diagnosed group was 28.2 months and 15.5 for the relapsed/refractory group. Median OS was 39.9 months for the relapsed/refractory group. After 50 months of follow-up for the newly diagnosed group, median OS has not been reached. In total, 464 cycles were administered, of which 225 were given with full dose V and 242 with reduced dose or eliminated V. Grade 3/4 neuropathy occurred in 22 patients. Univariate analysis revealed that reducing or eliminating V had a significant positive effect on PFS and OS (p = 0.0002 and 0.02 respectively). Multivariate analysis adjusting for age at start of study, platelet count, stage, quality of response [CR or near CR versus SD or PR], and thalidomide dose, similarly found that reducing or eliminating the dose of V had a significant positive effect (p = 0.0121) on PFS. However, multivariate analysis did not reveal the same effect on OS (p = 0.11). Conclusions: This subanalysis suggests that the use of full dose V in the DVd-T regimen may have a negative effect on PFS. The exact mechanism by which V affects PFS is not clear. Studies are now on-going investigating this regimen without V. Figure Figure

Final analysis of a phase IB/randomized phase II study of gemcitabine (G) plus placebo (P) or vismodegib (V), a hedgehog (Hh) pathway inhibitor, in patients (pts) with metastatic pancreatic cancer (PC): A University of Chicago phase II consortium study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4012-4012 ◽  
Author(s):  
Daniel Virgil Thomas Catenacci ◽  
Nathan Bahary ◽  
Sreenivasa R. Nattam ◽  
Robert de Wilton Marsh ◽  
James Alfred Wallace ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Disease Status ◽  
Serum Levels ◽  
Newly Diagnosed ◽  
Significance Level ◽  
Phase Ib ◽  
Randomized Phase Ii

4012 Background: Sonic Hh (SHh), the ligand for the Hh pathway, is over-expressed in >80% of PC. V had activity in preclinical murine PC models leading to increased tumor perfusion, enhanced tumor delivery of G, and an improvement in survival. Methods: We conducted a placebo-controlled, phase IB/randomized phase II trial of GV or GP. Eligible pts, KPS 80-100, had untreated metastatic PC, or had completed adjuvant therapy > 6 months (mo) prior. Primary endpoint: progression-free survival (PFS). Correlatives: serial SHh serum levels; serial perfusion CT imaging. All pts received G 1000mg/m2over 30 minutes, days (D) 1, 8, 15, Q28D. A lead-in phase IB was performed. Pts, stratified by KPS (80 v 90/100), and disease status (newly diagnosed/recurrent), were randomized to V (150 mg PO daily) or P. For pts on P, cross-over was allowed at progression. Assuming a mPFS of 3.5 months for GP and 5.7 months for GV (HR=0.61), a sample size of 106 subjects (53 per group) provided 85% power to detect this difference, using a one-sided test at the 0.10 significance level. Results: No safety issues were identified in 7 pts enrolled in the phase IB study. The phase II study enrolled 106 evaluable pts (V/P 53/53) at 13 sites 2/10-6/12. Pt characteristics: median age 65/64 (range 52-82/39-83); KPS (% pts) 80: 38/30; 90: 26/38; 100: 36/32; newly diagnosed 91%/91%; recurrent: 9%/9%. Grade 3/4 toxicity (V/P, % pts, >5% in either arm): neutropenia 32/28; lymphopenia 4/15; thrombocytopenia 9/11; anemia 9/23; hyponatremia 4/15; fatigue 13/8; hyperglycemia 23/19; elevated ALT 13/9; hyperbilirubinemia 11/6; nausea 11/11. Response (%): CR 0/2, PR 8/11, SD 51/38. mPFS: 4.0/2.5 mo (95% CI: 2.5-5.3/1.9-3.8; HR 0.81 [0.54-1.21], p=0.30). 22 pts (42%) on GP crossed over to GV at progression. mOS: 6.9/6.1 mo (95% CI:5.8-8.0/5.0-8.0, HR 1.04, [0.69-1.58], p=0.84). Updated laboratory/radiological correlatives will be presented. Conclusions: Toxicity between the groups was similar. The addition of V to G in an unselected cohort does not improve response, PFS, or OS in pts with metastatic PC. Funding NCI N01-CM-62201. Clinical trial information: NCT01064622.

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