Predicting outcomes of phase III oncology trials with Bayesian mediation modeling of tumor response

Purpose To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Patients and Methods Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m2/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m2 weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here. Results Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014). Conclusion Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.

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ACTR-47. PHASE-III TRIAL OF STANDARD CHEMOTHERAPY VS. CHEMOTHERAPY GUIDED BY CANCER STEM CELL TEST IN RECURRENT GLIOBLASTOMA (NCT03632135)

Neuro-Oncology ◽

10.1093/neuonc/noz175.089 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi24-vi24

Author(s):

Tulika Ranjan ◽

Dawit Aregawi ◽

Christine Lu-Emerson ◽

Jason Schroeder ◽

Mark Anderson ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Median Overall Survival ◽

Tumor Response ◽

Chemotherapeutic Agents ◽

Response To Therapy ◽

Phase Iii ◽

Recurrence Time ◽

Cell Kill ◽

Recurrent Gbm

Abstract Stupp treatment protocol for patients with glioblastoma (GBM) has improved the median overall survival to 14.6 months. However, no investigations have defined effective strategies against recurrence and the prognosis of recurrent GBM patients remains poor. Personalized medicine with assay-guided treatment targeting chemotherapy resistant cancer stem cells (CSCs) alongside the bulk tumor cells is a new paradigm in cancer treatment that may result in improved patient’s outcome. We are using ChemoID, a CLIA and CAP certified CSC cytotoxicity assay for predicting response to chemotherapeutic agents. Our prospective analysis of 61 GBM patients demonstrated that ChemoID-guided treatment significantly improved tumor response. For every 5% increase in cell kill of CSCs by assay-guided chemotherapy, 12-month patient response (non-recurrence of cancer) increased 2.5-fold, OR=2.3 (p=0.01). We also found that median recurrence time was 20-months versus 3-months for patients with a positive (>40% cell kill) CSC test versus negative, whereas median recurrence time was 13-months versus 4-months for patients with a positive (>55% cell kill) bulk test versus negative. We are conducting a multi-institutional phase-III clinical trial (NCT03632135) to determine the clinical validity of the ChemoID assay as a predictor of clinical response in recurrent GBM. The study has been designed as a parallel group controlled clinical trial and the participants are randomized to either standard of care chemotherapy chosen by the physician or ChemoID-guided therapy. Response to therapy will be measured by MRI imaging using RANO criteria. Primary endpoint of median overall survival (OS) and secondary endpoints of OS at 6, 9, and 12 months, median progression free survival (PFS), PFS at 4, 6, 9, and 12 months, objective tumor response, time to recurrence, and quality of life will be measured. Trial is open and currently 22 subjects have been enrolled. Interim analysis of the trial will be conducted in approximately 12 months.

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Gemcitabine, oxaliplatin and weekly high-dose 5-FU as a 24-hr-infusion in chemonaive patients with advanced or metastatic carcinoma of the gallbladder: Preliminary results of a multicenter phase II-study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4129 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4129-4129 ◽

Cited By ~ 2

Author(s):

A. D. Wagner ◽

P. Buechner-Steudel ◽

H. Schmalenberg ◽

M. Moehler ◽

O. Kuss ◽

...

Keyword(s):

Survival Rate ◽

Median Survival ◽

Phase Ii ◽

Tumor Response ◽

Phase Ii Study ◽

Metastatic Carcinoma ◽

Phase Iii ◽

Carcinoma Of The Gallbladder ◽

One Year ◽

The One

4129 Background: Combinations of gemcitabine (GEM)/5-FU, GEM/oxaliplatin (LOHP) or 5-FU/LOHP work synergistically in pancreatic and/or colorectal malignancies, and have non-overlapping safety profiles. This phase II-study was designed to evaluate the efficacy and safety of the triple combination GEM/LOHP/5-FU in patients (pts) with advanced or metastatic carcinoma of the gallbladder. Methods: One-stage, multicentre phase II study. Eligibility criteria: chemonaive pts with histologically proven advanced, recurrent or metastatic gallbladder carcinoma (ECOG 0–1; expected survival >3 months; measurable disease; adequate renal, hepatic and bone marrow function). According to the results of our previous phase I-study (Proc ASCO 2003, # 1298), pts were treated with GEM 900mg/m2 as a 30-min infusion, followed by LOHP 65 mg/m2 (2-hr infusion) after a 30 min rest and 5-FU 1500 mg/m2 (24-hr-infusion) on d 1, 8, every 3 weeks. Planned sample size: 35 response evaluable patients. The primary endpoint was tumor response, secondary endpoints were toxicity, median survival, the one-year-survival rate, clinical benefit and quality of life. Results: At time of abstract submission, median follow-up of 35 enrolled pts is 9.8 months. Pt. characteristics: m/f: 11/24, median age 61 (range 42–81), ECOG 0/1: 24/11 (69/31%) pts, locally advanced/metastatic disease 1/32 (3/91%) pts. Analysis of tumor response is still pending. Grade III/IV (NCI-CTC) toxicities occurred in 36/3% of 191 cycles and were: leucopenia 3/1%, neutropenia 4/1%, thrombocytopenia 4/1%, anemia 2/0%, nausea 1/0%, sensory neuropathy 4/0%, asthenia 1/0%, elevated bilirubin 2/0%, AP 4/0%, or elevated SGOT/SGPT 1/0%, edema 1/0%, infection 1/0%, dyspnoe 1/1%. Median survival of all pts is 9.9 months (95% CI: 7.5–11.5), the one-year-survival-rate is 30 % (95% CI: 16–47). Conclusions: GEM/LOHP/5-FU combination therapy is tolerated well in patients with gallbladder cancer. The promising survival data has to be confirmed in a phase III study. (Supported by grants from Eli Lilly and Company, Indianapolis, IN, USA and Sanofi-Synthelabo, Paris, France). [Table: see text]

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Tumor response category for the indicator of prognosis: Analysis of survival data in a Four-Arm Cooperative Study (FACS) for advanced non-small cell lung cancer (NSCLC)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8088 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8088-8088

Author(s):

H. Watanabe ◽

R. Leki ◽

K. Mori ◽

Y. Takada ◽

Y. Nishiwaki ◽

...

Keyword(s):

Survival Data ◽

Advanced Nsclc ◽

Tumor Response ◽

Cox Regression ◽

Surrogate Endpoint ◽

Response Category ◽

Phase Iii ◽

Cox Regression Analysis ◽

Overall Response ◽

Prognostic Groups

8088 Background: Tumor response, categorized into CR (complete response), PR (partial response), SD (stable disease) and PD (progressive disease), is a surrogate endpoint for survival and could be expected as a possible indicator of the prognosis. To evaluate whether the tumor response category might be used as an indicator of the prognosis, we conducted an analysis of the best overall response and survival data obtained from FACS, a phase III randomized trial comparing four platinum-based regimens for advanced NSCLC. Methods: A total of 602 patients (pts) with advanced NSCLC from 44 hospitals in Japan were registered in FACS. A retrospective review of the FACS database, including the tumor response and survival, was conducted. The tumor response as evaluated by the investigators was applied with and without confirmation of complete or partial responses at the determination of best overall response. Survival was calculated by the Kaplan-Meier method, and differences among prognostic groups were analyzed by Cox regression analysis. Results: Forty-five pts were excluded from the analysis due to nonavailability of sufficient data. The results are shown in the Table . The response categories of CR, PR and SD could not be categorized into prognostic groups, either with or without confirmation. There were, otherwise, two distinct prognostic groups: non-PD (CR, PR and SD) and PD. Conclusions: The disease control rate was a more sensitive indicator of the prognosis than the response rate in pts with advanced NSCLC registered in FACS. [Table: see text] [Table: see text]

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Comparison of progression-free survival (PFS) and tumor response as endpoints for predicting overall survival (OS) in untreated extensive-stage small cell lung cancer (ED-SCLC): Findings based on North Central Cancer Treatment Group (NCCTG) trials

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8085 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8085-8085

Author(s):

N. R. Foster ◽

Y. Qi ◽

J. E. Krook ◽

J. W. Kugler ◽

S. A. Kuross ◽

...

Keyword(s):

Tumor Response ◽

Logistic Models ◽

Progression Free Survival ◽

Phase Iii ◽

Prognostic Impact ◽

Cox Models ◽

Landmark Analysis ◽

Best Response ◽

Primary Endpoints ◽

Extensive Stage

8085 Background: Historically, tumor response has been the primary endpoint in phase II (P2) trials in ED-SCLC. We investigated the suitability of alternate PFS based endpoints to predict OS as early evidence of efficacy in the P2 setting. Methods: Individual patient (pt) data from 942 pts from 11 previously untreated ED-SCLC P2 and phase III (P3) platinum- or paclitaxel-based treatment trials were pooled. Best response (BR), response confirmed (RC), objective status at 16 weeks (RR16), and PFS rate at 5 and 6 months were considered. Percent agreement (PA) and kappa (k) for PFS5, PFS6, BR, RC, and RR16 with OS at 12 months (OS12) was calculated on a per-pt basis and predictive utility was assessed using the area under the receiver operating characteristic (A- ROC) curve in logistic models. Cox models were used to assess the prognostic impact of the endpoints on subsequent survival, using landmark analysis. Results: The median OS and PFS were 9.6 m and 5.5 m, respectively. PFS5 and PFS6 had the highest PA, k, and A-ROC values, and were predictive of subsequent survival in the landmark analysis (p <0.0001; c-statistics ≥ 0.60). While RR16 and BR were significantly associated with subsequent survival (p<0.0001, c-statistics of 0.61 and 0.57, respectively) the PA, k, and A-ROC values were lower. Conclusions: PFS rate at 5 and 6 months is more predictive of 12-month OS and subsequent survival than tumor response in untreated ED-SCLC. PFS based endpoints should be routinely used as primary endpoints in P2 trials within ED-SCLC. [Table: see text] No significant financial relationships to disclose.

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GOG0076-GG: A limited access phase II trial of pemetrexed (LY231514) (NSC #698037) in combination with cisplatin (NSC #119875) in the treatment of advanced, persistent, or recurrent carcinoma of the cervix—A Gynecologic Oncology Group study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.5527 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 5527-5527

Author(s):

David S. Miller ◽

John A. Blessing ◽

Lois M. Ramondetta ◽

Huyen Pham ◽

Krishnansu Sujata Tewari ◽

...

Keyword(s):

Radiation Therapy ◽

Tumor Response ◽

Gynecologic Oncology ◽

Progression Free Survival ◽

Response Duration ◽

Phase Iii ◽

Gynecologic Oncology Group ◽

Median Response ◽

Recurrent Carcinoma ◽

Common Grade

5527 Background: To estimate the antitumor activity of Pemetrexed and cisplatin with objective tumor response (partial and complete) in patients with advanced, persistent, or recurrent carcinoma of the cervix and to determine the nature and degree of toxicity of this regimen. Secondarily, to determine the effects of this regimen on progression-free survival and overall survival. Methods: Eligible, consenting patients received pemetrexed 500mg/m2 and cisplatin 50 mg/m2 IV repeated every 21 days until disease progression or adverse effects prohibited further therapy. Patients had received no prior therapeutic chemotherapy, except when administered concurrent with primary radiation therapy. Subsequent doses were adjusted according to observed toxicity and protocol guidelines. Adverse events were assessed with CTCAE v 3.0. Primary measure of efficacy was tumor response by RECIST. The study was stratified by prior radiation therapy. Results: From September 2008 to November 2011, 55 patients were enrolled by 5 GOG member institutions. Of those, 49 patients were eligible and assessable. The regimen was well tolerated with 14 (29%) receiving >9 cycles. Common grade >2 toxicities were neutropenia 35%, leukopenia 28%, and metabolic 28%. The overall response rate was 31% (one complete and 16 partial responses). The median response duration was 7 months and survival 12 months. Conclusions: Pemetrexed in combination with cisplatin has demonstrated activity in the treatment of advanced, persistent, or recurrent carcinoma of the cervix. Additional study of this regimen in a phase III setting is justified in this patient population. Clinical trial information: NCT00691301.

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Response-Independent Survival Benefit in Metastatic Colorectal Cancer: A Comparative Analysis of N9741 and AVF2107

Journal of Clinical Oncology ◽

10.1200/jco.2007.13.8099 ◽

2008 ◽

Vol 26 (2) ◽

pp. 183-189 ◽

Cited By ~ 124

Author(s):

Axel Grothey ◽

Eric E. Hedrick ◽

Robert D. Mass ◽

Somnath Sarkar ◽

Sam Suzuki ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Survival Benefit ◽

Tumor Response ◽

Objective Response ◽

Progression Free Survival ◽

Phase Iii ◽

First Line ◽

First Line Therapy ◽

Phase Iii Study

PurposeIn the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response.Patients and MethodsFor these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy.ResultsCompared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders.ConclusionIn both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.

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A survival mediation model with Bayesian model averaging

Statistical Methods in Medical Research ◽

10.1177/09622802211037069 ◽

2021 ◽

pp. 096228022110370

Author(s):

Jie Zhou ◽

Xun Jiang ◽

Hong Amy Xia ◽

Peng Wei ◽

Brian P Hobbs

Keyword(s):

Bayesian Model ◽

Bayesian Model Averaging ◽

Tumor Response ◽

Model Misspecification ◽

Model Averaging ◽

Hematologic Malignancies ◽

Phase Iii ◽

Phase Ii Trials ◽

Novel Therapy ◽

Phase Iii Trial

Determining the extent to which a patient is benefiting from cancer therapy is challenging. Criteria for quantifying the extent of “tumor response” observed within a few cycles of treatment have been established for various types of solids as well as hematologic malignancies. These measures comprise the primary endpoints of phase II trials. Regulatory approvals of new cancer therapies, however, are usually contingent upon the demonstration of superior overall survival with randomized evidence acquired with a phase III trial comparing the novel therapy to an appropriate standard of care treatment. With nearly two-thirds of phase III oncology trials failing to achieve statistically significant results, researchers continue to refine and propose new surrogate endpoints. This article presents a Bayesian framework for studying relationships among treatment, patient subgroups, tumor response, and survival. Combining classical components of a mediation analysis with Bayesian model averaging, the methodology is robust to model misspecification among various possible relationships among the observable entities. A posterior inference is demonstrated via an application to a randomized controlled phase III trial in metastatic colorectal cancer. Moreover, the article details posterior predictive distributions of survival and statistical metrics for quantifying the extent of direct and indirect, or tumor response mediated treatment effects.

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Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: an Eastern Cooperative Oncology Group Trial.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.8.2345 ◽

1996 ◽

Vol 14 (8) ◽

pp. 2345-2352 ◽

Cited By ~ 138

Author(s):

J H Schiller ◽

K Kim ◽

P Hutson ◽

R DeVore ◽

J Glick ◽

...

Keyword(s):

Partial Response ◽

Tumor Response ◽

Response Rate ◽

Response Duration ◽

Salvage Chemotherapy ◽

Small Cell ◽

Phase Iii ◽

Colony Stimulating Factor ◽

Extensive Stage ◽

Stimulating Factor

PURPOSE To determine the response rate and survival of chemotherapy-naive patients with extensive-stage small-cell lung cancer (SCLC) treated with topotecan, and to determine the relationship of topotecan pharmacokinetics with response and toxicity. PATIENTS AND METHODS Forty-eight patients with previously untreated, extensive-stage SCLC received 2.0 mg/m2 of topotecan daily for 5 days. The first 13 patients were treated without colony-stimulating factor (CSF) support; the next 35 patients received 5 micrograms/kg of granulocyte-colony-stimulating factor (G-CSF) for 10 to 14 days starting on day 6. Cycles were repeated every 3 weeks for a maximum of four cycles. Patients who had a partial response to topotecan after four cycles, stable disease after two cycles, or progressive disease at any time received salvage chemotherapy with cisplatin and etoposide. Topotecan pharmacokinetics were measured using a four-point sampling scheme. RESULTS Of 48 patients, none had a complete response and 19 had a partial response, for an objective response rate of 39% (95% confidence interval [CI], 25.2% to 53.0%). The median response duration was 4.8 months (95% CI, 3.0 to 7.3). After a median follow-up duration of 18.2 months, the overall median survival time was 10.0 months (95% CI, 8.2 to 12.7); the 1-year survival rate was 39% (95% CI, 25.2% to 53.0%). Eight of 34 patients (24%) who received salvage chemotherapy responded. Four of 17 patients who did not respond to first-line therapy with topotecan responded to cisplatin and etoposide. The most common toxicity was hematologic. Ninety-two percent of patients treated without G-CSF developed grade 3 or 4 neutropenia, compared with 29% who received G-CSF. However, the incidence of neutropenic fevers was similar between the two groups (8% and 11%, respectively), and one patient in each group died of neutropenic fevers. There were no differences in objective tumor response, duration of response, time to treatment failure, or survival between the 13 patients who entered the study before G-CSF administration was mandated and the 35 patients who entered after and received G-CSF. There was poor correlation between the WBC count and absolute neutrophil counts (ANCs) and both the area under the curve (AUC) and maximum concentration++ (Cmx) of total topotecan in plasma. There was no correlation between the tumor response and either AUC or Cmx of total topotecan. CONCLUSION The activity of topotecan in extensive-stage SCLC noted in this study warrants further investigation of this agent in phase III clinical trials.

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