Conditions: Gastroesophageal Junction Adenocarcinoma Stage IB Esophageal Adenocarcinoma AJCC v7 Stage II Esophageal Adenocarcinoma AJCC v7 Stage IIA Esophageal Adenocarcinoma AJCC v7 Stage IIB Esophageal Adenocarcinoma AJCC v7 Stage IIIA Esophageal Adenocarcinoma AJCC v7 Stage IIIB Esophageal Adenocarcinoma AJCC v7
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
This phase IB/II trial studies the side effects of taladegib, paclitaxel, carboplatin, and external beam radiation therapy and to see how well they work in treating patients with esophageal or gastroesophageal junction cancer found only in the tissue or organ where it began, and has not spread to nearby lymph nodes or to other parts of the body (localized). Taladegib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving taladegib, paclitaxel, carboplatin, and radiation therapy may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the toxicity of taladegib administered orally daily concurrently with weekly paclitaxel, carboplatin and radiation therapy in patients with localized nuclear glioma-associated oncogene homolog (Gli-1) expressing adenocarcinoma of the esophagus or gastroesophageal junction. (Phase IB) II. To assess the rate of pathologic complete response (pathCR) when taladegib is administered orally daily concurrently with weekly paclitaxel, carboplatin, and radiation therapy in patients with localized nuclear Gli-1 expressing adenocarcinoma of the esophagus or gastroesophageal junction. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the toxicity of biochemoradiation in the phase II study. II. To assess additional biomarkers (hedgehog \[Hh\] related and Hh unrelated) in sequentially procured tissues (biopsies and resected specimens).

III. Assess if taladegib down modulates its target (Gli-1) in the first cohort (where taladegib will be administered alone for the first 7 days) of the phase II study.

IV. Assess relapse-free survival and overall survival.

OUTLINE:

PHASE IB: Patients receive taladegib orally (PO) once daily (QD) on days 1-38, paclitaxel intravenously (IV) over 3 hours on the first radiation day of each week for 5 doses, carboplatin IV over 2 hours on the first radiation day of each week for 5 doses, and undergo external beam radiation therapy 5 days weekly on 28 consecutive weekdays for 5.5 weeks.

PHASE II: Patients are assigned to 1 of 2 steps.

STEP I: Patients receive taladegib PO for 7 days, followed by taladegib, paclitaxel, carboplatin, and external beam radiation therapy as in Phase IB.

STEP II: Patients receive taladegib, paclitaxel, carboplatin, and external beam radiation therapy as in Phase IB.

After completion of study treatment, patients are followed up at 3 months, every 3-6 months for 1 year, every 6 months for 2 years, and at years 4 and 5.

Arms:
arm 1: Patients receive taladegib PO for 7 days, followed by taladegib, paclitaxel, carboplatin, and external beam radiation therapy as in Phase IB. arm 2: Patients receive taladegib, paclitaxel, carboplatin, and external beam radiation therapy as in Phase IB.

Interventions: intervention 1: Carboplatin intervention 2: External Beam Radiation Therapy intervention 3: Laboratory Biomarker Analysis intervention 4: Paclitaxel intervention 5: Taladegib
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo external beam radiation therapy intervention 3: Correlative studies intervention 4: Given IV intervention 5: Given PO

Protocol document:
Prot_SAP_000.pdf: 
2014-0966 
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TITLE:  A Phase 1B/2 Study of *TALADEGIB in Combination with Weekly Paclitaxel, 
Carboplatin, and Radiation in Localized Adenocarcinoma of the Esophagus or Gastroesophageal 
Junction  
Study Site: 
The University of Texas MD Anderson Cancer Center  
Protocol Number  
2014-0966 
Version Date: 
November 18, 2015  
Principal Investigator: 
Jaffer A. Ajani, MD 
Department of GI Medical Oncology 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd, Unit 0426 
Houston, TX 77030 
713-792-2828 
713-745-1163 
jajani@mdanderson.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*TALADEGIB (RXDX-109) formally LY2940680 
 
 
 


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SCHEMA 
The general study design is sequential and it is a single-arm study. Please note that the number of 
patients in phase II will increase to 54 since we expect that 10% of patients will not go to 
surgery. 
 
TALADEGIB (LY2940680)  
 
 
 


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TABLE OF CONTENTS 
 
1. 
OBJECTIVES 5 
1.1 
Primary Objectives...................................................................................................5 
1.2 
Secondary Objectives...............................................................................................5 
2. 
BACKGROUND .................................................................................................................5 
2.1 
Adenocarcinoma of the Esophagus ..........................................................................5 
2.2 
Investigational Agent .............................................................................................14 
2.3 
Other Agents ..........................................................................................................22 
2.4 
Rationale ................................................................................................................23 
2.5 
Correlative Studies Background ............................................................................23 
3. 
PATIENT SELECTION ....................................................................................................24 
3.1 
Inclusion Criteria ...................................................................................................24 
3.2 
Exclusion Criteria ..................................................................................................26 
3.3 
Inclusion of Women and Minorities ......................................................................27 
4. 
REGISTRATION PROCEDURES ...................................................................................27 
4.1 
General Guidelines.................................................................................................27 
5. 
TREATMENT PLAN ........................................................................................................28 
5.1 
Agent Administration.............................................................................................28 
5.2 
Phase I B ................................................................................................................28 
5.3 
Definition of Dose-Limiting Toxicity ....................................................................29 
5.4 
Phase II...................................................................................................................31 
5.5 
Treatment Information ...........................................................................................33 
5.6 
General Concomitant Medication and Supportive Care Guidelines ......................37 
5.7 
Duration of Therapy ...............................................................................................38 
5.8 
Duration of Follow Up ...........................................................................................39 
5.9 
Criteria for Removal from Treatment ....................................................................39 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................39 
7. 
Safety Monitoring and reporting ........................................................................................41 
7.1 
Adverse Events ......................................................................................................41 
7.2 
Serious Adverse Events .........................................................................................42 
7.3 
Communications between Investigator and Ignyta ................................................43 
7.4 
Adverse Event List(s) for TALADEGIB ...............................................................44 
7.5 
Adverse Event List(s) for paclitaxel and carboplatin ............................................45 
7.6 
Adverse Event Characteristics ...............................................................................46 
7.7 
Data Confidentiality Plan .......................................................................................47 
8. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................48 
8.1 
Biomarker Studies ..................................................................................................48 
9. 
STUDY CALENDAR .......................................................................................................50 


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10. 
MEASUREMENT OF EFFECT........................................................................................52 
10.1 
Antitumor Effect – Solid Tumors ..........................................................................53 
10.2 
Other Response Parameters ...................................................................................59 
11. 
STATISTICAL CONSIDERATIONS...............................................................................59 
11.1 
Study Design/Endpoints.........................................................................................59 
11.2 
Sample Size/Accrual Rate ......................................................................................61 
11.3 
Stratification Factors ..............................................................................................61 
11.4 
Analysis of Secondary Endpoints ..........................................................................61 
11.5 
Reporting and Exclusions ......................................................................................61 
APPENDIX A - PERFORMANCE STATUS CRITERIA ...........................................................63 
APPENDIX B - ACCEPTABLE FORMS OF CONTRACEPTION ............................................64 
APPENDIX C - Patient INFORMATION ON POSSIBLE DRUG INTERACTIONS ................65 
Appendix D  - Prohibited Medications ..........................................................................................68 
Bibliography 
....................................................................................................................69 
 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.11. To evaluate the toxicity of TALADEGIB administered orally daily concurrently with weekly 
paclitaxel, carboplatin and radiation therapy in patients with localized nuclear Gli-1 expressing 
adenocarcinoma of the esophagus or gastroesophageal junction (Phase IB). 
1.12. To assess the rate of pathologic complete response (pathCR) when TALADEGIB is 
administered orally daily concurrently with weekly paclitaxel, carboplatin, and radiation therapy 
in patients with localized nuclear Gli-1 expressing adenocarcinoma of the esophagus or 
gastroesophageal junction (Phase II). 
 
1.2 
Secondary Objectives 
1.21.    To evaluate the toxicity of biochemoradiation in the phase II study. 
 
1.22.   To assess additional biomarkers (Hedgehog [Hh] related and Hh unrelated) in sequentially 
procured tissues (biopsies and resected specimens). Expression studies: (1) We will conduct a pre- 
and post-treatment read-out of the pathway in adenocarcinoma of the esophagus or 
gastroesophageal junction (EAC) biopsies by determining the expression of Shh, Ih, Gli1 and Gli2, 
Patch 2 and sFRP1 mRNA using real-time qPCR. (2) We will use the gene expression data to 
refine and expand the pathway-associated markers listed in item #1 above and attempt to predict 
sensitivity or/and resistance to therapy in pre-treatment EAC biopsies using real-time qPCR. (3) 
We will examine the levels and spatial localization of Shh, Ih and Gli-1 using quantitative 
immunohistochemistry (IHC) in pre- and post-treatment cancer biopsies. (4) We will use 
fluorescent TUNEL and laser scanning cytometry (LSC) to measure levels of apoptosis in pre- and 
post-treatment biopsies as a measure of biological response.  Biological response will be correlated 
with measures of Hh pathway inhibition and clinical response. 
 
1.23    Assess if TALADEGIB down modulates its target (Gli-1) in the first cohort (where 
TALADEGIB will be administered alone for the first 7 days) of the phase II study. 
 
1.2.4 Assess relapse-free survival and overall survival.  
 
2. BACKGROUND 
 
2.1 Adenocarcinoma of the Esophagus 
Carcinoma of the esophagus is a virulent disease and there are >600,000 new cases each year.[1]  
The incidence of EAC has increased rapidly in the West over the past 28+ years.[2-4]. White men 
more often get EAC compared to white women and other ethnicities.[2, 3, 5] Despite this marked 
increase in the incidence of EAC, an early diagnosis is not being made and its mortality continues 
to rise.[3] Localized EAC is diagnosed in ~50% of patients and they are eligible for multimodality 
therapy including preoperative chemoradiation (CTRT).  


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The 5-year cure rate from surgery alone is consistently low (≤20%) for the common clinical stage 
(II or III).[3, 6] Preoperative chemoradiation is now the best strategy for localized EAC, [7-12] 
however, the outcomes still remain suboptimal. [7-12] One of the major challenges in the treatment 
of patients with localized EAC is the lack of our ability to optimize therapy that is associated with 
significant morbidity and mortality.[3, 13, 14] Currently, no biomarker, baseline clinical parameter, 
or treatment parameter can help one to select a specific treatment or avoid a specific one.[15-17] 
There is an urgent need to develop an individualized approach to the treatment of localized EAC. 
Studies of the clinical biology of EAC suggest that there is considerable heterogeneity in the 
outcome of patients with EAC who seem to have a similar clinical baseline stage and are treated 
similarly.[6, 14, 18-23] This unpredictable heterogeneity is manifested not only if surgery is used as 
primary therapy but also when preoperative chemoradiation is utilized.[15, 17, 24-26] After 
preoperative chemoradiation, the degree of residual cancer (reflection of sensitivity or resistance 
to chemoradiation) correlates with overall survival (OS) and disease-free survival (DFS). [15, 17, 24-
26] Only 20-25% of EAC patients achieve a pathologic complete response (pathCR) and have a 5-
year survival (OS) rate of </= 65% but most patients do poorly and patients with considerable 
amount of cancer (>50% residual cancer[15, 27]; extreme chemoradiation resistance  (exCRTR) have 
the worst outcome.[15, 24, 27, 28] Chemoradiation is quite toxic (nausea, dehydration, fatigue, and 
weight loss) and surgery is life altering (severe reflux, dumping syndrome, micro-aspirations, and 
weight loss). Finally, there is agony of brain/appetite and stomach/reservoir disconnect that every 
patient experiences. Overcoming chemoradiation resistance in patients with EAC could provide a 
significant advantage. A biomarker-based approach would be rational and will allow optimization 
of therapy of individual patients. In addition, molecular biology studies have uncovered novel and 
potentially exploitable targets. Hedgehog (Hh) signaling is commonly observed in EAC. Our 
preliminary data below suggest that chemotherapy and radiation resistance is likely mediated by 
activation of the Hh pathway (at least in some cases).  
Preliminary data generated at the University of Texas M. D. Anderson Cancer Center 
Transcriptional Profiling Identifies Molecular (Hh) Pathways Associated with Resistance to 
Chemoradiation in EAC. We profiled untreated cancer tissue from patients with esophageal cancer 
(all had trimodality therapy) using the Affymetrix U133A platform and correlated their molecular 
signatures with pathologic response. [29] Unsupervised hierarchical cluster analysis segregated 
cancers into two molecular subtypes. All but one pathCR clustered in subtype I. Thus one subtype 
appeared less likely to achieve pathCR compared to the other. ~450 genes were differentially 
expressed between the two subtypes with an estimated false discovery rate of 5%. >2 fold 
differences in the expression levels were seen for 80 genes using the t-test (p<0.0001). Several 
genes, associated with apoptosis, calcium homeostasis, and stress response were collectively 
down- regulated in subtype II. Quantitative RT-PCR of several randomly selected genes confirmed 
the differential expression observed in the microarray data. Shh was prominent among the genes 
with high expression in resistant cancers (Figure 1).  


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Figure 1. Differential expression of Shh by qPCR correlates with response to 
chemoradiation 
Limited RNA (in small number) was studied for Shh, ptch1, and Gli-1; our qPCR data corroborated 
the cDNA data in showing that pretreatment Shh mRNA levels were significantly lower in pathCR 
cases compared to <pathCR cases (mean ±SD: 3.76±1.85 for pathCR vs 11.66±5.66 for <pathCR; 
p = 0.017; t-test). Expression of both ptch and Gli-1 was up in non- responders, but not significantly 
(ptch, P=0.15; Gli-1, P=0.42). However, at the protein level, Gli-1 performs as well as Shh (see 
below). Gli-1 performed better than Shh in a new and larger sample size (see Table 2 below). 
Nuclear Gli-1 may be a better biomarker than Shh. These data suggest that upregulation of the Hh 
pathway is associated with chemoradiation resistant EACs and Gli-1 plays an important role. 
Aberrant Hh Signaling is Associated with the Burden of Chemoradiation-Resistant EAC Cells. To 
validate our initial expression array findings and assess whether the pathway was activated 
(presence of nuclear Gli1) we determined the levels of Shh and Gli1 protein expression, using 
immunohistochemistry, in untreated cancer specimens obtained from 63 EAC patients treated with 
trimodality therapy. Shh expression was detected in all EACs, along with nuclear Gli1 in 59 
(93.6%) cases. The labeling indices (LI) of Shh and Gli1 positive EAC cells varied [median LI 
(range): Shh = 0.20 (0.01-0.80); Gli1 = 0.45 (0.00-0.90)], however, within the same EAC, the 
levels of Shh and Gli1 co-expressions were significant (P<0.0001, r=0.485, Spearman test), thus 
confirming the functional activation of the pathway. Shh expression was usually clustered in 
distinct tumor patches surrounded by larger tumor fields expressing nuclear Gli1 staining. The 
presence of positive staining for cytoplasmic Shh and nuclear Gli1, indicating activation of the Hh 
pathway, was not statistically associated with age, cancer location, histopathologic grade, or 
clinical stage. Pretreatment expression levels of Shh and Gli1 were significantly lower in cancers 
sensitive to chemoradiation and achieving pathCR compared to chemoradiation (CTXRT)-
resistant tumors (P<0.0001). Interestingly, the pretreatment labeling indices (LI) of both Shh and 
Gli1, proteins were significantly associated with the degree of residual cancer cells in the resected 
specimen.  


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Figure 2. LIs of Shh and Gli-1 correlate with the degree of resistance (right column 
shows resected specimens; 4 = highest resistance) 
The post-treatment expression of Shh and Gli-1 (in 47 patients with <pathCR) was noted in 41 
patients (87.2%) with resistant EACs. 
Aberrant Hh is Associated with Poor Overall Survival (OS): In the univariate Cox proportional 
hazards model for OS, Shh and Gli-1 were significant prognosticators. However, pretreatment Shh 
was the strongest prognosticator with a relative risk of death increasing proportionally with higher 
Shh LIs (Hazard Ratio [HR]=14.6; 95% CI: 2.41–87.8; P=0.004), compared to pretreatment Gli-1 
LIs (HR=3.93; 95% CI: 1.02–15.1; P=0.047). The Kaplan-Meier (KM) OS plots showed a 
difference between the two groups of patients using a cut-off value for Shh (P=0.01; log-rank test) 
or of Gli-1 (P=0.03). In a multivariate model, that included age, clinical stage, and tumor location, 
pretreatment Shh (cut-point=0.395) was the only independent prognosticator (HR=2.93; 95% CI: 
1.19–7.24; P=0.02). However, our focus is on prediction of response (and not on OS). In addition, 
for prediction of response, Shh, Gli-1, or NF-kB individually has unsatisfactory sensitivity and 
specificity levels for clinical implementation. Thus we combined them to produce a signature 
(details below). 
Hh Signaling Plays an Oncogenic Role in EAC in vitro and in vivo: Our reports[30] and by others[31] 
confirm that the majority of EAC cell lines and tumor tissues have high LIs for Shh/Gli-1. Hh 
signaling (constitutive/acquired) is important for growth/maintenance. Genetic knock down or 
inhibition by cyclosporine/GDC-0449 decreases proliferation, migration, invasion, and colony 
formation but increases apoptosis in vitro and decreases tumor growth in vivo.[30] An increase in 
proliferation (in SEG-1; previously considered EAC) treated with Shh and a decrease when treated 
with cyclopamine (Figure 3) was observed.  
 
 
 
 
 
 
Figure 3. Activation of Hh signaling induces proliferation and knock down Gli-1 decreases EAC 


2014-0966 
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cell growth. 
 
Reduced proliferation when treated with cyclopamine or Gli-1 siRNA compared to controls was 
noted. In contrast, increase in 3H-thymidine uptake in SEG-1 cells treated with Shh (P<0.01) or 
transiently overexpressing Gli-1 (P<0.05) compared to controls. Our recent data show that 
blocking Hh in vivo by GDC-0449 in a mouse xenograft reduced tumor growth (Figure 4). 


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Figure 4. Inhibition of Hh by GDC-0449 decrease EAC tumor growth in vivo. 
Hh Signaling Precedes Tumor Repopulation after Chemoradiation in Tumor Xenografts: We 
demonstrated that Shh and Gli-1 are among the “first responders” after chemoradiation injury and 
provide strong support for the clinical trial proposed.[32, 33] 
Hh Mediated Chemoradiation Resistance and in vivo Inhibition to Overcome it: Our new data show 
that EAC cells with high Shh and nuclear Gli-1 are resistant to fluorouracil (FU) and docetaxel 
while cells with low Shh and Gli-1 are sensitive (Figure 5). Inhibition of Hh by cyclopamine 
combined with docetaxel in vivo has dramatic results (Figure 6). This supports the combination of 
Hh inhibition with standard chemoradiation approach in an enriched EAC patient population. 
 
 
Figure 5. Hh signaling associated with chemotherapy resistance. 
 


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Figure 6. Hh inhibition by cyclopamine increased the effect of docetaxel on tumor growth delay (in vivo 
model). 
Inhibition of Hh signaling (by drugs, siRNAs, or genetic knock downs) sensitized cells to radiation 
in vitro.[33] Knockdown of Gli-1 by siRNA greatly increased caspase 3 activity which increased 
further when radiation was added.[33] 
Chemoradiation Resistance and Predictive Signature in EAC. The pathway analyses of cDNA 
array also indicated that NF-kB pathway was differentially upregulated in non-responders. 
Subsequent IHC studies on pre- and post chemoradiation cancer specimens confirmed NF-kB’s 
role and its association with aggressive phenotype and resistance.[34, 35] 
Combined Hh/NF-kB/Gli-1 Signature Predicts for pathCR after Chemoradiation: We analyzed 
NF-kB, Shh, and Gli-1 protein in untreated cancer of 60 EAC patients undergoing chemoradiation. 
No cut-points were used but only raw labeling indexes (LIs) of each of the 3 biomarkers for each 
patient was used to compute a single score that predicted response to therapy. A multiple logistic 
regression model was used to fit for the endpoint of pathCR with Gli-1, Shh, and NF-κB included 
as covariates. The goodness-of-fit was assessed by the method of Hosmer et al., where high p 
values indicate a well-calibrated model. The log-likelihood ratio test and Akaike information 
criteria was used for model selection. Based on the final fitted model, a linear Z score was 
computed for each patient. For example, if the final model contains all 3 biomarkers, the linear Z 
score for patient i can be 
expressed as follows: 
where xi1, xi2 and xi3 are the expression 
level of Gli-1, Shh, and NF-κB for the patient i, respectively, and i=1, 2, ..., 60. Also, the predicted 
probability of having pathCR for each patient i was computed based on the above formula. 
The functional relationship between the linear Z scores and the predicted probabilities of pathCR 
were plotted and the true pathCR patients were identified on this plot. The area under the receiver 
operating characteristic (ROC) curve, i.e., AUC, was used to assess the discriminating ability of 
the fitted model. Figure 7 shows the ROC curve for the discovery set. All pathCR patients had a 
similar score and only a few non-pathCR patients had a score approaching that for pathCR. This 
indicates that scoring model is highly accurate for pathCR prediction. The ROC curve for the fitted 
multiple logistic regression model, confirmed the high accuracy of the prediction, with corrected 
AUC values after cross-validation and bootstrapping were 0.943 and 0.940, respectively. 
 


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Table 1. Multivariate logistic regression model for pathCR (n=167) ALDH-1 can replace Shh 
Model 
Covariates 
AUC for ROC 
curve 
95% Confidence Interval 
1 
Shh, Gli-1, NFkB 
0.97 
0.95 – 0.99 
2 
Aldh-1, Gli-1, NFkB 
0.97 
0.95 – 0.99 
 
Validation of the Signature: In a unique set of 167 patients who had chemoradiation followed by 
surgery, untreated cancer was stained for Shh, Gli-1, and NF-kB (and others). Table 1 shows the 
AUCs with CIs and Figure 8 shows the ROC curve. Table 2 shows Likelihood Estimates for all 
biomarkers studied. These data suggest that the signature has been retrospectively validated and is 
ready for prospective validation as proposed. 
 


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Figure 8. Validation set. ROC curve  
 
Table 2. Analysis of Maximum Likelihood Estimates (pathCR; n=167) 
Parameter 
DF Estimate 
Standard 
Error 
Wald Chi-
Square 
P-value 
Intercept 
1 
3.7340 
1.0794 
11.9659 
0.0005 
NF-kB 
1 
-23.0420 
7.2880 
9.9960 
0.0016 
Shh 
1 
-2.9563 
3.5455 
0.6953 
0.4044 
Gli-1 
1 
-12.8989 
4.8566 
7.0540 
0.0079 
ALDH1 
1 
-1.8985 
3.0851 
0.3787 
0.5383 
ABCB1 
1 
0.1640 
1.5002 
0.0119 
0.9130 
Survivin 
1 
0.9916 
1.3300 
0.5558 
0.4559 
BCRP 
1 
-1.8382 
1.3346 
1.8970 
0.1684 
 
 


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Gli-1 Expression and Response to Chemoradiation (new): In 227 patients (we have clinical 
response data on all patients), the median Gli-1 LI was 0.25 (range, 0-0.95). In pathCR patients 
(n=56), the median was 0.05 (range, 0-0.5), and in <pathCR patients (n=171), the median was 0.35 
(range, 0-0.95). These data suggest a trend that the higher the Gli-1 LI, the more resistant the 
cancer. We are choosing ≥5% LI for enrichment based on these numbers. There is no other trial or 
publication using Gli-1 for enrichment. For our trial, it is very likely that the median Gli-1 LI will 
be around 0.25. It is highly unlikely that most tumors will have Gli-1 LI of ≤10%. 
 
2.2 
Investigational Agent 
 
2.2.1 TALADEGIB 
The Hh signaling pathway is a crucial mediator of embryogenesis[37]. Signaling is initiated by the 
binding of the secreted morphogen, Hh, to its receptor, patched 1 (Ptch1).  In the unbound state, 
Ptch1 inhibits SMO, a G-protein coupled phosphoprotein receptor, by preventing its localization 
to the cell surface; however, in the presence of the Hh ligand, the Hh-Ptch1 complex is internalized 
and the repression of Ptch1 on SMO is relieved.  Surface localization of SMO is thought to initiate 
a signaling cascade, leading to the activation of the glioma-associated (Gli) family of zinc finger 
transcription factors, many of which are involved in proliferation, survival, and angiogenesis. 
Aberrant activation of the Hh pathway in cancers is caused by mutations in the pathway or through 
Hh overexpression, termed either ligand-independent or ligand-dependent, respectively (for 
reviews, see [38, 39] Past studies have identified mutations in the Hh receptor components, Ptch1 or 
SMO in basal cell carcinoma (BCC) and medulloblastoma, resulting in constitutive pathway 
activation.[40, 41] Excessive or inappropriate expression of the Hh ligand has been found in a 
significant proportion of patients with sporadic cancers of the gastrointestinal tract, pancreas, lung 
and prostate, suggesting that disruption of Hh signal transduction could potentially be beneficial in a 
broad array of tumor types[42-45] Evidence suggests that antagonism of excessive Hh signaling may 
provide a route to unique mechanism-based anticancer therapies, blocking tumor growth and 
stimulating tumor regression without toxic effects on normal adjacent tissue.[45] 
TALADEGIB is a small-molecule antagonist of the Hh signal pathway (Investigator’s Brochure, 
2013). Specifically, TALADEGIB binds to and inhibits SMO, blocking Hh signal transduction. In 
vitro and in vivo preclinical studies have demonstrated inhibition of Hh signaling following 
TALADEGIB administration.  TALADEGIB has demonstrated efficacy against a variety of 
primary human tumor xenografts, including colorectal cancer (CRC) and pancreatic 
adenocarcinoma, and tumor cell-line xenograft models. Inhibition of Hh signaling in xenograft 
models has been correlated with a decrease in tumor growth. 
 
Nonclinical Studies 
 
Metabolism 
Evaluation of Cytochrome P450 Enzyme Induction Potential in Rats and Dogs 
 
The potential of TALADEGIB to induce total hepatic cytochrome P450 (CYP) was evaluated in 
male and female rats and dogs following oral drug administration daily for 28 days. TALADEGIB 
did not induce hepatic total CYP enzyme levels in rats or dogs. 


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In Vivo Metabolism 
The metabolism of [14C]TALADEGIB was examined in male and female Sprague Dawley rats 
and male beagle dogs. In the plasma of rats and dogs, parent compound and active metabolite 
LSN2941091 (amide N-desmethyl, M75) were the major circulating components. Plasma half-
lives in dogs were significantly longer (5.5- to 20-fold) for radioactivity than for either 
TALADEGIB or LSN2941091 following both oral and IV administration. 
 
Excretion 
In single-dose excretion studies with [14C]TALADEGIB in rats and dogs, the radioactivity was 
primarily eliminated in the feces (89% to 90% in male and female rats, and 90% in male dogs) 
following oral administration. In addition, studies of oral administration of TALADEGIB to bile 
duct-cannulated rats and IV administration of TALADEGIB to dogs demonstrated that biliary 
excretion plays a major role in the elimination of TALADEGIB.  
 
Toxicity Summary 
 
Long-term studies to evaluate the carcinogenic potential of TALADEGIB have not been 
conducted. TALADEGIB was negative in a bacterial mutation (Ames) assay. Animal studies to 
evaluate the impairment of fertility have not been conducted; however, TALADEGIB did cause 
testicular and epididymal injury, and uterine atrophy in repeat-dose studies in animals. These 
effects would be expected to impair fertility. 
 
TALADEGIB treatment produced anticipated embryo-fetal lethality in female Sprague-Dawley 
rats when administered orally. Given the understanding of the pivotal role Hh signaling plays in 
early embryonic development, as well as published reports of malformations in offspring of 
pregnant animals exposed to Hh inhibitors during pregnancy, the potential for embryotoxicity due 
to TALADEGIB exposure in pregnant woman is of particular concern. Therefore, administration 
of TALADEGIB to patients poses a significant risk to a pregnant mother and unborn child. 
 
Clinical Experience 
 
As of 12 August 2013, a total of 66 patients in Studies HHBB and HHBE were treated with at least 
1 dose of study drug. TALADEGIB has also been administered in a total of 36 healthy volunteers 
(Studies HHBG and HHBF). Study HHBD is being closed due to lack of accrual. 
 
Table 3 lists the planned, ongoing, and completed studies at the time of this update. 
 
 
 
 
 
 
 
Table 3. Planned, Ongoing, and Completed Studies for TALADEGIB 
Study 
Design 
Population 
Status 


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16 
HHBB 
Phase 1 FHD monotherapy 
Part A dose escalation QD 
50-600 mg 
Part B dose escalation BID 
(optional) 
Part C dose confirmation 
all comers 
400 mg 
Part D dose confirmation 
BCC patients 
only 400 mg 
Parts A to C: advanced 
cancer 
Part D: locally advanced 
or 
metastatic BCC patients 
Closed to enrollment 
Part A: MTD defined as 
400 mg QD 
84 patients: 
50 mg:    3 pts 
100 mg:  6 pts 
200 mg:  3 pts 
400 mg:  6 pts 
600 mg:  7 pts 
 
Part B: not enrolled 
 
Part C: 400 mg:  19 pts 
 
Part D: 400 mg:  40 pts 
HHBE 
Phase 1b/2 
TALADEGIB 100-400 mg 
and Carboplatin + 
Etoposide 
Extensive stage SCLC 
patients 
Part A ongoing 
24 patients: 
100 mg:  6 pts 
200 mg:  6 pts 
400 mg: 12 pts 
HHBH 
Phase 1 Study 100-400 mg 
Japanese patients with 
advanced solid tumors 
Ongoing 
15 patients: 
100 mg:  3 pts 
200 mg:  3 pts 
400 mg:  9 pts 
HHBJ 
Phase 1 Study  
Japanese patients with 
SCLC  
Planned 
HHBG 
SAD study 
Part A dose escalation 50-
400 mg 
Part B 
formulation/food/PPI effect 
100mg 
Healthy subjects 
Completed 
N=30 
HHBF 
14 C metabolism study 100 
mg 
Healthy subjects 
Completed 
N=6 
Abbreviations: BCC = basal cell carcinoma; BID = twice daily; FHD = first human dose; FPV = 
first patient visit; MTD = maximum tolerated dose; QD = once daily; PPI = proton pump inhibitor; 
pt = patient; SAD = single ascending dose; SCLC = small cell lung cancer. 
 
Pharmacokinetics in Patients 
Interim PK data are available for 56 patients across a dose range of 50 mg to 600 mg. Plasma 
concentration versus time profiles were analyzed using the noncompartmental method of analysis 
to determine the PK parameters for TALADEGIB and its equipotent metabolite LSN3185556. 
 
After single- and multiple-dose administration, TALADEGIB levels reach Cmax after 
approximately 3 hours, with food appearing to have no impact on rate or extent of absorption. The 
mean value for the apparent clearance is 7.6 L/hr (99% coefficient of variation [CV]); indicating 
that TALADEGIB is slowly eliminated from the plasma. The mean value for the apparent volume 
of distribution is 215 L (65% CV). The mean TALADEGIB terminal half-life (t 1/2) across all 
doses is estimated to be around 23 hours (range, 5 to 80, 70% CV). The exposure ratio between 
metabolite and parent was calculated from the AUC 0-24hr and is, on average, approximately 2.7 
(range, 0.8 to 5.4, 39% CV). From 50- to 100-mg doses, both C max and exposure don’t seem to 


2014-0966 
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17 
increase based on the limited data available. However, in doses ranging from 100 to 600 mg, 
TALADEGIB and LSN3185556 seem to exhibit dose-proportionality increases in exposure (C 
max and AUC on Day 1 and Day 15). In vitro data suggest that both TALADEGIB and 
LSN3185556 are 100% metabolized by CYP3A4. Given this patient population, with its 
concomitant medications and varying stages of disease, this could explain at least some of the PK 
variability. 
 
Figure 9 Arithmetic mean and SD plots per dose level for TALADEGIB (top) and LSN3185556 
(bottom) following single- and multiple-dose administration of TALADEGIB from Study HHBB 


2014-0966 
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(patient data). 
 
Pharmacokinetics in Healthy Volunteers 
In Study HHBF, 6 healthy subjects have been enrolled to study the disposition of radioactivity and 
TALADEGIB and its metabolite LSN3185556. The median time of maximum observed drug 
concentration (tmax) was observed at 1.5 hours postdose for TALADEGIB and 2.5 hours for 
metabolite LSN3185556. The mean t1/2 was 12.5 hours for TALADEGIB and 11.9 hours for 
metabolite LSN3185556. LSN3185556 was a major metabolite, with a ratio of metabolite to parent 
drug MR AUC0-72hr, MR AUC0-∞, and MR Cmax of 3.60, 3.68, and 1.49, respectively. 
 
TALADEGIB represents less than 1% of the excreted dose, indicating extensive metabolism with 
metabolites excreted primarily in the feces with minor urinary excretion of metabolites. In Study 
HHBG part A, 12 healthy subjects have been enrolled to explore the safety and tolerability features 
of TALADEGIB administration following single doses (50 to 400 mg). The median tmax across 
all doses was estimated to be approximately 2 hours for TALADEGIB and 9 hours for 
LSN3185556. The mean t 1/2 across all doses was estimated to be approximately 16 hours for 
TALADEGIB and 17 hours for LSN3185556. These PK properties are similar to those described 
in patients from the ongoing Phase 1 Study HHBB.  
 
In Study HHBG part B, 14 healthy subjects have been enrolled to receive a single 100-mg 
TALADEGIB dose. A minimal increase in both AUC and Cmax was seen following tablet 
administration compared to capsule following a 100-mg dose. This increase was approximately 
9% to 10% for AUC and 29% to 33% for Cmax for both TALADEGIB and LSN3185556. In the 
fed state, a slightly lower Cmax was observed for both TALADEGIB and LSN3185556 (38% and 
27%, respectively). There was no change in AUC for TALADEGIB and a 9% decrease in AUC 
for LSN3185556 in the fed state. With co-administration of a proton pump inhibitor (PPI), the 
AUC showed a slight decrease (3% and 11% for AUC of TALADEGIB and LSN3185556, 
respectively). There was a slight increase in the Cmax (8%) for parent and no change in the Cmax 
for metabolite following PPI administration. Overall, these results indicate that the tablet 
formulation of TALADEGIB should provide similar exposure to the capsule formulation, and that 
there are negligible food and gastric pH effects on the PK parameters following single 100-mg 
doses of this formulation. Therefore, no restrictions in food nor elevated gastric pH from a PPI are 
needed for TALADEGIB administration. 
 
Pharmacodynamics (PD) in Patients 
Despite variability in the PK results, the PD data demonstrate at least 50% inhibition of Gli1 in 
skin, which was observed in the majority of patients in Study HHBB. This is what was targeted 
from the preclinical studies, where efficacy has been associated with survival and a 50% PD 
response in skin for at least 4 hours 
 
Clinical Metabolism 
Results from a human radiolabeled metabolism study (Study HHBF) indicate that TALADEGIB 
is extensively metabolized. In plasma from 0-72 hours, the mean exposure to TALADEGIB was 
11% of the total plasma radioactivity. The major plasma metabolite is the free base of the active 
metabolite LSN2941091 (amide N-desmethyl, M75 or LSN3185556). This is the same metabolite 
that was found in plasma from both rats and dogs.  


2014-0966 
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19 
 
The mean total recovery of radioactivity in excreta was 97.3%, with 82.7% of the dose recovered 
in feces and 14.6% recovered in urine. The major excretory metabolite is M43, an amide N-
demethylation plus piperidine di-oxidation of parent. Metabolite M43 represented a combined total 
of approximately 40% of the radioactive dose, primarily excreted in feces. Parent TALADEGIB 
represented less than 1% of the dose in the excreta, indicating extensive metabolism. The major 
biotransformation pathways observed in humans included amide N-demethylation and piperidine 
ring oxidation. 
 
Safety and Efficacy 
Safety 
Clinical Pharmacology Studies 
There have been 2 studies of TALADEGIB in healthy subjects (Studies HHBG and HHBF). 
 
Study I4J-MC-HHBG 
Study HHBG was a single ascending dose and relative bioavailability study of TALADEGIB in 
healthy subjects. During Part A, 16 (2 male, 14 female) healthy subjects received TALADEGIB 
in a dose escalation manner (50, 100, 200, and 400 mg). During Part B, 14 female healthy subjects 
received 100 mg of TALADEGIB on 4 separate occasions. The incidence of treatment emergent 
adverse events (TEAEs) was comparable across the different treatments, and all TEAEs reported 
during the study were mild in severity. The most frequently reported TEAEs considered to be 
related to study drug were headache and nausea. Headache was reported by 11 of the 30 subjects 
(37%) following dosing with TALADEGIB and by 2 of the 9 subjects (22%) following dosing 
with placebo. Nausea was reported by 5 of the 30 subjects (17%) following dosing with 
TALADEGIB and by 1 of the 9 subjects (11%) following dosing with placebo. All other TEAEs 
were reported by no more than 3 subjects (≤10%). There were no clinically significant changes in 
the clinical laboratory results, vital signs, or 12-lead ECGs during the study. 
 
Study I4J-MC-HHBF 
Study HHBF was a disposition study of [14C]-TALADEGIB following oral administration in 
healthy subjects. Six female subjects received a single 100-mg oral dose of TALADEGIB 
containing approximately 100 mCi of [14C]-TALADEGIB. There were 5 TEAEs reported, all of 
which were mild in severity. The most frequently reported TEAEs considered to be related to study 
drug were headache and diarrhea. There were no clinically significant changes in the clinical 
laboratory results, vital signs, or ECGs during the study. 
 
Safety Data across Clinical Studies in Cancer Patients 
 
Study I4J-MC-HHBB 
The 58 patients exposed to TALADEGIB in the Phase 1 Study HHBB have received doses ranging 
from 50 mg to 600 mg daily. Data included are from electronic case report forms (eCRFs) from 
these patients through 12 August 2013, as well as any reported SAEs considered related to 
TALADEGIB administration as of 12 August 2013. In these patients, hyponatremia (n=1) was the 
only Grade 4 TEAE considered possibly related to TALADEGIB by the investigators; this event 
was also reported as serious. In addition, Grade 3 nausea/vomiting (n=1) and Grade 3 syncope 
(n=1) were reported as drug-related serious adverse events (SAEs) by the investigators. Other 


2014-0966 
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20 
Grade 3 TEAEs occurring at least once and considered possibly related to TALADEGIB by the 
investigators were fatigue (n=3); nausea, dysgeusia, vomiting, asthenia, and muscle spasms (n=2 
each); and maculopapular skin rash, diarrhea, myalgia, and decreased body weight (n=1 each). The 
most frequently reported TEAEs considered possibly related to TALADEGIB were fatigue 
(41.4%), dysgeusia (41.4%), nausea (39.7%), vomiting (31.0%), and decreased appetite (including 
1 report of early satiety) (31.0%). In addition, treatment-emergent muscle spasms (including 1 
report of tetany) considered possibly related to TALADEGIB occurred in 27.8% of treated 
patients. Alopecia (20.7%), rash (including rash maculopapular, dermatitis, and urticaria) (17.2%), 
diarrhea (15.5%), asthenia (13.8%), myalgia (13.8%), and decreased body weight (10.3%) were 
also TEAEs considered possibly related to TALADEGIB at a frequency of ≥10%. Of the 58 
patients treated, 51 (87.9%) patients experienced at least 1 treatment-emergent event considered 
possibly related to TALADEGIB by the investigators (all grades). The MTD in Study HHBB was 
defined as 400 mg QD in Part A (dose escalation) of Study HHBB; enrollment is ongoing in Part 
D (BCC-specific MTD expansion) of this study. The MTD of 400 mg QD was determined based 
on the observation of DLTs at the 600-mg QD dose level in 2 individual patients. The first DLT, 
observed at the 600-mg QD dose level, was Grade 3 maculopapular rash. The second DLT, also 
observed at the 600-mg QD dose level, was determined by the investigator based on numerous 
Grade 2 toxicities occurring within the same patient during Cycle 1 (confusion, nausea, and 
dehydration). Of note, another DLT was reported during the dose escalation phase (Part A) of 
Study HHBB: hyponatremia (initially Grade 3, but worsened to Grade 4) at the 100-mg QD dose 
level. 
 
Study I4J-MC-HHBE 
Study HHBE is a dose-escalation study of TALADEGIB in combination with the standard of care 
chemotherapy doublet of carboplatin and etoposide in patients with extensive stage small cell lung 
cancer. Patients have received doses ranging from 100 to 200 mg daily. Data included are from 
the eCRFs from 8 patients through 12 August 2013, as well as any reported SAEs considered 
related to TALADEGIB administration as of 12 August 2013. Compared to the TALADEGIB 
monotherapy Study HHBB, Study HHBE showed a relative increase in adverse events due to 
hemotoxicity. Besides Grade 3 and 4 neutropenia possibly related to TALADEGIB (n=1 each), 
there was one serious report of Grade 5 enterocolitis (with febrile neutropenia) considered possibly 
related to TALADEGIB. This event was also considered a DLT for Cohort 1 (100 mg QD 
TALADEGIB in combination with carboplatin and etoposide). Given the known hemotoxicity 
profiles of carboplatin and etoposide, the additional role of TALADEGIB in these adverse events 
is unclear at this stage of development. Other drug-related TEAEs reported in Study HHBE were 
generally consistent with the monotherapy data reported from the 58 patients treated in Study 
HHBB. 
 
 
 


2014-0966 
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21 
Table 4. Adverse Drug Reactions Occurring in ≥10% of Patients in Study HHBB (N=58) 
Event 
All Grades (%)  
Grade >3  
Dysgeusia 
46.2 
2.2 
 
Fatigue 
44.1 
4.3 
Nausea 
43.0 
2.2 
Muscle spasms (including 1 report of tetany) 
37.6 
5.4 
Decreased appetite (including 3 reports of early 
satiety) 
33.3 
0.0 
Alopecia 
32.3 
 
0.0 
Vomiting 
30.1 
2.2 
Decreased Weight 
25.8 
1.1 
Myalgia 
18.3 
2.2 
Diarrhea 
18.3 
2.2 
Rash (including rash maculopapular, dermatitis 
acneiform, and urticarial) 
16.1 
1.1 
Asthenia 
10.8 
2.2 
Constipation 
11.8 
0.0 
Patients will be only counted once in each preferred term but may be counted in more 
than one preferred term. 
Sources: 
Home/lillyce/ prd / ly2940680 /integrations / programs_stat / tfl_output / hhbb_smdrad12.rtf; Home / lillyce / prd / 
ly2940680 /integrations / programs_stat / tfl_output / hhbb_lspaed1.rtf 
Supplier: Ignyta Inc. (Ignyta) 
 
How supplied: The drug product is supplied for clinical trial use as 100-mg tablets.  
 
Administration: Oral 
 
Storage and Stability: The drug substance is stable when stored at room temperature. .The drug 
product should be stored according to instructions on the label. 


2014-0966 
June 27, 2017 
22 
 
 
 
2.3 
Other Agents 
Carboplatin 
Carboplatin is a second-generation platinum compound with a broad spectrum of antineoplastic 
properties. Carboplatin contains a platinum atom complexed with two ammonia groups and a 
cyclobutane-dicarboxyl residue. This agent is activated intracellularly to form reactive platinum 
complexes that bind to nucleophilic groups such as GC-rich sites in DNA, thereby inducing 
intrastrand and interstrand DNA cross-links, as well as DNA-protein cross-links. These 
carboplatin-induced DNA and protein effects result in apoptosis and cell growth inhibition. This 
agent possesses tumoricidal activity similar to that of its parent compound, cisplatin, but is more 
stable and less toxic.  
Supplier:  Carboplatin will be obtained from a commercial source.  Please refer to the current 
FDA-approved package insert provided with the drug for complete instructions for preparation, 
handling and storage of the drug and information about possible side effects.    
Solution preparation:  Preparation is per the package insert.   
Administration:  Intravenous   
Storage and Stability:  Store the unopened vials at 25°C (77°F); excursions permitted from 15°-
30°C (59°-86°F). Protect unopened vials from light. Solutions for infusion should be discarded 8 
hours after preparation. Unopened vials of carboplatin are stable for the life indicated on the 
package when stored at 25°C (77°F); excursions permitted from 15°-30°C (59°-86°F). Protect 
from light.  When prepared as directed, carboplatin solutions are stable for 8 hours at room 
temperature (25°C). Since no antibacterial preservative is contained in the formulation, it is 
recommended that carboplatin solutions be discarded 8 hours after dilution. Parenteral drug 
products should be inspected visually for particulate matter and discoloration prior to 
administration. 
 
Paclitaxel (Taxol) 
Paclitaxel (Taxol®) is an antineoplastic agent belonging to the taxoid family.  Paclitaxel Injection 
Concentrate is a sterile, pyrogen-free, non-aqueous, clear yellow to brownish-yellow viscous 
solution and is available in single-dose vials containing 20 mg (0.5 mL) or 80 mg (2 mL) paclitaxel 
(anhydrous), with an accompanying sterile, non-pyrogenic, diluent (13% ethanol in Water for 
Injection) vial. Each mL contains 40 mg paclitaxel (anhydrous) and 1040 mg polysorbate 80. 
Premedications are required and include: dexamethasone 10 mg IV, hydrocortisone 100 mg IV, 
and diphenhydramine hydrochloride 25 mg IV.  
Supplier:  Paclitaxel will be obtained from a commercial source. Please refer to the current FDA-
approved package insert provided with the drug for complete instructions for preparation, handling 
and storage of the drug and information about possible side effects.    
Solution preparation:  Preparation is per the Paclitaxel package insert.   


2014-0966 
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23 
Administration: Paclitaxel is administered through an intravenous infusion over 1 hour.   
Storage and Stability:  Store the vials in original cartons between 20°–25° C (68°–77° F). Retain 
in the original package to protect from light. Unopened vials of TAXOL (paclitaxel) Injection are 
stable until the date indicated on the package when stored between 20°–25° C (68°–77° F), in the 
original package. Neither freezing nor refrigeration adversely affects the stability of the product. 
Upon refrigeration, components in the TAXOL vial may precipitate, but will redissolve upon 
reaching room temperature with little or no agitation. There is no impact on product quality under 
these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial 
should be discarded. Solutions for infusion prepared as recommended are stable at ambient 
temperature (approximately 25° C) and lighting conditions for up to 27 hours. 
 
2.4 
Rationale 
Rationale for the Study: Localized EAC is a virulent cancer. Most patients are treated with 
chemoradiation followed by surgery. Most patients’ tumors are chemoradiation resistant. Patients 
whose tumors are chemoradiation sensitive tend to have a longer survival than those with tumors 
that are chemoradiation resistant. Therefore, overcoming chemoradiation resistance is of 
considerable importance. Varying degrees of Hh signaling are observed in most EAC. Hh signaling 
is also correlated with resistance to therapy in EAC patients and in preclinical studies in EAC.[32, 
36] Therefore, treatment with TALADEGIB, a Hh signaling inhibitor, would be of considerable 
interest as it may partially or completely overcome chemoradiation resistance in some patients.  
Rationale for Choosing This Combination: Chemoradiation therapy has been shown to be superior 
to radiation alone in patients with carcinoma of the esophagus.[46] Therefore, chemoradiation is 
preferred over radiation alone. However, there is no single combination of cytotoxic drug that has 
shown to be superior.[16, 47-49] We have previously reported on the schedule of taxane and 
fluoropyrimidines used concurrently with radiation therapy. [13, 50-52] In this study, we are using 
paclitaxel as our preferred taxane. This combination of weekly paclitaxel and weekly carboplatin 
with radiation has become the current standard approach for this group of patients with the 
publication of the CROSS trial. [53] The proposed radiation dose of 50.4 Gy in 28 fractions is the 
national standard.  
 
2.5 
Correlative Studies Background 
Hedgehog (Hh) Signaling: Hh signaling is critical for growth and differentiation during embryonic 
development.[54] Secreted Hh molecules (Sonic [Shh], Desert [Dhh], and Indian [Ihh]) bind and 
inhibit the cell surface receptor Patched (Ptch). This inhibition relieves the Ptch-mediated 
suppression of the transmembrane protein Smoothened (Smo), leading to intracellular events that 
cause activation (i.e. proteolytic processing) and nuclear translocation of the Gli family of 
transcription factors (Gli-1, -2 and -3).[55] The three Gli proteins vary considerably. While both 
Gli-2 and -3 have transcriptional activation and repression properties,[56] Gli-1 is a strong regulator 
of Hh targets and is itself a transcriptional target of the mammalian Hh pathway.[57] Transcriptional 
targets of Gli-1 include genes implicated in cell cycle control, cell adhesion, signal transduction, 
vascularization, apoptosis, stem cell maintenance and Ptch itself.[58-60]  
The Hh pathway is involved in the maintenance of the normal stem cells and production of the 
progeny that differentiate into specialized cell lineages.[59, 60] The different Hh ligand proteins, 
Shh, Ihh, and Dhh, appear to control independent stem cell pools. In physiologic conditions, the 


2014-0966 
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24 
Hh pathway is silent in the quiescent stem cells to become activated by other signaling, notably 
the Wnt/b-catenin axis[61-63] during the regeneration processes. Once activated, the Hh pathway is 
responsible for sustained gradient-dependent proliferation and progeny differentiation.  
Alterations of the Hh Pathway in Cancer: The initial observation of Gli-1 involvement in glioma 
development[64] suggested the importance of Hh in tumorigenesis. Later, a definite link between 
the Hh pathway and cancer was established by the identification of heterozygote germline 
mutations affecting PTCH and abnormal activation of the Hh pathway in basal cell carcinoma, 
rhabdomyosarcoma, and neural tumors.[65] Several in vitro and in vivo studies suggest constitutive, 
ligand-dependent, activation of Hh signaling in cancers of the GI tract.[42, 43, 66] Most GI cancers 
lack mutations in the Hh pathway genes, suggesting pathway activation distinct from other cancers. 
Studies suggest that Hh signaling promotes cellular proliferation by opposing signals to 
physiologic growth arrest. Most of the Hh pathway effects are transcriptionally mediated by the 
Gli family through the upregulation of cell cycle regulatory targets (i.e. N-Myc, D- and E-type 
cyclins, or phosphatase CDC25B) and anti-apoptotic proteins (i.e. Bcl2).[67] Additionally, other 
transcriptional targets of Hh include growth factors and pro-angiogenic factors, such as VEGF, 
EGF, and PDGF.[68] Thus, the deregulation of Hh pathway in cancer cells can contribute to cancer 
maintenance and progression by enhancing cell cycle alterations and production of cancer growth 
factors. 
Relevance of autocrine versus paracrine Hh signaling in cancer: Several studies have concluded 
that human cancer cell lines constitutively express high levels of Hh ligands and Smo leading to 
proliferation in response to autocrine ligand-mediated receptor activation.[42, 69, 70] Recent data 
strongly suggest that autocrine pathway activation is also important for the maintenance of cancer 
stem cells.[71, 72] However, paracrine signaling between tissue epithelial cells and associated stroma 
is critically important during normal development,[73] and the notion that human cell lines depend 
on autocrine signaling for proliferation has been challenged.[74] Yauch et al. directly investigated 
the relative importance of autocrine versus paracrine signaling in determining tumor 
responsiveness to their specific Hh pathway antagonist in vitro and in vivo.[75] They concluded that 
the effects of chemical pathway antagonists on proliferation observed in the previous studies[42] 
were probably due to off-target effects of the drugs and that the responses of xenografts tracked 
more closely with disruption of tumor-stromal paracrine Hh signaling.[75] 
It seems likely to us that both conclusions are correct and that the importance of autocrine versus 
paracrine signaling is highly tumor context-dependent.  The Yauch et al.’s[75] data do not rule out 
the possibility that autocrine Hh activation is generally required for the maintenance of cancer 
stem cells (which typically represent a small percentage of cells) and could be upregulated by 
inflammation and/or stress. Our data in preclinical models and patient tumors demonstrate that Hh 
pathway components are strongly induced by exposure to chemoradiation, raising the possibility 
that conventional therapies will stimulate autocrine and/or paracrine pathway activation in EAC. 
 
3. PATIENT SELECTION 
Except as indicated below, the inclusion and exclusion criteria will be the same for Phase IB and 
Phase II parts of this trial. 
 
3.1 
Inclusion Criteria  
 
3.1.1 Histologically or cytologically confirmed adenocarcinoma of the esophagus or 


2014-0966 
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25 
gastroesophageal junction (EAC).  
 
3.1.2 Male or female patients whose age is ≥18 years (Because nonclinical studies suggest that 
TALADEGIB may adversely affect the development and maintenance of teeth, bones, and growth 
plates in a pediatric population, children are excluded from this study.  In addition, EAC is 
extremely rare in children). 
 
3.1.3 Localized EAC and its baseline clinical stage determined as: T2-T3N0 or T1-3N+. Imaging 
studies suspicious for metastases must be followed with a negative biopsy before a patient can 
enter the study. 
 
3.1.4 Patients with malignant celiac nodes are eligible if the primary lesion is in the mid-thoracic 
or distal thoracic esophagus or it is involving the gastroesophageal junction. 
 
3.1.5 Tumor must have labeling index of ≥5% of the nuclear Gli-1 (integral biomarker) 
performed in the MD Anderson Cancer Center CLIA laboratory for patient to be eligible in this 
trial (if enough archival tissue is not available to determine labeling index, patient must agree to a 
biopsy to determine eligibility for the study).  
 
3.1.6 Tumor may not extend >4 cm below the gastroesophageal junction. 
 
3.1.7 ECOG performance status 0 or 1. 
 
3.1.8 All patients must be willing to provide research tumor tissue for biomarker studies at 
baseline, from archival tumor tissue or through endoscopy if sufficient archival tumor tissue is not 
available. All patients must also allow biomarker studies on the tissue obtained through surgery to 
remove the primary cancer.  
 
3.1.9 Phase II only: Patients volunteering for the Phase II part of the protocol must be willing to 
undergo a research endoscopy for tissue collection on day 8 (+/- 2 days) from the beginning of 
therapy.  
 
3.1.10: Absolute neutrophil count ≥ 1500/mm3; Platelets ≥100,000/mm3; Hemoglobin ≥8 g/dL; 
Serum creatinine ≤ 2 x Upper Limit of Normal (ULN); ALT and AST ≤2.5 x ULN; Serum bilirubin 
≤1.5 x ULN.   
 
3.1.11 Patient must be able to comprehend the approved consent document and have the 
willingness to sign it. The patient prior to enrollment and the administration of any protocol-
specific therapy must sign the consent document. 
 
3.1.12 Willingness and ability to comply with study procedures and follow-up examinations. 
 
3.1.13 Must be considered medically fit for operation as determined by multidisciplinary 
evaluation.   
3.1.14  Effects of TALADEGIB on the developing human fetus at the recommended therapeutic 
dose are unknown.  For this reason and because Hh signal pathway inhibitors as well as other 


2014-0966 
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26 
therapeutic agents used in this trial are known to be teratogenic, males and females with 
reproductive potential must agree to use 2 forms of medically approved contraceptive precautions 
(see Appendix B) and for at least 6 months following the last dose of biochemoradiation. Should 
a woman become pregnant or suspect she is pregnant while participating in this study, she should 
inform her treating physician immediately. 
Women of childbearing potential are defined as follows:  
• Having regular menstrual cycles 
• Has amenorrhea, irregular menstrual cycles or using a contraceptive method that precludes 
withdrawal bleeding.  
• Have had a tubal ligation.  
Women are considered not to be of childbearing potential for the following reasons: 
• Had hysterectomy and/or bilateral oophorectomy. 
• Post-menopausal defined by amenorrhea for at least 1 year in a woman >45 years old. 
3.1.15 Females with childbearing potential must have a negative serum pregnancy test within 14 
days prior to treatment start.  
 
3.2 
Exclusion Criteria 
3.2.1 
Baseline clinical stage of T1N0 or inoperable T4 (unequivocal organ involvement) are 
to be excluded. 
3.2.2 
Unequivocal metastatic tumor at baseline.  
3.2.3 
Tracheo-esophageal (TE) fistula or direct invasion into the tracheo-bronchial mucosa. 
A bronchoscopy (biopsy and cytology should be performed) is required to exclude TE fistula or 
tracheo-bronchial involvement in patients with a tumor located at <26 cm from the incisors. 
3.2.4 
Cervical esophageal cancer will not be entered in this study. 
3.2.5 
Any prior chemotherapy, surgery, or radiotherapy for EAC.  
3.2.6 
Prior mediastinal irradiation (for any reason). 
3.2.7 
Clinically significant ulcerative colitis, inflammatory bowel disease, or partial or 
complete small bowel obstruction are to be excluded. 
3.2.8 
Malabsorption syndrome or other condition that would interfere with intestinal 
absorption are excluded.  
3.2.9 
Pregnant or nursing females are to be excluded. Pregnant women are excluded from 
this study because TALADEGIB is a Hh pathway-inhibiting agent with the potential for 
teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with TALADEGIB, breastfeeding 
should be discontinued if the mother is treated with TALADEGIB. These potential risks may also 
apply to other agents used in this study.  


2014-0966 
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27 
3.2.10 Presence of other significant cancer(s) or history of other significant cancer(s) within the 
last 3 years (patients who have been cancer-free for 3 years, or have a history of completely 
resected non-melanoma skin cancer or successfully treated in situ carcinoma of the cervix are 
eligible).  
3.2.11 Known active viral or other chronic types hepatitides (Hepatitis B, C) or cirrhosis. 
3.2.12 Uncontrolled concurrent illness including, but not limited to: serious uncontrolled 
infection, symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac 
arrhythmia that interfere with blood pressure, uncontrolled diabetes, or psychiatric illness/social 
situations that would limit compliance with the study requirements. 
3.2.13 
Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or 
hypokalemia defined as less than the lower limit of normal for the institution, despite adequate 
electrolyte supplementation. 
3.2.14 Patients who are receiving concurrent non-protocol anti-cancer therapy (chemotherapy, 
radiation therapy, surgery, immunotherapy, hormonal therapy, targeted therapy, biologic therapy, 
or tumor embolization) are to be excluded.  
3.2.15 
Patients may not be receiving any other investigational agents. 
3.2.16 Patients with known hypersensitivity to taxanes or platinums are to be excluded. 
3.2.17 
Patients taking medications with narrow therapeutic indices that are metabolized by 
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible. Patients on 
strong CYP3A inhibitors will also be excluded. 
3.2.18 
Known HIV-positive patients on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with TALADEGIB.  In addition, these 
patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.  
3.2.19 Any other conditions or circumstances that would, in the opinion of the Investigator, make 
the patient unsuitable for participation in the study. 
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
Patients can begin study therapy only after the pretreatment evaluation is completed and eligibility 
criteria are met. Patients are registered prior to any protocol therapy through the Clinical Oncology 
Research (CORe) system developed and maintained by the Office of Protocol Research at MD 
Anderson Cancer Center.  


2014-0966 
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28 
 
Issues that would cause treatment delays should be discussed with the Principal Investigator. If a 
patient does not receive protocol therapy following registration, the patient’s registration on the 
study may be canceled.  
 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
Treatment will be administered on an outpatient basis. All patients will need intravenous (IV) 
access established prior to the beginning of therapy. 
Reported adverse events and potential risks for TALADEGIB and weekly paclitaxel, weekly 
carboplatin, and radiation therapy are described in Section 7. Appropriate dose modifications for 
TALADEGIB and weekly paclitaxel, weekly carboplatin, radiation therapy are described in 
Section 6. 
 
5.2 
Phase I B  
The purpose of phase IB study is to establish safety of TALADEGIB with standard 
chemoradiation. The starting dose is based on summarized data (and data in communication with 
Ignyta). This starting dose has resulted in objective responses in patients with locally advanced 
and metastatic BCC and has resulted in inhibition of HH signaling as measured by Gli-1 inhibition. 
We anticipate entering 6 patients to be recruited to complete the study as follows:  
 
 


2014-0966 
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29 
Table 5A 
 
Phase 1B REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
TALADEGI
B 
No premedication.  
Can take with or 
without food. 
400 mg (fixed 
dose) 
PO in A.M. Daily for 38 days, 
starting on first 
chemoradiation day 
NA 
Paclitaxel* Decadron up to 10 mg 
i.v.,  
hydrocortisone 100 
mg i.v.,  
diphehydramine 
hydrochloride 25 mg 
i.v. 
50 mg/m2/week 
IV 
 
IV 3 hr 
First radiation day of 
each week x 5 doses 
(usually on Mondays) 
Carboplatin None 
AUC 2mg/ml/min 
IV 2hr 
First radiation day of 
each week x 5 doses 
(usually on Mondays) 
Radiation 
None 
1.8 Gy 
External Beam On 28 consecutive 
weekdays  
 
* Paclitaxel to be given before Carboplatin. 
In the event of unexpected toxicities (i.e. More than 1 DLT in the first 6 patients) in the first 6 
patients, we will study additional 6 patients but TALADEGIB 200 mg will be administered 
every day.   
 
5.3 
Definition of Dose-Limiting Toxicity 
TOXICITY 
DLT CRITERIA 
Cardiac disorders 
Cardiac toxicity CTCAE Grade ≥ 3 or cardiac event that is symptomatic 
or requires medical intervention 
Congestive heart failure Grade ≥ 2 
Vascular disorders/ 
Hypertension 
Persistent hypertension CTCAE Grade ≥ 3 requiring more than one 
drug or more intensive therapy than previously 
Skin and 
subcutaneous 
tissue disorders: 
Rash and/or 
photosensitivitya 
Rash or photosensitivity CTCAE Grade 3 for > 7 consecutive days 
despite skin toxicity treatment 
Rash or photosensitivity CTCAE Grade 4 
Metabolism and 
nutrition disorders: 
Hyperglycemia Grade 2 (FPG 200 - 249 mg/dL; 11.2 - 13.8 mmol/L) 
(confirmed with a repeat FPG within 24 hrs) that does not resolve to 
Grade 0 (< 140 mg/dL; < 7.8 mmol/L) within 14 consecutive days (after 


2014-0966 
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30 
TOXICITY 
DLT CRITERIA 
Hyperglycemiab  
   
initiation of oral anti-diabetic treatment) 
Hyperglycemia Grade 3 (FPG 250 – 399 mg/dL; 13.9 - 22.2 mmol/L) 
(confirmed with a repeat FPG within 24 hrs) for > 7 consecutive days 
despite oral anti-diabetic treatment 
Hyperglycemia Grade 4 (FPG ≥ 400 mg/dL; ≥ 22.3 mmol/L) 
Hyperglycemia leading to diabetic keto-acidosis, hospitalization for IV. 
insulin infusion, or non-ketotic coma 
GI disordersa  
 
Diarrhea CTCAE Grade ≥ 3 for ≥ 48 hrs, despite the use of anti-
diarrhea therapy 
Nausea/vomiting CTCAE Grade ≥ 3 for ≥ 48 hrs, despite the use of 
anti- emetic therapy 
Pancreatitis CTCAE Grade ≥ 3 
Investigationsc  
 
Blood total bilirubin CTCAE Grade 2 for > 7 consecutive days 
Blood total bilirubin CTCAE Grade ≥ 3 
Serum Creatine Kinase (CK) > 3 
AST or ALT CTCAE Grade 3 in conjunction with blood bilirubind   
CTCAE Grade ≥ 2 of any duration 
AST or ALT CTCAE Grade 3 for > 7 consecutive days 
AST or ALT CTCAE Grade 4 
Serum alkaline phosphatase CTCAE Grade 4 
Serum lipase and/or serum amylase (asymptomatic) CTCAE Grade 3 
> 7 consecutive days 
Serum lipase and/or serum amylase (asymptomatic) CTCAE Grade 4 
Serum creatinine CTCAE Grade ≥ 3 
Hypomagnesaemia CTCAE Grade 3 for > 3 consecutive days and not 
correctable with supplements, or symptomatic 
Hypomagnesaemia CTCAE Grade 4 
Hypokalemia CTCAE Grade 3 for > 3 consecutive days and not 
correctable with supplements, or symptomatic 
Hypokalemia CTCAE Grade 4 
Platelet count CTCAE Grade 3 for > 7 consecutive days and/or with 
signs of Bleeding 
Platelet count CTCAE Grade 4 
ANC CTCAE Grade 3 for > 7 consecutive days 
 
ANC CTCAE Grade 4 
Febrile neutropenia CTCAE Grade ≥ 3 


2014-0966 
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31 
TOXICITY 
DLT CRITERIA 
Other hematologic 
& non-hematologic 
toxicities 
Any other CTCAE Grade ≥ 3 toxicity except: 
Lymphocyte count decreased (lymphopenia) CTCAE Grade ≥ 3 unless 
clinically significant 
Grade 3 Fatigue, Dehydration, Hiccups, Dysgeusia (as these are 
cumulative toxicities seen commonly with chemoradiation, and will only 
be considered DLTs if they do not resolve with appropriate supportive 
care) 
 
a Patients will not initially receive prophylactic treatment for skin toxicity or nausea/vomiting. However, prophylactic treatment 
may be initiated in all patients at the dose level where these toxicities have been observed and in all further patients if at least 1 
patient has experienced skin toxicity or nausea/vomiting CTCAE Grade ≥3 or if at least 2 patients experienced skin toxicity or 
nausea/vomiting CTCAE Grade ≥ 2. However anti-emetics may be applied for treatment if the patient has experienced 
nausea/vomiting CTCAE Grade ≥ 1, at the discretion of the physician. 
b Not according to CTCAE v4.0. Of note: Hyperglycemia occurring during corticosteroids administration will be only considered 
DLT if not resolved within 2 days after the end of corticosteroid treatment. 
c For any hepatic toxicity CTCAE Grade 4, or CTCAE Grade 3 that does not resolve within 7 days to CTCAE Grade ≥ 1 (or 
CTCAE Grade ≥ 2 if liver infiltration with tumor present), an abdominal CT scan should be performed to assess if it is related to 
disease progression. 
 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
5.4 
Phase II 
Following completion of the Phase IB part of the study, the phase II trial will be initiated.  
The phase II trial will be performed in two sequential steps: Step 1- single agent TALADEGIB for 
7 days followed by TALADEGIB plus chemoradiation (in 27 patients) and Step 2-   TALADEGIB 
plus chemoradiation  (in 27 patients). The patients will not be randomized but rather entered 
sequentially in to step 1 until full, followed by enrollment of  27 patients in to step 2. 
 
 


2014-0966 
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32 
Table 5B 
Phase II REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
TALADEGIB No premedication.  
Can take with or 
without food. 
As determined in 
Phase Ib mg (fixed 
dose) 
PO in A.M. FOR STEP 1 ONLY. 
TALADEGIB given 
alone orally for 7 
days prior to start of 
bio-chemo radiation 
as described below. 
NA 
 
TALADEGIB No premedication.  
Can take with or 
without food. 
As determined in 
Phase Ib mg (fixed 
dose) 
PO in A.M. Step 1 and Step 2: 
Daily for 38 days, 
starting on first 
chemoradiation day 
NA 
Paclitaxel* 
Decadron up to 10 
mg i.v.,  
hydrocortisone 100 
mg i.v.,  
diphehydramine 
hydrochloride 25 mg 
i.v. 
50 mg/m2/week 
IV 
 
IV 3 hr 
First radiation day of 
each week x 5 doses 
(usually on Mondays) 
Carboplatin 
None 
AUC 2mg/ml/min 
IV 2hr 
First radiation day of 
each week x 5 doses 
(usually on Mondays) 
Radiation 
None 
1.8 Gy 
External Beam On 28 consecutive 
weekdays  
 
* Paclitaxel to be given before Carboplatin. 
The purpose of the first step is to assess pharmacodynamic changes after TALADEGIB alone but 
also after TALADEGIB plus chemoradiation. We do believe the first step will not result in a 
different pathCR rate; therefore, all patients will be assessed similarly for pathCR (including those 
treated at the MTD in phase IB cohort).  
In the Phase II part of the trial, patients will undergo a research upper endoscopy on day 8 (+/- 2 
days) from the start of treatment (either starting with TALADEGIB alone or biochemoradiation) 
to obtain pictures of the tumor for comparison with the baseline and to obtain tumor tissue for 
biomarker assessment.  The research endoscopy will be performed only if deemed safe by the 
attending endoscopist.  Standard procedures will be followed. 
Treatment with TALADEGIB alone followed by biochemoradiation: Patients in Step 1 will 
receive TALADEGIB 400 mg PO in A.M. daily for 7 days and then patient will start 
biochemoradiation therapy as described in Table 5B.  
Treatment with biochemoradiation: Patients in Step 2 will proceed with biochemoradiation therapy 
as described in section Table 5B.  
 


2014-0966 
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33 
5.5 
Treatment Information 
 
5.5.1 TALADEGIB 
 
TALADEGIB is an oral drug.  Patients should take TALADEGIB in the morning at approximately 
the same time every day, with or without food.  If a patient misses a dose, he or she should be 
instructed not to take or make up that dose and to resume dosing with the next scheduled dose.  
Missed doses should not be made up.  Patients will be instructed to bring all unused tablets and 
their medication diary to each study visit for assessment of compliance. 
 
• 
Patients will be instructed not to share their supply of TALADEGIB. 
 
5.5.2 Other Agents 
Please see section 2.3 
 
5.5.3 Radiation therapy 
 
Definition of Target Volumes 
GTV  
Gross tumor volume is all known gross disease as demonstrated on the planning CT, 
and modified as deemed necessary based on PET and other clinical studies. 
iGTV  
GTV plus margin for tumor motion.  A maximum intensity projection (MIP) of the 4D 
CT image data set will be reconstructed.  MIP images will display the maximum extent of tumor 
motion during respiration. The delineated MIP-GTV will be compared with the actual motion of 
the GTV on each of the 10 phases and modified, if necessary, to encompass the extent of motion 
of the GTV (hence iGTV).  The iGTV will be modified as deemed necessary based on PET and 
other clinical studies. 
CTV  
Clinical target volume is the subclinical involvement around the GTV. The CTV is the 
GTV plus a 30-mm margin superiorly and inferiorly. CTV for lateral margin will be individually 
drawn by the radiation oncologist, usually 8 mm laterally for microextensions of the tumor.   
ITV  
Internal target volume is the envelope of the CTV during the time of irradiation, thus 
accounting for intrafractional motion.   
PTV  
Planning target volume is ITV plus a margin to ensure that the prescribed dose is 
actually delivered to the ITV. This margin accounts for variations in treatment delivery, including 
variations in setup between treatments. The ITV is expanded by 5 mm to generate the PTV in 
accordance with our current clinical practice.  The PTV is relevant to photon planning. 
Radiation will be either photon or proton. 
 
Radiation Doses 
The total radiation dose for the tumor target will be 50.4 Gy at 1.8 Gy per fraction and a total of 
28 fractions. Radiation will be once a day, 5 fractions per week. 
100% of the ITV will be covered by the prescribed dose. Greater than or equal to 95% of the 
prescribed dose to the ITV will be acceptable if 100% cannot be reached. 
95% of PTV should receive prescribed dose. 


2014-0966 
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34 
 
Tolerance Limits for Critical Structures 
Normal lung (right lung + left lung - GTV):  V10 ≤ 40%; and mean lung dose (MLD) ≤ 20Gy.   
Brachial Plexus:  Minimum dose to 2% highest dose volume ≤ 60 GY.  Doses ≤ 66 Gy will be 
considered as minor deviation. 
Spinal cord:  Maximum dose to 2% highest dose volume ≤ 50 Gy.   
Heart:  1/3 volume must be ≤ 60 Gy, 2/3 < 45 Gy and whole volume ≤ 30 GY. 
Liver:  1/3 volume must be ≤ 35 Gy and the whole liver must be ≤ 25 Gy. 
Kidney: 1/3 of one kidney should receive < 17 Gy.  One kidney should be kept out of the radiation 
beams if possible. 
 
Simulation, Immobilization, Image-Guided Radiation 
Simulation: All simulations will be done on CT scanners capable of acquiring 4D CT image data 
sets.   
For proton planning, only CTs, which have been calibrated for protons, should be used. 
Each patient will be positioned in an immobilization device in the treatment position on a flat table. 
The imaging session will consist of acquisition of a free-breathing treatment planning CT image 
data set and a 4D CT image data set.  
The pretreatment diagnostic PET/CT should be performed together with 4-D CT simulation if at 
all possible. 
Localization image studies with the patient in the treatment position will be obtained. 
 
Treatment Planning 
Critical structures 
The normal tissues including the right lung, the left lung, the esophagus, the heart, liver, kidneys, 
brachial plexus, and the spinal cord need to be contoured in their entirety.  
The lungs are expected to be the primary dose-limiting structure. Every effort should be made to 
keep the total lung dose (defined as the volume of both lungs minus the GTV in 50% phase of 4-
D CT) to a minimum. 
The tolerance doses to various organs shown in Table 6 and 7 below are to be used as guidelines. 
Physicians/dosimetrists should make every effort not to exceed these tolerance levels. (All 
tolerance doses are assumed to be delivered at 2 Gy/fx.) 
 
 
 
 
Table 6 


2014-0966 
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35 
Incidence of radiation pneumonitis (%) 
Quartile 
GTV 
(cc) 
Mean 
Dose (Gy) 
% of 
Ipsilateral 
Lung 
Receiving >20 
Gy 
% of Total 
Lung 
Receiving >20 Gy 
Veff 
>Grade 2 
1st 
32 
20 
7 
8 
0 
2nd 
12 
21 
10 
23 
23 
3rd 
27 
25 
38 
29 
25 
4th 
27 
29 
42 
33 
45 
>Grade 3 
1st 
11 
10 
7 
8 
0 
2nd 
6 
11 
0 
0 
5 
3rd 
3 
8 
21 
19 
14 
4th 
20 
24 
25 
27 
26 
                                                                                Table 7 
Radiation Tolerance Dose 
Organ                         Volume              TD 5/5              End Point 
Spinal Cord 
5 cm 
10 cm 
20cm 
50 Gy 
50 Gy 
47 Gy 
Myelitis 
Myelitis 
Myelitis 
Heart 
1/3 
2/3 
3/3 
50 Gy 
45 Gy 
40 Gy 
Clinical Pericarditis 
Clinical Pericarditis 
Clinical Pericarditis 
Liver 
½ 
2/2 
35 Gy 
30 Gy 
Clinical Hepatitis 
Clinical Hepatitis 
Kidney 
1/3 
17 Gy 
Clinical nephritis 
 
 
Therapy Interruptions 
If interruption of therapy (up to three weeks) becomes necessary, radiation therapy should be 
completed to the prescribed doses. Total number of fractions and elapsed days should be carefully 
reported. If an interruption of more than two weeks is necessary, resumption of treatment is at the 
discretion of the radiation oncology chairs. The patient will be considered a major deviation, but 
follow-up will be continued. 
If the patient develops > grade 3 RT-related toxicity, radiation therapy and biochemotherapy 
should be withheld. Treatment can resume once grade 3 RT-related toxicity is no longer present. 
If a patient develops grade 3 esophagitis in the last week of treatment (i.e. with 5 or fewer radiation 
treatments remaining), radiation therapy (but not chemotherapy) may continue at the discretion of 
the treating physician. 
 
Criteria for Toxicity 
Acute and late toxicity related to radiation therapy include fatigue, myelosuppression, skin 
erythema, subcutaneous fibrosis, esophagitis, carditis, myelitis, acute radiation pneumonitis and 
late pulmonary fibrosis, and esophageal stricture. 


2014-0966 
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36 
Acute toxicity monitoring: Acute (<90 days from RT start) side effects of  radiation therapy will 
be documented using the revised NCI Common Toxicity Criteria, Version 4.0, which can be 
downloaded from the CTEP home page (http://ctep.info.nih.gov). 
Late toxicity monitoring: Late (>90 days since RT start or persisting beyond 90 days) post-
treatment complications will be evaluated and graded according to the RTOG Late Effects 
Radiation Morbidity Criteria (RTOG.org). 
 
5.5.4 Surgery 
All patients will be allowed to recover from biochemoradiotherapy for 5-6 weeks and then undergo 
a complete preoperative evaluation. If there is no evidence of metastatic cancer, and patient is still 
medically fit for surgery, then an operation will be attempted. 
Details of Surgery 
After adequate preoperative evaluation, patients that are judged to be physiologically capable of 
undergoing resection are viewed as having a resectable lesion, and are without evidence of 
metastatic disease (M1b) will undergo surgery.  Patients will understand the risks of surgical 
resection. A feeding jejunostomy will be put in place for postoperative nutritional support. A 
diagnostic laparoscopy with peritoneal washings examined for cytology may be appropriate for 
patients with locally advanced gastroesophageal junction tumors prior to embarking on open 
esophagectomy. 
Lymphadenectomy 
Patients will undergo esophagectomy with removal of local-regional lymph nodes. It is 
recommended that resections of distal esophageal or gastroesophageal junction tumors include 
lymph nodes at levels 7-20 according to the AJCC lymph node station chart if deemed appropriate 
under clinical circumstances.  Level 10 would be omitted unless clinically indicated. 
Patients with mid to upper thoracic esophageal lesions should also undergo paratracheal lymph 
node sampling as deemed appropriate based on the level of the lesion and surrounding regional 
lymph nodes.  Sampling of level 1, supraclavicular lymph nodes is recommended when clinically 
indicated.  
Reconstruction 
Reconstruction will be completed in the chest or neck using stomach, small bowel, or colon as a 
conduit to re-establish gastrointestinal continuity.  
Approach to the resection may be via transthoracic, transhiatal, three-field, or minimally invasive 
technique.  The recommendations for surgical technique will depend upon the location of the lesion 
and surgeon/patient preference. 
Description of Surgical Techniques and Risks 
Transthoracic 
Patients who undergo transthoracic esophagectomy will have incisions in the abdomen and chest. 
Recommended lymphadenectomy and feeding jejunostomy will be performed during the 
abdominal portion of the procedure. Thoracotomy will be performed for mobilization of the 
esophagus and intrathoracic lymph node sampling.  A proximal and distal resection margin of 


2014-0966 
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37 
>4cm is preferable, and pleural/pericardial resection may be required to obtain negative radial 
margins. Gastrointestinal continuity will be re-established in the chest with the chosen conduit.  
Transhiatal 
Patients will undergo esophagectomy similar to the technique described above though lacking a 
thoracic incision. The esophagus and intrathoracic lymph nodes are removed through incisions in 
the abdomen and neck.  Reconstruction will be performed in the neck via the cervical incision.  
Three-field Approach 
A more extensive procedure that is recommended when an extensive lymph node dissection is 
desired or when greater exposure is required to complete the resection of the primary tumor with 
adequate proximal margins.  The reconstruction is performed in the neck.  Incisions are performed 
in the neck, chest and abdomen.  
Minimally Invasive Esophagectomy 
Surgeons may recommend a minimally invasive approach to esophageal resection.  This involves 
laparoscopy and possible thoracoscopy to achieve removal of the esophagus and reconstruction. 
Additionally, an incision in the left neck may be made to complete the pull-up procedure.  
Internally the operation is equivalent to the standard, open procedure, a lymph node dissection is 
recommended and the stomach is used to reconstruct gastrointestinal continuity.  The risks of the 
procedure are similar to a standard esophagectomy with the additional risk or understanding that 
a minimally invasive procedure may have to be converted to an open technique in certain 
circumstances.  Typically there is also an increase in operative time. 
Risks 
Risks of the procedure include but are not limited to: bleeding, internal or external wound 
healing complications (i.e. infection, hernia), pneumonia, cardiac arrhythmia, swallowing 
dysfunction, aspiration, hoarseness (temporary or permanent), gastrointestinal dysfunction 
(dumping, nausea, regurgitation, dysmotility, stricture, anorexia, weight loss, abdominal pain, 
reflux), anastomotic leak, graft loss, need for re-operation (acute or remedial), pain, and sepsis. 
The operation carries approximately a 4% risk of mortality within the operative and immediate 
(30 days) post-operative period. 
 
 
5.6 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of TALADEGIB with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies.  The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with the potential 
to affect selected CYP450 isoenzymes. In addition, patients and their caregivers should be 
provided the patient information sheet (see Appendix C) describing potential interactions of 
TALADEGIB with other drugs and other remedies and medications.  
 
 
 


2014-0966 
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5.6.1  
TALADEGIB 
 
• TALADEGIB and its major metabolite, LSN3185556 have both been evaluated for 
inhibition of CYP enzymes.  The table below shows the results of the in vitro interaction 
studies.  The CYP3A enzyme is predicted to be the enzyme most sensitive to inhibition by 
both compounds, where inhibition constant (Ki) values were 15 and 11 µM for 
TALADEGIB and LSN3185556, respectively.   
• A substrate depletion approach with recombinant human CYPs predicted that CYP3A4 
was the primary enzyme responsible for hepatic CYP-mediated clearance of both 
TALADEGIB and LSN3185556.  Thus strong CYP3A4 inhibitors should be excluded 
when co-administering TALADEGIB. 
 
Inhibition of the Catalytic Activities of CYP Enzymes by TALADEGIB and LSN3185556 in 
Human Liver Microsomes 
Isoform 
TALADEGIB  
Ki or IC50 (µM) 
LSN3185556 
Ki or IC50 (µM) 
CYP3A (midazolam) 
15 
11 
CYP2D6 
99 
53 
CYP2C19 
18 
31 
CYP2C9 
22 
14 
CYP2C8 
29 
11 
CYP2B6 
17 
41 
CYP1A2 
(>200) 
(>200) 
Abbreviations:  CYP = cytochrome P450; IC50 = half-maximal inhibitory concentration; Ki = inhibition binding 
constant. 
Use of medications or food that may interfere with the metabolism of TALADEGIB is 
prohibited, including ketoconazole and fresh-squeezed grapefruit juice. 
 
 
5.7 
Duration of Therapy 
 
The duration of biochemoradiation therapy for the Phase IB part will be 5.5 weeks (chemotherapy 
for 25 days, TALADEGIB for 38 days, and radiation for 28 days in 28 fractions). The duration of 
therapy in the Phase II Step 1 will be 45 days (TALADEGIB for 45 days, radiation for 28 days, 
and chemotherapy for 25 days). In Phase II Step 2 it will be 38 days (chemotherapy for 25 days, 
TALADEGIB for 38 days, and radiation for 28 days in 28 fractions). 
Therapy may be discontinued under the following circumstances: 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse events(s), 
• Patient decides to withdraw from the study, or 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 


2014-0966 
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5.8 
Duration of Follow Up 
For the purpose of assessing toxicity in phase IB, all patients will be seen in the clinic weekly, 
continuing for two weeks after the completion of biochemoradiation. Phase II patients will also be 
monitored closely in the first two weeks after the completion of biochemoradiation but will not be 
necessarily seen in the clinic. Patients will be telephone-interviewed weekly and seen if necessary. 
The information acquired during the interview will be documented in writing.  
Upon completion of the above evaluations, patients will be followed for 6 months after the 30 day 
safety evaluation or until death, whichever occurs first. Patients removed from the study for 
adverse events will be followed until resolution or stabilization of the adverse event. 
 
5.9 
Criteria for Removal from Treatment 
Patients will be removed from treatment when any of the criteria listed in Section 5.7 and the 
reason(s) will be documented in patients’ medical record.  
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
Dose modification during biochemoradiation: 
TALADEGIB: We do not anticipate any additional side effects in patients receiving the 
recommended 400 mg/day dose. However, if a DLT TALADEGIB-related toxicity during 
biochemoradiation is observed, then TALADEGIB will be administered every day at half the 
starting dose (200mg).  
Carboplatin and Paclitaxel:  Potential toxicities during chemoradiation include nausea, loss of 
appetite, vomiting, malaise, mucositis, hand-foot syndrome, dehydration, fatigue, and rarely 
myelosuppression and mild neuropathy. The following criteria will be used for modification of 
dose of carboplatin and paclitaxel.  
 
   Table 8 
Reaction 
Management of reactions 
 
Renal: 
 
Creatinine ≤ 1.5 × upper limit of normal 
at day of treatment 
Continue treatment 
Creatinine > 1.5 × upper limit of normal 
Establish intravenous infusion the evening preceding treatment  
at a rate to correct any volume deficits and produce a urine flow ≥ ml/h.  
Repeat serum creatinine value in the morning: 
 
≤ 1.5 × upper limit of normal → proceed treatment 
 
> 1.5 × upper limit of normal → stop chemotherapy, can re-start as 
clinically indicated 
 
Gastrointestinal: 
 
Mucositis with oral ulcers or protracted 
vomiting 
despite 
antiemetic 
premedication 
Delay chemotherapy one week 
 


2014-0966 
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40 
Neurologic: 
 
CTC grade ≤ 2 
Continue therapy 
CTC grade > 2 
Stop chemotherapy, can re-start when resolved to 1 or less as clinically 
indicated 
 
Cardiac: 
 
Asymptomatic bradycardia  
Cardiology Consult: Continue therapy under continuous cardiac 
monitoring by cardiologist 
First degree AV block 
Cardiology Consult: Continue therapy under continuous cardiac 
monitoring by cardiologist 
Symptomatic arrhythmia or AV block 
(except 1st degree) or other heart blocks 
Stop chemotherapy, manage arrhythmia according to standard practice;  
patient goes off protocol 
*Does not apply to alopecia, or grade 3 nausea and vomiting (if not adequately treated).  
 
Patients requiring pre-emptive outpatient hydration will not be subjected to automatic dose 
modification. 
                                                            Table 9 
 
 
 
 
 
 
 
 
 
 
 
Hypersensitivity reactions to Carboplatin 
 
Carboplatin, as is the case with all platins, is associated with a low incidence of hypersensitivity 
reactions, usually after multiple doses. This can be manifest as bronchospasm, hypotension, and 
even hemolytic anemia. 
. Cases of hypotension have been reported in spite of the use of glucocorticoids and antihistamine 
prophylaxis.  The following treatment recommendations should be followed:  Following a Grade 
1 or 2 acute hypersensitivity reaction that is assessed as related to Carboplatin administration, the 
following premedication should be administered prior to each subsequent dose of Carboplatin 
(patients who have grade 3 or 4 acute hypersensitivity reactions should discontinue Carboplatin  
therapy): Dexamethasone 20 mg PO or IV, 12 and 6 hours prior to the dose; Dexamethasone 20 
mg PO or IV, as well as diphenhydramine 50 mg IV, and one of the following: cimetidine 300 mg 
IV, ranitidine 50 mg IV, or famotidine 20 mg IV 30-60 minutes prior to Carboplatin administration.  
 
Radiotherapy:  See section 5.5.3 
 
 
Granulocyte Nadir 
 
Platelet Nadir 
Dose Modification 
>1,000 
And 
>75,000 
No Change 
≥500 but <1000 
And/Or 
≥50,000 but 
<75,000 
No Change 
<500 
And/Or 
<50,000 
Hold weekly doses until the granulocyte count 
is >1,000 and platelet count is >100,000 then 
resume  
Infection or bleeding 
directly related to 
myelosuppression 
 
 
Hold weekly doses until the granulocyte count 
is >1,000 and platelet count is >100,000 and 
the infection has resolved then resume  


2014-0966 
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41 
7. SAFETY MONITORING AND REPORTING  
Protocol specific data and adverse events will be documented in the medical record and entered 
into the MD Anderson PDMS/CORe system. PDMS/CORe will be used as the electronic case 
report form (CRF) for this protocol. 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all subjects 
enrolled on the trial. 
 
7.1 
Adverse Events  
Definitions and reporting 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the CRF Medical History. Adverse event monitoring should be continued for at least 
30 days following the last dose of biochemoradiation.  Adverse events (including lab abnormalities 
that constitute AEs) should be described using a diagnosis whenever possible, rather than 
individual underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign 
or symptom should be reported as a separate Adverse Event.  Abnormal laboratory values or test 
results constitute adverse events only if they induce clinical signs, symptoms or require therapy 
and are recorded as clinically significant by the physician.   
The occurrence of adverse events should be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by the 
patient during or between visits or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity Grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates or if continuing at the Safety Follow-up Visit) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)  
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, hospitalized, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Outcome 
(not 
recovered/not 
resolved, 
recovered/resolved, 
recovering/resolving, 
recovered/resolved with Sequelae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 7.2 
All adverse events should be treated appropriately. Such treatment may include changes in study 
treatment including possible interruption or discontinuation, starting or stopping concomitant 
treatments, changes in the frequency or nature of assessments, hospitalization, or any other 


2014-0966 
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42 
medically required intervention. Once an adverse event is detected, it should be followed until its 
resolution, and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to treat 
it, and the outcome. 
Information about common side effects already known about the study treatment can be found in 
the protocol and TALADEGIB Investigators’ Brochure. This information should be included in 
the patient informed consent and should be discussed with the patient during the study as needed. 
 
7.2 
Serious Adverse Events  
 
Definition of Serious Adverse Event (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, in 
the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe form, 
might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• A congenital anomaly/birth defect. 
 
 
Important medical events that may not result in death, be life threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
 
• Important medical events as defined above may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Sponsor, IND Office. 
 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”. Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the 
IND Office, regardless of attribution (within 5 working days of knowledge of the event). 
 


2014-0966 
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43 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event 
to the Safety Project Manager in the IND Office. 
 
• The MD Anderson electronic SAE application (eSAE) will be utilized for safety reporting to 
the IND Office and MDACC IRB.  
 
• Serious adverse events will be captured from the time of the patient signs consent until 30 days 
after the last dose of biochemoradiotherapy.  Serious adverse events must be followed until 
clinical recovery is complete and laboratory tests have returned to baseline, progression of the 
event has stabilized, or there has been acceptable resolution of the event. 
 
• Additionally, any serious adverse events that occur after the 30 day time period that are related 
to the study treatment must be reported to the IND Office. This may include the development 
of a secondary malignancy. 
 
• Events not considered to be serious are hospitalizations for the: 
 
o Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition. 
o Treatment which was elective or pre-planned, for existing condition that did not 
worsen. 
 
Reporting to FDA 
 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
 
• It is the responsibility of the PI and the research team to ensure that serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
 
7.3 
Communications between Investigator and Ignyta 
 
Reporting responsibility: The principal investigator has the obligation to report all serious adverse 
events to Ignyta.   
The investigator will submit a copy of the MD Anderson SAE form to Ignyta at the same time the 
form is submitted to the MD Anderson IND office.  Follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, and whether the patient 
continued or discontinued study participation.  
Pregnancies: Any pregnancy that occurs during study participation and for up to 6 months from 
the patients last dose must be reported. To ensure patient safety each pregnancy must be reported 


2014-0966 
June 27, 2017 
44 
to Ignyta within 24 hours of learning of its occurrence. The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of birth, and the 
presence or absence of any birth defects, congenital abnormalities or maternal and newborn 
complications. 
 
In addition, each pregnancy occurring for a female partner of a male study participant must be 
reported while the patient is on study treatment and for up to 6 months after the patient’s last dose.  
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
 
7.4 
Adverse Event List(s) for TALADEGIB  
 
Table 10 Adverse Drug Reactions Occurring in ≥10% of Patients in Study HHBB (N=58) 
Event 
All Grades (%)  
Grade >3  
Dysgeusia 
46.2 
2.2 
 
Fatigue 
44.1 
4.3 
Nausea 
43.0 
2.2 
Muscle spasms (including 1 report of tetany) 
37.6 
5.4 
Decreased appetite (including 3 reports of early 
satiety) 
33.3 
0.0 
Alopecia 
32.3 
 
0.0 
Vomiting 
30.1 
2.2 
Decreased Weight 
25.8 
1.1 
Myalgia 
18.3 
2.2 
Diarrhea 
18.3 
2.2 
Rash (including rash maculopapular, dermatitis 
acneiform, and urticarial) 
16.1 
1.1 
Asthenia 
10.8 
2.2 
Constipation 
11.8 
0.0 
Patients will be only counted once in each preferred term but may be counted in more 
than one preferred term. 


2014-0966 
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45 
Sources: Home / lillyce / prd / ly2940680 /integrations / programs_stat / tfl_output / hhbb_smdrad12.rtf; Home / 
lillyce / prd / ly2940680 /integrations / programs_stat / tfl_output / hhbb_lspaed1.rtf 
 
Table 10 Adverse Drug Reactions Occurring in ≥10% of Patients in Study HHBB (N=58) 
 
 
All Grades (%)  
Grade 3 and Above (%) 
Fatigue 
 
41.4 
 
5.2 
Dysgeusia 
 
41.4 
 
3.4 
Nausea 
 
39.7 
 
3.4 
Vomiting 
 
31.0 
 
3.4 
Decreased appetite (including 1 report of early satiety) 
31.0 
0.0 
Muscle spasms (including 1 report of tetany) 
 
27.8 
 
3.4 
Alopecia 
 
20.7 
 
0.0 
Diarrhea 
 
15.5 
 
1.7 
Asthenia 
 
13.8 
 
3.4 
Myalgia 
 
13.8 
 
1.7 
Decreased weight 
 
10.3 
 
1.7 
Rash (including rash maculopapular, dermatitis, and urticarial) 17.2 
1.7 
Sources: 
home/lillyce/prd/ly2940680/integrations/araug2013/programs_stat/tfl_output/smdrad12.rtf; 
home/lillyce/prd/ly2940680/integrations/araug2013/programs_stat/tfl_output / hhbb_lspaed1.rtf. 
 
7.5 
Adverse Event List(s) for paclitaxel and carboplatin 
 
Please refer to the package inserts for the comprehensive list of adverse events. The following 
are commonly listed adverse events:  
 


2014-0966 
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46 
                                                                           Table 11 
Organ system 
Adverse Event 
Dermatology/Skin 
XRT Dermatitis (chemoradiation-induced) 
Rash 
Gastrointestinal 
Dehydration 
Anorexia 
Esophagitis 
Diarrhea 
Constipation 
Nausea 
Vomiting 
Dyspepsia 
Mucositis/Stomatitis 
Dysphasia 
Weight loss 
Pain 
Odynophagia 
Abdominal Pain 
Substernal chest pain 
Constitutional 
Fatigue 
Insomnia 
Fever 
Pulmonary 
Dyspnea 
Pneumonitis/pulmonary infiltrates  
Hiccups 
 
Blood/Bone Marrow 
Anemia 
Leukopenia 
Granulocytopenia 
Thrombocytopenia 
Infection 
Febrile Neutropenia 
Infection 
Infection with normal neutrophil count 
Metabolic 
Hypokalemia 
Hypomagnesemia 
 
7.6 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 N/A 


2014-0966 
June 27, 2017 
47 
 
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting. 
However, they still must be reported through the routine reporting mechanism: 
 
                                                                         Table 12 
 
CTCAE 
Category 
Adverse Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
 
Fatigue 
3 or4 
Yes/No 
Chemoradiation 
This is a cumulative 
toxicity seen in 
some patients in the 
last 10 days of 
therapy and it fully 
reversible. 
 
Dehydration 
3 or 4 
No 
Chemoradiation 
Oral intake 
decreases in patients 
in the last 2 weeks 
of chemoradiation. 
Outpatient hydration 
is often needed 
 
Hiccups 
3 or 4 
No 
Chemoradiation 
In less than 5% of 
patients, intractable 
hiccups occur as a 
result of cumulative 
effects of 
chemoradiation. 
 
7.7 
Data Confidentiality Plan 
 
The Principal Investigator (PI) and study team will guard against any loss of confidentiality. 
Information about study participants will be kept confidential and managed under applicable 
laws, regulations and institutional requirements. The PI and all members of the research team 
have received training about maintaining confidentiality and safeguarding data. Study data will 
be stored on MD Anderson systems. These systems are secured by password protection, provide 
audit trails, and are backed up daily. Access to the systems are controlled by a sequence of 
individually assigned user identification codes and passwords, made available only to authorized 
personnel.  
 
Study summary results will be provided to the National Cancer Institute in yearly reports. Study 
summary results will be provided to Ignytain quarterly reports and a final report upon study 
completion. No protected health information (PHI) will be included in these reports.  
 
Only the principal investigator, study team, and other authorized entities identified in the IRB 
approved Consent/Authorization form will have access to view study PHI at MD Anderson.  
 
Serious Adverse Event and pregnancy reports will be sent to Ignyta. These reports will use 
participants’ protocol identification numbers, not names. 


2014-0966 
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48 
 
8. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
8.1 
Biomarker Studies 
Biomarker studies will be conducted in both phase Ib and phase II studies with the objectives to 
(1) confirm that TALADEGIB “hits” its target and produces the desired biological effects 
(apoptosis and/or growth inhibition) in tumors and (2) determine whether baseline autocrine and/or 
paracrine Hh pathway activation predicts clinical response to TALADEGIB. We will assess 
downregulation of Gli-1 and other ligand-dependent Gli-1 targets in post-treatment tissues, using 
the information obtained in Aims 1 and 2 to identify these markers. We will also use 
immunofluorescent TUNEL staining and laser scanning cytometry to compare pre- and post-
treatment apoptosis levels as a pharmacodynamic measure of biological response using methods 
we have published previously.[76]  
Expression studies: (1) We will conduct a pre- and post-treatment read-out of the pathway in EAC 
biopsies by determining the expression of Shh, Ih, Gli1 and Gli2, Patch 2 and sFRP1 mRNA using 
real-time qPCR. Endpoints: the primary end-points are to correlate the modulation of Hh signaling 
with therapy (single agent TALADEGIB and in combinations with CTXRT) and with clinical 
response. Secondary endpoint includes correlations with clinico-pathological variables.  
(2) We will use gene expression data to refine and expand the pathway-associated markers listed 
in item #1 above and attempt to predict sensitivity or/and resistance to therapy in pre-treatment 
EAC biopsies using real-time qPCR.  
(3) We will examine the levels and spatial localization of Shh, Ihh and Gli-1 using quantitative 
IHC in pre- and post-treatment cancer biopsies. Endpoints: to examine the spatial localization of 
these proteins, i.e. cancer cells vs. stromal component and to correlate the results to the Hh read-
out mRNA expression profile by real-time qPCR.  
(4) We will use fluorescent TUNEL and laser scanning cytometry (LSC) to measure levels of 
apoptosis in pre- and post-treatment biopsies as a measure of biological response.  Biological 
response will be correlated with measures of Hh pathway inhibition and clinical response.  
Mutation studies: Several in vitro and in vivo studies suggest a constitutive, ligand-dependent, 
activation of Hh signaling in cancers of the digestive tract without mutations in the pathway genes. 
To date, there are no systematic studies of the Hh genetic landscape is EAC. Thus, it cannot be 
excluded that ligand or Gli overexpressions, found in our own preliminary data, may be associated 
with genetic defects such as an increase copy numbers of their respective genes. This is a plausible 
hypothesis to be investigated in view of the reported gene amplification frequency at 7q36 and 
12q13.2 chromosomal regions that are the locations for Shh and Gli-1 genes, respectively. 
Therefore, this is a unique opportunity to characterize the mutational and expression status of Hh 
pathway and correlate it to TALADEGIB clinical activity. We will assess: (1) Shh, Ihh, and Gli1 
gene copy numbers using real-time qPCR; (2) PTCH1 loss of heterozygosity by multiplex capillary 
electrophoresis; (3) PTCH1, SMO and SUFU mutational analysis by gene sequencing in cancer 
specimens demonstrating Hh activation in the expression studies.  Assessment of proteins 
expression will be performed using IHC techniques as previously described by our group.[21, 32, 34-
36, 77-81] or others. 
 


2014-0966 
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49 
In consenting patients, residual tissue will be stored for potential future use after obtaining IRB 
approval.  
 
 


2014-0966 
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50 
 
9. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  
Table 13 
 
Clinical Assessments 
Within 14 
days of 
Registration 
Within 30 
days of 
Registration 
Day 1 
Day 
8 
Every 2 
weeks 
during 
therapy 
5-6 Weeks after 
completion of Bio-
chemoradiationµ 
Informed Consent 
X 
 
 
 
 
 
Gli-1 Testing 
 
X 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
Medical and Surgical 
History 
X 
 
 
 
X 
X 
Recording of Concurrent 
Illnesses 
X 
 
 
 
 
X 
Disease History/ TNM 
Staging* 
X 
 
 
 
 
X 
Height (screening only), 
Weight, and Vital Signs 
X 
 
 
 
X 
X 
BSA 
X 
 
 
 
X 
X 
ECOG Performance Status 
X 
 
 
 
 
X 
Electrocardiogram (12-lead) 
 
X 
 
 
 
 
EGD, EUS, biopsies, and 
photographs 
 
X 
 
 
 
X 
Review inclusion/ exclusion 
criteria 
X 
 
 
 
 
 
Physical Exam&& 
X 
 
 
 
X 
X 
Concomitant Medications 
(within 7 days) 
X 
 
 
 
X 
X 
Tumor Imaging (CTs and/or 
PET-CT**) 
 
X 
 
 
 
X 
Assess toxic effects& 
 
 
 
 
X&& 
X 
Research EGD, Biopsies, 
Photos (during phase II) 
X 
 
 
X 
 
 
Hematology (CBC, 
differential) 
X 
 
Weekly during 
therapy 
 
 
X 
Serum Chemistry Panel 
(sodium, potassium, , BUN, 
Cr, Calcium, Magnesium, 
ALT, AST, ALP, Total 
Bilirubin,creatinine 
phosphokinase (CPK)), 
Amylase, Lipase, glucose 
X 
 
Every 1 week 
during 
biochemotherapy  
 
 
X 
Serum Pregnancy Test@@ 
X 
 
 
 
 
 
Relapse-free survival and 
overall survival 
 
 
 
 
 
X## 
 


2014-0966 
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51 
 
 
 
Note:  All assessments should be performed within ± 3 days, unless otherwise specified.  On treatment 
days, all assessments should be performed prior to dosing, unless otherwise specified.   
* TNM clinical baseline staging will be determined by EGD, EUS, CTs, and PET-CT 
** PET-CT will be obtained whenever possible, if not possible and CT is done if there is a clinical 
indication/question that can be answered by PET/CT this will be allowed in addition to CT. 
& Adverse event reporting will be a continuous process 
µ Surgical resection will be performed approximately 6-8 weeks from the end of biochemoradiation. If a 
delay in operation occurs, the reason(s) will be noted.  
&&In phase IB, all patients will be seen in the clinic weekly, including having a physical exam, continuing 
for two weeks after the completion of biochemoradiation. Phase II patients will have a physical exam every 
2 weeks and will also be monitored closely in the first two weeks after the completion of biochemoradiation 
but will not be necessarily seen in the clinic. Patients will be telephone-interviewed weekly and seen if 
necessary. 
@@ In women with childbearing potential, serum pregnancy test will be performed within 14 days prior 
to the first dose of TALADEGIB. A serum pregnancy test will be administered every 4 weeks if their 
menstrual cycles are regular or every 2 weeks if their cycles are irregular while on biochemoradiation within 
the 24-hour period prior to the administration of TALADEGIB.  
## All patients will be followed for relapse-free survival and overall survival. Patients who continue to 
surgery will be followed as per Table 14. Other patients will be followed every 3 months starting 5-6 weeks 
after completion of biochemoradiation. Patient who no longer return to MD Anderson will be contacted by 
phone.  
Table 14   Follow Up Tests and Observations After Surgery 
 
Item 
At 3 months 
Every 3-6 
months in 
Year 1 
After year 1 
Every 6 months x 
4 
At years 4 
and 5 
History and physical 
Yes 
Yes 
Yes 
Yes 
CT scan or 
PET/CT* 
Yes 
Yes 
Yes 
Yes 
EGD/EUS/Bx 
Yes (with or 
without EUS) 
No 
As needed 
No 
CBC, diff 
Yes 
Yes 
Yes 
Yes 
Serum chemistries, 
Na, K, Ca, Mg, 
BUN, Cr, AST, 
ALT, ALP, Total 
Bilirubin 
Yes 
Yes 
Yes 
Yes 
PS 
Yes 
Yes 
Yes 
Yes 
* PET can be replaced by CTs if it is not approved. If a dedicated CT Chest/Abdomen 
is needed at  the 3 month visit in addition to the PET/CT it is allowed and left at the 
discretion of the treating physician. 
 
 


2014-0966 
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52 
10. MEASUREMENT OF EFFECT 
 
Although we propose to study adenocarcinoma of the esophagus and gastroesophageal junction in 
this protocol, the selected patient population will have only endoscopically assessable cancers 
(sometime, CTs or EUS can visualize lymph nodes). Endoscopic evaluation to assess objective 
response is not advised and standard criteria are lacking. Therefore, we will not use standard 
approach (RECIST) to assess response.  
“Response” assessment is not the primary objective of this study. In the phase II part of the 
protocol, we will have an opportunity to endoscopically view the cancer in every patient. We plan 
to digitally record the size and shape of cancer serially (baseline, during therapy, and at the end of 
the recovery from biochemoradiation). No claims will be made from these observational studies. 
Only highly experienced gastroenterologists will participate in this study.  
An example of digital photographs of an adenocarcinoma of the esophagus at baseline and 


2014-0966 
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53 
following therapy is provided above (top picture shows tumor before any therapy and bottom 
picture shows no tumor after chemoradiation).  
The RECIST criteria do not apply.  
 
10.1 
Antitumor Effect – Solid Tumors 
 
RECIST will not be applied to this study except in the event of progression during therapy. 
 
10.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with TALADEGIB. 
 
Evaluable for objective response. N/A 
 
Evaluable Non-Target Disease Response. N/A 
 
10.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.   
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 


2014-0966 
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54 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
10.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.  
 
Conventional CT and MRI This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 


2014-0966 
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55 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements. 
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, however, that 
the PET portion of the CT introduces additional data which may bias an investigator if it 
is not routinely or serially performed.   
 
Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement. Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation 
is not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 


2014-0966 
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56 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
10.1.4 Response Criteria 
 
10.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one 
or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 


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increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
10.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
10.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
 
 


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58 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
10.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 


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The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
 
10.1.6 Progression-Free Survival N/A 
 
10.2 
Other Response Parameters 
The surgical specimen will graded as pathCR or <pathCR based on a number of criteria 
previously described.[15, 27]In short, pathCR will be designated if there is not histologic evidence 
of residual cancer cell in the resected specimen (includes lymph nodes). <pathCR will be 
designated if cancer cells are found in the resected specimen (includes nodes).  
 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design/Endpoints 
The primary objective of the phase IB part of the study is to assess the safety of TALADEGIB 
when used in combination with paclitaxel and carboplatin and radiation therapy. Up to 12 patients 
will be enrolled in this phase of the study. Initially, 6 patients will receive TALADEGIB at 400 
mg/day for 38 days. If </=  1/6 patients develop dose-limiting toxicities (DLTs) (DLT period is 
from the start of TALADEGIB to 5 weeks after the completion of biochemoradiation) that are 
deemed to be associated with TALADEGIB, then the current dose/schedule combination of 
TALADEGIB (i.e., 400 mg/day for 38 days) is considered safe and will be used in phase II part of 
the study. Otherwise, if more than 1 DLT occurs in the first 6 patients, an additional cohort of 6 
patients will receive TALADEGIB at 200 mg every day for 38 days. If this dose/schedule 
combination is established to be safe (i.e., with </= 1/6 DLTs), then this dose/schedule 
combination will be used in phase II part.  
 
Phase II Design  
The primary objective of the phase II part of the study is to assess the efficacy of TALADEGIB 
when used in combination with paclitaxel, carboplatin and radiation therapy. This phase will be 
conducted in 2 steps- first step will include treating 27 patients with TALADEGIB alone for 7 
days (with a pre- and post- TALADEGIB endoscopic biopsy of EAC (7-10 days after the start of 
TALADEGIB but before starting chemoradiation); followed by administration of 
biochemoradiation (TALADEGIB, paclitaxel, carboplatin, radiation) and surgery. The second 
step will recruit additional 27 patients to undergo biochemoradiation and surgery.  
 
The primary endpoint for the phase II part of the study is the pathologic complete response 
(pathCR) rate and a pathCR rate of at least 35% (>/= 40% is desirable) will be of interest. 
However, it is uncertain whether or not the additional 7-day treatment with TALADEGIB will 
increase the pathCR rate, relative to using biochemoradiotherapy only. Therefore, our primary 
goal here is not to compare between the two treatment steps, rather, we would like to estimate 
the pathCR rate in the TALADEGIB + biochemoradiotherapy step, using the 


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biochemoradiotherapy only step as a reference. With 27 patients per step and assuming that 10% 
of patients will not go to surgery, this will result in 24 patients per step that will undergo surgery.  
Assuming a pathCR rate of 35%, the half-width of the two-sided 95% confidence interval will be 
0.191 given a sample size of 24.  
 
For each treatment step, the Bayesian method of Thall and Simon[82] will be employed to perform 
interim safety monitoring. Denote θT as the probability of toxicity and assuming a non-informative 
beta(1,1) prior for θT, we will stop a step if, at any time during the study, we determine that there 
is more than 95% chance that the posterior probability of toxicity is more than 33%. Specifically, 
our interim monitoring rule for toxicity is: Pr[θT > 33% | data] > 0.95. The stopping boundaries 
corresponding to the above monitoring rule are to terminate a step if (# patients with toxicities) / 
(# patients evaluated) ≥  4/5, 5/7, 6/9, 7/11, 8/13, 9/16, 10/18, 11/20, 12/23, 13/25.  
 
The operating characteristics of this stopping rule are illustrated in Table 15.  
 
Table 15. Operating characteristics of the Bayesian stopping rule for toxicity.  
 
True toxicity 
probability  
Early 
stopping 
probability 
Achieved sample size 
25th, 50th, 75th percentiles 
0.1 
0.002 
27 
27 
27 
0.2 
0.025 
27 
27 
27 
0.3 
0.136 
27 
27 
27 
0.4 
0.402 
12 
27 
27 
0.5 
 0.740 
6 
12 
27 
 
All patients (up to 12 in phase I and 54 in phase II) will be enrolled from MDACC, at an accrual 
rate of 1-2 patients per month. The PI and his team monitor this single arm study. For phase I part, 
the safety data will be summarized using frequencies and percentages by adverse event (AE) 
category, grade and attributions. For phase II part, the pathCR rate in each of the treatment steps 
will be estimated, along with the 95% confidence interval. 
 
Biomarker Studies: Several exploratory biomarkers will be studied. These will include potential 
biomarkers of primary and secondary resistance. For both the phase IB and phase II parts of the 
study, tissue samples will be collected and biomarker expression levels will be assessed at baseline 
and at the time of surgery. In addition, for phase II part of the study, patients will undergo a 
research endoscopy  (RE) on day 8 (+/- 2 days) from the start of treatment. A linear mixed effect 
model will be fit to assess the change of biomarkers over time, which takes into consideration of 
the association among multiple marker observations from the same patient. The outcome variable 
will be biomarker expression level and the covariates will include time, treatment step and time by 
treatment interaction. The biomarker expression may be log-transformed prior to fit the model in 
order to satisfy the normality assumption. Also, we will fit a logistic regression model for the 
binary outcome of pathCR, using treatment step, baseline biomarker and the change of biomarker 
between baseline and at surgery as covariates. The interaction effect between time and biomarker 
(either baseline expression or the change of biomarker expression over time) will also be assessed 
when we fit the model.  The biomarkers include expression of Shh, Ih, Gli1, and Gli2, Patch 2 and 
sFRP1 mRNA using real-time qPCR as well as refined and expand the pathway-associated markers 


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using gene expression signatures obtained from Aims 1 and 2.  The refined gene signature list, 
(most likely ~100 genes) obtained from Aims 1 and 2, will be assayed using Low Density Gene 
Expression Custom Array (Micro Fluidic Card) which has the capacity to accommodate at most 
100 genes. Custom tools have been developed at the Ohio State University Comprehensive Cancer 
Center by Dr. Kevin Coombes (a consultant for this SPORE) and will be used to analyze the data. 
 
To study the correlation between biomarkers and the overall response (pathCR), we propose the 
following validation procedure. Specifically, we will integrate the observed biomarker 
measurements and patients’ responses to form a combined data set. We will perform a leave-one-
out cross validation (LOOCV) using this data set. In each iteration of the LOOCV, we will first 
remove one patient’s response and biomarker measurements (denoted as the testing set), and use 
the measurements from the remaining patients (denoted as the training set) to train a logistic 
regression. Specifically, we will regress the binary responses from the training set on the 
corresponding biomarker measurements. Applying a step-wise variable selection in the logistic 
regression, we will select potentially predictive biomarkers for validation. This could be done in 
SAS, Splus, or other standard statistical software. We will estimate the regression coefficients after 
the final set of biomarkers is selected. Using the logit score based on the fitted logistic regression, 
we will develop a univariate prognostic index (a value between 0 and 1). We will compute the 
prognostic index for the patient in the testing set by plugging in their biomarker measurements. 
We will predict that the patient will respond to the treatment if the prognostic index is greater a 
predetermined threshold p0 between 0 and 1. Going through the LOOCV with a different patient 
removed at a time, we will compute the sensitivity and specificity of the prediction model. By 
varying p0 between 0 and 1 and, we will generate a receiver operating characteristic (ROC) curve. 
The area under the curve (AUC) will be computed to evaluate the performance of the prediction. 
An AUC value close to one indicates a good prediction while a value close to zero implies poor 
prediction. 
 
11.2 
Sample Size/Accrual Rate 
We anticipate to enroll up to 66 patients in total from MD Anderson (up to 12 in phase 1b and 54 
in phase II) at an enrollment rate of 1-2 patients per month. 
 
11.3 
Stratification Factors 
None 
 
11.4 
Analysis of Secondary Endpoints 
Stopping rule for toxicity are listed above and biomarker analysis is also discussed.   Kaplan-
Meier method will be used to estimate the probabilities of relapse-free survival and overall 
survival.   
 
11.5 
Reporting and Exclusions 
 
11.5.1 Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with 
TALADEGIB. 
 


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62 
11.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death 
from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result 
in exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 
will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation 
of treatment, major protocol violations, etc.).  However, these subanalyses may not serve 
as the basis for drawing conclusions concerning treatment efficacy, and the reasons for 
excluding patients from the analysis should be clearly reported.  The 95% confidence 
intervals should also be provided.  
 
 


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APPENDIX A - PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B - ACCEPTABLE FORMS OF CONTRACEPTION 
Birth control pills 
Depo-Provera® 
Norplant® 
IUD (intrauterine device) 
Diaphragm with spermicide 
Condom with spermicide 
 
Women of childbearing potential and men are required to use two forms of acceptable 
contraception, including one barrier method, during their participation in the study and 
for 6 months following discontinuation of TALADEGIB. 
The following are acceptable forms of  contraception: 
 
• Birth control pills 
• Depo-Provera® 
• Norplant® 
• IUD (intrauterine device) 
• Diaphragm with spermicide 
• Condom with spermicide 
 
 
 
 
 


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APPENDIX C - PATIENT INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
The patient ____________________________________ is enrolled on a clinical trial using the 
experimental agent. This form is addressed to the TALADEGIB patient, but includes important 
information for others who care for this patient.  A convenient wallet-sized information card is 
also included for the patient to clip out and retain at all times.  
 
TALADEGIB interacts with many drugs that are processed by your liver. Because of this, it is 
very important to tell your study doctors about all of your medicine before you start this study. It 
is also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study. When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the counter 
remedy), or anything that you buy from the health food store or grocery store (herbal 
supplement).  
 
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you. These are the thing that you and they need to know:  
 
• TALADEGIB and its major metabolite are CYP3A4 substrates.  TALADEGIB also inhibits 
CYP3A4.  These CYPs are enzymes in your liver. TALADEGIB must be used very carefully 
with other medicines that need certain liver enzymes to be effective or to be cleared from 
your system.  
o The specific enzymes are CYP3A4.  
o You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
o Before you start the study, your study doctor will work with your regular prescriber to switch 
any medicines that are considered “strong inhibitors of CYP3A4.” 
o Your regular prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.asp to see if any medicine they want to 
prescribe is on a list of drugs to avoid.   
o Please be very careful! Over-the-counter drugs have a brand name on the label—it’s usually 
big and catches your eye. They also have a generic name—it’s usually small and printed on 
the ingredient list. Find the generic name (your pharmacist can help) and look at the table on 
the back of this page. Be careful:  
 If you take acetaminophen regularly.  You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age.  
Read labels carefully!  Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold.  
 If you take herbal medicine regularly.  You should not take St. John’s wort while 
you are taking TALADEGIB. 
 
 


2014-0966 
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Other medicines can be a problem with your study drugs.  
 
• You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement.  
 
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you.  Your study doctor’s name is _______________   
 
and he or she can be contacted at  713-792-2828.    
 
_________________________________________________ 
 
 
 


2014-0966 
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67 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
TALADEGIB.  . TALADEGIB interacts with drugs that are processed by 
your liver.  Because of this, it is very important to: 
 Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 
TALADEGIB interacts with specific liver enzymes named CYP3A4/, 
and must be used very carefully with other medicines that interact 
with these enzymes.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inhibitors of CYP______.” 
 Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at 


2014-0966 
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68 
APPENDIX D  - PROHIBITED MEDICATIONS 
CYP3A4 INHIBITORS List of medications prohibited in this study (cyp 450) 
Strong Inhibitors of CYP3A 
boceprevir 
clarithromycin 
conivaptan 
grapefruit juicea 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
mibefradilb 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
Source:  US Food and Drug Administration.  
a The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent.  Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). 
b Withdrawn from the United States market because of safety reasons. 
 
 
 
 
 
 


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69 
 
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