Clinical trial NCT01633541
Conditions: Laryngeal Cancer
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2012-03-01; Completion date: 2021-11-06
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate a new treatment approach for adults with advanced laryngeal cancer: induction chemotherapy with platinum and docetaxel plus AT-101. AT-101 is an investigational drug for the treatment of advanced cancer. It is hoped that the combination of this chemotherapy regimen will allow cancer patients to keep their voice box and to improve/maintain voice-related quality of life. The ultimate goal of this study is to prevent the surgery to remove subjects voice box.

Detailed description:
Published data demonstrate equal efficacy and improved quality of life when platinum and a taxane were compared with platinum and 5-Fluorouracil \[31\]. Additionally, weekly cisplatin regimens (30-40 mg/m2) with radiotherapy appear to be equally efficacious and better tolerated than standard high-dose cisplatin (100 mg/ m2) regimens with radiation therapy for locally advanced SCCHN \[32\] The investigators will thus attempt to reduce toxicity from induction chemotherapy with the use of docetaxel/cisplatin (or carboplatin) (TP) in place of our previously used standard regimen of cisplatin and 5-fluorouracil (PF) and administer weekly cisplatin (or carboplatin) with radiation for those patients who are responders to induction therapy. Finally, Phase I/II testing of the small molecule inhibitor, AT-101, has recently been completed, and suggests activity in solid tumors when combined with cytotoxic agents. Since the investigators have achieved such high survival rates with our treatment selection approach in laryngeal cancer, our ultimate goal is to reduce the rate of salvage laryngectomy which should improve quality of life. The investigators hypothesize that specific inhibition of Bcl-2/Bcl-xL function can increase response rates to neoadjuvant chemotherapy and decrease the need for salvage laryngectomy. Hence, the investigators propose this study: the treatment of patients with advanced SCC of the larynx with one cycle of platinum plus docetaxel with AT-101, followed by chemoradiotherapy for those responding to this induction regimen and reserving total laryngectomy for those who are non-responders.

Arms: arm 1: platinum/docetaxel + AT-101 The platinum will either be cisplatin or carboplatin as deemed best by the medical oncologist.

(Both Arms) Day #1: Patients will undergo induction chemotherapy with (TP) docetaxel (Taxotere) 75 mg/m2 and cisplatin 100 mg/m2 (or Carboplatin AUC 6).

(AT-101 Arm) Days #1-3: Patients will receive AT-101 40 mg orally twice daily On Day 23 (+/- 3 days), there will be a direct laryngoscopy (DL) with tumor biopsy and blood draw, repeat CT scan of the neck with perfusion within a week biopsy. arm 2: (Both Arms) Day #1: Patients will undergo induction chemotherapy with (TP) docetaxel (Taxotere) 75 mg/m2 and cisplatin 100 mg/m2 (or Carboplatin AUC 6).

Day #23 (+/- 3 days): Patients will undergo a direct laryngoscopy (DL) with biopsy. Patients will also undergo a repeat CT scan of the neck with perfusion within a week (+/-) of their perspective biopsies.
Interventions: intervention 1: AT-101 intervention 2: Docetaxel intervention 3: Cisplatin intervention 4: Carboplatin
Intervention descriptions: intervention 1: Patients will receive AT-101 40 mg orally two times a day. intervention 2: Docetaxel (Taxotere) 75 mg/m2 intervention 3: Cisplatin 100 mg/m2 intervention 4: Carboplatin AUC (area under the curve) 6. Maximum dose of 700 mg

Protocol documents:
Prot_SAP_000.pdf: 
 
ID: UMCC 
2010.101 
    Chemotherapy AND Bcl-xL Inhibitor (AT-101) For Organ Preservation In 
Adults With Advanced Laryngeal Cancer 
    NCT01633541 
 


v. 6-12-18
1
University of Michigan Head and Neck SPORE 
CONCOMITANT CHEMOTHERAPY AND Bcl-xL INHIBITOR (AT-101) 
FOR BIOSELECTIONTM FOR ORGAN PRESERVATION IN PATIENTS 
WITH ADVANCED LARYNGEAL CANCER  
Principal Investigator: 
Francis P. Worden, M.D. 
Co-Investigators  
Otolaryngology:
Mark Prince, M.D. 
Thomas Carey, Ph.D.
Medical Oncology:
Susan G. Urba, M.D. 
Paul L. Swiecicki, M.D. 
Consultants 
Otolaryngology:
Carol Bradford, M.D. 
Keith Casper, M.D 
Norman Hogikyan, M.D. 
Kelly Malloy, M.D.   
Scott McClean, M.D.     
Jeffrey Moyer, M.D. 
Robbi Kupfer, M.D. 
Matthew Spector, M.D. 
Andrew Shuman, M.D.  
Chaz Stucken, M.D. 
Gregory T. Wolf, M.D. 
Radiology:
Ashok Srinivasan, M.D. 
Lubomir Hadjiiski, M.D. 
Radiation Oncology:     
Avraham Eisbruch, M.D. 
Aleksandar Dragovic, M.D. 
Michelle Mierzwa, M.D.  
Research Staff 
Nurse Coordinators:     
Tamara Miller, R.N., B.S.N. 
Nancy Wallace, R.N. 
Heidi Mason, N.P., B.S.N., O.C.N. 
Mary Beth DeRubeis, N.P., B.S.N., O.C.N. 
Leah Shults, R.N., B.S.N., O.C.N. 
Terri Jobkar, R.N., B.S.N., O.C.N 
Nancy Rogers, RN, B.S.N., CORLN 
Mary Lou Patterson, R.N., B.S.N 
Shantel Musser, R.N., B.S.N 
Statistician:
Emily Bellile, M.S. 


v. 6-12-18 
2
 
Table of Contents 
 
1.0 
Introduction.................................................................3  
2.0 
Objectives.....................................................................9  
3.0 
Eligibility Requirements...........................................10 
4.0 
Exclusion Criteria......................................................11  
5.0 
Initial Clinical Evaluation.........................................12 
 
6.0 
Schema........................................................................14  
7.0 
Study Design...............................................................15  
8.0 
Dose Delays and Treatment Modifications..............17  
9.0 
Study Calendars.........................................................18  
10.0 Response Criteria......................................................20  
11.0 Criteria for Discontinuation of Treatment..............21  
12.0 Drug Information......................................................21 
13.0 Radiation Therapy....................................................27 
 
14.0 Salvage Surgery........................................................29 
15.0 Informed Consent.....................................................30 
16.0 Patient Registration..................................................30 
17.0 Reporting Adverse Drug Events.............................30 
18.0 Data and Safety Monitoring....................................32 
19.0 Biologic Correlatives……………………………….32 
20.0 Statistical Considerations........................................33 
21.0 Quality of Life………………………………………35 
22.0 References.................................................................36  
23.0 Appendices................................................................39 
 
 
 


v. 6-12-18 
3
 
1.0 
Introduction: 
 
1.1 
Larynx Preservation 
 
The optimal treatment of patients with advanced laryngeal cancer remains controversial. 
Standard treatment options have included laryngectomy with or without radiation (RT) and 
radiation alone with surgical salvage (RTSS). In the United States, total laryngectomy has been 
the mainstay of treatment. RTSS is generally discouraged as historical data suggest a 15-20% 
lower survival rate when compared with surgery.  
 
Because of the significant functional morbidity associated with laryngectomy, the Department of 
Veterans Affair Cooperative Studies Program completed a randomized, prospective study of 332 
patients that compared a new organ preservation treatment strategy to conventional 
laryngectomy and radiation [1]. The experimental treatment arm involved using multiple cycles 
of neoadjuvant chemotherapy to select patients who had partial (>50%) clinical tumor response 
for definitive radiation. Thirty percent of patients achieved histologic complete response (CR) 
after two cycles of chemotherapy.  Laryngectomy was reserved for non-responders to the initial 
chemotherapy and for patients who developed local recurrence following definitive treatment. 
Final results of this study demonstrated comparable 2, 3, 4, and 10 year survival rates between 
treatment groups, with successful laryngeal preservation in 66% of the surviving patients 
randomized to receive neoadjuvant chemotherapy. Analysis of gene expression patterns from this 
trial indicated that the majority (74%) of patients had tumors with high expression of Bcl-xL. 
Additionally, successful larynx preservation was significantly associated with low expression of 
Bcl-xL, particularly among those with low p53 expression [2], [3]. 
 
These studies led to a dramatic re-assessment of our treatment approach for advanced laryngeal 
and hypopharyngeal cancer patients, who face total laryngectomy. Subsequent trials at other 
institutions have confirmed these results [4],[5]. At the University of Michigan, a retrospective 
analysis of the results of pilot induction chemotherapy regimens and a detailed analysis of the 
VA results indicated that a rapid response of a tumor (>50% reduction) to a single cycle of 
neoadjuvant chemotherapy was predictive of successful larynx preservation in 90% of patients 
[6]. Additionally, Grossi et al. have found that initial response to chemotherapy was predictive of 
ultimate response in 86% of patients [7]. Based on these results, a new treatment approach for 
bioselection was designed and tested in a Phase II study at the University of Michigan (UMCC 
9520). [8] In this study, 97 patients were treated with one cycle of induction chemotherapy.  
Seventy-five percent had a >50% reduction of tumor and were treated with chemo-RT (cisplatin 
100 mg/m2 x 3 cycles), and 20% were non-responders who underwent total laryngectomy 
followed by RT.  Nine percent had surgical salvage following chemoradiotherapy.  The overall 
3-year survival rate was 85%, the cause-specific survival was 87%, and the larynx preservation 
rate was 70%. Overall and cause-specific survival was similar in both chemotherapy/radiation  
and surgically treated patients indicating that appropriate therapy selection can lead to improved 
survival rates.   These represent the highest survival rates ever reported in patients with advanced 
laryngeal cancer. 
 


v. 6-12-18 
4
While it is not possible to conclude a true survival advantage from a phase II trial, these results 
(UMCC 9520) were also promising when compared with the results reported from two other 
large multi-institutional trials.  For example, RTOG 91-11 evaluated three treatment strategies in 
patients with advanced SCC of the larynx  (T4 patients were excluded) [5].  Patients were 
randomized to receive either concurrent cisplatin (100 mg/m2) with RT, induction chemotherapy 
with cisplatin and 5-fluorouracil followed by RT, or RT alone.  The 2-year laryngectomy-free 
survival rate from the best arm (RT concurrent with cisplatin) in RTOG 91-11 Intergroup Study 
was 66% similar to 63% at 2 years in UMMC 9520.  The overall survival rate of 88% at 2 years 
in UMCC 9520, however, is better than the best arm of 91-11 (74%) and better than the VA 
larynx trial (54%).  This improvement in results is observed in UMCC 9520 despite the fact that 
a higher percentage of patients on the Michigan study had stage T4 tumors and tumors arising 
from the supraglottic larynx, both of which are associated with poorer survival rates. 
 
 
In trials of concurrent chemoradiation, improved organ preservation outcome has been achieved 
at a price of enhanced toxicity. In the Intergroup study (RTOG 91-11), the rate of grade 3 and 4 
acute mucositis was 20% and 24% in the induction chemotherapy followed with radiotherapy 
and the radiotherapy alone arms, respectively, and was doubled in the concurrent chemo-RT arm 
(43%). Also, more deaths that may have been related to therapy were reported in the concurrent 
chemo-RT arm (5%, compared with 3% in each of the other arms). Enhanced toxicity, primarily 
mucositis and late dysphagia, is well documented in patients receiving concomitant chemo-RT. 
[9], [10], [11]  It has recently been recognized  that mucositis and dysphagia are the main 
barriers to overcome when treating head and neck cancer patients with cytotoxic chemotherapy 
and RT [12]. 
 
 
 1.2 The Bcl-2 Family 
 
Apoptosis is caused by activation of intracellular proteases, known as caspases, which are 
directly or indirectly responsible for the morphological and biochemical events that characterize 
the apoptotic cell. Defects in the regulation of apoptosis make important contributions to the 
pathogenesis and progression of most cancers including solid tumors, leukemia and lymphomas, 
and have also been associated with resistance to chemotherapy, radiotherapy, hormonal therapy, 
and immune-based treatments. Numerous proteins that regulate these cell death proteases have 
been discovered, including proteins belonging to the Bcl-2 family[13].   
 
Members of the Bcl-2 family play a major role in the pathobiology of head and neck cancer [14], 
[15]. The use of low-molecular-weight compounds to inhibit Bcl-2 and Bcl-XL function is a 
novel method with several potential therapeutic advantages. Small molecule inhibitors have the 
benefit of being more stable with better bioavailability as compared with other biologic and 
peptide inhibitors. They also may have the ability to penetrate the central nervous system blood 
brain barrier and do not require a central venous catheter for administration [16]  The search for 
small molecule inhibitors of Bcl-2 and Bcl-XL became possible with the understanding of the 
detailed atomic structure of both the pro-apoptotic and anti-apoptotic members. Both Bcl-2 and 
Bcl-XL bind, through their BH3 binding pockets, to the BH3 domains on pro-apoptotic 
members, an essential step in the execution of the anti-apoptotic signal. The BH3 domains of 
these pro-apoptotic members are also required for implementing the apoptotic signal [16], [17]. 


v. 6-12-18 
5
Based on these findings, non-peptide small molecules can be designed to compete with the pro-
apoptotic members for binding to the BH3 binding pocket and subsequently disrupting the 
function of the anti-apoptotic molecules. An excellent review by Wang et al. describes several of 
these small-molecule inhibitors of Bcl-2 and Bcl-XL and illustrates the various approaches 
entailed in discovering them [16].  
 
We have retrospectively analyzed biomarkers predictive of successful organ preservation in 
specimens from the randomized VA Laryngeal Cancer trial and from UMCC 9520.  We found 
that low tumor expression of anti-apoptotic Bcl-xL and overexpression of p53 were significant 
predictors of success [2], [3], [18], [19]. Over 70% of laryngeal cancer patients show increased 
expression of Bcl-xL.  However, in those with low or absent expression, over 90%  (10 of 11 
patients) enjoy successful larynx preservation.  In vitro data on cisplatin sensitivity of head and 
neck cancer cell lines and in vivo animal model studies have indicated that inhibition of Bcl-
2/Bcl-xL function by a small molecule  BH3 mimetic (AT-101) can increase platinum sensitivity 
[20], [21], [22], [23].   
 
 
1.3 AT-101  
 
AT-101 was developed by Ascenta Therapeutics, Inc. for the treatment of patients with advanced 
cancer. AT-101 is the levorotatory enantiomer of gossypol acetic acid, R-(-)-gossypol acetic 
acid. Through structure-based computational screening, Ascenta scientists discovered that 
gossypol is a potent, small-molecule inhibitor targeting the BH3 domain of Bcl-2/Bcl-XL 
proteins. Subsequently, AT-101 was found to bind to and inhibit the anti-apoptotic (pro-survival) 
function of Mcl-1 with similar potency to its inhibition of Bcl-2 and Bcl-XL (Yang, 2005). 
Therefore, AT-101 is appropriately described as a “pan” Bcl-2 inhibitor, by virtue of its similar 
effects against Bcl-2, Bcl-XL, and Mcl-1—the three Bcl-2 family proteins that promote cancer 
cell survival—as well as against Bcl-w, another pro-survival member of the Bcl-2 family.  
 
Ascenta is no longer manufacturing AT-101; it is currently manufactured and supplied by 
Ascentage Pharma Group Corporation (APGC) via a co-development collaboration with 
Ascenta. 
 
Studies by Ascenta and its collaborators have further demonstrated that:  
• AT-101 is more potent than S-(+)-gossypol or racemic gossypol at inhibiting proliferation and 
inducing apoptosis in cancer cell lines in vitro. For example, in the National Cancer Institute 
(NCI) in vitro screen of 60 cell lines from multiple human tumors the average 50% growth 
inhibition (GI50) value for R-(-)-gossypol was 0.57 μM, whereas the GI50 value was 2.1 μM for 
racemic gossypol and 14.5 μM for S-(+)-gossypol. R-(-)-Gossypol induced apoptosis in a dose 
dependent manner in cancer cells that over-express Bcl-2 or Bcl-XL, but has little effect on 
normal cells with low Bcl-XL and Bcl-2 expression. The ability of R-(-)-gossypol to induce 
apoptosis in cancer cells is correlated with the level of Bcl-XL; apoptosis is induced via caspase 
activation. R-(-)-gossypol’s anti-proliferative activity is correlated with target cell Bcl-XL/Bcl-
XS expression ratios.  
• AT-101 acts synergistically with standard chemotherapeutic agents and radiation in inhibiting 
cancer cell proliferation in vitro and in vivo tumor models.  


v. 6-12-18 
6
• AT-101 has in vivo tumor growth inhibition activity as a single agent or in combination in with 
docetaxel, cisplatin, CHOP (cyclophosphamide, doxorubicin, Oncovin, and prednisone) or 
radiation in human tumor xenograft models. The xenograft models tested include A549 
(NSCLC), PC-3 (prostate), MDA-MB-231 (breast) and others.  
• More recent studies have also indicated that AT-101 treatment results in potent induction of the 
natural ligands of Mcl-1, Bcl-2 and Bcl-xL, Noxa and Puma, which are pro-apoptotic, as well as 
inhibiting angiogenesis [24], [25].   
 
 
     
1.3.1 Pre-clinical Models with AT-101 in SCCHN: 
Data from the University of Michigan Comprehensive Cancer Center [26] have shown that Bcl-2 
orchestrates a cross talk between tumor cells and endothelial cells that have a direct effect on the 
progression of HNSCC.  Notably, Bcl-2 is significantly up-regulated in the tumor associated 
endothelial cells compared with the endothelial cells of normal oral mucosa in patients with 
HNSCC. In this investigation, the effect of AT-101, a small-molecule inhibitor of Bcl-2, was 
evaluated in conjunction with the cell cycle and survival of endothelial cells and HNSCC and on 
the progression of xenografted tumors.  The combination of AT-101 and cisplatin showed 
enhanced cytotoxic effects for endothelial cells and HNSCC in vitro, compared with single drug 
treatment.  Whereas cisplatin led to an expected G2-M cell cycle arrest, AT-101 mediated an S-
phase cell cycle arrest in endothelial cells and in HNSCC. In vivo, AT-101 inhibited tumor 
angiogenesis and induced tumor apoptosis without significant systemic toxicities. Combination 
of AT-101 and cisplatin enhanced the time to tumor failure (i.e., 4-fold increase in tumor 
volume), compared with either drug given separately. Collectively, these data reveal that 
therapeutic inhibition of Bcl-2 function with AT-101 is sufficient to arrest endothelial cells and 
HNSCC in the S phase of the cell cycle and to inhibit head and neck tumor angiogenesis. 
 
             1.3.2 Clinical Experience with AT-101 in Solid Tumors 
 
                   
1.3.2.1  AT-101 in Combination with Docetaxel in NSCLC 
Clinical trials conducted with AT-101 are ongoing.  Data in non-small cell lung cancer presented 
at the 2009 American Society Clinical Oncology Annual Meeting [27] demonstrated 
improvements in progression-free and overall survival when AT-101 (40 mg b.i.d. days 1-3) was 
administered with docetaxel (75 mg/m2 every 21 days).  Additionally, a biomarker of AT-101 
activity was developed to identify a genomic predictor of sensitivity to AT-101.  An analysis of 
gene expression data by Bayesian regression revealed a 500 gene predictor of sensitivity to AT-
101 that was cross validated in a leave one out analysis and in an independent cohort of 32 
NSCLC cell lines.   
1.3.2.2  AT-101 in Combination with Docetaxel and Prednisone in    
Prostate Cancer 
                          
A Phase 1/ 2 trial of AT-101, using a higher dose of AT-101 given for a shorter period of time 
(denoted as a pulse dose schedule) in combination with docetaxel and prednisone in hormone 
refractory prostate cancer (HRPC) has recently been published [28].  During the Phase 1 portion 
of this study, patients were enrolled in successive cohorts of 3 patients with doses of AT-101 of 
40-60 mg BID x 3 days on days 1-3 in combination with docetaxel 75 mg/m2 on day 1, every 21 


v. 6-12-18 
7
days. No dose limiting toxicities (DLTs) were observed and dose escalation was not increased 
beyond 60 mg BID x 3 days, as the dose of 80 mg BID x 3 days every other week was associated 
with ileus in a separate study.  
Three cohorts of patients were treated with the longest treatment duration being 12 cycles of 
therapy in one patient. All patients treated had decreases in PSA levels. All patients with 
chemotherapy-naïve HRPC had at least a 30% decrease in PSA and 75% of patients met the 
criteria for a PSA partial response (e.g. ≥ 50% decrease). Partial responses per RECIST were 
also observed.  
In the Phase 2 portion of the trial, patients were enrolled into 2 cohorts: chemotherapy naïve 
HRPC (cohort A) and docetaxel-refractory HRPC (cohort B).  40 mg of AT-101 was 
administered b.i.d. on days 1-3 in combination with docetaxel and prednisone.  Thirty six (36) 
patients were enrolled into cohort A.  AT-101 was well tolerated and the majority of Adverse 
Events (AEs) were Grade 1 or 2.  There were no notable differences in the rates or severities of 
fatigue, gastrointestinal toxicities (e.g. nausea, vomiting, and diarrhea), and grade 3 or 4 
cytopenia compared to historical controls.  Thirty six (36) percent of patients received 10 cycles 
of therapy and there were no cases of non-mechanical small bowel obstruction.  Efficacy data 
indicate that AT-101 has biological activity in combination with docetaxel and prednisone in 
men with HRPC: 
• 72% of patients achieved a 30% decrease in PSA. 
• 67% of patients achieved a PSA partial response (Bubley Criteria). 
• 45% of patients with measurable diseases achieved a partial 
responses per RECIST. 
Forty (40) patients were enrolled into cohort B.  AT-101 was well tolerated and 35% of patients 
received at least 4 months of therapy. One of 40 patients reported non-mechanical small bowel 
obstruction.  Efficacy data indicate that AT-101 has biological activity in combination with 
docetaxel and prednisone in men with docetaxel-refractory CRPC: 
• 41% of patients achieved a 30% decrease in PSA. 
• 22% of patients achieved PSA partial responses (Bubley Criteria). 
• 24% of patients achieved partial responses per RECIST. 
Ascenta conducted a randomized phase 2 study of AT-101 or placebo in combination with 
docetaxel and prednisone in 221 men with chemotherapy naïve HRPC.  This study opened for 
enrollment in October 2007 and was completed in April 2009.  Patients are randomly assigned to 
receive either Arm A: oral AT-101 (40 mg [4 tablets of 10 mg] b.i.d. on cycle days 1-3), with 
docetaxel (75 mg/m2 intravenously over 1 hour every 21 days [one cycle]), and oral prednisone 
(5 mg b.i.d. on days 1-21), or Arm B: docetaxel (75 mg/m2 intravenously over 1 hour every 21 
days [one cycle]), oral prednisone (5 mg b.i.d. on days 1-21), and oral placebo (4 tablets b.i.d. on 
cycle days 1-3). Randomization are stratified by ECOG performance status (0 or 1 versus 2) and 
baseline pain (absent versus present). 
In general, the treatment was well tolerated, with a median number of cycles administered of 
approximately 9 cycles in each arm of the study.  The majority of AEs of grade 1, 2, or 3 were 
similar between treatment arms.  There were more grade 3 or 4 AEs on the AT-101 arm of the 


v. 6-12-18 
8
study although only fatigue was statistically significant.  There were more patients who 
discontinued study treatment due to an adverse event on the AT-101 arm of the study and this 
was primarily due to grade 1 or 2 neuropathy.  There were more reports of pulmonary embolism 
on the AT-101 arm of the study compared to the placebo arm (6 vs. 2, respectively). 
 
 After 108 deaths, an overall survival (OS) analysis was performed and demonstrated no 
significant improvement in OS between treatment arms. There were trends favoring the AT-101 
arm in PSA, RECIST and PFS, but they did not reach statistical significance in this moderately 
sized Phase 2B trial. 
A subgroup analysis of treatment effect using the TAX327 study-defined risk groups (based on 
baseline anemia, visceral disease, bone progression at baseline, and baseline pain) was 
performed.  A difference between arms, favoring AT-101 treatment, was demonstrated in the 
high-risk group (N=32 patients). This difference was consistent across efficacy parameters and 
the improvement in OS was 5 months (14 v. 19 months). 
 
1.3.2.3 A Phase 1 Study of AT-101 in Combination with Paclitaxel and Carboplatin in Solid 
Tumors 
AT-101 is being investigated in combination with paclitaxel and carboplatinum in a Phase 1 
study being conducted by the NCI.  AT-101 is dosed 30-40 mg b.i.d. on days 1-3 in combination 
with paclitaxel and carboplatinum on day 1 on a 21 day cycle.  22 patients have been evaluated, 
including 8 patients treated with AT-101 40 mg, paclitaxel 175 mg and carboplatin AUC 6.  
Thus far, the treatment is well tolerated.  
 
1.4 CT with perfusion in locally advanced head and neck cancer 
 
CT perfusion (CTP) provides the unique ability to noninvasively quantify the microvascular 
blood flow of tumors and normal tissues.  CTP provides important information on the biologic 
response to non-surgical organ preservation and has the potential to determine whether the tumor 
is properly responding to NSOPT.  The ability to non-invasively monitor tumor response during 
non-surgical organ preservation therapy (NSOPT) is desirable in cancer treatment.  Accurate 
identification of non-responding tumors would permit early implementation of adaptive 
radiotherapy, adjuvant chemotherapy or surgical resection.  This would have widespread 
implications and increase patient survival, create a rational approach for implementation for 
costly new chemotherapy agents and help reduce the growing costs of salvage therapy and end of 
life care.  
 
The initial results investigating the role CTP for monitoring response to NSOPT are 
promising.  These results suggest that changes in CTP have the ability to non-invasively predict 
response to NSOPT.  [29], [30], [31], [32], [33]. There is also early evidence to suggest that CTP 
is correlated with molecular biomarkers that may increase the efficacy of targeted chemotherapy. 
Recent reports indicate new data suggesting that CT perfusion is predictive of the expression of 
the epidermal growth factor receptor (EGFR) which is the mechanism of the drug cetuximab and 
a correlation between CT perfusion and interleukin-8 [34].  


v. 6-12-18 
9
 
The most encouraging aspect of such investigations is that there is now consensus among 
radiation oncologists that biologic imaging response precedes changes in tumor volume for 
predicting response.  The early data from the University of Michigan shows that the CTP 
parameters vary during the course of treatment but blood flow and blood volume tend to be 
reduced in responders after approximately 4000Gy.  However, there is no clear consensus and 
more investigations need to be performed . 
 
 
 
1.5 Study Hypothesis and Rationale 
 
Treatment of patients with one cycle of induction chemotherapy to select for organ preservation 
of the larynx has become our standard approach at the University of Michigan. When compared 
to historical controls, our data from UMCC 9520 appears to have improved survival outcomes, 
which led us to believe that some patients are better suited to undergo early surgical salvage.  Of 
those treated with organ preservation, however, long-term toxicities remain barriers to successful 
outcomes.  Hence, we propose to study patients with a similar treatment strategy (i.e. one cycle 
of induction chemotherapy followed by chemoradiation for those responding to chemotherapy or 
surgical salvage for those failing to respond) with changes to the treatment regimen which will 
hopefully allow for increased organ preservation rates and reduced toxicity from induction 
chemotherapy and chemoradiotherapy.  Several randomized trials of induction chemotherapy 
have demonstrated that the combination of a taxane and platinum agent achieves response rates 
equal or better than our standard cisplatin and 5-fluorouracil [35], [36]  and improvements in 
overall survival with less toxicity have been noted.  The most significant and consistent 
biomarker of successful organ preservation and survival has been response to induction 
chemotherapy.   
 
While we have effectively used this response as a biologic indicator to select patients for either 
surgery or an organ preservation approach, the next step is to find substitute biomarkers and to 
increase complete response rates in order to improve on our 60-70% organ preservation rates.  In 
the original VA Larynx trial, we identified p53 expression and Bcl-xL expression as the most 
useful biomarkers for organ preservation.  We confirmed these findings in our Phase II trial, 
UMCC 9520 and extended the findings to improved overall survival in patients with low Bcl-xL.  
We have investigated the effects of  Bcl-xL gene expression and p53 mutation in cell lines that 
are sensitive and resistant to cisplatin and confirmed that sensitivity can be restored by inhibition 
of Bcl-xL using the small molecule inhibitor, AT-101[20], [21], [22].  We hypothesize that the 
combination of docetaxel and cisplatin will be less toxic than cisplatin/5-fluroruracil as induction 
therapy and that the addition of AT-101 will increase the clinical complete response rate by 
inhibiting Bcl-xL in treated patients.  An increase in CR rate will allow more patients to be 
effectively treated for organ preservation.  
 
Published data demonstrate equal efficacy and improved quality of life when platinum and a 
taxane were compared with platinum and 5-Fluorouracil [37].   Additionally, weekly cisplatin 
regimens (30-40 mg/m2) with radiotherapy appear to be equally efficacious and better tolerated 
than standard high-dose cisplatin (100 mg/ m2) regimens with radiation therapy for locally 


v. 6-12-18 
10
advanced SCCHN [38]   We will thus attempt to reduce toxicity from induction chemotherapy 
with the use of docetaxel/cisplatin (or carboplatin) (TP) in place of our previously used standard 
regimen of cisplatin and 5-fluorouracil (PF) and administer weekly cisplatin (or carboplatin) with 
radiation for those patients who are responders to induction therapy. Finally, Phase I/II testing of 
the small molecule inhibitor, AT-101, has recently been completed, and suggests activity in solid 
tumors when combined with cytotoxic agents.  Since we have achieved such high survival rates 
with our treatment selection approach in laryngeal cancer, our ultimate goal is to reduce the rate 
of salvage laryngectomy which should improve quality of life. We hypothesize that specific 
inhibition of Bcl-2/Bcl-xL function can increase response rates to neoadjuvant chemotherapy and 
decrease the need for salvage laryngectomy.  We also hypothesize that the addition of a second 
cycle of induction chemotherapy will improve response and decrease need for salvage 
laryngectomy.  Hence, we propose this study: the treatment of patients with advanced SCC of the 
larynx with one-two cycles of platinum plus docetaxel with AT-101, followed by 
chemoradiotherapy for those responding to this induction regimen and reserving total 
laryngectomy for those who are non-responders. 
 
 
 
1.6 Quality of Life 
 
The overall goal of this treatment approach is to optimize patient selection in order to 
decrease the need for protracted multi-modality, highly morbid treatment (surgery and radiation) 
and to eliminate therapeutic redundancy by identifying those patients who are unlikely to be 
responders to either chemotherapy or radiation therapy.  We expect to demonstrate a significant 
improvement in voice-related quality of life (V-RQOL) compared to patients in our prior 
(UMCC 9520) protocol [39].  Given the change in chemotherapy regimens throughout our 
proposed trial, we hypothesize that QOL scores will be improved in this evaluation.  Hence, we 
plan to evaluate physical and social well-being with the FACT-HN and speech and swallowing 
with the University of Michigan HN-QOL tool [40], [41]. 
 
 
2.0  
Objectives 
 
2.1 Primary 
 
2.1.1 
To determine the salvage surgery rates of this treatment paradigm 
compared to the salvage surgery rates of patients treated on UMCC 9520. 
2.1.2 
To estimate the overall response rate to induction chemotherapy with 
platinum and docetaxel plus AT-101 following one and/or two cycles in 
patients with advanced laryngeal cancer. 
2.1.3 
To determine the progression-free survival rates of this treatment 
paradigm compared to the progression-free survival rates of patients 
treated on UMCC 9520. 


v. 6-12-18 
11
2.1.4 
To determine toxicities of induction chemotherapy plus AT-101 and 
chemoradiation in patients on this treatment . 
 
 
             2.2 
Secondary 
 
2.2.1 
To determine expression of Bcl2/BclxL, EGFR and p53 in pre and  
posttreatment biopsy specimens 
 
2.2.2   To compare the overall response rates of the 1st cycle of  induction 
chemotherapy with   platinum and docetaxel to platinum and docetaxel plus 
AT-101.  
 
 
2.2.3   To compare the overall response rates of induction chemotherapy with 
platinum and docetaxel plus AT-101 to the rates of induction chemotherapy 
with cisplatin and 5-fluorouracil from the historical group treated on 
UMCC 9520.  
2.2.4 To estimate overall and cause-specific survival rates in patients on this 
treatment.  
 
2.2.5 To evaluate the quality of life (QOL) of this treatment paradigm 
 
2.2.6 To evaluate tumor vascular perfusion in response to induction 
chemotherapy utilizing CT with perfusion.   
 
3.0 
Eligibility Requirements 
3.1 
Patients must have pathologically confirmed, previously untreated, resectable, 
squamous cell carcinoma of the larynx or hypopharynx. 
 
3.2 
Disease must be Stage III or IV.  
 
3.3 
Tumor must be potentially surgically resectable and curable with conventional 
surgery and radiation therapy. 
 
3.4 
Patients must undergo pre-treatment DL endoscopic tumor staging and CT scanning. 
 
3.5 
ECOG Performance status 0-1 (See Appendix A). 
 
3.6 
Pre-treatment laboratory criteria: 
 
3.6.1 WBC > 3500/ul, granulocyte > 1500/ul. 
3.6.2 Platelet count > 100,000/ul. 


v. 6-12-18 
12
3.6.3 Calculated or measured creatinine clearance > 60 cc/min for cisplatin 
candidates, ≥ 30 cc/min for carboplatin candidates.  
3.6.4 Total Bilirubin < 1.5 X ULN. 
3.6.5 AST and ALT < 2.5 X ULN. 
 
3.7      Patients must give documented informed consent to participate in this study. 
 
4.0 
Exclusion Criteria 
 
 
4.1 
History of  secondary malignancy or history of other malignancy within the last three  
years (patients who have been disease-free for three years, or have a history 
of completely resected non-melanoma skin cancer or successfully treated in situ 
 
carcinoma are eligible). 
 
4.2 
Prior head and neck radiation or prior chemotherapy. 
 
4.3 
Documented evidence of distant metastases. 
 
4.4 
Active infection. 
 
4.5 
Pregnancy or lactation. Patients must agree to use adequate contraception 
(hormonal or barrier method of birth control) prior to study entry, for the duration 
of study participation and for 3 months after discontinuing therapy. 
 
4.6 
Any medical or psychiatric illness which in the opinion of the principal 
investigator would compromise the patient’s ability to tolerate this treatment. 
 
4.7 
Patients residing in prison. 
 
4.8 
Age < 18 years. 
 
4.9 
Patients with psychiatric/social situations that would limit compliance with study 
requirements are not eligible. 
 
4.10 
Patients with prior radiation to the head and neck.. 
 
4.11 
Patients with Grade > 2 peripheral neuropathy. 
 
4.12 
Any history of severe hypersensitivity reaction to docetaxel or other drugs 
formulated with polysorbate 80. 
 
 
4.13 
Class 3 or 4 cardiac disease as defined by the New York Heart Association 
Functional Classification (Appendix B). 
 
4.14 
Unstable angina or a history of myocardial ischemia within prior 6 months 


v. 6-12-18 
13
  
4.15 
Malabsorption syndrome, disease significantly affecting gastrointestinal function, 
or resection of the stomach or small bowel, ulcerative colitis, inflammatory bowel 
disease, partial or complete small bowel obstruction. 
4.16 
Prior use of gossypol or AT-101, or known hypersensitivity to gossypol or AT-101. 
4.17 
Patients taking any other concurrent approved or investigational anti-cancer 
therapy (e.g. chemotherapy, immunotherapy, targeted or biologic therapy).  
 
5.0 
Initial Clinical Evaluation  
 
Note:  All Initial Clinical Evaluations must occur  prior to Day 1  
5.1 
 Prior to day 1:Complete history and physical examination, multidisciplinary 
examination by Otolaryngology, Radiation Oncology, and Medical Oncology, 
with descriptive documentation of extent of primary tumor and regional disease.  
 
5.2 
Satisfactory biopsy of the primary tumor. 
 
5.3 
Representative tumor specimen sent to Head and Neck Cancer Research 
Laboratory for ancillary studies.  
 
5.4 
Pre-treatment blood sample (24 cc to Dr. Carey; 2 - 6mL red tops and 2 – 6mL 
green tops).  The blood serum will be stored for tumor marker analysis and to 
create lymphoblastoid cell lines for harvesting normal DNA.  
5.5 
Complete dental evaluation, if required as per radiation oncologist 
 
5.6 
Completion of laboratory studies: Comprehensive panel, CBC with differential 
and platelets, magnesium and creatinine clearance (calculated or measured).  
 
5.7 
Diagnostic CT scan of the neck with perfusion. (CT scan with perfusion is the 
same radiation exposure and risk as a standard CT scan.) 
 
5.8 
Chest X-Ray or diagnostic CT of chest/thorax, as determined by the treating 
physicians. (CT/PET may be used as an alternative to the diagnostic chest CT at 
the discretion of the investigator). 
 
5.9 
CT of the abdomen, if clinically warranted (as deemed necessary by the treating 
physicians). 
 
5.10 Bone scan, if clinically warranted (as deemed necessary by the treating 
physicians). 
 
5.11 Audiograms for patients with hearing complaints or hearing loss at the discretion 
of the prescribing physician. 
5.12 Quality of life assessments (FACT-HN: version 4, HN-QOL, AND V-RQOL) 


v. 6-12-18 
14
6.0 Schema     
Anti - apoptosis Inhibitor AT101 in Advanced Laryngeal Cancer 
CT perfusion 
Bx , Markers 
Endoscopic laryngoscopy/ 
BX, Markers
CT perfusion
CR 
PR,NR
XRT+Chemo
TP 
CR,PR 
NR 
Surgery 
XRT+Chemo
OTO Eval/ endoscopic
laryngoscopy
Imaging (per MD)
Untreated Stage III, IV Larynx Cancer 
TP = docetaxel / cisplatin (carboplatin); 
Days in this schema are approximate only; see Calendar, Section 9.0. 
TP 
Bx , Markers 
CT/PET 
Endoscopic 
laryngoscopy 
3 
Mo 
f/u 
CYCLE 1 
CYCLE 1             CYCLE 2      CYCLE 2 
DAY 1              DAY 23                DAY 1           DAY 23


v. 6-12-18 
15
7.0 
Study Design 
 
7.1 
Chemotherapy/Radiation/Surgery schedule (see schema section 6.0)  
 
 
NOTE: Carboplatin may be substituted for cisplatin at any time if patients are  
 
 
  not candidates for cisplatin or are not able to tolerate cisplatin  
  secondary to toxicity, as deemed necessary by the patient’s   
  prescribing medical oncologist. 
 
7.1.1 Following enrollment, patients will be randomized to one of two arms  
of induction chemotherapy (in a 2:1 ratio):  TP + AT-101 or TP alone (see Schema, 
Section 6.0). 
 
 
 
7.1.2 (Both Arms) Day #1: Patients will undergo induction chemotherapy with (TP) docetaxel 
(Taxotere) 75 mg/m2 and cisplatin 100 mg/m2 (or Carboplatin AUC 6 with max dose 700 
mg). 
 
7.1.3  (AT-101 Arm): On day 1, patients will initiate AT-101 40 mg orally every 12 hours (+/- 
1 hour)  for a total of 6 doses. 
 
 
7.1.4 Cycle 1 Day #23 (+/- 3 days): Patients will undergo an endoscopic laryngoscopy with 
biopsy.  Patients will also undergo a repeat CT scan of the neck with perfusion within a 
week (+/- 7 days) of their perspective biopsies. 
 
7.1.5    Patients with a > 50% but < 100% response (PR) or no response (NR) to  
induction chemotherapy will undergo a repeat cycle of TP and AT-101 (as outlined in 
sections 7.1.1-7.1.3).  
 
Cycle 2 Day #23 (+/- 3 days): Patients will have radiographic imaging per 
investigator/MD discretion, modality of choice;  OTO clinical evaluation and endoscopic 
laryngoscopy by otolaryngology 
 
                        7.1.6    Treatment with Chemoradiotherapy:  
 
                        After induction chemotherapy, patients with > 50% response or 100% response  
                        (PR, CR) following  clinical evaluation (Cycle 2 Day 23 +/- 3 days) 
 will undergo treatment with RT (Total dose 70 Gy) in combination with weekly 
Cisplatin (50 mg/m2 ) or  Carboplatin (AUC 2.5 with max dose 230 mg). The tumor dose 
may be exceeded by <10% in protocol subjects based on clinical judgement. 
 
Twelve weeks following the completion of RT, patients will undergo a repeat endoscopic 
laryngoscopy and PET imaging at the discretion of the prescribing physicians. The 
primary tumor site will be biopsied if clinically indicated.  Neck nodes that are persistent, 
clinically suspicious nodes, including PET positive nodes, will be excised.   
 
Patients with positive laryngeal biopsies following chemoradiation will undergo salvage 
laryngectomy. If the laryngeal biopsy is negative but clinically or PET positive neck 
lymph nodes remain, patients will undergo neck nodal dissection alone.  Patients with 
PET negative necks and no clinically suspicious adenopathy may have the neck observed. 
 
                       7.1.7     Early Salvage Laryngectomy: Those patients who remain NR after 2 cycles 


v. 6-12-18 
16
                                    of induction chemotherapy, will be treated with salvage laryngectomy  
                                    followed by RT.  Cisplatin or Carboplatin will be added to radiation for  
patients whose surgical pathology reveals high-risk features (i.e. extracapsular spread, > 2 
positive lymph nodes, perineural invasion, or positive margins.)  Cisplatin will either be 
dosed a 100 mg/m2  (or Carboplatin AUC 6 with max dose 700 mg) every 21 days or 50 
mg/m2 (or Carboplatin AUC 2.5 with max dose 230 mg)  weekly at the discretion of the 
prescribing physician.  See section 7.2 for  
                                    prescribing details for cisplatin. 
 
7.1.8 Late Salvage Laryngectomy: Once patients are disease-free following chemoradiation 
and nodal neck dissections (if needed), patients will be followed at regular intervals as 
prescribed by their treating surgeon.  Patients whose physical examination or whose 
imaging studies are concerning for recurrent disease will undergo biopsy.  If positive, 
they will undergo salvage laryngectomy. 
  
7.2 
Chemotherapy Administration with Cisplatin (Carboplatin), and Docetaxel 
 
 
 
7.2.1 Docetaxel (Taxotere): Docetaxel 75  mg/m2 administered as an IV infusion over one 
hour on day #1. 
 
7.2.2 With Docetaxel administration, all patients will receive dexamethasone 8 mg PO BID for 
3 consecutive days, starting 1 day before docetaxel administration.  Dexamethasone 20 
mg IV (x1) may be administered in place of oral dexamethasone  as deemed necessary by 
the prescribing  physician. 
 
7.2.3 Cisplatin: Cisplatin 100 mg/m2, administered as an IV infusion will run over one hour on 
day #1 following docetaxel. 
 
7.2.4 An aggressive antiemetic regimen is required before the administration of cisplatin, 
consisting of a neurokinin 1 antagonist, sertotonin (5-HT3) antagonist and a steroid 
(dexamethasone). 
 
7.2.5 Pre-cisplatin hydration: normal saline plus 1 gram/L Magnesium Sulfate  plus KCl 20 
mEq/L i.v. infusion at 500 mL/hr x 3 hours before cisplatin.  Alternative pre-hydration 
regimens may also be administered at the discretion of the prescribing physicians. 
 
7.2.6 Mannitol 12.5 gm i.v. bolus may be given immediately prior to cisplatin, followed by 25 
gm of mannitol in 500 mL of normal saline with cisplatin as deemed necessary. 
 
7.2.7 Post-hydration: Normal saline plus KCl 20 mEq/L plus MgS04 1 gm/L at 500 mL/hr x 3 
hours.  Alternative post-hydration regimens may also be administered at the discretion of 
the prescribing physicians. 
 
7.3 
Evaluation of Response to Treatment 
 
7.3.1 Careful evaluation of tumor extent will be separately recorded for the primary tumor and 
regional nodes at specified intervals. These will be based on laryngoscopies performed 
pre-treatment, Day 23 (+/- 3 days) after start of induction chemotherapy and AT 101, and 
12 weeks after completion of chemoradiation, if clinically indicated. Standardized 
response criteria will be used.  CT scans will be used at the discretion of the clinician to 


v. 6-12-18 
17
supplement clinical exams.  However, it is not necessary for imaging abnormalities to 
revert to normal in order for a patient to be considered a clinical CR.   
 
7.3.2 Open biopsy of any clinically persistent or PET positive neck nodes is required at the 12 
week post chemoradiation.   Patients with any nodes initially > 3 cm in size who are PET 
positive at 12 weeks post chemo-RT will undergo neck dissection.  Patients whose PET 
shows a CR at 12 weeks post chemo-RT, will undergo clinical observation. 
 
7.3.3 For post treatment evaluations, diagnostic CT scans and/or PET scans will be obtained 
prior to scheduled endoscopies for tumor assessment.  
 
7.3.4 Outpatient clinical examinations will be performed at the completion of radiation therapy, 
and for 3 years with timing of evaluations at the discretion of the treating physician.  
Clinical examinations will be performed by one, but not all three, of the following 
disciplines: medical oncology, radiation oncology, or surgical oncology.  To meet the 
examination requirements, patients need to be seen by at least one discipline (but not all 
three) during their followup up period. 
 
8. 0 Dose Delays and Treatment Modifications 
 
Toxicity  
Action Taken  
Abdominal Pain/Nausea/Vomiting 
See Section 8.1 of the Protocol  
 
 
• Total bilirubin is > ULN  
 
• AST and/or ALT is > 2.5 x ULN  
• Alkaline phosphatase ≥ 2.5 x ULN and 
AST and ALT is > 1.5 x ULN  
 
Step 1: Interrupt treatment (AT-101 + TP) or (weekly 
platinum) until the toxicity has resolved, up to 2 weeks 
(14 days).  
Step 2: For AT-101 + TP: Restart treatment with TP 
and AT-101. Docetaxel should be reduced by 15 mg/m2   
and cisplatin by 20 mg/m2 and carboplatin by an AUC 
1 for the 1st and 2nd events and AT-101 should be 
reduced to 30 mg b.i.d.  
Step 2: For Weekly Platinum:  Cisplatin should be 
reduced by 10 mg/m2   and Carboplatin by an AUC 0.5.  
Monitor as clinically indicated.  
CrCl < 60:  Discontinue cisplatin, change to carboplatin if CrCl ≥ 30 
If CrCl < 30, hold carboplatin.  When CrCl returns to ≥ 30, initiate/resume carboplatin at previous 
dose.  
Tinnitus: if observed on cisplatin, may change to carboplatin at the discretion of the prescribing MD 
Hematologic Toxicity  
 
• Neutrophil count is < 1000 cells/ mm3 
  
• Platelet count is < 75,000 cells/mm3  
 
Step 1: Interrupt treatment (AT-101 and TP) or 
(weekly platinum) until the toxicity has resolved to < 
Grade 1 or pre-therapy baseline, up to 2 weeks (14 
days).  
Step 2: Restart treatment with TP and AT-101 or 
weekly platinum; monitor as clinically indicated.  


v. 6-12-18 
18
 
• Grade 4 neutropenia (< 500 cells/mm3) 
lasting 7 days or more  
 
• Grade 3 or 4 neutropenia with an oral 
temperature of at least 38.5°C  
 
Step 1: Interrupt treatment with (TP and AT-101) or 
(weekly platinum) until resolved to ≤ Grade 1, up to 2 
weeks (14 days).  
Step 2: For TP and AT-101: Restart treatment with 
TP and AT-101. Docetaxel should be reduced by 15 
mg/m2   , cisplatin by 20 mg/m2, carboplatin by an AUC 
1for the 1st and 2nd events and AT-101 should be 
reduced to 30 mg b.i.d.  
Step 2:  For Weekly Platinum:  Cisplatin reduced by 
10 mg/m2   and carboplatin by AUC 0.5.  
Monitor as clinically indicated. 
Other Toxicities  
 
• Any Grade 2 or 3, if clinically 
significant with the exception of 
mucositis (Grade 2 and 3 mucositis is 
expected with chemoRT) 
 
Step 1: Interrupt treatment of (AT-101and TP) or 
(weekly platinum) up to 2 weeks (14 days), until 
toxicity resolves to < Grade 1.  
Step 2: For TP and AT-101: Restart treatment with 
TP and AT-101. Docetaxel should be reduced by 15 
mg/m2 , cisplatin by 20 mg/m2 and carboplatin by an 
AUC 1 for the 1st and 2nd events and AT-101 should be 
reduced to 30 mg b.i.d.  
Step 2: For Weekly Platinum:  Cisplatin should be 
reduced by 10 mg/m2   and Carboplatin by an AUC 0.5.  
Monitor as clinically indicated. 
 
• Any recurrent Grade 2 or 3 after two (2) 
dose reductions, if clinically significant 
with the exception of mucositis (see 
above) 
 
For TP and AT-101 OR Weekly Platinum: 
Discontinuation of treatment with AT-101 and 
docetaxel and follow-up per protocol.  
 
• Any Grade 4  
 
Discontinuation of treatment with AT-101and TP OR 
Weekly Platinum and follow-up per protocol.  
 See Section 8.1 for additional guidelines  
 
 
8.1 Guidelines for Nausea, Vomiting or Abdominal Pain  
 
If a patient has ≥ Grade 2 nausea, ≥ Grade 2 vomiting, or any abdominal pain that lasts for longer than 
48 hours, (AT-101 and TP) dosing should be held and the following actions are recommended:  
1. Physical examination, including the performance of vital signs  
2. Screening abdominal radiography to include an abdominal series to exclude  
    ileus, SBO, or pneumatosis intestinalis  
3. Consideration for obtaining a CT scan with contrast of the abdomen should be 
    made based on clinical judgment  
 
If ileus, SBO, or pneumatosis intestinalis are excluded, dosing of AT-101 may be reinstated following 
the provisions in Section 8.0, Dose Delays and Dose Modifications for Toxicity.   If a patient is 


v. 6-12-18 
19
determined to have ileus, SBO, or pneumatosis intestinalis, dosing of AT-101 and TP will be held and 
expectant management with supportive care is recommended, unless clinical signs or symptoms are 
present that suggest septicemia or abdominal catastrophe that warrants surgical management.  No further 
AT-101 can be administered following recovery from these events. 
 
9.0   Study Calendars 
 
9.1  Induction Chemotherapy (TP and AT-101) 
 
*Evaluations by Radiation Oncology, Otolaryngology, and Medical Oncology prior to day 1.   
1 If clinically warranted, as determined by the treating physicians. 
2  If clinically warranted, as determined by the treating physicians. 
3  At the discretion of the prescribing physician for patients with c/o hearing loss. 
4  Either a CXR or a chest CT must be performed.  The prescribing physicians will determined which imaging study is most 
appropriate. (CT/PET may be used as an alternative to the diagnostic chest CT at the discretion of the investigator).5PET 
also repeated at least 12 weeks post completion of concurrent chemoradiation.per the discretion of the prescribing physician 
6 Calculated or measured.  Must be > 60 cc/min for cisplatin and > 30 cc/min for carboplatin. 
7 May be performed (+/-) one week the patient’s scheduled biopsy. 
Assessment 
Pre-Therapy 
 
C1D1 
C1D2 
C1D 
C1D14 
+/- 3 
days 
C1D23 
+/- 3 
days 
 
C2D1/ 
 
+4 -18 
days 
from 
C1D23 
DL 
C2D2/ 
C2D3/ 
 
C2D23  
+/- 3 
days 
H&P*   
X 
 
 
 
 
 
 
 
 
 
Medical Oncology Exam 
           X 
 
 
 
 
  
X 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Endoscopic laryngoscopy  
with Biopsy 
X 
 
 
 
 
X8 
 
 
 
 
Dental Eval, if required2 
X 
 
 
 
 
 
 
 
 
 
CBC with diff 
X 
X14 
 
 
X8 
 
X8 
 
 
 
Comp and Mg 
X 
X14 
 
 
 
 
X8 
 
 
 
Creatinine Clearance6 
X 
 
 
 
 
 
 
 
 
 
CXR/chest CT4 
X 
 
 
 
 
 
 
 
 
 
Neck CT w/ perfusion 
X 
 
 
 
 
X7 
 
 
 
 
PET scan5 
X 
 
 
 
 
 
 
 
 
 
Radiographic Imaging 
 
 
 
 
 
 
 
 
 
X¹² 
Abdomen CT1 
X 
 
 
 
 
 
 
 
 
 
Bone scan, if required2 
X 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
Audiogram, if required3 
X 
 
 
 
 
 
 
 
 
 
Quality of Life 
Assessments10  
X 
 
 
 
 
 
X 
 
 
 
Biologic Correlatives11 
X 
 
 
 
 
 
X8 
 
 
 
AT-101 
 
 X¹³ 
X¹³ 
X¹³ 
 
 
X9, ¹³ 
X9, ¹³ 
X9, ¹³ 
 
Chemo (TP) 
 
X 
 
 
 
 
X 9 
 
 
 
Otolaryngology 
exam/response assessment 
 
 
 
 
 
 
 
 
 
X 


v. 6-12-18 
20
8 May be performed (+/-) 3days if scheduling conflicts arise. 
9 Patients who attain PR/SD will be evaluated on day 27 (+/- 14 days) and will be treated with one additional cycle of TP + AT-101. 
Patients are permitted to begin subsequent TP outside of window, if medically warranted, as determined by treating physicians prior to 
TP. Patients will remain in initial randomized arms in subsequent TP. 
10 Quality of life instruments (FACT-HN: version 4, HN-QOL, and V-RQOL) to be administered pre-therapy. 
11 Correlative Blood draw(s): 2 - 6mL red tops and 2 – 6mL green tops. 
¹² Imaging and modality will be performed per investigator/MD discretion 
¹³ Cycle 1, only if randomized  to AT101 arm.  All patients will receive AT-101 in cycle 2.  Diary will be provided for completion w/ 
AT-101 dispensation.   
14 Ok to use screening labs if obtained within 14 days of day 1.  
 
9.2 CR/PR Study Arm: RT + Weekly Cisplatin/Carboplatin 
 
 
Assessment 
Pre-Therapy 
Weekly during RT 
12 weeks post RT 
Follow Up 
Comp and Mg 
X 
X 
 
 
CBC with diff 
X 
X 
 
 
Cisplatin (50mg/m2)  or 
Carboplatin  (AUC 2.5 with max 
dose 230 mg) 
 
X 
 
 
PET/CT scan of neck1 
 
 
X 
 
Endoscopic laryngoscopy with 
biopsy5 
 
 
X 
 
Medical Oncology Exam 
 
X 
 
X2 
Toxicity Evaluation 
 
 X4 
 
  X2,4 
Surgical Evaluation 
 
 
X 
X2 
Radiation Oncology Evaluation 
 
X 
 
X2 
QOL Assessments 
 
X 
 
X3 
 
1 Pet imaging is at the discretion of the prescribing physician.  If performed, may be scheduled  up to one week prior to 
scheduled laryngoscopy  (in office or OR). 
2 Outpatient clinical examinations will be performed at the completion of radiation therapy  and for 3 years with timing of 
evaluations at the discretion of the treating physician.   Clinical examinations must include an evaluation by one, but not 
all three, of the following disciplines:  Medical Oncology, Radiation Oncology, and/or Surgical Oncology.  Moreover, it is 
NOT necessary for the patients to see each discipline during their follow-up period. 
3 Quality of life instruments (FACT-HN: version 4, HN-QOL, and V-RQOL) will be administered pre-therapy, and at 6, 
12, and 24 months post cisplatin-RT or surgery-RT (+/- 4 months post RT or  surgery RT). See section 21.0. 
4 Toxicities will be evaluated using the CTCAE, version 3. 
5Biopsies as deemed necessary by the evaluating surgeon. 
 
10.0     Response Assessment Criteria:   
 
10.1 
With over 15 years of experience in the clinical evaluation of tumor response after  induction 
chemotherapy, the Head and Neck surgical faculty have arrived at a consistent system of 
classifying clinical tumor response.  The “consistent system” refers to evaluating the primary 
tumor during endoscopic laryngoscopy; following chemotherapy, the same surgeon will again re-
evaluate the product of the dimensions to evaluate for response (see CR and PR below).  These 
criteria have been developed and applied uniformly across the protocols conducted by the Head 
and Neck Oncology Program.  They pertain only to the primary tumor.  Standard response 
criteria for chemotherapy response are used for nodal assessments.  Treatment decisions (i.e. 
surgery vs Chemo+RT) are based on response of the tumor at the primary site as assessed 
by the Head and Neck surgeon 


v. 6-12-18 
21
 
10.2 
Tumor responses to chemotherapy or chemoradiation will be determined clinically by the 
surgeon performing the laryngoscopy. 
 
10.3     Radiologic imaging studies (CT perfusion) will be used in conjunction with the physical 
examination in determining tumor response to chemotherapy or chemoradiation. 
 
10.4 
Clinical CR: No visible or palpable evidence of gross tumor at time of direct laryngoscopy.  
This does not include vocal cord function or changes in mobility.  Visible ulceration, induration 
or mass lesion is recorded as partial response or stable disease, depending on percent reduction in 
the product of longest diameter at its perpendicular.  In some cases, specific tumors have deeply 
invasive components for which surface assessment of tumor extent is inaccurate.  Pre-treatment 
assessment is provided by CT scan and a decision to use imaging for response assessment is 
made prior to beginning protocol treatment.  Post-treatment response assessment is determined 
by comparing pre to post treatment CT scans as appropriate.  Specific examples would include 
some supraglottic cancers with extensive pre-epiglottic space extension, clinical CR would 
require complete disappearance of pretreatment enhancing mass (other than edema) effect on the 
post treatment imaging study. 
 
Histologic CR:  Primary tumors exhibiting a clinical CR or at least a 90% PR and having a 
negative post-treatment biopsy are classified as histologic CR. Biopsies are specifically obtained 
from any masses or suspicious ulceration, induration or from the geographic center of the 
primary tumor site radiated on pre-treatment tumor diagrams.   
 
Clinical PR:  Significant (>50%) reduction in the product of the longest primary tumor 
dimension and its perpendicular compared to pre-treatment clinical (endoscopic) measurements 
or imaging study as necessary. 
 
Non-Responders (< PR):  A 50% or less reduction in the product of the longest primary tumor 
dimension and its perpendicular compared to pre-treatment clinical (endoscopic) measurement or 
imaging study as necessary. 
 
 
11.0    Criteria for Discontinuation of Treatment 
 
11.1   Unacceptable adverse event(s). 
 
11.2   Intercurrent illness, which prevents further administration of treatment. 
 
11.3   Patient preference. 
 
11.4   Progressive disease. 
 
11.5   Life threatening or other unacceptable drug-related toxicity. 
 
11.6   General or specific changes in the patient’s condition that render the patient unacceptable      
for further treatment in the judgment of the investigator(s). 
 
12.0    Drug Information 
 
12.1  Docetaxel 


v. 6-12-18 
22
 
12.1.1 Chemistry: Docetaxel is prepared by semisynthesis of the noncytotoxic precursor 10-
deacetyl baccatin III that is extracted from the renewable needles of the European yew 
tree. Structurally, docetaxel is identical to paclitaxel except that modification in two side 
chains of paclitaxel increase the water solubility of docetaxel.  
 
12.1.2 Biochemistry: Docetaxel binds to free tubulin and promotes its assembly into 
microtubule bundles while inhibiting their disassembly. This stabilization of 
microtubules interferes with their normal function and result in inhibition of cell mitosis. 
 
12.1.3 Human pharmacokinetics:  Following the intravenous administration of docetaxel its 
pharmacokinetic profile is consistent with a three compartment model with half-lives for 
the α, β, and γ phases of 4 minutes, 36 minutes, and 11.1 hours, respectively. The initial 
rapid decline is due to distribution to peripheral compartments while the late terminal 
phase is partially due to slow efflux from peripheral compartments. The mean total body 
clearance is 21 L/hour/m2 and the mean steady state volume of distribution is 113L. In 
vitro studies showed that docetaxel is about 94% protein bound and is metabolized by 
the CYT3A4 isoenzyme. It is likely that CYT3A4 inhibitors or inducers such as 
ketoconazole, erythromycin, troleandomycin, nifedipine, cyclosporine or terfenadine 
modify docetaxel blood concentration. To date, no formal clinical studies have been 
performed to evaluation these interactions. The main route of docetaxel elimination is 
fecal excretion as metabolites. Within 7 days of intravenous administration, 6% and 75% 
of the dose is excreted via the urine and feces, respectively. 
 
12.1.4 Human toxicology:  
 
12.1.4.1 Hematological: Severe leukopenia and neutropenia that increase susceptibility to 
infection, febrile neutropenia, anemia and thrombocytopenia. Reversible bone 
marrow suppression was the major dose limiting toxicity of docetaxel in clinical 
trials with a median time to nadir of seven days and a median duration of severe 
neutropenia of seven days. 
 
12.1.4.2 Hypersensitivity reaction: Within few minutes of the start of the infusion patients 
may develop severe hypersensitivity reaction with hypotension, bronchospasm or 
generalized rash/erthema. Other events include chills, rigors, back pain, drug 
fever, dyspnea, and chest tightness. These events are usually resolved after 
discontinuation of the infusion and administration of appropriate therapy. 
Premedication with corticosteroids for three days starting one day prior to 
docetaxel administration reduces the severity of hypersensitivity. 
 
12.1.4.3 Fluid retention: Peripheral edema, general edema and weight gain that are 
occasionally associated with pleural effusion, dyspnea at rest, pericardial effusion, 
ascitis or abdominal distention were reported. The incidence and severity are 
reduced with premedication with corticosteroids.  
 
12.1.4.4 Skin: Severe skin toxicity including localized erythema with edema followed by 
desquamation has been observed. Rash, including localized eruptions, usually 
associated with pruritus have been seen. Nail disorders include hypo- or 
hyperpigmentation and pain. Total alopecia is common. 
 


v. 6-12-18 
23
12.1.4.5 Neurological: Reversible neurological toxicology manifested as parasthesias or 
dysesthesia, pain and peripheral motor neuropathy. 
 
12.1.4.6 Asthenia: Symptoms of fatigue and weakness may last from few days to few 
weeks. 
 
12.1.4.7 Hepatic: Increase in bilirubin, transaminases, and alkaline phosphatase were 
observed. Patients with increased bilirubin and liver enzymes are at increased risk 
of severe adverse effects. 
 
12.1.4.8 Gastrointestinal: Nausea or vomiting and /or diarrhea are generally mild to 
moderate.  
 
12.1.4.9 Stomatitis, including severe stomatitis, has been reported. 
 
12.1.4.10 Muscle: Arthralgias and myalgias were reported Local site reaction: Infusion site 
reactions include hyperpigmentation, inflammation, redness or dryness of the 
skin, phlebitis, extravasation or swelling of the vein.  
 
12.1.4.11 Pregnancy and lactation: Docetaxel is pregnancy category D. Mothers should 
discontinue nursing before receiving docetaxel. 
 
12.1.5 Pharmaceutical Data: 
 
12.1.5.1 Formulation: Docetaxel is commercially available as Taxotere. It is supplied as a 
clear, viscous, yellow to brown-yellow solution containing 40mg/mL anhydrous 
docetaxel in polysorbate 80. This pyrogen-free, non-aqueous solution is available 
in single use vials of 20 mg and 80 mg. Taxotere vials are provided with diluent 
vials containing sterile, non-pyrogenic 13% Ethanol in Water. 
 
12.1.5.2 Storage and stability: Prior to dilution, Taxotere vials are stored between 2° and 
25°C (36° and 77°F) in the original package to protect from bright light.  
 
12.1.5.3 Preparation: Since docetaxel is a cytotoxic drug it should be handled with caution 
and according to the procedures of proper handling and disposal of anticancer 
drugs. 
 
12.1.5.4 Preparation of the initial diluted solution:  
 
12.1.5.4.1 The whole content of the appropriate diluent vial is aseptically drawn into 
a syringe and transferred into the Taxotere for Injection Concentrate. The 
concentration of the diluted docetaxel is 10mg/mL. 
 
12.1.5.4.2 The diluted solution should be rotated gently for 15 seconds for mixing 
and allowed to stand for few minutes to let any foam to dissipate. The 
diluted solution should be clear. 
 
12.1.5.4.3 The initially diluted solution may be used immediately or stored 
refrigerated or at room temperature for up to 8 hours. 
 


v. 6-12-18 
24
12.1.5.5 Preparation of the final dilution for infusion: 
 
12.1.5.5.1 The required amount of docetaxel 10mg/mL should be aseptically 
withdrawn with a graduated syringe and injected into an infusion bag 
(polypropylene or polyolefin, not PVC) or bottle (glass of polypropylene) 
of 0.9% sodium chloride solution or 5% Dextrose in Water. The final 
concentration should be between 0.3 and 0.74 mg/mL.  
 
12.1.5.5.2 The solution needs to be mixed by manual rotation and inspected visually 
for particulate matter or discoloration. If the initial diluted solution or final 
dilution is not clear or appears to have a precipitation it should be 
discarded. 
 
12.1.5.5.3 The diluted docetaxel solution is stale between 2° and 25°C (36° and 
77°F) for 4 hours and should be used within 4 hours of preparation 
(including the 1 hour of  intravenous administration). 
 
12.1.6 Administration:  The final docetaxel diluted for infusion is administered intravenously 
over 1 hour through a polyethylene–lined tubing (non-PVC). 
 
12.1.7 Supplier:  Docetaxel is commercially available and should be purchased by a third party. 
 
12.2 
Cisplatin  
 
12.2.1 Biochemistry: cis-diamminedichloroplatinum (cis-DDP) is a heavy metal compound 
which a divalent platinum molecule binds two potential leaving groups, the chloride ions. 
Two NH3 groups are bound in a firm covalent linkage in transposition to the chloride 
moieties. Both chloride ions undergo a slow displacement by water, generating a 
positively charged aquated complex, which is capable of interacting with a nucleophilic 
site on DNA, RNA, or protein. 
 
12.2.2 Pharmacokinetics: The dominant action of cisplatin appears to be inhibition of the 
incorporation of DNA precursors, although protein and RNA synthesis are also inhibited. 
Plasma levels of cisplatin decay in a biphasic mode with an initial half-life of 25-49 
minutes, and a secondary phase ranging from 58-73 hours. This prolonged phase is due to 
protein binding, which exceeds 90% of the activity in the second phase. Urinary 
excretion is incomplete with only 27-45% excreted in the first five days. Largely 
unchanged drugs are the initial fraction excreted. Although this drug seems to act as an 
alkylating agent, there are data to indicate that its mode and sites of action are different 
from those of nitrogen mustard and the standard alkylating agents. 
 
12.2.3 Pharmaceutical Data:  
 
12.2.3.1 Formulation: Cisplatin (Platinol) is available as an aqueous solution in a 
concentration of 1 mg/mL. 
 
12.2.3.2 Storage and Stability: The aqueous solution is stored at room temperature 
protected from light. Cisplatin is stable in mannitol/NS/ D5W mixtures for 48 to 
72 hours at room temperature and up to 72 hours when refrigerated (per Trissel’s 
Handbook on Injectable Drugs, 11th edition). Cisplatin should be given 
immediately after preparation over one hour. 


v. 6-12-18 
25
 
12.2.4 Human Toxicology: Human toxicity from cisplatin includes: nausea, vomiting, anorexia, 
loss of taste, renal toxicity (with an elevation of BUN, creatinine, and impairment of 
endogenous creatinine clearance, as well as renal tubular damage, which appears to be 
transient), ototoxicity (with hearing loss, which initially is in the high-frequency range, as 
well as tinnitus), peripheral neuropathy, allergic reactions, and uricemia. Much more 
severe and prolonged toxicity has been observed in patients with abnormal or obstructed 
urinary excretory tracts. Myelosuppression, often with delayed erythrosuppression, is 
expected. In the high-dose treatment regimen with osmotic diuresis, the nadir of white 
blood cells and platelets occurred regularly at about two weeks with recovery generally at 
about three weeks after the initiation of therapy. 
 
12.2.5  Supplier: Cisplatin is commercially available, and should therefore be purchased by the 
third party. 
 
12.3  Carboplatin 
 
12.3.1 Chemistry: Carboplatin (CBDCA) is a hydrophilic platinum coordination compound and 
is an analog of cisplatin, producing intrastrand DNA cross-links. 
 
 
12.3.2 Human Toxicology: Side effects of CBDCA include: myelosuppression, nausea, 
vomiting, abdominal pain, diarrhea, and constipation. Other toxicities include: allergic 
reactions (including hypersensitivity, i.e. rash, urticaria, erythema, pruritis, 
bronchospasm, and profound hypotension), peripheral neuropathy, paresthesias, loss of 
hair, hearing loss, visual disturbances, and change in taste. Serum creatinine elevations 
and blood urea elevations have occurred as well as abnormal liver function tests and 
decreased serum electrolyte values. Although rare, pain asthenia, cardiovascular, 
respiratory, genitourinary, and mucosal side effects have occurred in some patients. 
Cancer-associated hemolytic uremic syndrome has been reported rarely carboplatin may 
cause fetal harm; therefore, women of childbearing potential should be advised to avoid 
becoming pregnant. The renal effects of nephrotoxic compounds may be potentiated by 
carboplatin. Carboplatin is contraindicated in patients with a history of severe allergic 
reactions to cisplatin or to other platinum-containing compounds or mannitol. This drug 
should not be used in patients with severe bone marrow depression or significant 
bleeding. The occurrence of acute leukemia has been reported rarely in patients treated 
with anthracycline/alkylator combination chemotherapy. 
 
12.3.3 Pharmaceutical Data 
 
12.3.3.1 Kinetics: The differences in potencies of carboplatin as cisplatin are due to 
differences in equation rates. The initial half-life of carboplatin is 1.1-2.0 hours 
and the post-distributional half-life is 2.5-5.0 hours. Sixty-five percent of the dose 
is excreted into the urine within twelve hours. Carboplatin is not bound to plasma 
proteins. 
 
12.3.3.2 Formulation: Carboplatin is supplied as a sterile lyophilized powder available in 
single-dose vials containing 50 mg, 150 mg, and 450 mg of carboplatin for 
administration by intravenous injection. Each vial contains equal parts by weight 
of carboplatin and mannitol. Immediately before use, the content of each vial 
must be reconstituted with either sterile water for injection, USP, D5W, or normal 
saline injection, USP, according to the following schedule: 


v. 6-12-18 
26
 
Vial Strength 
Diluent Volume 
 
50 mg 
5 mL 
 
150 mg 
15 mL 
 
450 mg 
45 mL 
 
These dilutions all produce a carboplatin concentration of 10 mg/mL. Carboplatin 
can be further diluted to concentrations as low as 0.5 mg/mL with D5W or normal 
saline injection, USP. 
 
12.3.3.3Storage and Stability: Unopened vials of carboplatin for injection are stable for 
the life indicated on the package when stored at controlled room temperature (15-
30oC), and protected from light. When reconstituted as directed, the solution of 
carboplatin exhibits no decomposition for eight hours at room temperature (25 
oC). Like cisplatin, this drug should not be given through aluminum needles. 
Caution: The single-use lyophilized dosage form contains no antibacterial 
preservatives. Therefore, it is advised that the reconstituted product be discarded 
eight hours after dilution. 
 
12.3.3.4 Administration: Intravenous infusion. 
 
12.3.4 Supplier: Carboplatin is commercially available and should be  
purchased by a third party. 
 
 
12.4  AT-101 
 
12.4.1 Description: AT-101 is the levorotatory enantiomer of gossypol acetic acid, R-(-)-
gossypol acetic acid; the chemical name is R-(-)-1,1’, 6,6’,7,7’-hexahydroxy-3,3’-
dimethyl-5,5’-bis (1-methylethyl) [2,2’-Binapthalene]-8, 8’-dicarboxaldehyde acetic acid. 
AT-101 will be administered orally using an immediate release (IR) solid oral dosage 
form. Each AT-101 tablet contains 10 mg R-(-)-gossypol acetic acid. In addition, each 
tablet of AT-101 also contains excipients.  
 
 12.4.2  Toxicity Associated with AT-101: 
As of 23 June 2009, approximately 699 patients have received AT-101 across multiple 
Ascenta-sponsored Phase I and Phase II trials as a single agent or in combination with 
other anticancer therapies.  An additional 92 patients have been treated under a separate 
IND by the DCTD of CTEP.  The most frequent adverse events associated with AT-101 
dosing have been gastrointestinal findings such as nausea and vomiting; anorexia and 
fatigue have also been frequent.  Most adverse events have been of low grade (Grade 1-2 
on the NCI Common Toxicity Criteria scale), but a clinical picture of ileus/non-
mechanical small bowel obstruction has also been observed in approximately 10-15% of 
patients receiving 30 mg of AT-101 daily or daily for 21 of 28 days.  Following these 
initial observations, as part of Ascentage’s ongoing pharmacovigilance program, 
Ascentage has modified the dosing schedule of single-agent AT-101 and reduced the 
dose when administered daily for multiple cycles (from 30 mg/day to 20 mg/day for 
21/28 days).  The incidence of ileus/non-mechanical small bowel obstruction was 
reduced to approximately 5% in patients treated with reduced doses of AT-101 daily for 
21 of 28 days.   
 


v. 6-12-18 
27
Ileus/non mechanical small bowel obstruction has also been observed as a DLT in 
patients treated with alternative schedules of AT-101.  The MTD for b.i.d. x 3 day 
administration of AT-101 every fourteen (14) days has been determined to be 30 mg 
b.i.d. and for weekly administration is 80 mg.   The incidence of the most common Grade 
1-2 and grade 3-4 AEs (nausea, vomiting, fatigue, and diarrhea) were lower using these 
alternative schedules of AT-101.  Among approximately two hundred fourty (240) 
patients treated with AT-101 40 mg b.i.d. days 1-3 in combination with docetaxel 75 
mg/m2 day 1, q 21 days, there have been 2 reports of drug-related ileus/non-mechanical 
small bowel obstruction, including one in a patient treated on a randomized blinded trial.  
In a completed, blinded, randomized trial in 2L NSCLC in one hundred five (105) 
patients testing the combination of docetaxel (75 mg/m2 day 1, q 21 days) and AT-101 
(40 mg b.i.d. days 1-3, q 21 days) compared to docetaxel and placebo, unblinded AE 
tables and listings have been reviewed.  There were no notable differences in AE 
incidence or severity for the placebo treated patients compared to the AT-101 treated 
patients.  This supports the conclusion that severe gastrointestinal toxicity is less common 
when AT-101 is dosed intermittently and that AT-101 is well tolerated in combination 
with docetaxel using these doses and schedules of administration.   
 
The AT-101 pharmacovigilance program included monitoring of troponin and 
electrocardiograms.  AT-101 administration may be associated with a risk of developing 
troponin elevations; however, these elevations were generally minimal, asymptomatic 
and not associated with drug-related SAEs of the cardiovascular system.  The importance 
of identifying these elevations is uncertain at this time. In the completed, blinded, 
randomized trial of AT-101 or placebo in combination with docetaxel in 2L NSCLC (CS-
204, N=105), unblinded AEs have been reviewed.  There were similar numbers of 
patients who were reported to have elevated troponin values who received AT-101 
compared to placebo. Troponin monitoring is no longer recommended as part of routine 
pharmacovigilance.  
 
 
 
12.4.3 Medications Prohibited From Use with AT-101: 
 
Patients may not receive any of the following medications or therapies while receiving study 
treatment:  
• Other investigational agents are not to be used within 4 weeks of initial dosing  
  or while receiving treatment.  
 
• Concurrent approved or investigational anti-cancer therapy (e.g., chemotherapy,  
   immunotherapy, targeted therapy, biologic therapy) other than protocol  
   therapies.  
 
 
 
12.4.4  Study Drug Packaging and Labeling:  
AT-101 10 mg tablets will be packaged in high density polyethylene (HDPE) opaque 
bottles, each containing 24 tablets. The bottles will employ a child-resistant 
polypropylene cap with pressure sealed liners. Each bottle will be labeled in the 
appropriate language, including the required regulatory text for each country and labeled 
with a bottle number.  
           12.4.5 Study Drug Storage: 
 


v. 6-12-18 
28
AT-101 tablets should be stored under refrigeration, (2°C-8°C) and protected from direct 
heat. To assure maximal stability, AT-101 should not be handled at ambient temperatures 
for more than 24 hours (e.g. for the purpose of delivery or dispensing). During shipments, 
temperature deviations of up to 25°C for 24 hours and greater than or equal to -20°C for 16 
hours fall within current stability conditions and hence would allow for continued use of 
clinical trial material. Ascentage will assure that the stability of the drug is monitored to 
ensure suitability for continued use in the clinic.  
 
13.0 
Radiation Therapy  
 
13.1. General Considerations: All the patients in this study will receive either definitive radiotherapy 
or post-operative irradiation. Definitive radiotherapy will begin within three weeks following the 
induction cycle of chemotherapy. Post-operative radiation should begin as soon as adequate 
healing has been established. Usually, this will be within three to four weeks of the surgical 
procedure but must begin by six weeks. 
 
13.2 
Radiation Fields: The treatment volumes will be individual as for each patient depending upon 
the extent of disease. Tumor volumes will be outlined on the planning CT scans with the aid of 
pre-chemotherapy CT and, if available, PET scans, to ensure adequate irradiation of the pre-
chemotherapy tumor volume. Treatment techniques will aim at adequate irradiation of the 
clinical and the sub-clinical disease. The therapy goals, specifying the intended doses to the 
primary tumor and lymph node metastases, and the intended doses to each lymph node level 
treated adjuvantly, will be detailed in the therapy chart. A CT-based display of the isodoses will 
be recorded,  such that it will be feasible to assess whether the intended (prescribed) isodoses 
cover the targets adequately. 
 
13.3 
Doses: 
 
13.3.1 Radiation with chemotherapy: Tumor doses will be expressed in Gy . The prescribed 
doses should encompass the targets. Treatment plans will  be generated demonstrating 
adequate coverage of the target volume. The dose across the target volume should not 
vary by more than +/- 10% of the prescribed dose. When an anterior-posterior low neck 
field is treated, the dose will be prescribed to 3cm depth. For electron beam treatments, 
the dose will be prescribed to the depth at which maximum dose is obtained (Dmax). 
When treating the posterior cervical nodes, either six or nine MeV electrons may be used. 
Treatment will be given once daily, five days per week, two Gy per fraction to gros 
disease, and 1.6-2.0 Gy per fraction to subclinical disease. Total gross dose will be 70 Gy 
and subclinical disease dose will be 50-60 Gy. 
 
13.3.2 Post-Operative Radiation Therapy: The patient will be treated with conventional 
fractionation, 1.8-2.0 Gy per fraction, five fractions per week in a continuous course. The 
dose to the tumor bed and lymph nodes will be 56-64 Gy, depending of the existence of 
extranodal extension or the existence of close surgical margins. Patients with gross 
residual disease or positive resection margins will receive total 66-70 Gy to the sites of 
residual disease. 
 
13.4 
Immobilization and Positioning: All patients will be treated in a position that affords maximal 
daily reproducibility. Commonly, it will be in the supine position. Immobilization devices such a 
head masks or bite blocks are mandatory to ensure that target volumes are adequately treated. 


v. 6-12-18 
29
Cradles or arm restraints may be needed to allow adequate exposure of the lower neck area in 
selected patients.  
 
13.5 
Simulation and CT Scanning: All patient will undergo simulation including a CT scanning. 
Treatment planning CT scans with contrast will be obtained on each patient prior to or during the 
first week of the first cycle of chemotherapy to ensure adequate radiation of the pre-
chemotherapy tumor extent. 
 
13.6 
Technical Factors: Equipment - Megavoltage equipment with a source to skin distance of 80-
100cm (or source-axis distance), or greater, will be used. Megavoltage machines with an energy 
equal to 6 MeV photons will be used, rarely higher energy may be used if necessary.  
 
13.7 
Treatment Planning: CT based planning may be used for the total course of radiation, especially 
if necessary for parotid sparing purposes. Otherwise, the final boost may be planned or the full 
course of radiation may be planned using orthogonal simulation fields alone, using the 
information from the pre-chemotherapy planning CT  for verification of the adequacy of the 
radiation fields. 
 
13.8 
Treatment Interruptions: It is expected that the entire treatment for definitive irradiation will be 
completed in about seven weeks. Treatment interruptions due to symptomatic mucositis or skin 
reactions should be minimal. In the case of severe mucositis, a gastric tube will be inserted and 
radiation will continue uninterrupted at the discretion of the treating physician. Weight will be 
recorded weekly in the Radiation Oncology chart. If the patient's weight loss exceeds 10% of the 
initial weight or if the patient is malnourished before radiation, a feeding tube will be inserted. 
 
 
14.0 
Salvage Surgery 
 
14.1 
The extent of salvage surgery for either the primary tumor or regional nodes is dictated by the 
extent of tumor present at time of initial tumor staging or may be increased if tumor progression 
has occurred.  
 
14.2 
Salvage surgery may be required at the times of scheduled tumor assessments or any time tumor 
progression or recurrence is  demonstrated by adequate biopsies of areas clinically suspicious for 
tumor involvement. 
 
14.3 
Primary site: total laryngectomy will be required in all cases except those rare situations in which 
a partial laryngectomy can be safely and adequately performed based on careful pre-treatment 
and post-treatment assessment of tumor extent (see 14.1). 
 
14.3.1 Neck: Bilateral selective neck dissections will be performed in conjunction with salvage 
total laryngectomy for any patient initially staged N0 in the neck. Ipsilateral modified 
radical or radical neck dissection is required for any patient initially staged N+ who 
recurs or persists with cancer in that neck. Neck dissection alone without laryngectomy is 
required for any patient who is PET positive or with biopsy proven palpable neck 
diseaseat the discretion of the treating surgeon.      Neck dissection alone is also required 
any time during the follow-up period that the neck recurrence is documented and 
satisfactory negative biopsies are obtained from the primary tumor site.   
 
 


v. 6-12-18 
30
14.4 
Primary closure of the surgical defect is to be accomplished whenever possible. Reconstructive 
closure with grafts or free flaps is at the discretion of the surgeon.  
 
 
15.0 
Informed Consent  
 
 
15.1 
Alternative treatment options include total laryngectomy followed by radiation therapy with or 
without chemotherapy or radiation therapy alone.  
 
15.2 
Patients who meet the inclusion criteria will be approached for possible participation in this 
study. The nature of the investigation will be described to the patient including the risks and side 
effects of study treatments, the potential benefit of the study to themselves and others, and the 
time commitment and frequency of patient visits and the clinical evaluations they will be 
required to undergo. The patient will then have the opportunity to ask questions. The patient will 
be given the appropriate informed consent form for consideration. Each patient will be allowed 
to read (or have read to them) the informed consent form and understand before discussing 
consent with the investigator. If consent to participate is granted, the patient’s signature will be 
obtained on the informed consent form. The original consent form will be kept in the patient’s 
chart at the Clinical Trials Office. Copies of the informed consent will be provided to the patient, 
and will also be available to the principal investigator and the nurse coordinator. 
 
16.0 
Patient Registration 
 
16.1 
All patients will be registered with the University of Michigan Comprehensive Cancer Center 
Clinical Trials Office prior to initiating treatment. 
 
 
17.0 
Reporting Potentially Serious Adverse Events 
 
 
17.1 Definitions 
 
17.1.1 
An adverse event is any new, undesirable medical experience or  
change of an existing condition which occurs during or after treatment, whether or not 
considered product-related. 
 
17.1.2          A serious adverse event is any untoward medical occurrence that  
  
 
suggests significant hazard or side effect that: 
1. 
results in death. 
2. 
is life-threatening (places the patient at immediate risk of death). 
3. 
requires or prolongs inpatient hospitalization 
is disabling or incapacitating. 
4. 
is a congenital anomaly/birth defect. 
 
The definition of serious adverse event (experience) also includes important medical 
event.  Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the patient 
or may require intervention to prevent one of the other outcomes listed in the definition above.  
These should also usually be considered serious.  Examples of such events are intensive 


v. 6-12-18 
31
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization.   
    17.1.3  Attribution: Definitions of relationship to study medication are as follows: 
 
UNRELATED: The AE is clearly NOT related to the intervention/investigational agent. 
UNLIKELY: The AE is doubtfully related to the intervention/investigational agent.  
POSSIBLY: The AE may be related to the intervention/investigational agent.  
PROBABLY: The AE is likely related to the intervention/investigational agent. 
DEFINITELY: The AE is clearly related to the intervention/investigational agent. 
 
Additionally, adverse events should be categorized as expected or unexpected.  Adverse events 
not attributed to the chemotherapy agents will be considered unexpected.  Adverse events 
attributable to the chemotherapy will be reported if the adverse events are at an intensity that is 
more severe that previously documented or considered significant by the investigator.  The 
definition of “related” is that there is a reasonable possibility that the drug caused the adverse 
experience. 
 
 
17.2   
Reporting Procedures 
“Serious” adverse events which occur after the initial dose of AT-101, during treatment, or 
within 30 days of the last dose of AT-101 (including all deaths), MUST be reported  
immediately, i.e., within one day (24 hours) of being identified, to the study coordinator at the 
Clinical Trials Office, and to the Ascentage Pharma Group Corporation (APGC) 
Pharmacovigilance (PV) Department to drugsafety@ascentagepharma.com. 
 
An initial written report of the serious adverse event must be prepared by the investigator using 
the MedWatch Form (Form FDA 3500 A), and emailed within 48 hours. This report should 
provide a detailed description of the adverse event and include copies of hospital records and 
other relevant documents, when possible. Autopsy results, if applicable, should also be sent as 
soon as they become available. Copies of each report will be kept in the Investigator's File and 
patient’s research chart. The investigator will submit, on request, copies of all these reports to the 
relevant ethics committee.  Follow-up will be conducted by Ascentage Pharma Group 
Corporation (APGC) as needed with investigational site personnel to obtain any additional 
information needed to complete the reporting of the event. 
 
All fatal or life threatening serious adverse events must be reported to the Ascentage Pharma 
Group Corporation (APGC)  Medical Monitor IMMEDIATELY and the initial SAE report must 
be emailed to Ascentage Pharma Group Corporation (APGC), as described previously, within 24 
hours. 
   
All adverse events will be noted in the study forms.  Any serious adverse events, unexpected 
adverse events or adverse events > grade 3 will be reported immediately to the principal 
investigator.  All serious adverse events will be reported on Form FDA 3500 A (MedWatch 
Form) 
 
 
  
 17.2.1  Reporting to the Medical IRB: 


v. 6-12-18 
32
          The investigator or delegate is responsible for notifying the IRB/IEC of serious adverse events in 
accordance with the policy of the IRB/ IEC.  
 
17.2.2  Serious Adverse Events Reporting to the FDA: 
  The Clinical Trials Office Staff will coordinate with the Michigan Institute for Clinical and    
  Health Research (MICHR) IND/IDE Investigator Assistance Program (MIAP) office for the    
  reporting of any and all IND safety reports to the FDA as per the requirements outlined in 21  
  CFR 312.32.  
 
A summary of all non-expedited safety reports will be submitted in the annual report.  
 
 
18.0 
Data and Safety Monitoring 
 
Scheduled meetings will take place monthly. Attendees at these meetings will include the protocol 
investigators (will always include the PI), the CTO data manager, the CTO regulatory manager, the 
Cancer Center clinical research nurse, the biostatistician, and the clinic nurses, all of whom are involved 
with the conduct of the protocol.  The University of Michigan Cancer Center DSMB will oversee this 
clinical study.   
 
During these meetings the investigators will discuss matters related to: 
1. safety of protocol participants (AE reporting) 
2. validity and integrity of the data 
3. enrollment rate relative to expectation, characteristics of participants 
4. retention of participants, adherence to protocol (potential or real protocol violations) 
5. data completeness 
 
Data and Safety Monitoring Reports of these regular meetings will be kept on file in the Cancer Center 
Clinical Trials Office.  The data manager assigned to the trial will be responsible for completing the 
report. The reports will be signed by the principle investigator or by one of the Co-PI. 
 
 
The University of Michigan Comprehensive Cancer Center’s Data Safety Monitoring Board will meet 
on a monthly basis to review the prior months SAEs and Data and Safety Monitoring study specific 
reports that have been filed. 
 
 
19.0 
Biologic Correlatives 
19.1 Biomarker Anaylsis 
Overexpression of p53, p16 (INK4a), EGFR, VEGF, and apoptosis inhibitors of the Bcl2 family are 
consistently identified markers of increased risk for head and neck cancer recurrence. Inactivation of 
p16 maybe a central defect by allowing overexpression of COX-2 in response to smoking and other 
stress signals and thereby result in secondary increases and activation of MDM2, p53, nuclear p65 and 
increased serum levels of IL6 and VEGF.  The role of p16 in laryngeal cancer is still unknown.  
However, we have previously demonstrated that both p53 mutation status and low Bcl-xL expression are 
significant predictive factors for response to induction chemotherapy and larynx preservation in two 
prospective trials.   We hypothesize that AT-101  can modulate the expression of  Bcl-xL, and Bcl-2, in 
tumor and adjacent non-tumor mucosa  in patients with head and neck cancer. To understand the effects 
of AT101, we will need to know the status of p53 expression.  We will also explore other potentially 
important markers such as p16, VEGF and EGFR expression.  Loss of p16 has been identified as a 


v. 6-12-18 
33
critical event in breast cancer carcinogenesis and leads to increased COX-2 expression in response to 
oxidative stress factors such as smoking or chronic inflammation. Most patients with laryngeal cancer 
are chronic smokers.  Hypermethylation of p16 is frequent in HNSCC tumor tissue, adjacent mucosa 
and saliva. The p16 locus also encodes p14 ARF which normally activates p53 and inhibits NF-kB.  In 
cancers without p14/p16, a defect in p53 activation occurs and NF-kB activation can promote Bcl-xL 
expression and survival rather than repress anti-apoptotic genes.  If these observations are related, p16 
defective tumors should have increased NF-kB, phospho p65 and/or Bcl-xL expression.  We will collect 
pre and post treatment tumor and serum samples to measure these biomarkers.  These samples will be 
collected at the baseline visit and and after one cycle of docetaxel/platinum induction chemotherapy and 
at time of any salvage surgery and are for research purposes.  They will be processed for the appropriate 
assays and formalin fixed histopathologic blocks will be obtained from the Pathology Department for 
creation of a tissue microarray (TMA) that will be utilized for immunhistologic analysis.  DNA will be 
prepared from each sample at time of TMA creation.  Each patient and corresponding samples will be 
assigned a unique SPORE (BioDBx) number and will be stored for analysis in the Tissue Core 
Laboratory at the University of Michigan (Room 5110 Cancer Center). These research studies will be 
paid for by the research study. These collections and processing are routine procedures for our SPORE 
study participants.    
19.2 CT Perfusion analysis 
 
CT perfusion will be performed to establish baseline values for tumor angiogenesis. CT perfusion scans 
will be repeated after the first cycle of therapy to evaluate tumor vascular perfusion in response to 
treatment. CT perfusion studies have shown that tumors that demonstrate increased blood flow and 
blood volume frequently respond better to induction chemotherapy and chemoradiation compared with 
tumors that have decreased blood flow and blood volume.  Our preliminary studies have also shown 
correlation of blood flow and blood volume in tumors will correlate positively with p16 status, and 
negatively with EGFR, suggesting that CT perfusion can be a noninvasive predictor of these important 
biomarkers [34].  Other biomarkers have shown correlations with CT perfusion as it relates to 
angiogenesis.  In particular, other published data from the University of Michigan demonstrates that the 
serum biomarker CXCL8 is significantly correlated with CT capillary blood flow, which is likely 
secondary to increased angiogenesis in locally advanced head and neck tumors [42].  
 
 
 
20.0 
Statistical Considerations 
 
Design 
This is a Phase II, single-arm study with an initial randomized component. The primary clinical 
objective of this trial is to compare the larynx preservation rates in a treatment paradigm that uses 
induction chemotherapy plus AT-101 to select patients for either concurrent chemoradiation or surgery. 
Organ preservation rate, defined as alive and free from indication for laryngectomy three months post 
treatment, was chosen as the primary endpoint because it provides evidence to fully characterize 
clinically the effect of the treatment strategy 
 
Patients will be randomly assigned to one of two treatment arms and receive arm specific therapy for 
one cycle. After 1 cycle, subjects who have complete response will undergo chemoradiation. Patients 
without complete response will receive a second neoadjuvant course of TP plus AT-101 for their second 
cycle and be reassessed for response. After completion of the second cycle, those with response 
(CR+PR) will undergo chemoradiation while those with NR will undergo surgery. 
 


v. 6-12-18 
34
We incorporate an early stopping rule into the design for overall salvage laryngectomy rates at 3 
months. The treatment paradigm will be considered promising if the overall salvage laryngectomy rate is 
30% or less. Alternatively, if the rate of salvage laryngectomy is over 50%, there would be little interest 
in pursuing the therapy in further studies. In this case, we would like to stop accrual to the trial and call a 
meeting to discuss discontinuation. The optimal two-stage accrual design [Simon, Controlled Clinical 
Trials 10:1-10 1989] has been adopted.  
In the first stage, we will accrue 17 response-evaluable patients. In order for a patient to be evaluable, 
two response evaluations must be available. Patients who do not undergo two response evaluations will 
be replaced.If 8 or more patients have had a laryngectomy anytime up to 3 months after completion of 
treatment of the 17th patient, the trial will stop accruing and a meeting will be called to discuss 
discontinuation.  If 10 or more patients have achieved early larynx preservation we will continue and 
accrue an additional 35 patients. Based on all 52 subjects, if 31 or more patients have achieved 
successful organ preservation, further studies will be proposed. 
 
Randomization 
The purpose of the randomization is to enable a comparison between TP and TP+AT101 based on the 
clinical and laboratory measures that will be assessed after one cycle.  
 
Randomization, TP+AT-101:TP alone will be 2:1, stratified by clinical stage (III or IV) and blocked to 
ensure balance in treatment assignments. The study statistician will set up the randomization prior to 
beginning the study.  
 
Sample Size and Design Justification  
This trial design provides 85% statistical power and 5% overall type I error rate for detecting early 
larynx preservation rates of 50% versus 70%. Table 1 gives the operating characteristics of this design 
under various scenarios for the underlying population response.  For example, if the therapy has a larynx 
preservation rate of only 40%, there would be a 91% chance of stopping the trial after just 17 patients.  
If the therapy leads to organ preservation (salvage laryngectomy) in 70% (30%) of patients, only 11% of 
trials using this design would terminate early after enrolling 17 subjects.  Furthermore, because this 
study has 85% power, 85% (15%) of trials using this design would conclude that the therapy is effective 
(ineffective).  The expected sample size is 48.2 subjects because 89% of trials would accrue all 52 
subjects, while 11% of trials would accrue only 17 subjects. 
  
Table 1: Design operation characteristics for Larynx preservation rates 
 
Larynx preservation rate  
(Salvage Laryngectomy rate) 
 
40% 
(60%) 
50% 
(50%) 
55% 
(45%) 
60% 
(40%) 
65% 
(35%) 
70% 
(30%) 
75% 
(25%) 
Probability of terminating 
the trial at first stage 
0.91 
0.69 
0.53 
0.36 
0.21 
0.11 
0.04 
Overall probability of 
rejecting the therapy 
 
1.0 
0.95 
0.83 
 
0.61 
0.34 
0.15 
0.04 
Expected sample size 
20.15 
27.9 
33.5 
39.4 
44.7 
48.2 
50.6 
Note: Computation is based on 17 evaluable patients at first stage and 52 total evaluable patients at the end of the 
trial, with the constraint of stopping the trial if 9 or less subjects with preserved larynx at the first stage or if a 
total of 31 or fewer subjects have preserved larynx at the end of second stage. 
 


v. 6-12-18 
35
If total accrual is met, the trial will provide an estimate of overall clinical (CR or PR) response after one 
cycle of TP+AT101 from approximately 35 patients. The operating characteristics for response rate 
estimates (𝒑𝒑ෝ) with n=35 are summarized in Table 2 under various scenarios of true response (p). Table 2 
is based on 10,000 simulations and binomial exact confidence intervals. For example if the true response 
rate is 75%, 47% of trials would observe a rate greater than 0.75, while the lower bound of a 95% 
confidence interval will only be greater than 0.75 in 2% of trials.  
 
True p 
Proportion of Trials 
where (𝒑𝒑ෝ) > 0.75 
Proportion of Trials where 95% CI lower 
bound of (𝒑𝒑ෝ)  >0.75 
0.75 
0.47 
0.02 
0.80 
0.75 
0.06 
0.85 
0.93 
0.21 
0.90 
0.99 
0.53 
0.95 
1.00 
0.91 
 
The University of Michigan will accrue patients to the study. Based on previous experience, the accrual 
to this trial is expected to be 15 eligible patients per year.  Thus, it will take approximately 14 months to 
reach 17 response-evaluable patients for the first stage, and the accrual period required to reach the 
overall target of 52 response-evaluable patients is expected to be approximately 3.5 years.  
 
Analysis Plan 
 
Overall salvage laryngectomy rate will be assessed 3 months after completion of surgery or 
chemoradiation. Successful organ preservation will be defined as a patient who is alive and free of 
indication for surgery. Patients with no response to induction chemotherapy but do not undergo surgery 
will be considered in the indication for surgery group. The rate of successful organ preservation will be 
compared to the same measure in UMCC9520.  
Progression-free survival will be defined as the time from randomization to the time of first indication of 
local failure or metastases.  
 
Overall response rate (CR +PR) after first cycle of chemotherapy will estimated for the TP+AT101 
group and compared to the TP alone arm as well as the rate observed after 1 induction chemotherapy 
cycle in UMCC 9520.  
 
We plan to look at the data from all patients for an overall summary of success of the treatment 
paradigm. We will analyze the two arms of the trial both separately and together. We acknowledge there 
may be some patients who achieve CR after one cycle of TP alone and never receive AT101. We 
anticipate that this will be a small proportion (CR was observed in approximately 15% after 1 cycle in 
UMCC 9520). Not including these subjects in our overall assessment may introduce bias to our 
conclusions. To avoid this bias, we plan include these patients in the analysis of the treatment strategy 
under the assumption that they would have responded to TP+AT101 if that was assigned. 
 
Statistical methods 
 
 
Primary Objectives: 
 
We will perform a two-sided Pearson chi-square test of proportions to test organ preservation rate. We 
will construct a binomial confidence interval for the estimate of response rate using the exact method. 
Progression-free survival at 3 years will be estimated non-parametrically using the Kaplan-Meier 


v. 6-12-18 
36
method and compared to the rates observed in UMCC 9520. A Cox proportional hazards model will be 
used to evaluate progression-free survival across the studies adjusting for site (glottis vs. supraglottic) 
and tumor stage (T3 vs. T4).  
 
 
 
Secondary Objectives: 
 
A single Tissue microarray will be created for pre and post treatment biopsy specimens. Bcl2/BclxL, 
EGFR and p53 expression will be rated by a pathologist blinded to patient data.  A mixed model 
approach will be used to assess if there are significant changes in the mean levels of expression between 
pre and post treatment specimens.  Empiric estimates of the standard errors will be used to avoid bias 
due to within-subject variability.  
 
21. 0  Quality of Life Analyses 
 
 
Quality of life (QOL) assessments will be made prior to treatment (i.e. pre-induction chemotherapy) and 
at 6 months, 12 months, and 24 months (+/- 4 months) after completion of chemo-RT or surgery-RT (or 
surgery–chemoRT, as indicated).  Three QOL instruments will be administered: the University of 
Michigan Head and Neck Quality of Life Instrument (HN-QOL) [40], the University of Michigan Voice 
Related Quality of Life Measure (V-RQOL) [39], and the FACT Head and Neck (version 4) (FACT 
H&N) [41].   
 
 
22.0     References 
 
1. 
Wolf GT, The VA Laryngeal Cancer Study Group: Induction chemotherapy plus radiation 
compared with surgery plus radiation in patients with advanced laryngeal cancer. New Engl J of 
Med 324:1685-1690, 1991. 
2. 
Bradford CR, Wolf GT, Carey TE, Zhu S, Beals T, Truelson J, McClatchey KD, Fisher SG.  
Predictive markers for response to chemotherapy, organ preservation and survival in patients 
with advanced laryngeal carcinoma.  Otolaryngol Head Neck Surg.  121(5) 534-538 , 1999.  
3. 
Trask DK, Wolf GT, Bradford CR, Fisher SG, Devaney K, Johnson M, Singleton T, Wicha M:  
Expression of Bcl-2  family proteins in advanced laryngeal squamous cell carcinoma:  
correlation with response to chemotherapy and organ preservation. Laryngoscope 112:638-44, 
2002. 
4. 
Lefebvre JL, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: 
Preliminary results of a European Organization for Research and Treatment of Cancer Phase III 
Trial. J Natl Cancer Inst 898:890-899, 1996. 
5. 
Forastiere A,  Goepfert H, Moar M, et al. Concurrent chemotherapy and radiotherapy for organ 
preservation in advanced laryngeal cancer. N Engl J Med 349:2091-98, 2003. 
6. 
Eisbruch A, Thornton AF, Urba SG, Wolf GT, Esclamado RM, Carroll WR, Bradford CR, 
Hazuka MB, and Littles JF: Chemotherapy followed by accelerated hyperfractionated radiation 
for larynx preservation in patients with advanced laryngeal cancer. J Clin Onc 14:2322-2330, 
1996. 
7. 
Grossi M, Rischin D, Stewart J, et al: Identification of patients suitable for larynx preservation 
following the first cycle of induction chemotherapy. Aust Head Neck Soc., Abst., 1996. 
8. 
Urba S, Wolf G, Eisbruch A, et al. Single-cycle induction chemotherapy selects patients with 
advanced laryngeal cancer for combined chemoradiation: a new treatment paradigm. J Clin Onc. 
24:593-8, 2006. 


v. 6-12-18 
37
9. 
Eisbruch A, Lyden T, Bradford C, et al. Objective assessment of swallowing dysfunction and 
aspiration after radiation concurrent with chemotherapy for head-and-neck cancer. Int J 
Radiation Oncol Biol Phys 53:23-28, 2002. 
10. 
Nguyen NP, Molrz CC, Frank C, et al. Dysphagia following chemoradiation for locally advanced 
head and neck cancer. Ann Oncol 15:383-388, 2004. 
11. 
Smith RV, Kotz T, Beitler JJ, et al. Long-term swallowing problems after organ preservation 
therapy with concomitant radiation therapy and intravenous hydroxyurea: Initial results. Arch 
Otolaryngol Head Neck Surg 126:384-389, 2000. 
12. 
Robbins KT, Samant S, Vieira F, et al. Presurgical cytoreduction of oral cancer using intra-
aterial cisplatin and limited concomitant radiation therapy (Neo-RADPLAT). Ach Otolaryngol 
Head Neck Surg 130:28-32, 2004. 
13. 
Reed, JC. Apoptosis mechanisms: implications for cancer drug discovery. Oncology. 2004; 
Nov;18 (13 Suppl 10): 11-20.  
14. 
Zeitlin BD, Joo E, Dong Z, Warner K, Wang G, Nikolovska-Coleska Z, Wang S, Nör JE. Anti-
angiogenic effect of TW37, a small molecule inhibitor of Bcl-2. Cancer Res. 66: 8698-8706, 2006. 
 
15. 
Zeitlin BD, Zeitlin IJ, Nör JE. An expanding circle of inhibition: small molecule inhibitors of Bcl-
2 as anti-cancer cell and anti-angiogenic agents. J. Clin. Oncol. 26:4180-4188, 2008.  
16. 
Wang S, Yang D, Lippman ME. Targeting Bcl-2 and Bcl-XL with nonpeptidic small-molecule 
antagonists. Semin Oncol. 2003 Oct 30(5 Suppl 16): 133-42. 
17. 
Cosulich SC, Worrall V, Hedge PJ, Green S, Clarke PR. Regulation of apoptosis by BH3 
domains in a cell-free system. Curr Biol. 1997 Dec 1;7(12):913-20.  
18. 
Bauer JA, Kumar B, Cordell KG, Prince ME, Tran HH, Wolf GT, et al.  Targeting   Apoptosis to 
Overcome Cisplatin Resistance: A Translational Study in Head and Neck Cancer. Int J Rad 
Oncol Biol Phys. 69:5106-5108, 2007. 
19. 
Kumar B, Cordell KG, D’Silva N, Prince ME, Adams ME, Fisher SG, Wolf GT, Carey TE, 
Bradford CR. Expression of p53 and Bcl-xL as predictive markers for larynx preservation in 
advanced laryngeal cancer. Arch Otolaryngol Head Neck Surg, 134:363-369, 2008. 
20. 
Wolter KG, Wang SJ, Henson BS, Wang S Griffith KA, Kumar B, Chen J, Carey TE, Bradford 
CR, D’Silva NJ. (-) gossypol inhibits growth and promotes apoptosis of human head and neck 
squamous cell carcinoma in vivo. Neoplasia, 8:163-172, 2006. 
21. 
Bauer JA, Trask DK, Kumar B, Los G, Castro J, Lee JS, Chen J, Wang S, Bradford CR, Carey 
TE. Reversal of cisplatin resistance with a BH3 mimetic, (-) gossypol, in head and neck cancer 
cells: role of wild-type p53 and Bcl-xL. Mol Cancer Ther. 4:1096-1104, 2005. 
22. 
Oliver CL, Bauer JA, Wolter KG, Ubell ML, Narayan A, O’Connell KM, Fisher SG, Wang S, 
Wu Ji M, Carey TE, Bradford CR. In vitro effects of the BH3 mimetic, (-) gossypol, on head and 
neck squamous cell carcinoma cells. Clin Cancer Res. 15:7757-7763, 2005. 
23. 
Bradford CR, Zhu S, Oqawa T, Ubell M, Narapan A, Johnson G, Wolf GT, Fester SG, Carey 
TE:  p53 Mutation correlates with cisplation sensitivity in head and neck squamous carcinoma 
cell lines Head and Neck 25: 654-61, 2003. 
24. 
Zietlin B, Joo E, Dong Z, et al. Antiangiogenic effect of TW37, a small-molecule inhibitor of 
Bcl-2. Cancer Res. 66:8698-8706, 2006. 
25. 
Zieltin BD, Zeitlin IS, Nor JE, Expanding circle of inhibition: small-molecule inhibitors of Bcl-2 
as anticancer cell and antiangiogenic agents. J Clin Oncol. 26:4180-88, 2008. 


v. 6-12-18 
38
26. 
Ashimori N, Zeitlin BD, Zhang Z, Warner K, Spalding A, Turkienicz IM, Teknos TN, Wang S, 
Nör JE. TW-37, a small molecule inhibitor of Bcl-2, mediates S phase cell cycle arrest and 
suppresses head and neck tumor angiogenesis. Mol. Cancer Ther. 8:893-903, 2009.  
27. 
Ready N, Potti A, Karaseva N, Orlov S, Luft A, Popovych O, Liu PY, Holmlund JT,  Wood BA, 
Leopold L. AT-101 or placebo with docetaxel in second-line non-small cell lung cancer with 
gene signature biomarker development. J Clin Oncol. 2009 27:15s (suppl; abstr 3577). 
28. 
Liu G, Kelly WK, Wilding G, Leopold L, Brill K, et al. An open label, multicenter, phase I/II 
study of single-agent AT-101 in men with castrate-resistent prostate cancer. Clin Cancer Res. 
15:3172-3176, 2009. 
29. 
Zima A, Carlos R, Gandhi D, Case I, Teknos T, Mukherji SK.  Can pretreatment CT perfusion 
predict response of advanced squamous cell carcinoma of the upper aerodigestive tract treated 
with induction chemotherapy? AJNR 28, 2007. 
30. 
Truong MT, Saito N, Ozonoff A, Wang J, Lee R, Qureshi MM, Jalisi S, Sakai O. Prediction of 
locoregional control in head and neck squamous cell carcinoma with serial CT perfusion during 
radiotherapy. Am J Neuroradiol. 32:1195-201, 2011. 
31. 
Surlan-Popovic K, Bisdas S, Rumboldt Z, Koh TS, Strojan P. Changes in perfusion CT of 
advanced squamous cell carcinoma of the head and neck treated during the course of 
concomitant chemoradiotherapy. AJNR 31, 2010. 
32. 
Bisdas S, Rumboldt Z, Surlan-Popovic K, Baghi M, Koh TS, Vogl TJ, Mack MG. Perfusion CT 
in squamous cell carcinoma of the upper aerodigestive tract: long-term predictive value of 
baseline perfusion CT measurements. AJNR 31, 2010. 
33. 
Gandhi, D, Chepeha DB, Miller T, Carlos RC, Bradford CR, Karamchandani R, Worden F, 
Eisbruch A, Teknos TN, Wolf GT, Mukherji SK. Correlation between initial and early follow-up 
CT perfusion parameters with endoscopic tumor response in patients with advanced squamous 
cell carcinomas of the oropharynx treated with organ-preservation therapy. Am J Neuroradiol. 
27:101-06, 2006. 
34. 
Hoefling NL, McHugh JB, Light E, Kumar B, Walline H, Prince M, Bradford C, Carey TE, 
Mukherji SK. Human papillomavirus, p16, and epidermal growth factor receptor biomarkers and 
CT perfusion values in head and neck squamous cell carcinoma. AJNR Am J Neuroradiol. 2013 
May;34(5):1062-6. 
35. 
Pointreau Y, Garaud P, Chapet S, Sire C, et al. Randomized trial of induction chemotherapy with 
cisplatin and 5-flurouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst. 
101:498-506, 2009. 
36. 
Posner MR, Hershock DM, Blajman CR, Mickiewicz E, et al. Cisplatin and fluorouracil alone or 
with doctexal in head and neck cancer. N Engl J Med. 357:1705-15, 2007. 
37. 
Gibson M, Li Y, Murphy B, Hussain MH, DeContit RC, et al. Randomized phase III evaluation 
of cisplatin plus fluorouracil versus cisplatin plus paclitxel in advanced head and neck cancer 
(E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 20:3562-
3568, 2005. 
38. 
Traynor AM, Richards GM, Hartig GK, et al. Comprehensive IMRT plus weekly cisplatin for 
advanced head and neck cancer: The University of Wisconsin experience. Head Neck. [Epub 
ahead of print], 2009. 
39. 
Fung K, Lyden T, Lee J, et al. Voice and swallowing outcomes of an organ-preservation trial for 
advanced laryngeal cancer. Int J Radiat Oncol Biol Phys. 1395-9, 2005.  


v. 6-12-18 
39
40. 
Terrell J, Ronis D, Fowler K, et al. Clinical predictors of quality of life in patients with head and 
neck cancer. Arch Otolaryngol Head Neck Surg.  130:401-8, 2004. 
41. 
Cella DF. Manual for the Functional Assessment of Cancer Therapy (FACT) Measurement 
System (version 3). Chicago:Rush Medical Center, 1994. 
42. 
Jo SY et al. CT Perfusion Can Predict Overexpression of CXCL8 (Interleukin-8) in Head and 
Neck Squamous Cell Carcinoma. AJNR Am J Neuroradiol. 2013 Jul 4. [Epub ahead of print] 
 
 
23.0  Appendices 
 
Appendix A: ECOG Performance Status Scale 
 
 
 
DESCRIPTION 
SCALE 
Normal Activity 
 
0 
Symptoms of disease, able to carry out activities of daily living 
 
1 
Out of bed >50% of time; occasionally needs help 
 
2 
In bed >50% of time; needs nursing care 
 
3 
Bedridden; may need hospitalization 
4 
 
 
 
Appendix B 
Functional Capacity  
Objective Assessment  
Class I. Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, dyspnea, or anginal pain.  
A. No objective evidence of cardiovascular disease.  
Class II. Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.  
B. Objective evidence of minimal cardiovascular disease.  
Class III. Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. 
Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.  
C. Objective evidence of moderately severe cardiovascular disease.  
Class IV. Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. 
Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, 
discomfort is increased.  
D. Objective evidence of severe cardiovascular disease.  
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.  
 
Appendix B: Univeristy of Michigan HN-QOL (attached) 
 
Appendix C: FACT-HN (version 4) (attached) 
 
Appendix D : University of Michigan V-RQOL (attached) 


v. 6-12-18 
40
 
Appendix E:  University of Michigan AT-101 Dosing Diary  
 

ICF_001.pdf: