Clinical trial NCT01016769
Conditions: Squamous Cell Cancer Head and Neck Cancer
Keywords: Paclitaxel Carboplatin Temsirolimus Head and Neck recurrent and/or metastatic 09-131
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2009-11-01; Completion date: 2018-06-01
Enrollment: 48 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out the good and bad effects that occur when temsirolimus is added to standard chemotherapy with carboplatin and paclitaxel.

Detailed description:

Arms: arm 1: In Part 1 (Phase I) of the study, the primary endpoint is to establish the phase II recommended dose for the combination of temsirolimus + weekly paclitaxel + carboplatinPart 1 (Phase I) features a standard 3 + 3 phase I dose escalation design. Up to 3 dose levels are planned in the Phase I portion of the study.

In Part 2 (Phase II) of the study, the primary endpoint is to determine the objective response rate (CR or PR) after two cycles (approximately 6 weeks) of treatment with the combination of temsirolimus + weekly paclitaxel + carboplatin as palliative therapy for recurrent or metastatic HNSCC. A two-stage design will be employed.
Interventions: intervention 1: Temsirolimus + Weekly Paclitaxel + Carboplatin
Intervention descriptions: intervention 1: Temsirolimus Per dose escalation scheme Level 1 (15 mg) 2 (20 mg) Level 3 (25 mg) IVPB 30 minutes weekly (3 weeks on, 1 week off) days 1 and 8.

Paclitaxel 80 mg/m2 IVPB 1 hour weekly (2 weeks on, 1 week off) days 1 and 8. Carboplatin AUC 1.5 IVPB 30 minutes days 1 and 8. On Day 15 of each cycle, patients begin the rest week.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center
IRB Protocol 
IRB#: 09-131 A(15)
Amended:  04/22/15
 
 
 
 
 
 
 
A Phase I/II Study of Temsirolimus + Weekly Paclitaxel + Carboplatin for Recurrent or 
Metastatic Head and Neck Squamous Cell Cancer (HNSCC) 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal 
Investigator/Department: 
David Pfister, MD 
Medicine 
 
Co-Principal 
Investigator(s)/Department: 
Han Xiao, MD 
Medicine- Basking Ridge 
 
Investigator(s)/Department: 
Eric Sherman, MD 
Alan Ho, MD 
Shrujal Baxi, MD 
 
Sofia Haque, MD 
Hilda Stambuk, MD 
Eric Lis, MD 
Sasan Karimi, MD 
John Lyo, MD 
Vaios Hatzoglou, MD 
 
Ronald Ghossein, MD 
Marija Drobnjak, MD 
Nora Katabi, MD 
Michael Berger, MD 
 
Camelia Sima,  MD 
Medicine 
Medicine 
Medicine 
 
Radiology 
Radiology 
Radiology 
Radiology 
Radiology 
Radiology 
 
Pathology 
Pathology 
Pathology 
Pathology 
 
Epidemiology and Biostatistics 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. New 
York, NY 10021 


Memorial Sloan-Kettering Cancer Center
IRB Protocol 
IRB#: 09-131 A(15)
Amended:  04/22/15
 
 
 
Ephraim Casper, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Sree Chalasani, MD 
Stefan Berger, MD 
Asma Latif, MD 
Afsheen Iqbal, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Steven Sugarman, MD 
Avni Desai, MD 
Julie Fasano, MD 
Marisa Siebel, MD 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Michelle Boyar, MD 
Philip Caron, MD, PhD 
Nancy Mills, MD 
Carolyn Wasserheit-Leiblich, 
MD 
Stephanie Smith-Marrone, 
MD 
Michael Fanucchi, MD 
Medicine – All Networks 
Medicine – Basking Ridge 
Medicine – Basking Ridge 
Medicine – Basking Ridge 
Medicine – Basking Ridge 
Medicine – Basking Ridge 
Medicine – Basking Ridge 
Medicine – Commack 
Medicine – Commack 
Medicine – Commack 
Medicine – Commack 
Medicine – Commack 
Medicine – Commack 
Medicine – Mercy 
Medicine – Mercy 
Medicine – Mercy 
Medicine – Mercy 
Medicine – Mercy 
Medicine – Phelps 
Medicine – Phelps 
Medicine – Phelps 
Medicine – Phelps 
 
Medicine – Phelps 
 
Medicine – Phelps 


Memorial Sloan-Kettering Cancer Center
IRB Protocol 
IRB#: 09-131 A(15)
Amended:  04/22/15
 
 
 
Consenting 
Professional(s)/Department: 
David Pfister, MD 
Eric Sherman, MD 
Alan Ho, MD 
Shrujal Baxi, MD 
 
Ephraim Casper, MD 
Sree Chalasani 
Martin Brower, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Han Xiao, MD 
Asma Latif, MD 
Afsheen Iqbal, MD 
 
Stefan Berger, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Steven Sugarman, MD 
Julie Fasano, MD 
Marisa Siebel 
Avni Desai 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Michelle Boyar, MD 
Philip Caron, MD, PhD 
Nancy Mills, MD 
Carolyn Wasserheit- 
Leiblich, MD 
Stephanie Smith-Marrone, 
MD 
Michael Fanucchi, MD 
Medicine 
Medicine 
Medicine 
Medicine 
 
Medicine – All Networks 
Medicine – Baskign Ridge 
Medicine – Basking Ridge 
Medicine – Basking Ridge 
Medicine – Basking Ridge 
Medicine – Basking Ridge 
Medicine – Basking Ridge 
Medicine – Basking Ridge 
 
Medicine – Commack 
Medicine – Commack 
Medicine – Commack 
Medicine – Commack 
Medicine – Commack 
Medicine – Commack 
Medicine – Commack 
Medicine – Mercy 
Medicine – Mercy 
Medicine – Mercy 
Medicine – Mercy 
Medicine – Mercy 
Medicine – Phelps 
Medicine – Phelps 
Medicine – Phelps 
Medicine – Phelps 
 
Medicine – Phelps 
 
Medicine – Phelps 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 


Memorial Sloan-Kettering Cancer Center
IRB Protocol 
IRB#:09-131A(14)
Amended:  04/16/14
 
 
 
Table of Contents 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL .............................................................. 1 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA................................................................ 2 
1.1 
SUMMARY ............................................................................................................ 2 
1.2 
SCHEMA ................................................................................................................ 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS.......................................................................... 4 
2.1 
PRIMARY OBJECTIVES...................................................................................... 4 
2.2 
SECONDARY OBJECTIVES................................................................................ 4 
3.0 
BACKGROUND AND RATIONALE............................................................................... 4 
3.1 
PALLIATIVE CHEMOTHERAPY FOR RECURRENT/METASTATIC HNSCC 
................................................................................................................................. 4 
3.2 
RATIONALE FOR MTOR INHIBITION IN HNSCC .......................................... 5 
3.3 
MTOR INHIBITORS + PLATINUM/TAXANE AGENTS IN HNSCC .............. 6 
3.4 
TEMSIROLIMUS (TORISEL®, CCI-779) ........................................................... 7 
3.5 
RATIONALE FOR DOSE AND SCHEDULE ...................................................... 8 
3.6 
RATIONALE FOR TISSUE CORRELATES........................................................ 8 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................... 10 
4.1 
DESIGN ................................................................................................................ 10 
4.2 
INTERVENTION ................................................................................................. 12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ..................................................................... 12 
5.1 
TEMSIROLIMUS................................................................................................. 12 
5.2 
PACLITAXEL ...................................................................................................... 13 
5.3 
CARBOPLATIN................................................................................................... 15 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ..................................................................... 16 
6.1 
SUBJECT INCLUSION CRITERIA.................................................................... 16 
6.2 
SUBJECT EXCLUSION CRITERIA................................................................... 16 
7.0 
RECRUITMENT PLAN................................................................................................... 17 
8.0 
PRETREATMENT EVALUATION ................................................................................ 18 
8.1 
REQUIRED DATA .............................................................................................. 18 
9.0 
TREATMENT/INTERVENTION PLAN ........................................................................ 18 
9.1 
SCHEDULE OF EVENTS ................................................................................... 18 
9.2 
CORRELATIVE STUDIES ................................................................................. 20 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ........................................ 22 
11.0 
TOXICITIES/SIDE EFFECTS ......................................................................................... 23 
11.1 
TOXICITY MANAGEMENT:  GENERAL CONSIDERATIONS .................... 23 
11.2 
HEMATOLOGIC TOXICITY MANAGEMENT ............................................... 24 
11.3 
HEPATIC TOXICITY MANAGEMENT ............................................................ 25 
11.4 
MUCOSITIS/STOMATITIS................................................................................. 27 
11.5 
NAUSEA/VOMITING ......................................................................................... 27 
11.6 
DIARRHEA .......................................................................................................... 28 
11.7 
SENSORY NEUROPATHY ................................................................................ 29 
11.8 
RENAL  TOXICITY MANAGEMENT .............................................................. 30 
11.9 
DERMATOLOGIC TOXICITY........................................................................... 31 


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11.10   HYPERLIPIDEMIA ............................................................................................. 31 
11.11   INTERSTITIAL LUNG DISEASE (ILD)............................................................ 32 
11.12  TOXICITIES NOT OTHERWISE SPECIFIED ................................................... 34 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT............... 34 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................ 36 
14.0 
BIOSTATISTICS ............................................................................................................. 37 
14.1 
PART 1 (PHASE 1) .............................................................................................. 37 
14.2 
PART 2 (PHASE II) ............................................................................................. 38 
14.3 
ACCRUAL RATE ................................................................................................ 40 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES............................................................................................................................. 40 
15.1 
RESEARCH PARTICIPANT REGISTRATION................................................. 40 
 
16.0 
DATA  MANAGEMENT ISSUES .................................................................................. 41 
16.1 
QUALITY ASSURANCE .................................................................................... 41 
16.2 
DATA AND SAFETY MONITORING ............................................................... 41 
17.0 
PROTECTION OF HUMAN SUBJECTS ....................................................................... 42 
17.1 
PRIVACY ............................................................................................................. 42 
17.2 
SERIOUS ADVERSE EVENT (SAE) REPORTING.......................................... 42 
17.3 
RISKS, BENEFITS, TOXICITIES/SIDE EFFECTS ........................................... 44 
17.4 
ALTERNATIVES/OPTIONS............................................................................... 44 
17.5 
FINANCIAL COSTS/BURDENS........................................................................ 44 
18.0 
INFORMED CONSENT PROCEDURES ....................................................................... 45 
19.0 
REFERENCES ................................................................................................................. 45 
20.0 
APPENDICES .................................................................................................................. 49 


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Amended: 04/22/15
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
1.1 
Summary 
 
This is a single institution, single arm study that will be open at MSKCC and regional network 
affiliates. 
 
Patients will not have received more than 2 prior chemotherapy regimens in the 
recurrent/metastatic disease setting. 
 
In Part 1 (Phase I) of the study, the primary endpoint is to establish the phase II recommended 
dose for the combination of temsirolimus + weekly paclitaxel + carboplatin.  Part 1 (Phase I) 
features a standard 3 + 3 phase I dose escalation design.  Up to 3 dose levels are planned in the 
Phase I portion of the study.  Rules for dose escalation are provided in Section 4.1.1.  The dose 
of temsirolimus (the experimental drug) is escalated at each dose level, and the doses of 
paclitaxel and carboplatin (the standard chemotherapeutic agents) are fixed.  The phase II 
recommended dose will be the maximum dose level at which <2/6 patients experience DLT. 
 
In view of the available PK evidence regarding everolimus + paclitaxel [1], everolimus + 
cisplatin [2], and the planned phase I study temsirolimus + q 3 week paclitaxel + carboplatin [3], 
PK studies are not planned in Part 1 of this study. 
 
Note:  The dose escalation plan was revised in August 2010, and patients were enrolled 
on dose level 2 of the revised protocol. 
 
Table 1:  Phase I Dose Levels (21 day cycle) 
Dose 
Level 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1 and 8 
1 
N/A 
N/A 
N/A 
2 
20 mg 
80 mg/m2 
AUC 1.5 
3 
25 mg 
80 mg/m2 
AUC 1.5 
 
In Part 2 (Phase II) of the study, the primary endpoint is to determine the objective response rate 
(CR or PR) after two cycles (approximately 6 weeks) of treatment with the combination of 
temsirolimus + weekly paclitaxel + carboplatin as palliative therapy for recurrent or metastatic 
HNSCC.  A two-stage design will be employed. 
 
Radiologic imaging of evaluable disease will take place after every 2 cycles.  Patients may 
remain on study until progression of disease or unacceptable toxicity. 


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Amended: 04/22/15
- 3 - 
 
 
 
1.2 
Schema 
 
 
 
 
 
• 
Recurrent/metastatic HNSCC 
• 
No more than 2 prior cytotoxic therapies for recurrent/metastatic disease 
 
 
 
 
 
Pre-treatment evaluation and Informed Consent 
 
 
 
 
21 day cycle 
Day 1:  Carboplatin (C), Paclitaxel (P), Temsirolimus (T) 
Day 8:  Carboplatin (C), Paclitaxel (P), Temsirolimus (T) 
Day 15:  rest 
 
 
 
 
Radiologic imaging after every 2 cycles (preferably CT or MRI) 


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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 
Primary Objectives 
 
 
 
2.1.1 
Part 1:  To establish the phase II recommended dose for the combination of temsirolimus 
+ weekly paclitaxel + carboplatin 
 
2.1.2 
Part 2:  To determine the objective response rate (CR or PR) after two cycles 
(approximately 6 weeks) of treatment with the combination of temsirolimus + weekly 
paclitaxel + carboplatin as palliative therapy for recurrent or metastatic HNSCC 
 
2.2 
Secondary Objectives 
 
2.2.1 
To establish the safety of temsirolimus + weekly paclitaxel + carboplatin 
 
2.2.2 
To estimate median overall survival 
 
2.2.3 
To identify potential molecular markers of resistance to mTOR inhibition in tumor 
specimens obtained as part of routine clinical care 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
 
 
3.1 
Palliative chemotherapy for recurrent/metastatic HNSCC 
 
Single agent chemotherapy as palliative treatment typically achieves objective responses in 10- 
30% of patients.  Combination chemotherapy regimens appear to be associated with increased 
response rates and often with increased toxicities, but generally not with increased survival [4]. 
 
No combination chemotherapy regimen appears to be superior to another in terms of survival for 
patients with advanced head and neck cancer.  A Southwest Oncology Group study reported by 
Forastiere randomized 277 patients with advanced head and neck cancer to treatment with 
cisplatin plus 5-fluorouracil, carboplatin plus 5-fluorouracil, or methotrextate monotherapy.   In 
the comparision of the doublet regimens, cisplatin plus 5-fluorouracil yielded a higher response 
rate than carboplatin plus 5-fluorouracil (32%  versus 21 %, p = 0.05). However, median 
survival times were similar in all three treatment groups in the study [5].  Gibson reported a 
randomized comparison of cisplatin plus 5-fluorouracil (CF) versus cisplatin plus paclitaxel (CP) 
for 218 patients with advanced head and neck cancer.  Response rate (27% in CF group, 26% in 
CP group) and median survival (8.7 months in CF group, 8.1 months in CP group) did not differ 
signicantly [6]. 


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Amended: 04/22/15
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These studies indicate the limitations of cytotoxic chemotherapy in the recurrent or metastatic 
disease setting, and highlight the need for new agents.  Cetuximab, a mononoclonal antibibody 
directed against the epidermal growth factor receptor (EGFR), demonstrated an objective 
responsre rate of 13% in a phase II study of 103 patients with platinum-refractory recurrent 
and/or metastatic HNSCC [7].   Treatment was generally well tolerated and the most common 
adverse event was rash. In a phase III study by Burtness for patients with recurrent or metasatic 
disease who had not received any prior palliative chemotherapy, 117 subjects were randomized 
to cisplatin plus cetuximab versus cisplatin plus placebo. Objective response rate was higher for 
cisplatin plus cetuximab (26% versus 10%, p = 0.03),  but there was no significant difference in 
survival between the two groups [8]. 
 
The addition of cetuximab to platinum-based chemotherapy was investigated further in a 
randomized clinical trial for 442 patients with untreated recurrent or metastatic head and neck 
cancer [9].  Patients were randomized to cisplatin (or carboplatin, at the disretion of the 
investigator) plus 5-fluorouracil in the control group  versus the cisplatin (or carboplatin)/5- 
fluorouracil doublet plus weekly cetuximab in the experimental group.  Objective response rate 
(20% v. 36%, p < 0.001), progression-free survival (3.3 v. 5.6 months, p<0.001), and overall 
survival (7.4 versus 10.1 months, p = 0.04) all favored the experimental group.  Despite the 
addition of cetuximab as a therapeutic option, outcomes for patients with recurrent or metasatic 
head and neck cancer remain poor.  The median survival in this group of patients is typically 10 
months or less. 
 
3.2 
Rationale for mTOR inhibition in HNSCC 
 
EGFR and other transmembrane receptors converge to control a variety of intracellular signaling 
pathways, such as the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin 
(mTOR) pathway.   The importance of the PI3K/Akt/mTOR pathway in HNSCC was 
demonstrated in a study by the Head and Neck Cancer Tissue Array Initiative, which evaluated 
the this pathway in a study of 547 pathology cores, including controls, in a tissue microarray 
(TMA) [10].  The TMA was interrogated with antibodies directed against key signaling 
molecules in head and neck cancer, including p53, the epidermal growth factor receptor (EGFR), 
and components of the Akt-mTOR pathway.  Alterations of the PI3K/Akt/mTOR pathway were 
found in most cases.  As shown in Figure 1, pAKTSer473, pAKTThr308, and pS6 were significantly 
higher in HNSCC tumors, compared with normal mucosa, across all degrees of differentiation. 


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Figure 1:  Distribution of immunoreactivity segregated by differentiation groups. 
Differences in normal (N) tissue versus well differentiated (W), moderately differentiated 
(M), and poorly differentiated (P) tumors were significant (*) for all proteins except 
pEGFR (NS) [10]. 
 
A key finding in this work was that the majority of head and neck cancers appear to have EGFR- 
independent activation of the PI3K/Akt/mTOR pathway.  Within the collection of HNSCC 
samples, an unsupervised clustering approach provided a clear separation of certain clusters, and 
demonstrated that the pathway often appeared to be activated in the setting of negative staining 
for pEGFR [10].  This suggests that activation of the PI3K/Akt/mTOR pathway may occur 
independently of EGFR activation in many head and neck cancer patients.  These findings may 
provide insight into the relatively low-to-modest clinical efficacy of EGFR inhibition strategies 
in this disease [11], and suggest that downstream inhibition of mTOR merits further study as a 
potential therapeutic strategy in HNSCC. 
 
3.3 
mTOR inhibitors + platinum/taxane agents in HNSCC 
 
Rapamycin, the prototypic mTOR inhibitor, demonstrates modest antiproliferative effects against 
HNSCC cell lines, with IC50s in the range of 5 – 20 µM [12].  In HNSCC xenografts, dramatic 
tumor growth inhibition was achieved with temsirolimus [13] or rapamycin [14]. 
Because it is 
probable that mTOR inhibitors will have no better than modest clinical activity against HNSCC 
when given as single agents, the true utility of these agents may derive from their ability to 
potentiate the antitumor effects of other cytotoxic chemotherapeutic agents. 
 
In 1995, Mills and coworkers reported that rapamycin enhances the cytotoxic effects of cisplatin 
against a human leukemia cell line (HL-60) and an ovarian cancer cell line (SKOV3) [15]. 
Subsequent pre-clinical studies demonstrated additive or synergistic effects when mTOR 
inhibitors are combined with platinum or taxane chemotherapy agents in studies of non-small 
cell lung cancer [16], breast cancer [17],  and more recently HNSCC cell lines [12].   In the study 
of HNSCC cell lines, mTOR inhibition yielded synergistic effects when combined with 
carboplatin and paclitaxel [12]. The authors proposed that mTOR inhibition may be a strategy to 
decrease resistance to paclitaxel and carboplatin. Consistent with this, mTOR inhibition appears 
to reverse resistance to paclitaxel in a cervical cancer cell line (CaSki) [18], and also appears to 
reverse resistance to cisplatin in lung cancer cell line (SCLCSR2) [19]. 


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Amended: 04/22/15
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We have recently completed the dose escalation phase of IRB 06-129, “A Phase I study of 
Weekly Low-Dose Cisplatin Plus Escalating Doses of Oral RAD001 (Everolimus) for Patients 
with Advanced Solid Tumors.”   Partial response has been seen in pulmonary carcinoid (n=1) 
and HNSCC (n=1).  Another HNSCC patient achieved a minor radiographic response, but was 
removed from study after experiencing a pulmonary embolus during cycle 2 of RAD001 + 
cisplatin.  Off study, the patient subsequently received an additional 2 cycles of cisplatin alone 
with progression of disease [2]. 
This phase I experience suggests that mTOR inhibitors + 
platinum based chemotherapy may achieve greater activity than would be seen with cisplatin 
alone, although no firm conclusions can be drawn from this small study.  The favorable safety 
profile of the IRB 06-129 regimen suggests that it should be feasible to add paclitaxel to the 
mTOR inhibitor + platinum backbone, which is an obvious research direction to pursue because 
paclitaxel has significant palliative activity in HNSCC [20]. 
 
3.4 
Temsirolimus (Torisel®, CCI-779) 
 
Temsirolimus (Torisel®, CCI-779)  and other rapamycin analogues (“rapalogues”), such as 
everolimus and deforolimus, share the same mechanism of action:  binding  to the intracellular 
protein FKBP-12 to form a complex that inhibits mTOR signaling [21].  In phase I studies, 
temsirolimus demonstrated encouraging activity against renal cell carcinoma [22].   A phase II 
study randomized 111 patients with cytokine-refractory metastatic renal carcinoma to receive 
one of three doses of temsirolimus, either 25, 75 or 250 mg intravenously (IV) once weekly. 
Median time to progression was 5.8 months, which compared favorably to the typical 2.5 to 3.0 
months time to progression seen with other investigational agents following cytokine therapy 
[23].  Given the similar outcomes with the three doses of temsirolimus, the lowest dose of 25 
mgIV once weekly was chosen for the subsequent pivotal phase III trial [24]. 
 
The pivotal phase III trial included 626 previously untreated patients with advanced renal cancer 
randomized to one of three arms; a control group receiving escalating doses of alpha interferon 
alone, one treatment arm of 25 mg IV once weekly temsirolimus and another treatment arm 
consisting of a lower dose of temsirolimus (15 mg) IV once weekly combined with interferon 
alpha 6 MU subcutaneously three times per week [24].  The overall survival was significantly 
greater in the temsirolimus group (median value 10.9 months) compared with the interferon 
monotherapy group (median value 7.3 months).  The overall survival of patients receiving the 
combination of temsirolimus and interferon was not greater than that of patients receiving 
interferon alone.   Among the grade 3 and 4 toxicities, asthenia was the most common. 
Temsirolimus was also associated with a variety of laboratory anomalies, including anemia, 
hyperglycemia, hyperlipidemia and hypercholesterolemia.  In 2007, temsirolimus received FDA 
approval for use in patients with advanced kidney carcinoma. 


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3.5 
Rationale for Dose and Schedule 
 
We feel that the appropriate follow-up clinical trial is a phase I/II study of temsirolimus + weekly 
paclitaxel + carboplatin. Studies in other tumor types suggest that paclitaxel on a weekly 
schedule has a more favorable toxicity profile than q 3 week paclitaxel [25] [26].   The weekly 
paclitaxel schedule pairs well with weekly temsirolimus administration.  Weekly everolimus 
was well tolerated when combined with weekly paclitaxel in a phase I study, and no significant 
pharmacokinetic interaction between the mTOR inhibitor and paclitaxel was identified [1].   The 
regimen of carboplatin (day 1) and paclitaxel (days 1, 8, and 15) on a 28-day schedule has 
excellent activity as  induction chemotherapy for patients with local-regionally advanced 
HNSCC [27].  In the current study, we propose somewhat lower doses of carboplatin and 
paclitaxel in the palliative-intent setting for pre-treated patients.  The regimen in this proposal, if 
it shows significant activity in this study, would be attractive for further study as an induction 
chemotherapy regimen in HNSCC because the carboplatin-based regimen may be better 
tolerated than the widely-used cisplatin-based induction chemotherapy regimens [28-30]. 
 
The dose escalation scheme selected for this study builds upon the phase I experience reported 
by Oza et al [31], in which temsirolimus (25 mg intravenously, day 1 and day 8) was well 
tolerated when combined with paclitaxel (175 mg/m2, day 1) + carboplatin (AUC 5, day 1) on a 
21 day cycle.  However, when temsirolimus was given on Days 8 and 15 (combined with 
paclitaxel 175 mg/m2 and carboplatin AUC 5 on day 1 of a 21 day cycle), treatment was not 
feasible due to myelosuppression. 
 
The current study features a 21-day cycle with a break week. In view of the potential for 
myelosuppression with the addition of temsirolimus to standard chemotherapy, 3 dose levels of 
temsirolimus (15 mg, 20 mg, and 25 mg) are planned.  The doses of the standard 
chemotherapeutic agents (carboplatin, paclitaxel) are fixed. Dose escalation beyond 
temsirolimus 25 mg weekly is not planned because this is the FDA-approved dose for this agent 
in advanced renal cell cancer [24]. 
 
3.6 
Rationale for Tissue Correlates 
 
Basic and preclinical studies from the laboratories of Dr. Wendel and others have established the 
striking synergy of drugs like temsirolimus with conventional chemotherapeutic drugs, and 
revealed a strong dependence of this anti-tumor effect on the genetics of the tumor [32-33]. 
Accordingly, Secondary Aim 2.2.4 of the protocol is “To identify potential molecular markers of 
resistance to mTOR inhibition in tumor specimens obtained as part of routine clinical care.”  The 
intent of this secondary aim is to collect pilot data that may guide the development of a new 
HNSCC research program in Dr. Wendel’s lab. 


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Our working hypothesis is that HNSCC tumors with constitutive activation of the Akt/mTOR 
pathway (i.e. due PI3K mutation or PTEN loss) will be associated with responsiveness to 
temsirolimus-based treatment, and HNSCC tumors with lesions that act downstream of mTOR 
(ie, eIF4E) or disable apoptosis (bcl-2 or loss of p53) will be associated with resistance to 
temsirolimus-based treatment. 
 
HNSCC is a genetically heterogeneous disease and we have assembled a panel of cell lines that 
represents this heterogeneity.   Specifically, we will study cell lines with known mutational 
activation of the Akt-mTOR signaling pathway, such as Detroit 562 cells, which harbor a 
PIK3CA mutation [34], RPMI 2650 cells that activate mTOR via a LKB1 exon 5 missense 
mutation [35], the FaDu line lacks PTEN [36]. We will also include cell lines harboring 
mutations in apoptotic regulators, such as SCC-15, which is p53 mutant and expresses high 
levels of Bcl2 [37]. Lines like CAL27 [38], SCC-25 [39] are less well characterized and will be 
examined here. Finally, while A549 cells are not primarily HNSCC, but a pathologically similar 
lung cancer line, this line is especially interesting as it maintains an intact mTOR-mediated 
feedback signal that has been reported to counter the cellular effects of mTOR inhibition [40]. 
Thus, these cell lines represent the major types of genetic lesions seen in HNSCC. 
 
We will analyze these HNSCC lines for markers that have been implicated in rapamycin 
(temsirolimus) responses. Briefly, we will use established assays (immunoblot, expression and 
sequence analyses) to probe mTOR activation, parallel and downstream signaling pathways, and 
regulators of cell death. These cell lines will also provide us with an opportunity to evaluate 
response patterns to temsirolimus in a panel of HNSCC lines, and to identify associations with 
marker expression as determined above.  Ultimately, these in vitro studies will inform our 
interpretation of data obtained from clinical specimens. 
 
The proposed tissue correlative studies, which are described in Section 9.2 of this protocol, build 
largely on previous investigations of PI3K/Akt/mTOR signaling in other tumor types by Dr. 
Wendel.  Key observations from this body of work include the following: 
 
1)   There is dramatic synergy of mTOR inhibition with chemotherapeutics in vivo [33, 41]. 
2)   This effect was strictly dependent on the tumor genotype, e.g. PTEN, Akt, Rheb and 
TSC2 were positive and Bcl2 negative predictors [42]. 
3)   The  eIF4E  translation  factor  is  an  oncogene  in  vivo  and  can  block  responses  to 
rapamycin [33]. Of note: eIF4E is an independent predictor of outcome in HNSCC [43]. 
4)   eIF4E functions in cancer require the eIF4E kinase MNK [44-45]. 
5)   Direct mTOR activation by the Rheb GTPase is sufficient for oncogenesis [46]. 
6)   Tumors that express Rheb are particularly sensitive to rapamycin (temsirolimus) and that 
inhibitors of farnesyltransferase direct block Rheb activity [47]. 
7)   Apoptotic regulators including p53 or Bim, and also parallel kinase pathways (e.g. Pim 
kinases) can affect rapamycin (temsirolimus) activity in vivo [42, 48]. 
8)   Levels of the anti-apoptotic Mcl1 protein are regulated by mTOR and eIF4E. Moreover, 
Mcl1 can block the therapeutic effect of mTOR inhibition [46, 49]. 


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4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This will be an open-label non-randomized phase I/II study open at MSKCC and regional 
network affiliates. 
 
 
 
4.1.1 
Part I (Phase I) 
 
Part 1 (phase I) features three planned dose levels. 
 
Note:  The dose escalation plan was revised in August 2010, and patients were enrolled 
on dose level 2 of the revised protocol. 
 
Table 1:  Phase I Dose Levels (21 day cycle) 
 
Dose Level 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1 and 8 
1 (starting dose) 
N/A 
N/A 
N/A 
2 
20 mg 
80 mg/m2 
AUC 1.5 
3 
25 mg 
80 mg/m2 
AUC 1.5 
 
Cycle length is 21 days.  If 0/3 patients experience DLT during Cycle 1 at a given dose level, 3 
patients will entered at the next higher dose level.  If 1/3 patients experienced DLT during Cycle 
1, 3 additional patients will be entered at this dose level (for a total of 6). 
 
If none of these additional 3 patients experience DLT during Cycle 1, escalation to the next 
higher dose level will take place. If at least one of the additional patients experience DLT during 
Cycle 1, the MTD is exceeded. 
 
If the MTD is exceeded at a dose level, patients may be enrolled at the next lower dose level. 
This lower dose at which patients tolerate the combination would then become the phase II 
recommended dose if no more than 1/6 patients experience a DLT during Cycle 1. 
 
There will be no escalation beyond Level 3.  If 0/3 or 1/3 patients experience dose-limiting 
toxicity at Level 3, this dose level will be expanded to 6 patients.  If no more than 1/6 patients 
experience DLT at Level 3, this will be the phase II recommended dose. 
 
Adverse events (AEs) will be assessed according to NCI common toxicity criteria (CTC) 
version 3.0.  Dose Limiting Toxicity (DLT) include all toxicities of grade 3 or higher, with 
the exception of those listed below: 


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The following will not be considered to be DLT: 
● 
Grade 3 dysphagia and/or grade 3 odynophagia (pain) (even if PEG tube is 
required), if the investigator’s impression is that dysphagia/odynophagia is due to 
head and neck cancer 
● 
Grade 3 or 4 lymphopenia 
● 
Grade 3 fatigue 
● 
Grade 3 acneiform rash 
● 
Grade 3 hypomagnesemia 
● 
Grade 3 diarrhea lasting ≤  48 hours 
● 
Grade 3 nausea and/or grade 3 vomiting lasting ≤ 72 hours 
● 
Uncomplicated Grade 3 or 4 neutropenia lasting ≤ 7 days 
● 
Grade 3 thrombocytopenia 
● 
Grade 3 low hemoglobin, even if treatment is given with stimulators of 
erythropoiesis or pack red blood cell transfusions 
● 
Non-infectious pneumonitis, because this is an uncommon temsirolimus-related 
toxicity that is not strictly related to the dose levels in this study 
● 
Deep vein thrombosis or pulmonary embolus, because such events are common in 
patients with cancer and are not strictly related to chemotherapy dose 
● 
Hypersensitivity reaction to any of the study drugs regardless of grade, because 
such events are not strictly dose-related. 
● 
Grade 3 hyperglycemia 
● 
Uncomplicated Grade 4 hyperglycemia for ≤ 24 hours 
● 
Grade 3 hypercholesterolemia 
● 
Uncomplicated Grade 4 hypercholesterolemia for  ≤ 7 days 
● 
Grade 3 hypertriglyceridemia 
● 
Uncomplicated Grade 4 hypercholesterolemia for  ≤ 7 days 
● 
Grade 3 hypokalemia 
● 
Grade 3 hypocalcemia 
● 
Grade 3 hypophosphatemia 
● 
Grade 3 leukopenia 
 
 
 
4.1.2 
Part 2 (Phase II) 
 
Part 2 (Phase II) of the study will open after the phase II recommended dose is established in Part 
1.  In Part II, all patients will be treated at the phase II recommended dose. 
 
In the first stage of this design, 11 patients will be accrued.  If 2 or less patients among the first 
11 patients have a response after 2 cycles of treatment, then the study will be terminated and 
declared negative. If 3 or more patients have a response, than an additional 25 patients will be 
accrued to the second stage. At the end of the study, if 12 or more patients have a response after 
2 cycles of treatment out of a total of 36 patients enrolled, the regimen will be considered worthy 
of further investigation. 


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4.2 
Intervention 
 
In Part 1, on Cycle 1/Day 1 patients receive paclitaxel (P), carboplatin (C), and temsirolimus (T) 
intravenously on Days 1 and 8 of each cycle, according the dose level plan.  The sequence of 
administration will be P→C→T, in view of preclinical data that administration of mTOR 
inhibitor prior to paclitaxel is suboptimal in HN cell lines [12].  Cycle 1/Day 15 marks the 
beginning of the rest week in the 21 day cycle.  During Cycle 1, patients are evaluated for each 
weekly treatment  in clinic.  For Cycle 2 and beyond, clinic evaluation will occur on Day 1 of the 
cycle, and additional clinic evaluations may be scheduled as needed on other dates.  During the 
rest week at the end of Cycle 2, patients undergo response assessment imaging (CT and/or MRI) 
of sites of measurable disease.  Patients may remain on study until time of progression of disease 
and/or unacceptable toxicity. 
 
In view of the available PK evidence regarding everolimus + paclitaxel [1], everolimus + 
cisplatin [2], and the planned phase I study temsirolimus + q 3 week paclitaxel + carboplatin [3], 
PK studies are not planned in Part 1 of this study. 
 
In Part 2, of the study, patients are treated according to schedule used in Part 1, at the phase II 
recommended dose established in Part 1.  Adverse event management guidelines, including dose 
reductions for toxicity, will be provided in Section 11 of this protocol document. 
  
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
Temsirolimus 
 
Availability 
 
Temsirolimus is provided by Pfizer in kits containing 25 mg/mL temsirolimus plus a 1.8 
mL diluent vial. 
 
Storage and Stability 
 
Temsirolimus should be stored at refrigerated temperature (2 – 8  C).  Do not freeze. 
Protect vials from light. Reconstituted vials are stable for 24 hours at room temperature 
in the original vial.  Infusions prepared in Normal Saline are stable for 6 hours. 
 
Preparation and Administration 
 
Temsirolimus must be diluted prior to infusion.  Inject 1.8 mL of the diluent into the vial 
of temsirolimus injection.  The temsirolimus vial contains an overfill of 0.2 mL (30 
mg/1.2 mL).  Therefore, addition of the diluent yields a concentration of 10 mg/mL, with 
a total volume of 3 mL.  Mix well by inversion of the vial. Allow sufficient time for air 
bubbles to subside. 


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Do not use PVC infusion bags or infusion sets. Add the calculated dose to 250 mL NS. 
Dispense infusions in amber bag.  Premedication with diphenhydramine 25 – 50 mg IV 
should be given to prevent/reduce the severity of reactions, at the discretion of the 
investigator. Administer temsirolimus as an IV infusion over approximately 30 minutes. 
 
 
 
Toxicities 
 
Metabolic: hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypophosphatemia, 
hypokalemia 
 
Hematologic:  anemia, thrombocytopenia, leukopenia, lymphopenia 
Gastrointestinal:  mucositis, anorexia, nausea, vomiting, diarrhea 
Renal:  elevated serum creatinine, renal failure 
Hepatic:  elevated liver function tests 
 
Pulmonary:  dyspnea, cough, interstitial lung disease (ILD) 
Reproductive:  possible infertility; may be teratogen 
Miscellaneous:  fatigue, asthenia, moderate-severe hypersensitivity reactions, abnormal 
wound healing, rash, edema, headache, temporary muscle and joint aches/pains 
 
5.2 
Paclitaxel 
 
Availability 
 
Paclitaxel is commercially supplied as a non-aqueous solution intended for dilution with 
suitable parenteral fluid prior to intravenous infusion.  Paclitaxel is available as 30 mg 
(5ml), 100 mg (16.7 ml) and 300 mg (50 ml) multiuse vials. 
 
Storage and Stability 
 
Unopened vials of paclitaxel are stable until the date indicated on the package when 
stored between 20 – 25 C, in the original package. Neither freezing nor refrigeration 
adversely affects the stability of the product.  Upon refrigeration, components of the 
paclitaxel vial may precipitate, but will re-dissolve upon reaching room temperature with 
little or no agitation. 


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Preparation and Administration 
 
Prior to infusion paclitaxel should be diluted in 0.9% Sodium Chloride injection or 5% 
Dextrose injection or 5% Dextrose and 0.9% Sodium Chloride or 5% Dextrose in Ringers 
Lactate to a final concentration of 0.3 to 1.2 mg/mL.  Paclitaxel must be prepared in 
glass, polypropylene or polyolefin containers and non-PVC containing infusion sets. 
Prepared solutions are stable at room temperature (20-25 C) and protected from light, up 
to 72 hours. In-line filtration with micropore no greater than 0.22 micron filter is 
required.  Chemo dispensing pin devices or similar devices should not be used with 
paclitaxel vials since they can cause the stopper to collapse resulting in loss of sterile 
integrity 
 
Safety Precautions – Paclitaxel 
 
Paclitaxel does not contain antimicrobials; therefore, extreme care must be taken to 
ensure sterility of the prepared solution. 
 
Subjects should be pre-medicated to reduce risk of severe hypersensitivity reaction. 
Decadron pre-medication prior to paclitaxel will follow institutional guidelines, and may 
be tapered at the discretion of the investigator. 
 
Toxicities 
 
Hematologic:  neutropenia, leukopenia, thrombocytopenia, anemia 
 
Gastrointestinal:  nausea/vomiting, diarrhea, mucositis 
 
Hepatic:  elevated liver function tests 
 
Cardiac:  heart block, bradycardia 
 
Neurologic: peripheral neuropathy, arthralgia/myalgia 
 
Dermatologic:  alopecia, onycholysis 
 
Reproductive:  Infertility; may be teratogen 
 
Miscellaneous:  moderate – severe hypersensitivity reactions, flushing, rash, dyspnea, 
fatigue 


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5.3 
Carboplatin 
 
Availability 
 
Carboplatin is commercially supplied as a sterile lyophilized powder in single-dose vials 
containing 50 mg, 150 mg, or 250 mg of the drug, in equal parts by weight with mannitol. 
 
Storage and Stability 
 
Carboplatin in unopened vials is stable for as long as three years when stored at 
temperatures of 15-30 C and when protected from light. 
 
Preparation 
 
Immediately prior to use, each vial of carboplatin should be reconstituted with either 
sterile water for injection, D5W, or sodium chloride injection, in sufficient volume to 
produce a carboplatin concentration of 10 mg/ml. 
 
Administration 
 
IV infusion over 30 minutes.  Do not use aluminum products in the mixing or 
administration of carboplatin because aluminum may react with it and cause potential 
loss of potency.  Anti-emetics generally will follow institutional guidelines, but may be 
altered at the discretion of the investigator. 
 
Toxicities 
 
Hematologic:  leukopenia, anemia, thrombocytopenia 
 
Gastrointestinal: anorexia, nausea, vomiting, hyperbilirubinemia, elevated liver enzymes. 
Renal:  rarely, alterations in renal function are seen. 
Neurosensory:  sensory neuropathy, tinnitus, high frequency hearing loss 
 
Reproductive:  Infertility; may be teratogen 
 
Miscellaneous:  rarely, severe allergic reaction; hair thinning and hair loss 


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6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
6.1.1 
Patients must have microscopically confirmed head and neck squamous cell carcinoma 
(HNSCC), recurrent and/or metastatic. 
 
Note: Confirmation of HNSCC may be obtained from the primary site or metastatic 
disease. 
 
6.1.2 
Patients must be at least 18 years of age. 
 
6.1.3 
Karnofsky Performance status must be ≥ 70%. 
 
6.1.4 
Disease must be measurable by RECIST criteria. 
 
6.1.5 
At least 6 weeks must have elapsed from previous radiation therapy.  Patient must have 
recovered from the acute toxic effects of treatment prior to study enrollment. 
 
6.1.6 
Adequate organ function, as follows: 
Adequate bone marrow reserve:  absolute neutrophil count (ANC) ≥ 1.5 X 109/L, 
platelets ≥ 100 X 109/L, and hemoglobin ≥ 9 g/dL. 
 
Hepatic:  total bilirubin within normal limits (≤ 1.0 mg/dL); alkaline phosphatase 
(AP), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 X 
ULN  (upper limit of normal) 
 
Renal:  Serum creatinine ≤ 1.3 mg/dL.  Patients with serum creatinine > 1.3 
mg/dL may be eligible if creatinine clearance (CrCl) ≥ 45 mL/min based on the 
standard Cockroft and Gault formula. 
 
6.1.7 
Patients of childbearing potential must have a negative serum pregnancy test within 14 
days of treatment. Patients must agree to use a reliable method of birth control during and 
for 3 months following the last dose of study drug. 
 
6.1.8 
Patients must sign an informed consent document. 
 
6.2 
Subject Exclusion Criteria 
 
6.2.1 
Previous exposure to temsirolimus or other mTOR inhibitors 
 
6.2.2 
More than 2 prior cytotoxic regimens in the recurrent/metastatic disease setting 
 
6.2.3 
History of any brain metastases 


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6.2.4 
Patients who require concomitant medications that are metabolized by hepatic CYP3A4, 
due to potential drug-drug interaction with temsirolimus (prohibited medication list 
provided in Appendix A.) 
 
6.2.5 
Patients with known active interstitial pneumonitis 
 
6.2.6 
Active infection or serious underlying medical condition that would impair the patient’s 
ability to receive protocol treatment. 
 
6.2.7 
Women who are pregnant or lactating 
 
6.2.8 
Other active malignancy, other than indolent malignancies which the investigator 
determines are unlikely to interfere with treatment and safety analysis 
 
6.2.9 
Diagnosis of Nasopharyngeal cancer is excluded. 
 
6.2.9 
Patients with multifocal peripheral sensory alterations or paresthesias (including tingling) 
interfering with function, per patient report (example: activities of daily living) 
 
6.2.10  Therapeutic anticoagulation with Coumadin (warfarin) 
 
6.2.11  Hypertriglyceridemia  ≥ grade 2 (CTCAE version 3.0). 
 
6.2.12  Impaired lung function: O2 saturation 88% or less at rest on room air by Pulse Oximetry. 
If O2 saturation is ≤ 88% at rest, further pulmonary function tests (PFTs) should be 
ordered to confirm normal pulmonary function and eligibility. 
 
7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or research team at Memorial Sloan-Kettering Cancer Center (MSKCC). 
Patient recruitment will occur in medical oncology clinics of the Head and Neck Disease 
management team at main campus and in medical oncology clinics of MSKCC regional network 
sites.  If the investigator is a member of the treatment team, s/he will screen their patient’s 
medical records for suitable research study participants and discuss the study and their potential 
for enrolling in the research study.  Potential subjects contacted by their treating physician will 
be referred to the investigator/research staff of the study. 


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8.0 
PRETREATMENT EVALUATION 
 
8.1 
Required Data 
 
8.1.2 
Complete medical history including current medications, physical examination including 
evaluation of Karnofsky performance status. 
 
8.1.3 
Pathology review at MSKCC must confirm diagnosis of HNSCC prior to treatment. 
Confirmation of HNSCC may be obtained from the primary site or metastatic disease. 
 
8.1.4 
The following laboratory studies will be obtained within 21 days prior to therapy: 
Complete blood count with white blood cell differential and platelet counts; 
Comprehensive profile (including electrolytes, bicarbonate, blood urea nitrogen (BUN), 
creatinine, glucose, alkaline phosphatase, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin, total protein, albumin, and glucose); lipid panel; 
prothrombin time and activated partial thromboplastin time. 
 
8.1.5 
Serum pregnancy test for women of childbearing potential within 14 days prior to 
therapy. 
 
8.1.6 
Electrocardiogram within 8 weeks prior to therapy 
 
8.1.7 
Radiologic imaging of neck (preferably, CT scan or MRI), chest (preferably, CT scan), 
and any other sites of measureable disease will be obtained within 4 weeks prior to 
therapy.  Dermal lesions may be evaluated by physical exam, supplemented by 
photographs. 
 
 
8.1.8 
CT scan of the chest (with or without contrast). 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
Schedule of Events 
9.1.1 
Every attempt will be made to administer chemotherapy on schedule. Treatment may be 
given 2 working days before or after the scheduled date, if necessary.  Treatment delay of 
up to 21 days  may be allowed for medical or personal reasons.  Reasons for treatment 
delay will be outlined in the medical record. 
 
9.1.2 
To faciliate the timely administration of chemotherapy on treatment days, CBC and BMP 
with magnesium level  may be obtained 1 calendar day prior the chemotherapy treatment 
date, if need be.  For Day 1 of each cycle, liver Function Tests and Lipid Panel may be 
obtained within 7 calendar days prior to the chemotherapy treatment date, if need be. For 
Cycle 1 only,  Liver Function Tests and Lipid Panel are optional if previously obtained 
within 14 days prior. 


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9.1.3 
On (or before, See Section 9.1.2) Day 1 of each cycle, complete blood count and basic 
metabolic panel with magnesium level, liver function tests, and lipid panel will be 
checked. 
 
Note in clarification: Lipid panel results are not necessary to clear a patient for treatment. 
 
9.1.4 
Patients will be examined on Day 1 of each cycle.  During Cycle 1 of the Phase I portion 
of the study patients will be evaluated for each weekly treatment in clinic by  physician 
and/or nurse.  After  Cycle 1 in Phase 1, the requirement will be one MD clinic visit per 
cycle, with additional clinic visits scheduled as needed.  In Phase II of the study, again 
the requirement will be one MD clinic visit per cycle, with additional clinic visits 
scheduled as needed. 
 
9.1.5 
On Day 1 and Day 8 of each Cycle, patients receive paclitaxel (P), carboplatin (C), and 
temsirolimus (T) intravenously according the dose level plan. The sequence of 
administration will be P→C→T. 
 
 
Carboplatin dose iscalculated according to the Cockcroft and Gault Method.  For Cycle 
1/Day 1 dose, the investigator (at his/her discretion) may use either (a) the serum 
creatinine and body weight measurements obtained on Cycle 1/Day 1, or (b) the most 
recent serum creatinine and body weight measurements prior to Cycle 1/Day 1, if this 
was obtained within 21 days prior to therapy. 
For overweight patients (body mass index ≥ 27), adjusted body weight is allowed for the 
calculation of carboplatin and paclitaxel dosing in this protocol [50], but is not mandatory, at the 
discretion of the investigator. 
 
The study will adhere to recent FDA guidelines regarding capping of carboplatin dosage 
(http://www.hematology.org/News/?filter_Id=335).  Specifically, the FDA recommends capping 
the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to 
overdosing. Based on the Calvert formula described in the carboplatin label, the maximum doses 
were calculated as follows in the recent FDA memorandum regarding carboplatin dosing: 
Total Carboplatin Dose (mg) = (target AUC) x (GFR +25)  [Calvert formula] 
 
Maximum Carboplatin Dose (mg) = target AUC (mg•min/mL) x (150 
mL/min) 
 
The maximum dose is based on a GFR estimate that is capped at 125 mL/min 
for patients with normal renal function.  No higher estimated GFR values 
should be used. 
 
For a target AUC = 1.5, the maximum dose is 1.5 x 150 = 225 mg 
For a target AUC = 1, the maximum dose is 1 x 150 = 150 mg 


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9.1.6 
On Day 15 of each cycle, patients begin the rest week. 
 
9.1.7 
Guidelines for dose reductions are provided in Section 11. 
 
 
If carboplatin dose reduction is not required at the completion of a cycle, the investigator 
may use the same “flat dose” of carboplatin for the next cycle.  Alternatively, at his/her 
discretion, the investigator may re-calculate the dose of carboplatin for Day 1 of the new 
cycle, according the Cockcroft and Gault Method, as discussed in Section 9.1.5. 
 
9.1.8 
Radiologic imaging of indicator lesions will be performed after every 2 cycles of therapy. 
Either CT scans and/or MRI scans will be performed to evaluate a particular lesion. 
Additional imaging may be obtained as clinically indicated. Dermal lesions may be 
evaluated by physical exam, supplemented by photographs. 
 
 
Radiologic response assessment typically will take place during the “break week” of each 
even-numbered cycle.  For patients who develop intercurrent medical problems or 
logistical issues, response assessment and study treatment may be delayed at the 
discretion of the treating physician. 
 
9.1.9 
Treatment may be discontinued at any time for progression of disease, unacceptable side 
effects, life-threatening toxicity, patient request, or investigator judgment. 
 
9.1.10  At any time after 6 cycles of study treatment, patients who maintain stable disease (or 
better) have the option of remaining on treatment with temsirolimus alone.  The 
temsirolimus dose and schedule would be unchanged (2 weeks on, 1 week off). 
However, a clinic visit with laboratory studies would only be required on week 1 of each 
cycle for patients who opt to receive temsirolimus alone.  Response assessment interval 
typically would remain q 2 cycles. (For patients who remain on study beyond the imaging 
assessment at the end of cycle 6, the interval of subsequent response assessment imaging 
studies may be increased to q3 cycles, at investigator discretion.)   For any patient who 
opts to receive temsirolimus alone after 6 cycles, the reasons for the treatment change 
will be documented in a clinic note. 
 
 
Alternatively, patients may continue to receive temsirolimus + carboplatin + paclitaxel, 
per protocol, after completion of 6 cycles of treatment.  If a patient opts to receive 
temsirolimus alone, he/she will not be allowed to receive additional carboplatin + 
paclitaxel on the study. 
 
9.2 
Correlative Studies 
 
Secondary Aim 2.2.4 of the protocol is “To identify potential molecular markers of resistance to 
mTOR inhibition in tumor specimens obtained as part of routine clinical care.”  We expect to 
collect approximately 30 HNSCC tissue paraffin-embedded specimens from patients enrolled in 
the clinical study.  No research biopsies are planned in the course of the study. 


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Tissue correlates will be performed on biopsy or surgical pathology material that was obtained as 
part of routine care at time of diagnosis or at any point in the management of the patients 
HNSCC.  Tumor tissue from the primary site or from a metastatic deposit would be considered 
to be acceptable for purposes of the study. 
 
To characterize the expression patterns of biomarkers, conventional immunohistochemistry (IHC)  
or tissue microarray (TMA) analysis will be performed.  Dr. Wendel’s group has used the same 
TMA analyses in hematopoietic cancers before and is experienced with the techniques and the 
antibody and staining parameters [51-52].  In the Core Facility of the Department of Pathology, 
Dr. M. Drobnjak will supervise tissue TMA construction from all patient samples (typically, 
paraffin sections approximately 5 µm thick)  as previously described [51-55].  Normal squamous 
epithelium will be included as negative controls with each array.  For biopsies where material is 
inadequate for TMA construction, immunohistochemistry will be performed on whole mount 
tissue sections instead. 
 
We have established positive and negative controls for each antibody to ensure correct 
interpretation of stains [51-52].   Antibodies to be used in TMA interrogation include:  total and 
phosphorylated eIF4E (Cell Signaling, #9742 and  #2215); total and phosphorylated 4E-BP1 
(Cell Signaling, #9644 and #2855), total and phosphorylated (Ser 473) Akt (1:1000; Cell 
Signaling #9272, #9271); total and phosphorylated (Ser240/244) ribosomal S6 (1:1000; Cell 
Signaling, #2317, #2215); p53 (1:500; Novocastra, NCL-p530505); p21 (1:1000, Santa Cruz 
Biotechnologies, c-19); Rheb (1:1000; Cell Signaling, #4935); MCL1 (1:1000, Santa Cruz 
Biotechnologies, S-19); Actin (1:5000; Sigma, AC-15); and anti-HA (1:5000, Roche, 
#12013819). 
 
If sufficient tissue is available, we will also  perform genomic analysis. DNA will be extracted 
from FFPE surgical pathology samples. We will perform the MSK-IMPACT assay (Integrated 
Mutation Profiling of Actionable Cancer Targets), as follows. Barcoded sequence libraries will 
be prepared (Kapa Biosystems, New England Biolabs) according to a modified protocol. We will 
perform exon capture on barcoded pools of libraries by hybridization (Nimblegen EZ SeqCap) 
using custom oligonucleotides to capture all exons and select introns of approximately 279 
cancer genes. These oligonucleotides have been optimized to achieve uniform sequence coverage 
across all targets. The resulting selected libraries will be sequenced on an Illumina HiSeq 2000 
and analyzed for somatic point mutations, small indels, copy number amplifications and 
deletions, and structural rearrangements. 


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10.0  EVALUATION DURING TREATMENT/INTERVENTION 
 
Pre-Rx
a 
Day 1 
(of 21)g 
Day 8 
(of 21)g 
Day 15 
(of 21)g 
Dx HNSCC 
X 
Carboplatin 
X 
X 
Paclitaxel 
X 
X 
Break 
Week 
Temsirolimus 
X 
X 
H and P
b 
X 
X 
Complete blood cell 
counts (CBC)c 
X 
X 
X 
Basic Metabolic Panel 
(BMP), with magnesium
c 
X 
X 
Liver Function Tests 
(LFTS), Lipid Panel
c,d 
X 
X 
PT, aPTT 
X 
EKG 
X 
Pregnancy Test
e 
X 
Imaging Studies
f 
X 
Adverse Event 
Monitoring 
Continuous Monitoring for 
Adverse Events 
 
aSee Section 8 for required time frames for pre-treatment studies 
bDuring Cycle 1 of the Phase I portion of the study, patients will be evaluated for each weekly 
treatment in clinic by  physician and/or nurse.  After  Cycle 1 in Phase 1, the requirement 
will be one MD clinic visit per cycle, with additional clinic visits scheduled as needed. In 
Phase II of the study, the requirement will be one MD clinic visit per cycle, with additional 
clinic visits scheduled as needed. 
cTo faciliate the timely administration of chemotherapy on treatment days, CBC and BMP with 
magnesium level may be obtained 1 calendar day prior the chemotherapy treatment date, if 
need be.  For Day  1 of each cycle, Liver Function Tests and Lipid Panel may be obtained 
within 7 calendar days prior to the chemotherapy treatment date, if need be. 
Note in clarification:  On Day 8, the  only required lab test is CBC. 
dFor Cycle 1 only,  Liver Function Tests and Lipid Panel are optional if previously obtained 
within 14 days prior. 
eSerum pregnancy test for women of childbearing potential within 14 days prior to therapy. 


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fRadiologic imaging (CT scan and/or MRI of neck, CT chest [with our without contrast], and 
appropriate imaging of other sites of measureable disease) will be obtained at baseline 
and after every 2 cycles to assess for response to treatment (Please see Section 9.1.10 
regarding option to perform subsequent imaging q3 cycles for patients who remain on 
study after the imaging studies at end of cycle 6).  For patients who do not follow up at 
MSKCC after completion of study treatments, the investigator and/or the study team may 
attempt to  contact the patient by telephone for intermittent follow up.g  Treatment may be 
given 2 working days before or after the scheduled date, if necessary.  Treatment delay of 
up to 21 days  may be allowed for medical or personal reasons.  Reasons for treatment 
delay will be outlined in the medical record. 
 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 
Toxicity management: general considerations 
 
Potential toxicities of Temsirolimus, Paclitaxel, and Carboplatin are discussed in Section 5 of 
this protocol.  The following sections provide guidelines for mandatory dose delays and/or dose 
reductions for treatment-related toxicities. 
 
For patients who experience more than one toxicity, it is possible that subsections 11.2-11.12 
may provide conflicting recommendations for dose reductions.  If a patient experiences more 
than one toxicity requiring dose delay and/or dose reduction and there are conflicting 
recommendations for each, the investigator will select the reduction to the lower dose and/or the 
longer treatment delay. 
 
Even when the patient meets criteria for continued treatment at full dose per the protocol, the 
investigator retains the discretion to delay  the next treatment and/or reduce dose  if there are 
safety concerns and/or logistical issues.  Any dose reductions not specified in the protocol should 
be discussed with the principal investigator. 
 
Any patient who requires dose reduction in temsirolimus below 15 mg weekly will be removed 
from study.  Any patient who requires reduction in paclitaxel below 60 mg/m2 weekly will be 
removed from study.  Any patient who required reduction in carboplatin below AUC 1 will be 
removed from study. 
 
Doses that have been reduced for toxicity must not be re-escalated. 
 
Treatment delays of up to 21 total days per cycle in temsirolimus (and/or carboplatin and/or 
paclitaxel) are allowed. 
 
In the phase I portion of the study, dose reductions are not allowed during cycle 1.  Patients who 
require dose reduction during cycle 1 will be removed from study.  Sections 11.2 -11.12 provide 
toxicity management guidelines for patients in the phase II portion of the study, and for patients 
in the phase I portion of the study who have completed at least one cycle of treatment. 


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11.2 
Hematologic Toxicity Management 
 
The dose reduction plan reflects concern for the potential of temsirolimus to worsen the 
myelosuppression associated with carboplatin and paclitaxel. As such, the initial dose 
reductions are for the study drug, temsirolimus. 
 
The following dose reduction table will be used for myelosuppression: 
 
 
Dose 
Level 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1 and 8 
Minus 1 
15 mg 
60 mg/m2 
AUC 1.0 
1 
15 mg 
80 mg/m2 
AUC 1.5 
2 
20 mg 
80 mg/m2 
AUC 1.5 
3 
25 mg 
80 mg/m2 
AUC 1.5 
 
 
Dose reductions begin from the patient’s current dose level. For example, if a patient is 
being treated at Dose Level 2 and requires dose reduction, his next treatment would be at 
Dose Level 1. 
 
Day 1 of Cycle 
 
ANC (K/mcL) and 
Platelet Count (K/mcL) 
ANC ≥ 1.5 and Plts ≥ 100:  Treat 
without dose reduction 
ANC < 1.5 and/or Platelets <100: 
Hold.  If repeat ANC the next week 
≥ 1.5 and repeat Plts next week ≥ 
100, resume treatment.  Dose 
reduction by one dose level is not 
mandatory, but is allowed at the 
discretion of the investigator. 
Febrile Neutropenia*: Hold until 
resolution. When ANC ≥ 1.5 and 
afebrile and Plts ≥ 100, may proceed 
but reduce by 1 dose level 


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Day 8 of Cycle (ie, treatment week 2 of Cycle) 
 
ANC (K/mcL) and 
Platelet Count (K/mcL) 
ANC ≥ 1.0 and Plts ≥ 75: Treat 
without dose reduction 
ANC < 1.0 and/or Platelets <75: 
Hold.  If repeat ANC the next week 
≥ 1.0 and repeat Plts next week ≥ 
75, resume treatment without dose 
reduction 
Febrile Neutropenia*: Hold until 
resolution. When ANC ≥ 1.5 and 
afebrile and Plts ≥ 100, may proceed 
but reduce by 1 dose level 
 
For patients who require dose reductions on Day 8  (ie, treatment week 2 of the Cycle), the dose 
reduction will also apply to carboplatin on Day 1 of the next cycle. 
 
 
 
 
*Febrile neutropenia: The definition of febrile neutropenia is ANC < 1.0 and fever ≥ 38.5oC 
(CTCAE v. 3.0).  Any patient with febrile neutropenia will undergo appropriate pre-antibiotic 
evaluation and will be admitted to hospital for empiric antibiotic therapy.  At the discretion of 
the investigator, inpatient hospitalization for empiric antibiotics may be instituted for any patient 
with ANC ≤ 1.5 and fever ≥  38.0oC. 
 
Use of stimulators of erythropoiesis is allowed, according to established guidelines. 
 
11.3 
Hepatic Toxicity Management 
This section provides guidelines for dose delays and reductions for the first incidence of hepatic 
toxicity.   Temsirolimus, paclitaxel, and carboplatin can be associated with abnormalities in liver 
function tests (LFTs).  Because of concern for the potential of the study drug (temsirolimus) to 
worsen LFT abnormalities associated with the standard drugs (carboplatin and paclitaxel), the 
initial dose reductions are for the study drug temsirolimus. 
The following dose reduction table will be used for hepatic toxicity: 
Dose 
Level 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1and 8 
Minus 1 
15 mg 
60 mg/m2 
AUC 1 
1 
15 mg 
80 mg/m2 
AUC 1.5 
2 
20 mg 
80 mg/m2 
AUC 1.5 
3 
25 mg 
80 mg/m2 
AUC 1.5 
 
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Dose reductions begin from the patient’s current dose level. For example, if a patient is 
being treated at Dose Level 2 and requires dose reduction, his next treatment would be at 
Dose Level 1. 
 
11.3.1  Alkaline Phosphatase, ALT, AST 
 
Both AST and ALT should be drawn.  The more abnormal of the two values (AST or ALT) 
should be used in determining the dose. 
 
AST or ALT: 
ALK PHOS: 
≤ ULN 
>1X but ≤1.5X ULN 
>1.5X but ≤5X ULN 
>5X ULN 
≤ 1.5 X ULN 
Full Dose 
Full Dose 
Treat at Full Dose, Or 
Treat at Reduced Dose, 
Or Hold, at discretion 
of investigator* 
Hold* , 2 
>1.5 X but ≤ 
2.5X ULN 
Full Dose 
Full Dose 
Hold or Treat at 
Reduced Dose, at 
discretion of 
investigator* 
Hold* ,2 
>2.5X but ≤ 
5X 
Full Dose 
Hold* 
Hold*, 1 
Hold*,2 
>5X ULN 
Hold* 
Hold* 
Hold*, 2 
Hold*, 2 
 
*If treatment is held, treatment should not resume until liver function tests have “recovered”, 
maximum 21 days.  “Recovered” is defined as meeting requirements for treatment according 
to this table. 
 
1 Upon recovery, resume treatment at full dose or reduced by 1 dose level, at the discretion 
of the investigator. 
 
2Upon recovery, resume treatment at next lower dose level 
 
11.3.2 
Bilirubin 
 
Total bilirubin > ULN but ≤ 1.5 X ULN:  May hold treatment, treat at full dose, or treat at 
reduced dose, at the discretion of the investigator 
 
Total bilirubin > 1.5 X ULN:  Hold treatment  until serum total bilirubin is ≤ 1.5 X ULN 
(maximum 21 days), then re-treat at next lower dose level 


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11.4 
Mucositis/Stomatitis 
 
Mucositis/Stomatitis will be assessed according to clinical exam criteria. For management of 
musositis, supportive measures such as analgesics and oral rinses will be administered according 
to standard practice. 
 
Systemic administration of imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, etc.) should be avoided in all patients due to their potential to alter the 
metabolism of temsirolimus and paclitaxel.  Therefore, topical antifungal agents are preferred if 
an infection is diagnosed. 
 
Temsirolimus and paclitaxel may be associated with mucositis.  Because of concern for the 
potential of temsirolimus to cause mucositis and/or intensify mucositis associated with 
paclitaxel, the following table calls for initial dose reductions in temsirolimus. 
 
The following dose reduction table will be used for mucositis: 
 
 
Dose 
Level 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1 and 8 
1 
15 mg 
80 mg/m2 
AUC 1.5 
2 
20 mg 
80 mg/m2 
AUC 1.5 
3 
25 mg 
80 mg/m2 
AUC 1.5 
Dose reductions begin from the patient’s current dose level. For example, if a patient is being 
treated at Dose Level 2 and requires dose reduction, his next treatment would be at Dose Level 1. 
If a patient at Dose Level 1 experiences mucositis that requires dose reduction, the patient will be 
removed from study. 
Guidelines for dose reductions/dose delays are as follows: 
 
Grade 1 or Grade 2 Mucositis: May hold, treat at full dose, or treat at next lower dose 
level, at the discretion of the investigator.  Dose reduction is at the discretion of the 
investigator. 
 
Grade 3 Mucositis:  Hold until ≤ Grade 2, then resume treatment at next lower dose level 
Grade 4 Mucositis:  Off Study 
 
11.5 
Nausea/Vomiting 
 
All patients will receive anti-emetics and hydration, per institutional guidelines. 
 
The dose reduction plan reflects concern for the potential of temsirolimus to worsen 
nausea/vomiting associated with carboplatin +  paclitaxel.  As such, the initial dose reductions 
are for the study drug, temsirolimus. 


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The following dose reduction table will be used for nausea/vomiting: 
 
 
Dose 
Level 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1 and 8 
Minus 1 
15 mg 
60 mg/m2 
AUC 1 
1 
15 mg 
80 mg/m2 
AUC 1.5 
2 
20 mg 
80 mg/m2 
AUC 1.5 
3 
25 mg 
80 mg/m2 
AUC 1.5 
 
 
Dose reductions begin from the patient’s current dose level. For example, if a patient is being 
treated at Dose Level 2 and requires dose reduction, his next treatment would be at Dose Level 
1.For any patient experiencing nausea and/or vomiting, the chemotherapy treatment will be 
delayed until any vomiting has resolved to ≤ Grade 1 (1 episode in 24 hours) and any nausea has 
resolved to ≤ Grade 1 (loss of appetite without alteration in eating habits). 
 
For any patient experiencing ≥ Grade 3  nausea and/or vomiting, treatment will be given at the 
next lower dose level when nausea and vomiting are ≤ Grade 1. 
 
11.6 
Diarrhea 
Because of concern for the potential for temsirolimus-associated diarrhea, the initial dose 
reductions are for the study drug, temsirolimus. 
 
The following dose reduction table will be used for diarrhea: 
 
Dose 
Level 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1 and 8 
Minus 1 
15 mg 
60 mg/m2 
AUC 1.5 
1 
15 mg 
80 mg/m2 
AUC 1.5 
2 
20 mg 
80 mg/m2 
AUC 1.5 
3 
25 mg 
80 mg/m2 
AUC 1.5 
Dose reductions begin from the patient’s current dose level. For example, if a patient is being 
treated at Dose Level 2 and requires dose reduction, his next treatment would be at Dose Level 1. 
 
Grade 1 or Grade 2 Diarrhea: 
Chemotherapy treatment may be continued at full dose, continued at the next 
lower dose level, or held.  Antidiarrheals may be used as needed.  Dose reduction 
is at the discretion of the investigator. 
 
Grade 3 Diarrhea: 
In the event of diarrhea requiring hospitalization (ie, Grade 3), supportive 
measures may include hydration, octreotide, and antidiarrheals. 


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Chemotherapy treatment will be held until diarrhea has improved to ≤ Grade 1, 
with dose reductions as follows: 
 
If Grade 3 diarrhea duration is ≤ 48 hours, the next treatment may be 
given at full dose or at the next lower dose level, at the discretion of the 
investigator. 
 
If Grade 3 diarrhea duration is > 48 hours, the next cycle will be given at 
the next lower dose level 
 
Grade 4 diarrhea:  Off Study 
 
11.7 
Sensory Neuropathy 
 
Paclitaxel and carboplatin can be associated with sensory neuropathy.  Temsirolimus is unlikely 
to cause sensory neuropathy but we cannot exclude the possibility that temsirolimus could 
worsen to neuropathy associated with carboplatin and paclitaxel.  Therefore, sensory neuropathy 
management features dose reductions for all three agents. 
 
If the patient develops Grade 1 or Grade 2 sensory neuropathy, chemotherapy treatment may be 
given at full dose or may be held for ≤ 21 days, at the discretion of the investigator. 
 
If a patient develops ≥ Grade 3 sensory neuropathy, treatment will be held. Upon resolution to 
grade 1, treatment may resume at the dose and schedule shown in the following table (regardless 
of the current dose level): 
 
 
 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1 and 8 
15 mg 
60 mg/m2 
AUC 1 
 
An patient who requires reduction below this dose and schedule will be removed from the study. 


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11.8 
Renal  Toxicity Management 
 
If serum creatinine is ≥ 1.5 on planned treatment date, estimate the creatinine clearance (CrCl) 
by the Cockcroft and Gault Equation. 
 
Calculated Creatinine 
Clearance (CrCl) 
Management 
≥ 45 ml/min 
Hydrate as clinically indicated.   May treat at full dose, 
treat at next lower dose level, or hold treatment, at the 
discretion of the investigator. 
<  45 ml/min 
Hold treatment for the week and hydrate as clinically 
indicated. 
If repeat CrCl ≥ 45 ml/min, may resume treatment at the 
next lower dose level. 
 
Carboplatin and temsirolimus may be associated with renal toxicity.  Paclitaxel is unlikely to 
cause renal toxicity. 
Therefore, dose reduction for renal toxicity involves carboplatin and 
paclitaxel. 
 
For patients who require dose reduction for renal toxicity, upon resolution of renal toxicity (ie, 
creatinine clearance ≥ 45 ml/min) treatment will be at the reduced doses shown in the following 
table: 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1 and 8 
15 mg 
80 mg/m2 
AUC 1 
  
 
If a patient requires dose reduction during the middle of a cycle (ie, the Day 8 or Day 15 dose), 
the dose reduction will continue for subsequent cycles as well. 
 
Any patient who requires reduction below the temsirolimus dose (15 mg) or the carboplatin dose 
(AUC 1) will be removed from study. 


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11.9 
Dermatologic Toxicity 
 
Temsirolimus and has been associated with rash.  Paclitaxel is less likely to be associated with 
rash.  As such, the toxicity management plan calls for dose reductions in temsirolimus. 
 
The following dose reduction table will be used for rash: 
 
 
Dose 
Level 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1 and 8 
1 
15 mg 
80 mg/m2 
AUC 1.5 
2 
20 mg 
80 mg/m2 
AUC 1.5 
3 
25 mg 
80 mg/m2 
AUC 1.5 
 
 
Dose reductions begin from the patient’s current dose level. For example, if a patient is being 
treated at Dose Level 2 and requires dose reduction, his next treatment would be at Dose Level 1. 
If a patient at Dose Level 1 experiences rash that requires dose reduction, the patient will be 
removed from study. 
 
Grade 1:  No specific supportive care is usually needed or indicated. 
 
Grade 2:  May treat with supportive measures, at the discretion of the investigator. 
Options include: oral minocycline, topical tetracycline, topical clindamycin, topical silver 
sulfadiazine, diphenhydramine, and oral prednisone (short course).  Interruption of 
chemotherapy will be at the discretion of the investigator.  Dose reductions are not 
necessary. 
 
Grade 3:  Hold chemotherapy treatment until resolution ≤ Grade 2.  The need for oral or 
topical treatments will be at the discretion of the investigator and may be accompanied by 
a culture of the affected area and a dermatology consult.   When toxicity resolves to 
Grade 2 or better, the patient may resume treatment at the next lower dose level. 
 
Grade 4:  Off Study 
 
11.10   Hyperlipidemia 
 
Lipid panel is checked according on the dates indicated in Section 10. 
 
Temsirolimus and has been associated with hyperlipidemia.  As such, the dose reduction scheme 
calls for dose reductions in temsirolimus. 


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The following dose reduction table will be used for hyperlipidemia: 
 
 
 
Dose 
Level 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1 and 8 
1 
15 mg 
80 mg/m2 
AUC 1.5 
2 
20 mg 
80 mg/m2 
AUC 1.5 
3 
25 mg 
80 mg/m2 
AUC 1.5 
 
 
Any patient who is being treated at the lowest dose level of temsirolimus (15 mg weekly) who 
meets criteria for further temsirolimus dose reduction will be removed from study. 
 
Grade 1 hypercholesterolemia (> upper limit of normal to 300 mg/dL or 7.75 mmol/L) or 
grade 1 hypertriglyceridemia (> upper limit of normal to 2.5X upper limit of normal): 
Continue chemotherapy treatment without any dose reductions.  A statin or appropriate 
lipid-lowering agent may be started at the discretion of the investigator. 
 
Grade 2 hypercholesterolemia (> 300 - 400mg/dL, or >7.75 - 10.34 mmol/L) or grade 2 
hypertriglyceridemia (> 2.5 -5.0 X upper limit of normal):  Continue chemotherapy 
treatment without any dose reductions.  A statin or appropriate lipid-lowering medication 
should be used in addition to diet, per investigator’rs discretion. 
 
≥Grade 3 hypercholesterolemia (> 400 mg/dL or > 10.34 mmol/L)  or ≥ grade 3 
hypertriglyceridemia (> 5X upper limit of normal):  Hold chemotherapy treatment.  A 
statin or appropriate lipid-lowering medication should be used in addition to diet, per 
investigator’rs discretion.  When toxicity resolves to Grade 2 or better, may resume 
treatment at full dose or at the next lower  dose level, at the discretion of the investigator. 
 
11.11   Interstitial Lung Disease (ILD) 
 
Both asymptomatic radiological changes (grade 1) and symptomatic non-infectious pneumonitis 
(grade 2 = not interfering with activities of daily living or grade 3 = interfering with activities of 
daily living and oxygen indicated) have been noted in patients receiving temsirolimus therapy. 
Any patient who develops any new or worsening pulmonary symptoms (ie, dyspnea and/or 
cough) should undergo either chest X-ray and/or CT scan of the chest. 
 
The dose reduction scheme calls for dose reductions in temsirolimus. 


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The following dose reduction table will be used for ILD: 
Dose 
Level 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1 and 8 
1 
15 mg 
80 mg/m2 
AUC 1.5 
2 
20 mg 
80 mg/m2 
AUC 1.5 
3 
25 mg 
80 mg/m2 
AUC 1.5 
Any patient who is being treated at the lowest dose level of temsirolimus (15 mg weekly) who 
meets criteria for further temsirolimus dose reduction will be removed from study. 
 
Management on Interstitial Lung Disease (ILD) 
 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis 
Chemotherapy Treatment 
Grade 1 
Chest X-ray and/or CT 
scans of chest.  Consider 
pulmonary function testing 
including: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat 
chest x-ray/CT scan every 
2 months until return to 
baseline. 
No specific therapy is 
required 
May continue at Full Dose, 
Continue at next lower dose 
level, or hold treatment for up to 
21 days, at the discretion of the 
investigator 
Grade 2 
CT scan of chest.  Consider 
pulmonary function testing 
including: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat 
imaging each month until 
return to baseline. Consider 
bronchoscopy 
Symptomatic only. 
Prescribe 
corticosteroids if cough 
is troublesome. 
May continue at Full Dose, 
Continue at next lower dose 
level, or hold treatment for up to 
21 days, at the discretion of the 
investigator 
Grade 3 
CT scan of chest and 
pulmonary function testing 
including: spirometry, 
DLCO, and room air O2 
saturation at rest.  Repeat 
imaging each month until 
return to baseline. Consider 
bronchoscopy. 
Prescribe 
corticosteroids if 
infective origin is ruled 
out. Taper as medically 
indicated. 
Hold treatment until recovery to 
≤ Grade 1. May restart protocol 
treatment within 3 weeks at a 
reduced dose (by one level) if 
evidence of clinical benefit. 
Patients will be withdrawn from 
the study if they fail to recover 
to Grade 1within 21 days. 
Grade 4 
CT scan of chest and 
required pulmonary 
function testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. Repeat imaging each 
month until return to 
baseline. Bronchoscopy is 
recommended. 
Prescribe 
corticosteroids if 
infective origin is ruled 
out. Taper as medically 
indicated. 
Discontinue treatment. 


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11.12  Toxicities Not Otherwise Specified 
 
For toxicities not specifically addressed in Section 11, this subsection provides general 
guidelines. Because a potential role for the study drug temsirolimus may be suspected in 
unanticipated toxicities, the dose reduction scheme will initially call for dose reductions in the 
study drug, as follows: 
 
Dose 
Level 
Temsirolimus, 
Days 1 and 8 
Paclitaxel, 
Days 1 and 8 
Carboplatin 
Days 1 and 8 
Minus 1 
15 mg 
60 mg/m2 
AUC 1 
1 
15 mg 
80 mg/m2 
AUC 1.5 
2 
20 mg 
80 mg/m2 
AUC 1.5 
3 
25 mg 
80 mg/m2 
AUC 1.5 
 
 
 
Any patient who requires reduction below “Dose Level Minus 1” will be removed from the 
study. 
 
The general approach to toxicity management will be: 
Grade 1:  Treat at full dose. 
Grade 2:  May hold, treat at full dose, or treat at next lower dose level, at the discretion of 
the investigator.  Dose reduction is at the discretion of the investigator. 
 
Grade 3:  Hold until ≤ Grade 2, then resume treatment at next lower dose level 
 
Grade 4:  Hold treatment.  When toxicity resolves to ≤ Grade 2, may resume treatment at 
the next lower dose level. 
 
The investigator retains the authority to remove any patient from study for any toxicity if he/she 
believes that it is in the best interest of the patient to discontinue study treatment. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Radiologic response criteria are based on previously published RECIST guidelines [56].  At 
baseline, tumor lesions will be categorized as follows:  Measurable: lesions that can be 
accurately measured in at least one dimension (longest diameter to be recorded as > 10 mm with 
spiral CT scan); Nonmeasurable: all other lesions, including small lesions (<10 mm with spiral 
CT scan).  All measurements will be recorded in metric notation by use of a ruler or calipers.  All 
baseline evaluations will be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of treatment. 


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Lesions considered to be truly nonmeasurable include the following: bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed by imaging 
techniques, and cystic lesions.  Tumor lesions that are situated in a previously irradiated area are 
measurable only if unequivocal growth can be documented in the baseline scan compared to a 
scan obtained within one month of radiation treatment. 
 
MRI or Spiral CT scanning, using a contiguous reconstruction algorithm, will be used to 
characterize each identified and reported lesion at baseline and during follow-up.  Intravenous 
contrast agents will be given, unless contraindicated for medical reasons such as allergy or other 
reasons, at the discretion of the treating physician.  This is to accentuate vascular structures from 
adjacent lymph node masses and to help enhance liver and other visceral metastases. In patients 
in whom the abdomen and pelvis are being imaged, oral contrast agents should be given to 
accentuate the bowel against other soft-tissue masses.  During physical exam assessment, 
clinically detected lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes).  Lesions on chest x-ray are acceptable as measurable 
lesions when they are clearly defined and surrounded by aerated lung. However, CT is 
preferable.  The same imaging modality will be used throughout the study to measure disease, 
without interjection of data from ultrasound or MRI examinations, unless contraindicated for 
medical reasons such as allergy or other reasons, at the discretion of the treating physician 
 
Baseline Evaluation:  Only patients with measurable disease at baseline will be included in this 
protocol.  Only known sites of disease, or areas clinically suspected of disease involvement, need 
be imaged.  All measurable lesions up to a maximum of five lesions per organ and 10 lesions in 
total, representative of all involved organs, will be identified as target lesions and recorded and 
measured at baseline. Target lesions will be selected on the basis of their size (those with the 
longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter for all target lesions will be calculated 
and reported as the baseline sum longest diameter. The baseline sum longest diameter will be 
used as the reference by which to characterize the objective tumor response.  All other lesions (or 
sites of disease) will be identified as nontarget lesions and will also be recorded at baseline. 
Measurements of these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up. 
 
Evaluation of target lesions:  Complete Response (CR):  the disappearance of all target lesions; 
Partial Response (PR): at least a 30% decrease in the sum of the longest diameter of target 
lesions, taking as reference the baseline sum longest diameter; Progressive Disease (PD):  at least 
a 20% increase in the sum of the longest diameter of target lesions, taking as reference the 
smallest sum longest diameter recorded since the treatment started, or the appearance of one or 
more new lesions; Stable Disease (SD):  neither sufficient shrinkage to qualify for partial 
response nor sufficient increase to qualify for progressive disease, taking as reference the 
smallest sum longest diameter since the treatment started. 


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Evaluation of nontarget lesions:  Complete Response (CR): the disappearance of all nontarget 
lesions; Stable Disease (SD):  the persistence of one or more nontarget lesion(s); Progressive 
Disease (PD):  the appearance of one or more new lesions and/or unequivocal progression of 
existing nontarget lesions. Data from observation of all target and non-target lesions will be 
combined in order to determine overall response, according to the following table: 
Target  
Non-Target  
New Lesions  
Overall Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
 
The best overall response is the best response recorded from the start of treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  In some circumstances, it may be difficult to distinguish 
residual disease from normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated by fine-needle 
aspiration/biopsy or PET scan before confirming the complete response status. 
 
The minimal time interval required between two measurements for determination of overall 
response is 4 weeks.  The duration of overall response is measured from the time that 
measurement criteria are met for complete response or partial response (whichever status is 
recorded first) until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded since the 
treatment started). The duration of overall complete response is measured from the time 
measurement criteria are first met for complete response until the first date that recurrent disease 
is objectively documented.   Stable disease is measured from the start of the treatment until the 
criteria for disease progression is met (taking as reference the smallest measurements recorded 
since the treatment started). 
 
Radiologic scans will be reviewed by a designated member of the MSKCC Department of 
Radiology. When nonmeasurable disease is being assessed, the radiologist and attending 
physician will confer to determine the presence or absence of unequivocal disease progression. 
  
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient develops progressive disease he/she will be taken off study and 
referred for alternative therapy. 
 
Patients may be removed from the study for protocol non-compliance. 


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If at any time the patient develops unacceptable toxicity he/she will be removed from study. 
Participants can be removed from the study at any time if the study doctor feels that it is in 
their best interest to do so. 
 
14.0 
BIOSTATISTICS 
 
This is a single arm Phase I/ Phase II trial open to patients with recurrent/metastatic HNSCC 
who did not receive more than 2 prior cytotoxic therapies for recurrent/metastatic disease. 
  
 
14.1 
Part 1 (Phase 1) 
 
The primary objective of this part is to determine the phase II-recommended dose of 
temsirolimus, when given in combination to paclitaxel and carboplatin. This will be the 
recommended dose that will be used in the Part II (Phase II) of the trial. 
 
Patients will be treated in cohorts of size three-six and the dosage will be escalated if the clinical 
toxicity is acceptable. A patient is considered toxicity-free for the purpose of the trial if he/she 
completes the first cycle of therapy (21 days) without experiencing dose limiting toxicity (DLT, 
as described in section 4.1.1). If therapy is discontinued during the first cycle for reasons other 
than toxicity (see Section 13.0), an additional patient may be enrolled at that dose level to ensure 
adequate evaluation of toxicity. However, patients will not be replaced unless they cannot be 
evaluated for DLT in cycle 1 of the Phase I portion of the study. Three dose levels will be 
considered for escalation, as described in Section 4.1.1. No within-patient escalation will be 
performed. 
 
The dose escalation scheme is as follows: 
1.   If none of the initial three patients at a given dose level experience DLT, the next dose 
level will be studied. 
2.   If one of the initial three patients at a given dose level experiences DLT, three additional 
patients will be treated at the same dose level. Escalation will continue only if there has 
been no additional DLT observed. 
3.   If two or more patients experience DLT at a given dose, the previous dose will be 
declared the maximum tolerated dose (MTD). 
4.   If only three patients were treated at a dose under consideration as MTD, an additional 
three patients will be treated at that level to confirm previous results. 
The MTD will be the phase II recommended dose.  However, if the MTD is not exceeded at dose 
level 3, then dose level 3 will be the phase II recommended dose. 
 
The design is constructed to minimize the chances of escalating the dose when the probability of 
DLT is high, and maximize the chance of escalating the dose when the probability of DLT is 
low. The probabilities of escalating to the next dose level under this scheme for various true 
toxicity rates are given in the table below. 


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Toxicity rate 
0.10 
0.20 
0.30 
0.40 
0.50 
Probability of escalation 91% 71% 49% 31% 17% 
 
 
A minimum of 2 and a maximum of 18 patients will be required to complete this phase of the 
trial. With a planned accrual of 2 patients/month, this part of the study should be completed 
within ≤ 9 months. 
 
 
14.2 
Part 2 (Phase II) 
 
In Part 2, the primary endpoint will be objective radiographic response rate (CR+PR) after 2 
cycles (6 weeks) of therapy.  As a historical control, Gibson et al reported a response rate of 26% 
with cisplatin + paclitaxel as palliative therapy for patients who had not received prior 
chemotherapy for recurrent/metastatic HNSCC [6].  In the current study, we estimate that half of 
patients will receive study treatment as first line therapy for recurrent/metastatic disease.  We 
estimate that half of the study patients will receive study treatment as second or third line 
therapy, for which the historical estimate for objective response rate with palliative 
chemotherapy is 15% [57-58].  As such, the estimated response rate for this patient population is 
p0= (.26 X 0.5) +  (0.15 X 0.5) = 0.21. 
 
A Simon optimal two-stage design will be employed to assess the primary endpoint of 
radiographic response rate (by RECIST criteria) at 6 weeks after therapy start (2 cycles).  A 21% 
response-rate is considered not promising, a 41% response rate is considered promising, and the 
probabilities of a Type I error (falsely accepting a non-promising therapy) and Type II error 
(falsely rejecting a promising therapy) are set to 0.05 and 0.2, respectively.   In the first stage of 
this design, 11 patients will be accrued.   If 2 or less patients among the first 11 patients have a 
response, then the study will be terminated and declared negative. If 3 or more patients have a 
response, than an additional 25 patients will be accrued to the second stage. At the end of the 
study, if 12 or more patients have a response out of a total of 36 patients enrolled, the regimen 
will be considered worthy of further investigation. 


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We anticipate that the patient population in the study will be consistent with the historical control 
population as regards prior treatment.  To ensure consistency between the study population and 
the historical control population: 
● 
In the first part of the two stage design, no more than 6 of 11 patients will have 0 
prior chemotherapy regimens for recurrent/metastatic disease, and no more than 6 
of 11 patients will have had 1 or 2 prior chemotherapy regimens for recurrent 
metastatic disease.  No more than 6 patients in each group (no previous therapy 
vs. 1-2 previous cycles) should be included in first part of the two stage design. 
Accrual in each group will stop when the maximum number of patients per group 
is reached. 
● 
For the entire accrual to the phase II portion of the study, no more than 20 of 36 
patients will have 0 prior chemotherapy regimens for recurrent/metastatic disease, 
and no more than 20 of 36 patients will have had 1 or 2 prior chemotherapy 
regimens for recurrent metastatic disease.  No more than 20 patients in each group 
(no previous therapy vs. 1-2 previous cycles) should be included in the total phase 
II population.  Accrual in each group will stop when the maximum number of 
patients per group is reached. 
 
All the patients enrolled in the trial will be included in the main analysis of the objective 
response rate, even if there are major protocol deviations. Patients who do not complete the first 
two cycles of treatment (due to any of the criteria listed in Section 13.0 or to death) are 
considered non-responses. 
 
The 6 patients from Part 1 who are treated at the phase II recommended dose will be included in 
the efficacy analysis for response rate.  As such, a minimum of 5 and a maximum of 30 
additional patients need to be enrolled in Part 2 to achieve the sample size of 11 to 36 evaluable 
patients. With an expected accrual rate of 1.5 patients/month, this phase of the study should be 
completed in ≤ 15 months. 
 
Safety will be assessed in terms of AEs, laboratory data and vital sign data, which will be 
collected for all patients. Appropriate summaries of these data will be presented. AE will be 
listed individually per patient according to CTCAE version 3.0, and the number of patients 
experiencing each AE will be summarized. The safety population will comprise all patients who 
receive at least one dose of study treatment. 
 
Overall survival will be estimated using Kaplan-Meier methodology, with time origin at the start 
of the treatment. 
 
Data analysis for correlative studies will be descriptive. The antibodies whose expression 
patterns will be investigated by tissue microarray (TMA) interrogation are listed in section 9.2. 
For each antibody, each tumor sample will be scored as “positive” or “negative.” For 
immunohistochemistry, positivity will be defined as at least 30% of tumor cells stained for the 
probed antigen  [51]. 


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We will explore if positive/negative status for each antibody may be associated with objective 
radiographic response to study treatment using non-parametric Wilcoxon statistics.  Only 
patients who already have biopsy or surgical pathology material collected as part of routine care 
at time of diagnosis or at any point in the management of the patients HNSCC will contribute to 
this analysis. No research biopsies are planned in the course of the study. We anticipate that 
archived tissue for correlative studies will be available for approximately 30 subjects in the 
study. 
 
14.3 
Accrual rate 
 
The projection of 2 accruals per month is based on prior accrual rates in the HN DMT, and also 
reflects the expansion of the HN research program.  Our service recently completed a phase II 
study of gemcitabine + pemetrexed for patients with advanced HNSCC (MSK IRB 06-087). 
Accrual of 25 patients was completed between 10/2006 and 2/2008 (1.5 accruals per month). 
Our HN service included 2 medical oncologists during that time.  Currently our HN group 
includes 3 full time medical oncologists, plus the addition of a 4th  medical oncologist who will 
join our group in  8/2009.  Of note, IRB 06-087 was open only at MSKCC main campus.  For the 
proposed study, the four MSKCC regional network affiliates (Commack, NY; Phelps, NY; 
Rockville Center, NY; Basking Ridge, NJ) will be participating sites to further enhance accrual 
in the phase II portion of the study. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject 
Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/). The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other 
relevant documents must be uploaded via the PPR Electronic Registration System. 


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16.0 
DATA  MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study.  The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol 
study team. 
 
The data collected for this study will be entered into a secure database.  Source documentation 
will be available to support the computerized patient record. 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data.  Routine data quality reports will be generated to assess missing data and 
inconsistencies.  Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action. 
 
 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001.  The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research.  The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb5.mskcc.org/intranet/_assets/_tables/content/359709/DSMPlans07.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs.  The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and 
II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical 
trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol is assessed for it’s level 
of risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, in- 
house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and the 
monitoring procedures will be established at the time of protocol activation. 


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17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Inclusion of Children in Research 
 
This protocol/project does not include children because the number of children is limited 
and because the majority are already accessed by a nationwide pediatric cancer research 
network.  This statement is based on exclusion 4b of the NIH Policy and Guidelines on 
the Inclusion of Children as Participants in Research Involving Human Subjects. 
 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form.  The use 
and disclosure of protected health information will be limited to the individuals described 
in the Research Authorization form.  A Research Authorization form must be completed 
by the Principal Investigator and approved by the IRB and Privacy Board. 
 
 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be 
submitted electronically to the SAE Office at sae@mskcc.org containing the following 
information: 
Fields populated from the CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 


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The PI’s signature and the date it was signed are required on the completed report. 
 
17.2.1  SAE Reporting to Pfizer and NCCN 
 
Adverse Event Reporting.  Institution shall ensure that Investigator will report all Adverse 
Events to Regulatory Authorities, health authorities and the IRB as required by applicable law, 
within the required timeframes. Investigator also will conduct follow-up on Adverse Events as 
required by law. 
 
The term “Serious Adverse Event” (or “SAE”) shall mean any adverse drug experience 
occurring at any dose that results in any of the following outcomes: death, is Life-Threatening, as 
defined below, requires inpatient hospitalization or prolongation of an existing hospitalization, 
results in a persistent or significant disability or incapacity, results in a congenital anomaly or 
birth defect, results in cancer, or results in an important medical event. Important medical events 
which are AEs that may not result in death, be Life-Threatening, or require hospitalization may be 
considered SAEs when, based upon appropriate medical judgment, they may jeopardize the 
Study Subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
In addition to complying with all applicable regulatory reporting laws and regulations, Institution 
will ensure that the Investigator report the following information to Grantor and NCCN in 
writing via fax within one business day of the occurrence, using the cover page provided as 
Appendix B hereto, and referencing the applicable Protocol number that is assigned by Grantor 
upon approval of the Study. Such report shall be directed to NCCN via fax at 215-358-7699 or e- 
mailed to ORPReports@nccn.org and to Pfizer U.S. Clinical Trial Department at 1-866-997- 
8322: 
 
(a) 
All SAEs; 
 
(b) 
Reports of pregnancy exposure (pregnancy encompasses the entire course of 
pregnancy and delivery, perinatal and neonatal outcomes, even if there were no abnormal 
findings; both maternal and paternal exposure is collected); 
 
(c) 
Reports of lactation exposure; 
 
(d) 
Overdose (with or without an SAE); 
 
(e) 
Abuse (use for non-clinical reasons with or without an SAE); 
(f) 
 Inadvertent or accidental exposure; and 


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(g) 
Follow-up information regarding any of the above. 
 
The Investigator should include his or her assessment of the causal relationship between each 
SAE and the Grantor product in the form faxed to Grantor and NCCN. 
 
17.3 
Risks, Benefits, Toxicities/side effects 
 
Potential risks to human subjects include drug related toxicity, pain and discomfort 
associated with mucositis, temsirolimus side effects (Section 5.1), paclitaxel side effects 
(Section 5.2), carboplatin side effects (Section 5.3) , placement of IV catheters, 
phlebotomy, and possible psychological discomfort from the stresses associated with 
obtaining imaging studies (eg, CT scan, PET scan).  All efforts will be made to avoid any 
complication by completely reviewing patients’ symptoms, providing appropriate 
management, and monitoring blood tests. 
 
If an adverse medical event occurs, the patient will first contact the primary oncologist or 
the Principal Investigator. At nights and on weekends, there is an oncology physician on 
call at all times.  Patients may either call or come directly to the urgent care center at 
Memorial Hospital (or to their local emergency room) to be seen.  Patients suffering 
serious adverse reactions must be carefully followed and all follow-up information also 
recorded. 
 
17.4 
Alternatives/options 
 
Participation in this trial is voluntary. Depending on the specific details of the situation, 
patient options without being in a study might include: 
• 
Other palliative chemotherapy off study.  For example, carboplatin and paclitaxel, 
without temsirolimus. 
• 
Participation in a different clinical trial 
• 
Best supportive care 
 
 
 
17.5 
Financial Costs/Burdens 
 
The patient will be responsible for all costs related to treatment and complications of 
treatment.  Costs to the patient (third party insurer) will include the costs of carboplatin, 
paclitaxel, hospitalizations, routine blood tests and diagnostic studies, office visits, 
baseline EKG, and doctor’s fees.  Patients will not be charged for any research tests 
performed on research specimens. 
 
Temsirolimus is provided by Pfizer and therefore is not billable to research participants. 


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18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
 
1.   The nature and objectives, potential risks and benefits of the intended study. 
2.   The length of study and the likely follow-up required. 
3.   Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4.   The name of the investigator(s) responsible for the protocol. 
5.   The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
19.0 
REFERENCES 
 
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Harding, M.W., Immunophilins, mTOR, and pharmacodynamic strategies for a targeted 
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Atkins, M.B., et al., Randomized phase II study of multiple doses of CCI-779, a novel 
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Hudes, G., et al., Temsirolimus, Interferon Alfa, or Both for Advanced Renal Cell 
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Perez, E.A., et al., Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab 
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Salama, J.K., et al., Induction chemotherapy and concurrent chemoradiotherapy for 
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Hitt, R., et al., Phase III study comparing cisplatin plus fluorouracil to paclitaxel, 
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20.0 
APPENDICES 
 
Appendix A - PROHIBITED MEDICATION LIST 
Appendix B - SAE FAX COVER SHEET