Conditions: Squamous Cell Carcinoma of the Head and Neck
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
The purpose of this study is to test the effectiveness (how well the drug works), safety, and tolerability of the investigational drug combination of palbociclib (Ibrance) plus carboplatin in patients with metastatic head and neck squamous cell cancer.

Detailed description:

Arms:
arm 1: Treatment with Palbociclib and Carboplatin for up to 6 cycles:

Palbociclib (Ibrance) (PO), dose= 125 mg PO daily, days=1-14, cycle length: 21 days Carboplatin (IV), dose= AUC 5, day= 1, cycle length: 21 days

Maintenance Palbociclib after 6 cycles Palbociclib (Ibrance) 125 mg PO daily, days 1-21, cycle length: 28 days

Interventions: intervention 1: Palbociclib intervention 2: Carboplatin
Intervention descriptions: intervention 1: Palbociclib (Ibrance) (PO), dose= 125 mg PO daily, days=1-14, cycle length: 21 days

Maintenance Palbociclib:

Palbociclib (Ibrance) 125 mg PO daily, days 1-21, cycle length: 28 days intervention 2: Carboplatin (IV), dose= AUC 5, day= 1, cycle length: 21 days

Protocol document:
Prot_SAP_000.pdf: 
UMCC 2017.054 
A Multi-Center open label single arm phase II trial evaluating the efficacy of palbociclib in 
combination with carboplatin for the treatment of unresectable recurrent or metastatic head and 
neck squamous cell carcinoma 
 (Short Title: CarPal Head and Neck)  
Principal Investigator: 
Paul L. Swiecicki, M.D. 
University of Michigan Rogel Cancer Center 
N13A23 North Ingalls Building, 300 N Ingalls St., SPC 5419 
Ann Arbor MI 48109 
Phone: 734-647-1017, Fax: 734-647-9480 
 pswiecic@med.umich.edu 
Coordinating Center: 
University of Michigan 
Biostatistician: 
Emily Bellile, M.S. 
University of Michigan, Department of Biostatistics 
lighte@med.umich.edu 
Study Drug: 
Palbociclib (Ibrance®) 
Carboplatin 
Initial version: 
05/01/2017 
Amended: 
05/10/2017 
05/26/2017 
06/19/2017 
09/05/2017 
12/05/2017 
03/13/2018 
10/04/2018 
NCT03194373


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TABLE OF CONTENTS 
ABBREVIATIONS ............................................................................................................1 
STUDY SYNOPSIS ..........................................................................................................3 
1.0 
BACKGROUND AND RATIONALE ...................................................................6 
1.1 
Disease Background........................................................................................................ 6 
1.2 
Palbociclib- Background and Associated Known Toxicities ............................................ 6 
1.3 
Carboplatin- Background and Rationale for Synergy ...................................................... 9 
1.4 
Rationale in Head and Neck Cancer ............................................................................. 11 
1.5 
Correlative Studies ........................................................................................................ 11 
2.0 
STUDY OBJECTIVES.........................................................................................12 
2.1 
Primary Objectives ......................................................................................................... 12 
2.2 
Secondary Objectives .................................................................................................... 12 
2.3 
Exploratory Objectives ................................................................................................... 12 
2.4 
Endpoints ....................................................................................................................... 12 
3.0 
PATIENT ELIGIBILITY .......................................................................................13 
3.1 
Inclusion Criteria ............................................................................................................ 13 
3.2 
Exclusion Criteria ........................................................................................................... 13 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES ..............14 
5.0 
TREATMENT PLAN ............................................................................................15 
5.1 
Treatment Dosage and Administration .......................................................................... 15 
5.2 
Toxicities and Dose Modifications ................................................................................. 17 
5.3 
Concomitant Medications .............................................................................................. 20 
5.4 
Duration of Therapy ....................................................................................................... 20 
5.5 
Treatment Beyond Disease Progression ....................................................................... 20 


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5.6 
Off Treatment Criteria .................................................................................................... 21 
5.7 
Duration of Follow-Up .................................................................................................... 21 
5.8 
Discontinuation Criteria ................................................................................................. 22 
5.9 
Patient Replacement ..................................................................................................... 22 
6.0 
STUDY PROCEDURES ......................................................................................22 
7.0 
MEASUREMENT OF EFFECT ..........................................................................25 
7.1 
Antitumor Effect- Solid Tumors ...................................................................................... 25 
7.2 
Safety/Tolerability .......................................................................................................... 28 
8.0 
ADVERSE EVENTS ............................................................................................28 
8.1 
Experimental Therapy with Carboplatin......................................................................... 28 
8.2 
Adverse Event Reporting Requirements ....................................................................... 30 
8.3 
Definitions ...................................................................................................................... 31 
8.4 
Adverse Event Characteristics ...................................................................................... 32 
8.5 
Serious Adverse Event Reporting Guidelines ............................................................... 32 
8.6 
Routine Reporting .......................................................................................................... 33 
8.7 
Reporting of Unanticipated Problems ............................................................................ 33 
9.0 
DRUG INFORMATION .......................................................................................34 
9.1 
Carboplatin .................................................................................................................... 34 
9.2 
Palbociclib ...................................................................................................................... 35 
10.0 
CORRELATIVES/SPECIAL STUDIES .........................................................37 
10.1 
Sample Collection Guidelines ........................................................................................ 37 
10.2 
Assay Methodology ....................................................................................................... 38 
10.3 
Specimen Banking ......................................................................................................... 41 
11.0 
STATISTICAL CONSIDERATIONS .............................................................41 
11.1 
Study Design/Study Endpoints ...................................................................................... 41 


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11.2 
Sample Size and Accrual .............................................................................................. 42 
11.3 
Data Analyses Plans...................................................................................................... 42 
12.0 
DATA AND SAFETY MONITORING ............................................................42 
13.0 
QUALITY ASSURANCE AND AUDITS .......................................................43 
14.0 
CLINICAL MONITORING PROCEDURES ..................................................43 
15.0 
APPENDICES ...................................................................................................44 
16.0 
REFERENCES .................................................................................................52 


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ABBREVIATIONS 
 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSU 
Clinical Trials Support Unit 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
PRC 
Protocol Review Committee 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
UaP 
Unanticipated Problem 
WBC 
White Blood Cells 
 
 
 


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STUDY SCHEMA 
 
 
 
 
 
 


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STUDY SYNOPSIS 
Title 
A Multi-Center open label single arm phase II trial evaluating the efficacy 
of palbociclib in combination with carboplatin for the treatment of 
unresectable recurrent or metastatic head and neck squamous cell 
carcinoma (Short Title: CarPal Head and Neck) 
Phase 
Phase II 
Methodology 
Open label, single arm trial 
Study Duration 
36 months 
Study Center(s) 
Multicenter - up to 3 sites including the lead site University of Michigan 
Objectives 
Primary Objective 
1. To assess evidence of anti-tumor activity by assessment of disease 
control rate (CR + PR + SD) at 12 weeks in patients with metastatic 
head and neck squamous cell cancer treated with carboplatin and 
palbociclib  
 
Secondary Objectives 
1. To assess survival in patients with metastatic head and neck 
squamous cell cancer treated with carboplatin and palbociclib 
2. To describe the adverse events associated with use of carboplatin 
and palbociclib  
 
Exploratory Objectives 
1. Explore the response to therapy based on CDK4, CDK6, Cyclin D1, 
CDKN2A and HPV genetic status 
2. Evaluate whether molecular and biochemical markers are predictive 
of tumor response including: 
- 
Correlate genetic subtype with response via targeted DNA and 
RNA-sequencing of pre-treatment biopsy. 
- 
Assess the expression of CDK4, CDK6, Cyclin D1, CDKN2A in 
tumors as well as level of vascularization (CD31+ cells), 
apoptosis (TUNEL), proliferation (Ki67), and tumor infiltrating 
lymphocyte content (CD4/CD8, etc.). 
3. Assess whether the dynamics of circulating tumor DNA (ctDNA) are 
associated with clinical and radiographic responses to therapy as 
well as monitor for the presence and quantity of HPV DNA or DNA 
containing somatic mutations identified in the targeted sequencing of 
the biopsy specimen.     
Number of Subjects 
40 evaluable patients 


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Inclusion Criteria 
1. Histologically documented progressive squamous cell head and 
neck cancer with or without metastases, not amenable to curative 
treatment; or the patient has documented refusal of curative 
treatment. 
2. ECOG performance status of 0-2 
3. Presence of measurable disease by CT scan by RECIST v1.1. 
4. Adequate bone marrow, hepatic, and renal function (including 
WBC≥ 3x109 cells/ml, ANC ≥ 1.5x109 cell/ml, platelets ≥75,000 
cells/mm3, hemoglobin ≥ 9.0 g/dL, concentrations of total serum 
bilirubin within 1.5 x upper limit of normal (ULN), AST, ALT within 
2.5x institutional upper limits of normal unless there are liver 
metastases in which case AST and ALT within 5.0 x ULN, serum 
creatinine clearance ≥ 30 ml/min).  
5. Age ≥18 years. 
6. Life expectancy of ≥12 weeks. 
7. Women of childbearing potential must have a negative serum or 
urine pregnancy test at time of screening and confirmed within 3 
days prior to treatment. Women not of child-bearing potential will 
be defined as all women older than age 50 and anovulatory for 
12 months. 
8. Signed and dated informed consent document indicating that the 
patient (or legally acceptable representative) has been informed 
of all pertinent aspects of the trial prior to enrollment. 
9. Willingness and ability to comply with scheduled visits, treatment 
plans, laboratory tests, and other study procedures. 
.  
Exclusion Criteria 
1. Previous treatment with cytotoxic chemotherapy therapy in the 
recurrent/metastatic setting. Previous treatment with non-
cytotoxic agents and/or concurrent chemoradiation in the 
recurrent/metastatic setting is permitted. 
2. Gastrointestinal abnormalities causing impaired absorption 
precluding administration of medications by mouth or feeding 
tube. 
3. Evidence of untreated or progressive brain metastases, spinal 
cord compression, or carcinomatous meningitis. 
4. A serious uncontrolled medical disorder or active infection that 
would impair their ability to receive study treatment. 
5. Dementia or significantly altered mental status that would prohibit 
the understanding or rendering of informed consent and 
compliance with the requirements of this protocol. 
6. Patients (male and female) having procreative potential who are 
not willing or not able to use 2 adequate methods of 
contraception or practicing abstinence during the study and for 90 
days following their last dose of treatment. 
7. Women who are pregnant or breast-feeding. 
8. Patients residing in prison. 
9. Prior experimental therapy within 30 days of enrollment. 
10. Availability of curative treatment option for the patient’s cancer, 
whether surgery, chemotherapy, radiation, or combination 
thereof, unless the patient has documented refusal of curative 
treatment. 
11. Patients with a history of severe allergic reaction to cisplatin or 
carboplatin 
 


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Study Product(s), Dose, 
Route, Regimen 
Carboplatin + Palbociclib Cohort 
Palbociclib (Ibrance), dose= 125 mg daily, days=1-14, cycle length: 21 
days 
Carboplatin (IV), dose= AUC 5, day= 1, cycle length: 21 days 
 
Maintenance Palbociclib 
Palbociclib (Ibrance) 125 mg daily, days 1-21, cycle length: 28 days 
Duration of Administration 
Study drugs will be administered in an open label fashion until 
progression, intolerance, or patient preference.   
Reference Therapy 
A historical control will be utilized 
Statistical Methodology 
This is an open-label multi-institution single arm Phase II study with a 
two-stage design 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Head and neck squamous cell cancer (HNSCC) is the sixth most common cancer 
worldwide. Despite the prevalence of this disease, a significant proportion of patients 
progress despite appropriate therapy in which case treatment is palliative in intent. 
Unresectable recurrent or metastatic (R/M) HNSCC has a dismal survival and 
development of novel therapeutics has been met with little success.  
 
Platinum compounds historically are the backbone of first line therapy however 
documented response rates to cytotoxic chemotherapy range between 10-30% with 
single agent regimens and 20-40% for multi-drug regimens.  Although increased 
response rates are seen with doublet regimens, progression free survival (4.2-5.1 
months) and overall survival (5.7-6.6 months) have not been significantly increased with 
the addition of further cytotoxic agents2-4.  To date, the regimen associated with the best 
survival outcomes in the first line setting are seen with the use of a triplet consisting of 
cetuximab, a platinum, and 5-flurouracil (the ‘EXTREME’ regimen’).  In a sentinel 
publication when compared to platinum plus 5-flurouracil, the EXTREME regimen 
resulted in improved overall survival (10.1 vs 7.4 months) and response rate (36 vs 20%). 
However this aggressive regimen is accompanied by significant rates of serious toxicities 
significantly limiting its use5. Given issues with toxicities and the baseline mediocre 
performance status at diagnosis, many patients with R/M HNSCC are not candidates for 
the EXTREME triplet regimen. Therefore, novel therapeutic approaches are necessary. 
 
Now with a greater understanding of aberrant cellular signaling and function in 
carcinogenesis, there has been a shift in modern chemotherapeutics towards targeted 
therapies specific to the molecular drivers of each distinct malignancy. Commonly altered 
genes include cell cycle regulatory genes CDKN2A and CCND17.  These cell cycle 
regulatory genes encode a complex group of proteins including cyclin dependent kinases 
and cyclin D which regulate progression through the cell cycle. Sustained CDK 4/6 
activation is believed to be present in the majority of tumors as a mechanism to 
continually allow transition from G1 to S phase12.  In R/M HNSCC, alterations in CCND1 
or CDKN2A are two genomic events which lead to loss of checkpoint control.  In patients 
with R/M HNSCC CDKN2A alterations include homozygous deletions in 30%, additional 
gene mutations in 10-20%, and epigenetic alterations leading to inactivation in up to 80%. 
CCND1 has been noted to be amplified in 20%7-10.  Between the two, genomic alterations 
in either CCND1 or CDKN2A have been identified in between 60-94% of R/M HNSCC 
making these potential targets of interest7,10,11. 
1.2 
Palbociclib- Background and Associated Known Toxicities 
• 
Palbociclib is a reversible, oral, highly selective inhibitor of CDK 4 and 6 (CDK 4/6)13 
approved in combination with either fulvestrant or letrozole as first line treatment for 
hormone receptor positive metastatic breast cancer. 
• 
The predominance of the clinical experience with palbociclib comes from the 
PALOMA trials (-1,-2, and -3) evaluating its efficacy in the first line treatment of 
hormone receptor positive metastatic breast cancer.  When considered together, over 
870 patients have been treated with palbociclib in combination with hormone therapy 
(letrozole or anastrozole) on these trials14-16.  These trials demonstrated significant 
improvement in median progression free survival with the addition of palbociclib (14.5 
to 24.8 months with the addition to Letrozole, 4.6 to 9.5 months with the addition to 
Fulvestrant).  Response information from these trials are summarized in Table 1.  
Interestingly, although the rate of objective response was somewhat increased with 
the addition of palbociclib, the biggest impact with the addition of palbociclib was 


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increase in the rate of stable disease and clinical benefit (defined as percentage of 
patients who had a confirmed complete response, partial response, or stable disease 
for 24 weeks or more).  Given the mechanism of CDK4/6 inhibition, response has 
been evaluated by biomarker status (CCND1 amplification, p16 loss, PIK3CA mutant) 
in PALOMA -1 and -3.  These trials have demonstrated responses and improvement 
in survival in both biomarker positive negative populations14,16.  Based on the results 
of these studies, palbociclib has been approved in combination with either fulvestrant 
or letrozole as first line treatment for hormone receptor positive metastatic breast 
cancer. 
 
Table 1: Summary of Response Rates from PALOMA Trials 
PALOMA 1: Phase 2 Trial of Palbociclib + Letrozole vs Letrozole 
 
Palbociclib + Letrozole 
(n=83) 
Letrozole (n=77) 
Complete Response 
1% 
1% 
Partial Response 
42% 
32% 
Stable Disease 
>24 weeks 
44% 
38% 
37% 
25% 
Clinical Benefit 
68% 
47% 
Progressive Disease 
4% 
22% 
Indeterminate 
10% 
7% 
 
PALOMA 2: Phase 3 Trial of Palbociclib + Letrozole vs Letrozole + Placebo 
 
Palbociclib + 
Letrozole 
(n=444) 
Placebo + 
Letrozole 
(n=222) 
P value 
Objective 
Response* 
42.1% 
34.7% 
0.06 
Clinical 
Benefit 
Response** 
84.9% 
70.3% 
<0.001 
Median 
Duration of 
Response 
22.5 mo 
16.8 mo 
 
*Objective response defined as percentage of patients who had a confirmed 
complete response or a partial response 
**Clinical benefit response defined as percentage of patients who had a confirmed 
complete response, partial response, or stable disease for 24 weeks or more 
 
PALOMA 3: Phase 3 Trial of Palbociclib + Fulvestrant vs Fulvestrant + Placebo 


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*Clinical benefit defined as percentage of patients who had a confirmed complete 
response, partial response, or stable disease for 24 weeks or more 
 
• 
There is a significant amount of safety information available surrounding the use of 
palbociclib, most comprehensively documented through the PALOMA trials.  The 
most common SAEs are hematologic including neutropenia, leukopenia, and anemia 
as summarized below in Table 2. Interestingly, despite the rate of neutropenia, febrile 
neutropenia and discontinuation due to adverse events has repeatedly been noted to 
be extremely low14-16.  A complete description of the safety information can be found 
in the current Investigator’s Brochure or Study Agent Prescribing Information. 
 
Table 2: Summary of Adverse Events from PALOMA Trials 
PALOMA 1: Phase 2 Trial of Palbociclib + Letrozole vs Letrozole 
 
Palbociclib + 
Letrozole 
Letrozole 
 
Grade 3 
Grade 4 
Grade 3 
Grade 4 
Any AE 
59% 
17% 
21% 
0% 
Neutropenia* 
48% 
6% 
1% 
1% 
Anemia 
5% 
1% 
5% 
1% 
Leukopenia 
19% 
0% 
0% 
0% 
Fatigue 
2% 
2% 
1% 
0% 
*No cases of neutropenic fever were reported in the Palbociclib + Letrozole group 
despite high rate of Grade 3/4 neutropenia 
 
PALOMA 2: Phase 3 Trial of Palbociclib + Letrozole vs Letrozole + Placebo 
 
Palbociclib + 
Letrozole 
Placebo + Letrozole 
 
Grade 3 
Grade 4 
Grade 3 
Grade 4 
Any AE 
62% 
13.5% 
22.1% 
2.3% 
Neutropenia* 
56.1% 
10.4% 
0.9% 
0.5% 
Anemia 
5.2% 
0.2% 
1.8% 
0% 
Leukopenia 
24.1% 
0.7% 
0% 
0% 
Fatigue 
1.8% 
0% 
0.5% 
0% 


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*Febrile neutropenia was reported as serious in 1.6% the Palbociclib + Letrozole 
group 
 
PALOMA 3: Phase 3 Trial of Palbociclib + Fulvestrant vs Fulvestrant + Placebo 
 
Palbociclib + 
Fulvestrant 
Fulvestrant + 
Placebo 
 
Grade 3 
Grade 4 
Grade 3 
Grade 4 
Neutropenia 
55% 
10% 
0% 
1% 
Anemia 
3% 
0% 
2% 
0% 
Leukopenia 
27% 
1% 
1% 
1% 
Infections 
2% 
1% 
3% 
0% 
Fatigue 
2% 
0% 
1% 
0% 
 
• 
Recognizing the potential as a targeted therapy in other cancers with CDK 
abnormalities, palbociclib has been evaluated in advanced CDK4-amplified well-
differentiated or dedifferentiated liposarcoma.  The study met its primary end point 
with a 12 week PFS of 66% (historical PFS for a second line agent 20-40%).  
Treatment was reasonably well tolerated with predominantly hematologic adverse 
events.  Grade 3 to 4 hematologic toxicities included anemia (17%), neutropenia 
(50%), and thrombocytopenia (30%).  Only one episode of grade 3 febrile 
neutropenia was noted17. This study acts not only to demonstrate a signal of 
response in CDK4-amplified well-differentiated or dedifferentiated liposarcoma but 
also demonstrates the promise of this agent for the treatment of diverse malignancies 
with cyclin-dependent kinase dysregulation. 
• 
Palbociclib is a novel therapeutic in R/M HNSCC. Only one small phase I trial utilizing 
a doublet of palbocicilb and cetuximab (an IgG1 anti-EGFR monoclonal antibody) has 
been conducted in R/M HNSCC. This phase 1 study, presented at ASCO 2015, 
demonstrated suggestion of activity in both p16 negative and positive patients18.  
Nine patients were enrolled in this Phase 1 study; 5 of whom were both platinum and 
cetuximab resistant, 1 of whom was cetuximab resistant.  Of the nine patients, 5 
patients were p16- and 4 p16+.  No dose limiting toxicities or AE related treatment 
discontinuations were encountered hence the maximum tolerated dose (MTD) was 
not reached.  Tumor assessment after cycle 2 demonstrated partial response (PR) in 
2 patients, stable disease (SD) in 5 patients, progressive disease (PD) in 1 patient, 
and one patient was non-evaluable.  Responses were seen in patients who were 
cetuximab resistant as well as those resistant to platinum and cetuximab. Based on 
the results of this trial, a Phase II utilizing cetuximab with palbociclib in HPV- patients 
is ongoing (NCT02101034).  Therefore, the early results of this trial support further 
exploration of palbociclib in R/M HNSCC. 
1.3 
Carboplatin- Background and Rationale for Synergy 
 
1.3.1 
Background 
 
Carboplatin is a commercially available cytotoxic chemotherapeutic which is a 
standard first line agent for the management of R/M HNSCC19. Please see 
detailed information on adverse events and potential risks in Section 9.0. 
 
1.3.2 
Rationale for Synergy 
 
Two preclinical studies have explored the role of combining cytotoxic 
chemotherapy with CDK4/6 inhibitors.  Matranga et al examined demonstrated 
exquisite sensitization to the pan-CDK flavopiridol following chemotherapeutic 
exposure.  This effect was seen with numerous agents including cisplatin and 


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gemcitabine. This was demonstrated to be due to chemotherapy induced tumor 
S-Phase recruitment/synchronization resulting in a greater degree of cell cycle 
arrest and apoptosis with flavopiridol.  Interesting, the increased apoptotic effect 
was observed only in immortalized cells20. Similar synergistic lethality was 
observed in a study examining other chemotherapeutics in a xenograft model21. 
 
Preclinical and phase II studies have previously demonstrated potentiation of 
doxorubicin efficacy by flavopiridol.  In the Phase II study by Jones et al, the 
doublet of doxorubicin and flavopiridol in well and de-differentiated liposarcoma 
resulted in improved response rates compared to historical controls without 
encountering a MTD22. 
 
Within our institution, combination of CDK4/6 inhibitors and platinum 
chemotherapy has been of significant interest.  Unpublished research from our 
colleagues (Coffman, Buchanovich, et al) has explored the role for combining 
cisplatin with CDK 4/6 inhibition in ovarian cancer cell lines and xenografts.  
Publication of this work is expected in the near future but they clearly 
demonstrated a synergistic effect with concurrent cisplatin and CDK 4/6 inhibition 
using Ribociclib.   Interestingly, they demonstrated reduction in stem-like cells in 
both Rb mutant and wild type cell lines.  This treatment was found to lead to 
complete and more permanent cell arrest (Personal Communications, 
Unpublished Data).  Similarly, Baldassarre et al presented data at the 2015 
AACR Ovarian Cancer Meeting demonstrating CDK 6 inhibition inhibited ART 
and led to platinum sensitization. Based on this compelling data, a clinical trial 
evaluating the efficacy of concurrent carboplatin and Ribociclib in platinum 
sensitive ovarian cancer is underway. 
 
Preclinical work in head and neck squamous cell lines has similarly 
demonstrated suggested synergistic potential of palbociclib and platinum 
therapy.  Two HNSCC cell lines, UMSCC-59 and UMSCC-103 HNSCC, have 
been examined both of which were derived from stage IV oral cavity carcinomas.  
Cells were plated and allowed to expand into logarithmic growth phase, then 
treated with either vehicle (DMSO), cisplatin alone, palbociclib alone, or cisplatin 
and palbociclib in combination.  Cell response was analyzed with cell proliferation 
with resazurin assays and clonogenic cell survival assays.  Enhanced response 
was seen with the combination of cisplatin and palbociclib in comparison to either 
agent alone.  For UMSCC-59, survival fractions were 33% for combination 
therapy, 71% for cisplatin alone, and 88% for palbociclib alone.  For UMSCC-
103, survival fractions were 34% for combination therapy, 40% for cisplatin 
alone, and 80% for palbociclib alone.  There was suggestion of increased 
sensitivity with the presence of a CDKN2A mutation (UMSCC-59) compared to 
wildtype CDKN2A (UMSCC-103) (Brenner, Unpublished Data- Manuscript in 
progress). 
 
1.3.3 
Dosing Rationale 
 
Dosing of carboplatin and palbociclib for this trial is adapted from the results of 
the PALOMA trials as well as standard of care dosing for carboplatin.  We will 
utilize a dose of Carboplatin AUC 5, day 1, and Palbociclib 125 mg daily, 2 
weeks on and one week off.  Cycle length will be 21 days.  Support of this 
doublet is supported by an ongoing phase I Trial “Palbociclib with Cisplatin or 
Carboplatin in Advanced Solid Tumors” (NCT02897375) which has demonstrated 
non-overlapping toxicities or dose limiting toxicities (Unpublished Personal 
Communication).  We will be performing frequent interim analysis to evaluate 
toxicities of this dosing regimen and adjust if necessary. 
  


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1.4 
Rationale in Head and Neck Cancer 
 
Given the molecular alterations (CDKN2A, CCND1) seen in R/M HNSCC and signal of 
efficacy with the use of palbociclib in patients in other malignancies with these alterations, 
exploration in R/M HNSCC is warranted.  Based on preclinical evidence, the combination 
of a CDK 4/6 inhibitor with cytotoxic chemotherapy in the first line setting is a rational 
therapeutic approach and holds promise as an effective doublet in head and neck cancer. 
 
 
We propose a phase II trial to evaluate the combination of palbociclib and carboplatin for 
the first-line cytotoxic treatment of R/M HNSCC. This will be a single arm, non-
randomized, non-blinded phase II trial.  Patients with unresectable recurrent or metastatic 
HNSCC with no previous cytotoxic chemotherapy therapy in the recurrent/metastatic 
setting will be included. Previous treatment with immunotherapeutics in the 
recurrent/metastatic setting will be permitted. 
 
Based on pre-clinical data, we hypothesize that this doublet will have activity in eliciting a 
greater antitumor response and hence improved disease control rate. Much of the benefit 
seen in previous palbociclib trials was SD and clinical benefit (CR + PR + SD at 24 
weeks) rather than improvement in ORR, CR, or PR.  As the increase in SD was 
associated with improved PFS compared to placebo in these trials, we believe this 
represents drug effect rather than disease biology. Therefore, we believe disease control 
rate (DCR) at 12 weeks is an appropriate primary end point for this phase II trial. 
1.5 
Correlative Studies 
 
Recently published results from Palbociclib clinical trials and our internal in vitro studies 
described above have shown a correlation between response to therapy and molecular 
genetics for genetic networks centers on RB1 amplification and/or CDKN2A loss. Some 
studies have used RB1 phosphorylation as a marker for enrollment, others have 
retrospectively assessed molecular profiles. Thus, to assess the potential of using 
molecular genetics to enrich for responsive populations in future studies of head and 
neck cancer, we propose to determine correlations of the molecular networks with 
Palbociclib-based therapy. According to our recent and published NGS data (including 
with the TCGA network) patients with R/M HNSCC have CDKN2A alterations (30% 
homozygous deletion, 10-20% mutations, and epigenetic alterations) leading to loss of 
RNA expression. Likewise, CCND1 as a gene within the 11q13 ampicon has been noted 
to be amplified and overexpressed in 20% of cases7-10.  With low rates of alterations also 
seen in RB1 and CDK4/6 at the DNA level, the role of these genes as prognostic 
biomarkers may be more informative at RNA or protein expression levels. However, in 
primary untreated disease, potentially activating CDK4 and CDK6 mutations are rare and 
have only been reported in 0.5% of the population and it will be important to identify 
patients with these alterations. Given the overall alteration frequency of the genes as well 
as the potential to define a companion molecular diagnostic for this therapy, we propose 
the following hypothesis: Specific genetic networks will correlate with response to 
Palbociclib-based therapy including patients with alterations in CDKN2A, CyclinD1, 
CDK4/6, RB and/or human papilloma virus.  
 
In addition to advancing studies of pre-enrollment companion diagnostics, we also 
propose to leverage our experience with analyzing ctDNA in the saliva and serum to 
assess ctDNA for its ability to identify response to therapy. In other cancers, ctDNA is 
routinely monitored as a potential biomarker to assess response to therapy as well as to 
provide early identification of obvious mutations that drive resistance to targeted 
inhibitors23-26. With the recent advances in the utility of molecular barcoding for next 
generation sequencing, quantification of low yield DNA samples has become a pivotal 
method for the detection of ctDNA in patients and is a technology that we propose to 


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leverage in this proposal. Thus, we also propose the following hypothesis:  Cancer 
response to therapy can be detected in saliva and serum biospecimens collected at 
routine interval time points and will identify tumor recurrence earlier than interim imaging. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
2.1.1 
To assess evidence of anti-tumor activity by assessment of disease control rate 
at 12 weeks in patients with metastatic head and neck squamous cell cancer 
treated with carboplatin and palbociclib 
2.2 
Secondary Objectives  
 
2.2.1 
To describe the adverse events associated with use of carboplatin and 
palbociclib 
 
2.2.2 
To assess survival in patients with metastatic head and neck squamous cell 
cancer treated with carboplatin and palbociclib 
2.3 
Exploratory Objectives 
 
2.3.1 
Explore the response to therapy based on CDK4, CDK6, Cyclin D1, CDKN2A 
and HPV genetic status. 
 
2.3.2 
Evaluate whether molecular and biochemical markers are predictive of tumor 
response.  
 
2.3.2.1 Correlate genetic subtype with response via targeted DNA and RNA-sequencing 
of pre-treatment biopsy. 
 
2.3.2.2 Assess the expression of CDK4, CDK6, Cyclin D1, CDKN2A in tumors as well as 
level of vascularization (CD31+ cells), apoptosis (TUNEL), proliferation (Ki67), 
and tumor infiltrating lymphocyte content (CD4/CD8, etc.). 
 
2.3.3 
Assess whether the dynamics of circulating tumor DNA (ctDNA) are associated 
with clinical and radiographic responses to therapy as well as monitor for the 
presence and quantity of HPV DNA or DNA containing somatic mutations 
identified in the targeted sequencing of the biopsy specimen.     
2.4 
Endpoints 
2.3.1 
Primary Endpoint 
 
2.3.1.1 Disease control rate will be defined as the proportion of patients 
achieving either complete response (CR), partial response (PR), or 
stable disease (SD) at 12 weeks.  Response will be assessed via 
RECIST v1.1.  
 
2.3.2 
Secondary Endpoints 
 
2.3.2.1 Adverse events will be evaluated by clinical evaluation as well as routine 
lab work.  Toxicities will be assessed via CTCAE v 4.03. 
 


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2.3.2.2  Survival endpoints to be assessed will include both overall survival and 
progression free survival time 
 
 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled to the study. Study 
treatment may not begin until a subject is enrolled. 
3.1 
Inclusion Criteria 
 
3.1.1 
Histologically documented progressive squamous cell head and neck cancer with 
or without metastases, not amenable to curative treatment; or the patient has 
documented refusal of curative treatment. 
 
3.1.2 
ECOG performance status of 0-2 
 
3.1.3 
Presence of measurable disease by CT scan per RECIST v1.1. 
 
3.1.4 
Age ≥18 years. 
 
3.1.5 
Life expectancy of ≥12 weeks. 
 
3.1.6 
Women of childbearing potential must have a negative serum or urine pregnancy 
test at time of screening and confirmed within 3 days prior to treatment. Women 
not of child-bearing potential will be defined as all women older than age 50 and 
anovulatory for 12 months.  
 
3.1.7 
Signed and dated informed consent document indicating that the patient (or 
legally acceptable representative) has been informed of all pertinent aspects of 
the trial prior to enrollment. 
 
3.1.8 
Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures. 
 
3.1.9 
Adequate organ and marrow function as defined below: 
WBC 
≥ 3 x 109 cells/mL 
ANC 
≥ 1.5 x 109 cells/mL 
Hemoglobin 
≥ 9 g/dL 
Platelets 
≥ 75,000 cells/mm3 
Total Serum Bilirubin 
Within 1.5 x upper limit of normal (ULN) 
AST 
Within 2.5 x ULN unless there are liver 
metastases in which case, AST within 5 x ULN  
ALT 
Within 2.5 x ULN unless there are liver 
metastases in which case, ALT within 5 x ULN 
Serum Creatinine 
Clearance 
≥ 30 mL/min 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Previous treatment with cytotoxic chemotherapy therapy in the 
recurrent/metastatic setting. Previous treatment with non-cytotoxic agents and/or 
concurrent chemoradiation in the recurrent/metastatic setting is permitted. 
 


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3.2.2 
Gastrointestinal abnormalities causing impaired absorption precluding 
administration of medications by mouth or feeding tube. 
 
3.2.3 
Evidence of untreated or progressive brain metastases, spinal cord compression, 
or carcinomatous meningitis. 
 
3.2.4 
A serious uncontrolled medical disorder or active infection that would impair their 
ability to receive study treatment. 
 
3.2.5 
Dementia or significantly altered mental status that would prohibit the 
understanding or rendering of informed consent and compliance with the 
requirements of this protocol. 
 
3.2.6 
Patients (male and female) having procreative potential who are not willing or not 
able to use 2 adequate methods of contraception during the study and for 90 
days following their last dose of treatment.  Adequate contraception is defined as: 
 
a. 
Total abstinence or 
b. 
Male or female sterilization or 
c. 
Combination of any two of the following (i+ii or i+iii, or ii+iii): 
i. Use of oral, injected or implanted hormonal methods of contraception 
ii. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
iii. Barrier methods of contraception: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository 
 
3.2.7 
Women who are pregnant or breast-feeding. 
 
3.2.8 
Patients residing in prison. 
 
3.2.9 
Prior experimental therapy within 30 days of enrollment. 
 
3.2.10 Availability of curative treatment option for the patient’s cancer, whether surgery, 
chemotherapy, radiation, or combination thereof, unless the patient has 
documented refusal of curative treatment. 
 
 
3.2.11 Patients with a history of severe allergic reaction to cisplatin or carboplatin 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
 
Patient registration for this trial will be centrally managed by the Coordinating Center of The 
University of Michigan Rogel Cancer Center as described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log provided by the Coordinating Center. 
 
It is the responsibility of the local site investigator to determine patient eligibility prior to submitting 
patient registration request to the Coordinating Center. After patient eligibility has been 
determined, a copy of the completed Eligibility Worksheet together with all the pertinent de-
identified source documents will be submitted by the requesting site to the Coordinating Center, 
by email to CTSU-Oncology-Multisite@med.umich.edu.   
 


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The Multi-Site Coordinator, who acts as the registrar, will review the submitted documents and 
process the registration. Sites should inform the Multi-Site Coordinator of a potential registration 
by 5 p.m. on the day prior to registration.  Same day registrations cannot be guaranteed.   
 
An email will be sent by the registrar to the requesting site registrar to confirm patient registration 
and to provide the study identification number that has been assigned to the patient. In addition, a 
copy of the Eligibility Worksheet signed and dated by the registrar, will be sent back to the 
requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
have study identification number assigned to them, and will not receive study treatment. 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within 5 business days of enrollment to the study. 
 
5.1.1 
This study will be a non-randomized phase II trial. We will enroll 40 patients with 
R/M HNSCC. Patients will be treated with Carboplatin (AUC=5, IV, day 1) as well 
as Palbociclib (125 mg,daily, days 1-14). Cycle length will be 21 days.  Patients 
will be monitored closely for toxicity and undergo imaging to evaluate efficacy 
once every 2 cycles.  After 6 cycles of Carboplatin + Palbociclib, if patients 
continue to garner a response to therapy, they will be transitioned to 
maintenance single agent palbociclib at a dose of 125 mg daily, days 1-21, cycle 
length: 28 days 
  
5.1.2 
Carboplatin + Palbociclib Regimen 
 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Carboplatin 
Premedications 
per discretion of 
prescribing 
physician 
 
AUC=5 
IV 
Days 1, 
week 1 
3 weeks 
(21 
days) 
 
Palbociclib 
Capules 
-Swallow 
capsules whole. 
Do not cut, chew, 
or crush 
-Should be taken 
with food at 
approximately 
the same time 
each day 
Solution 
-Should be taken 
at approximately 
the same time 
each day.  Does 
not need to be 
taken with food. 
125 mg daily 
Capsule or 
Solution 
Days 1-14 
 


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5.1.2.1 Carboplatin Administration 
5.1.2.1.1 Carboplatin is an IV drug which will be administered as an 
outpatient 
5.1.2.1.2 Premedications per discretion of prescribing physician 
 
5.1.2.2 Palbociclib Administration 
5.1.2.2.1 Palbociclib will be self-administered and may be taken by 
mouth or via feeding tube. 
5.1.2.2.1.1 
If patients can swallow pills, Palbociclib will be 
administered as a capsule formulation 
5.1.2.2.1.1.1 
Swallow palbociclib capsules whole.  Do not cut, 
chew, or crush capsules 
5.1.2.2.1.1.2 
Palbociclib capsules should be taken with food 
at approximately the same time each day 
5.1.2.2.1.2 
If patients are unable to swallow pills, or rely on feeding 
tube for administration of medications (ie PEG, NG 
tubes) then solution formulation Palbociclib will be 
utilized  
5.1.2.2.1.2.1 
Palbociclib solution should be taken at 
approximately the same time each day.  It does 
not need to be taken with food. 
5.1.2.2.1.2.2  
Patient administration directions using syringe 
are detailed in Pfizer Approved ‘Administration 
Instruction’ Handouts (Appendix C- 
Administration Instructions for Oral Dose Using 
Syringe and Appendix D- Administration 
Instructions for Each Dose via NG Tubes) 
5.1.2.2.2 Palbociclib solution will be available by late January/ early 
February 2018 for patients who cannot swallow the Palbociclib 
capsules. 
5.1.2.2.2.1 
Patients who begin the study receiving the oral solution 
will remain on the solution for the duration of their time 
on treatment in the study. 
5.1.2.2.2.2 
Patients, who begin the study receiving capsules but 
develop difficulty swallowing the capsules and did not 
have disease progression, will be allowed to switch to 
the Palbociclib oral solution. These patients will then 
remain on the oral solution for the duration of their time 
on treatment in the study. 
5.1.2.2.3 Patients should be instructed that if they vomit any time after 
taking a dose of Palbociclib, that they must not “make it up” 
with an extra dose, but instead resume subsequent doses as 
prescribed. Missed doses may be taken late, up to 6 hours 
after the scheduled dose, otherwise should be skipped and 
reported to the investigators. 
 
5.1.3 
Maintenance Single Agent Palbociclib  
 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Palbociclib 
Capsules 
-Swallow 
capsules whole. 
Do not cut, chew, 
or crush 
125 mg daily 
 
Capsule or 
Solution 
Days 1-21 
4 weeks 
(28 
days) 
 


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-Should be taken 
with food at 
approximately 
the same time 
each day 
Solution 
- Should be 
taken at 
approximately 
the same time 
each day. Does 
not need to be 
taken with food 
 
5.1.3.1 Single agent palbociclib will be administered in a matter identical to that 
described in Section 5.1.2.2 
 
5.1.4 
Compliance and Monitoring 
 
5.1.4.1 The patients will be asked to bring medication bottles to each follow-up 
visit, and remaining pills in bottle will be counted at each visit to 
document compliance. This information will be recorded in each patient’s 
data file. 
5.1.4.1.1 
If patients are being treated with oral solution, they will be asked 
to return the bottles in clear Ziplock bag.  For drug accountability, 
research staff may use a best approximation (in units of 
milliliters) as to the remaining solution as they may be unable to 
open HDPE bottles 
 
 
5.1.4.2 Drug Administration will be provided to record compliance with drug 
administration, route of administration (by mouth or feeding tube) as well 
as document dose adjustments. 
 
5.2 
Toxicities and Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.1). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity. 
 
5.2.1 
Dosing Interruptions 
 
Patients experiencing any of the following adverse events should have their 
treatment interrupted/delayed 
 
• 
Uncomplicated Grade 3 neutropenia (ANC<1000/mm3) 
• 
Grade 3 neutropenia (ANC <1000/mm3) associated with a documented 
infection of fever ≥ 38.5° C 
• 
Grade 4 neutropenia (ANC <500/mm3) 
• 
Grade 4 thrombocytopenia (platelet count < 25,000/mm3) 
• 
Grade ≥ 3 non-hematologic toxicity (including nausea, vomiting, diarrhea, 
fatigue, and hypertension only if persisting despite optimal medical 
treatment) 


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Appropriate follow up assessments should be done until adequate recovery 
occurs as assessed by the investigator. Criteria required before treatment can 
resume are described in Section 5.2.2. 
 
Doses of palbociclib ± carboplatin infusions may be held as needed until toxicity 
resolution. Depending on when the adverse event resolved, a treatment 
interruption may lead to the patient missing all subsequent planned doses within 
that same cycle or even delay the initiation of the subsequent cycle.  If the 
adverse event that led to the treatment interruption recovers within the same 
cycle, then re-dosing in that cycle is allowed.  Doses omitted for toxicity are not 
replaced within the same cycle.  The need for a dose reduction at the time of 
treatment resumption should be based on the criteria in Section 5.2.3. 
 
In the event of a treatment interruption for reasons other than treatment-related 
toxicity (ie non-cancer related surgery) lasting >2 weeks, treatment resumption 
will be decided in consultation with the co-principal investigators. 
 
5.2.2 
Dose Delay 
 
Retreatment following treatment interruption for treatment-related toxicity or at 
the start of a new cycle may not occur until all of the following parameters have 
been met: 
 
• 
Platelet count ≥ 50,000/mm3 
• 
ANC ≥ 1000/mm3 and no fever 
• 
Grade 3 or higher treatment-related non-hematologic AEs (including 
nausea, vomiting, diarrhea, and hypertension only if persisting despite 
optimal medical treatment), with the exception of alopecia, have 
recovered to Grade ≤ 1 or baseline (or, at the investigator’s discretion, 
Grade ≤ 2 if not considered a safety risk for the patient) 
 
If a treatment delay results from decline in hematologic parameters, the 
frequency of blood count assessments should be increased as clinically 
indicated. G-CSF (Filgrastim or Peg-filgrastim) may be given for neutropenia at 
the investigator’s discretion. 
 
If these parameters are met within 2 weeks of treatment interruption or cycle 
delay, treatment may be resumed. Please see Section 5.2.3 for dose reductions 
at the time of treatment resumption. 
 
If these parameters have not been met after 2 weeks of dosing interruption 
(including the scheduled 1 week off Palbociclib treatment) or 2 weeks of cycle 
delay, permanent treatment discontinuation should be considered.  Treatment 
resumption for patients recovering from toxicity after > 2 weeks of treatment 
interruption of cycle delay but deemed to be deriving obvious clinical benefit per 
the investigator’s best medical judgement is left at the investigator’s discretion. 
 
A new cycle only starts when the criteria listed above are met and treatment with 
palbociclib ± carboplatin may be administered.  Otherwise, initiation of the new 
cycle must be delayed until such criteria are met.  In the event that the start of a 
new cycle is delayed due to treatment related toxicity, procedures required on 
Day 1 of the given cycle will be performed when palbociclib ± carboplatin is 
resumed. New Day 1 procedures that were performed prior to knowing the need 
to delay the start of the cycle do not need to be repeated 1) if not required to 


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determine whether study drugs may be resumed and 2) if performed within 7 
days prior to study drug resumption. 
 
 
5.2.3 
Dose Reductions 
 
Following dosing interruption or cycle delay, the dose of the study drugs may 
need to be reduced when treatment is resumed. 
 
No specific dose adjustments are recommended for Grade 1/2 treatment-related 
toxicity. 
 
Dose reduction of palbociclib and carboplatin by 2 dose levels will be allowed 
depending on the type and severity of toxicity encountered (Table 3 and 4).  
Patients requiring more than 2 dose reductions will be discontinued from the 
study and entered into the follow-up phase. 
 
Once a dose has been reduced for a given patient, all subsequent cycles should 
be administered at that dose level, unless further dose reduction is required.  
Dose re-escalation is not allowed. 
 
Table 3: Study Drug Dose Levels 
 
Palbociclib Dose Levels 
 
Dose Level 
 
 
Dose 
 
 
 
Dispensed as 
0 (starting dose) 
 
125 mg daily, days 1-14  
125 mg capsules 
 
 
 
 
 
 
 
 
OR 5 mL solution  
 
-1 
 
 
 
100 mg daily, days 1-14  
100 mg capsules 
 
 
 
 
 
 
 
 
OR 4 mL solution 
 
-2 
 75 mg daily, days 1-14  
75 mg capsules 
 
  
 
 
 
OR 3 mL solution 
 
 
 Carboplatin Dose Levels 
 
Dose Level 
 
 
Dose 
0 (starting dose) 
 
AUC= 5, day 1 
-1 
 
 
 
AUC= 4, day 1 
-2 
 
 
 
AUC= 3, day 1 
 
 
 
Table 4: Dose Modifications for Treatment Related Toxicities Requiring Treatment 
Interruption/Delay or Persisting Despite Optimal Medical Treatment 
 
Toxicity 
Restart Palbociclib Treatment 
at: 
Restart Carboplatin Treatment 
at: 
Uncomplicated Grade 3 
neutropenia (ANC <1000 
mm/mm3) 
Same dose level 
Same dose level 
Grade 3 neutropenia (ANC 
<1000/mm3) associated with a 
documented infection or fever ≥ 
38.5° C 
↓ 1 dose level 
↓ 1 dose level 


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Grade 4 neutropenia 
(ANC<500/mm3) 
↓ 1 dose level 
↓ 1 dose level 
Grade 4 thrombocytopenia 
(platelet count <25,000/mm3) 
↓ 1 dose level 
↓ 1 dose level 
Grade ≥3 non-hematologic 
toxicity (including nausea, 
vomiting, diarrhea, and 
hypertension only if persisting 
despite optimal medical 
treatment) 
↓ 1 dose level 
↓ 1 dose level 
Note: G-CSF (Filgrastim or Peg-filgrastim) may be added for low ANC at treating physician’s discretion. 
 
 
5.3 
Concomitant Medications 
 
5.3.1 Patients will be allowed to take supportive medications as needed.  Anti-emetic 
medications should be used to treat nausea/vomiting at physicians’ discretion. 
 
5.3.4 G-CSF (Filgrastim and Neulasta) may be added for low ANC at treating 
physician’s discretion. 
 
5.3.5 Other concomitant medications and therapies deemed necessary for the 
supportive care and safety of the patient are allowed at the discretion of the 
treating physician. 
 
5.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria apply: 
• 
Disease progression as defined in Section 7.0 unless evidence of clinical 
benefit per the judgement of the treating clinician as per Section 5.5 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient voluntarily withdraws from treatment OR 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
5.5 
Treatment Beyond Disease Progression 
 
Subjects will be permitted to continue on treatment beyond RECIST v1.1 defined PD as 
long as they meet the following criteria: 
 
- 
Investigator-assessed clinical benefit and do not have rapid disease progression 
- 
Tolerance of study drug 
- 
Stable performance status 
- 
Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (i.e. CNS metastases) 


UMCC 2017.054 
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- 
Subject provides written informed consent prior to receiving any additional 
treatment with Carboplatin and Palbociclib, using an informed consent describing any 
reasonably foreseeable risk or discomforts, or other alternative treatment options. 
 
The assessment of clinical benefit should take into account whether the subject is 
clinically deteriorating and unlikely to receive further benefit from continued treatment. 
 
All decisions to continue treatment beyond initial progression must be documented in the 
study records. Subjects will be re-consented with an informed consent describing any 
reasonably foreseeable risks or discomforts. 
 
Subjects should discontinue study therapy upon further evidence of further progression, 
defined as an additional 10% or greater increase in tumor burden volume from time of 
initial progression (including all target lesions and new measurable lesions). 
 
New lesions are considered measurable at the time of initial progression if the longest 
diameter is at least 10 mm (except for pathological lymph nodes, which must have a 
short axis of at least 15 mm). Any new lesion considered non-measurable at the time of 
initial progression may become measurable and therefore included in the tumor burden 
measurement if the longest diameter increases to at least 10 mm (except for pathological 
lymph nodes, which must have an increase in short axis to at least 15 mm). 
 
For statistical analysis that include the investigator-assessed progression date, subjects 
who continue treatment beyond investigator-assessed, response defined progression will 
be considered to have investigator-assessed progressive disease at the time of the initial 
progression event. 
5.6 
Off Treatment Criteria  
Patients will be removed from protocol therapy when any of the criteria listed in Section 
5.4 apply. Document in the source the reason for ending protocol therapy and the date 
the patient was removed from treatment. All patients who discontinue treatment should 
comply with protocol specific follow-up procedures as outlined in Section 5.6. The only 
exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 
5.7 
Duration of Follow-Up 
Patients will be followed for survival until death. Patients removed from treatment for 
unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event.  End of treatment visit will be conducted within 30 days (+/- 5 days) of 
treatment discontinuation, however if patient refuses to present for a clinic visit, phone 
contact will be made within 30 days after study discontinuation of study treatment.  
Survival assessment can be done by phone and will be performed once every three 
months (+/- 1 month) until death. 


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5.8 
Discontinuation Criteria 
5.8.1 
Disease progression with lack of investigator-assessed clinical benefit 
5.8.2 
Patient withdraws consent (termination of treatment and follow-up); 
5.8.3 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
5.8.4 
Patient is unable to comply with protocol requirements; 
5.8.5 
Treating physician judges continuation on the study would not be in the patients 
best interest; 
5.8.6 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.8.7 
Lost to Follow-up. If a research subject cannot be located to document survival 
after a period of 1 year, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the one year must be documented; 
5.8.8 
Termination of the study by The University of Michigan or any other regulatory 
body 
 
5.9 
Patient Replacement 
 
Patients enrolled but who do not receive protocol treatment will be replaced.  Protocol 
treatment is defined as at least one dose of each drug. 
 
6.0 
STUDY PROCEDURES 


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6.1 
Time and Events Table 
 
6.1.1 
Calendar 
 
 
Screening1
End of 
Treatment
Survival
Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7
Cycle 
8+
Every 8 
weeks from 
Cycle 7, 
Day 1
Day of Cycle
1
8
14
1
14
1
1
1
1
1
1
EOT9
Survival10
Informed 
Consent
X
Demographics
X
Inclusion/Excl
usion Criteria
X
Tumor Biopsy 
for Correlative 
Analysis 14
X
Interim Biopsy 
for Correlative 
Analysis 12,16
X3
Tumor Biopsy 
to confirm 
progression15,1
6
X
H&P, Relevant 
Medical 
History
X
Pregnancy Test
X
X
Clinic Visit4
X
X
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
X
Performance 
Status
X
X
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
Physical Exam4
X
X
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
QOL Survey4
X
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
Adverse 
Effects 
Assessment5
X
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
X
Cycle 2
Treatment
Maintenance
Cycle 1
 
 
 


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Screening1
End of 
Treatment
Survival
Cycle 3
Cycle 4 Cycle 5 Cycle 6
Cycle 7 Cycle 8+
Every 8 
weeks from 
Cycle 7, Day 
1
Day of Cycle
1
8
14
1
14
1
1
1
1
1
1
EOT9
Survival
CBC6
X
X
X2
X2,13
X2
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
X
CMP6
X
X
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
X
Correlative: 
Salivary Rinse7
X
X2
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
Correlative: 2 
Serum Tubes 7
X
X2
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
X2,13
Correlative: 1 
Serum Tube7
x
CT Imaging8
X
X3
X3
X3
X3
Palbociclib 
Dosing11
125 mg daily, days 1-14. Cycle Length: 21 Days
Carboplatin 
Infusion
X
X
X
X
X
X
Survival 
Assessment
X10
16= FFPE core biopsy is preferred, However, if not clinically feasible or safe to obtain a core biopsy, contact coordinating site PIs (P.S. and F.W.) as a block made from several FNA passes is 
acceptable after PI approval. 
9= Will be performed within 30 days after discontinuation of study treatment. If the patient refuses to present for a clinic visit, phone contact will be made within 30 days after discontinuation of  study 
treatment
13= In the event that the start of a new cycle is delayed due to treatment related toxicity, procedures required on Day 1 of the given cycle will be performed when palbociclib ± carboplatin is 
resumed. New Day 1 procedures that were performed prior to knowing the need to delay the start of the cycle do not need to be repeated 1) if not required to determine whether study 
drugs may be resumed and 2) if performed within 7 days prior to study drug resumption.
8= CT Neck and Chest will be obtained in all patients. Further imaging (ie CT Abdomen/Pelvis, Bone Scan) will be performed as deemed appropriate by the treating physician. Initial 
staging imaging may be performed within 28 days prior to treatment
14= A biopsy demonstrating metastatic disease must be obtained within the 56 days prior to study treatment.  FFPE core biopsy is preferred, however, if not clinically feasible or safe to 
obtain a core biopsy a block made from several FNA passes is acceptable.  No systemic therapy (i.e. immunotherapy) may have been administered since obtaining the biopsy, if so, a 
new biopsy is needed.
Cycle 2
12=Biopsy at Cycle 2 will be offered if clinically safe and feasible. Patients may refuse repeat biopsy
11= Will be administered orally on a daily basis, dose as defined per protocol
15= If treating physician deems biopsy to be either unsafe or not clinically feasible, this must be documented and patient may forego repeat biopsy
Treatment
Maintenance
125 mg daily,     
days 1-21.          
Cycle Length: 28 
Days
10= Survival assessment can be done by phone and will be performed once every three months (+/- 1 month)
1= May be performed within 28 days of Cycle 1, Day 1 unless otherwise specified
2= May be performed +/- 4 days
5= Toxicities will be evaluated using CTCAE version 4.03
4= Vital signs, physical exam, ECOG performance status will be checked at each visit as well administration of FACT H&N  questionnaire (see Appendices B and C)
3= May be performed +/- 7 days
6= Labs will be obtained pre-dose. CMP includes Basic Metabolic Profile (Na, K, Cl, CO2, BUN, Cr, Glu), AST/SGOT, ALT/SGPT, Alk Phos, T Bili, Albumin, Ca, and Total Protein
7= Collection tubes (see lab manual) will be drawn and sent to the Brenner lab for DNA isolation and long term storage. May be performed +/- 4 days
Cycle 1


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7.0 
MEASUREMENT OF EFFECT 
7.1 
Antitumor Effect- Solid Tumors 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [EJC 45 (2009) 228-247]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria.  
 
7.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with study drug. 
 
7.1.2 
Evaluable for response. Only those patients who have measurable disease 
present at baseline and have at least one dose of each drug will be 
considered evaluable for response. These patients will have their response 
classified according to the definitions stated below. In the case of death or 
disease progression before response classification, the outcome will be 
considered PD for calculation of disease control rate. Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
 
• 
10mm by CT scan (irrespective of scanner type) for studies with a slice 
thickness of <5mm or twice the slice thickness or MRI 
• 
10mm caliper measurement by clinical exam (lesions which cannot be 
             accurately measured with calipers should be recorded as  
             non-measurable)          
• 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
                           
                         All tumor measurements must be recorded in millimeters (or decimal fractions of     
                         centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Tumor lesions in previously irradiated areas are considered measurable if there 
has been progression in the lesion since completion of radiotherapy 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
CT scan), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organ, 


UMCC 2017.054 
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but in addition should be those that lend themselves to reproducible repeated 
measurements. 
 
Lymph nodes merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. Pathological 
nodes which are defined as measurable and may be identified as target lesions 
must meet the criterion of a short axis of ≥15mm by CT scan. Only the short axis 
of these nodes will contribute to the baseline sum. The short axis of the node is 
the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, sagital or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as 
being 20mm x 30mm has a short axis of 20mm and qualifies as a malignant, 
measurable node. In this example, 20mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 
mm) should be considered non-target lesions. Nodes that have a short axis 
<10mm are considered nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum. The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required and these lesions should 
be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
7.1.3 
Guidelines for Evaluation of Measurable Disease 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging based evaluation should always be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5mm or 
less. When CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness. 
 
7.1.4 
Response Criteria 
7.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 


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Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions (with a minimum absolute increase of 5 mm), taking as 
reference the smallest sum LD recorded since the treatment started, or 
the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR (taking 
as reference the baseline sum LD) nor sufficient increase to qualify for 
PD (taking as reference the smallest sum LD since the treatment 
started). 
7.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesion(s) and/or maintenance of tumor marker level above the 
normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions. 
7.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The patient's best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/SD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at 
least once >4 
wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, 
PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 


UMCC 2017.054 
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“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of 
treatment. 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
7.1.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
7.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression. 
7.2 
Safety/Tolerability 
 
 Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 4.03 for reporting of non-hematologic 
adverse events. 
8.0 
ADVERSE EVENTS 
8.1 
Experimental Therapy with Carboplatin 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 
8.1.1 
Contraindications 
8.1.1.1 Carboplatin is contraindicated in patients with a history of severe allergic 
reactions to cisplatin or other platinum containing compounds 
 
8.1.1.2 Carboplatin should not be employed in patients with severe bone marrow 
depression or significant bleeding 
8.1.2 
Special Warnings and Precautions for Use 
8.1.2.1 Needles or intravenous administration sets containing aluminum parts 
that may come in contact with carboplatin should not be used for the 
preparation or administration of the drug as aluminum can react with 
carboplatin causing precipitate formation and loss of potency 
 


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8.1.2.2 Bone marrow suppression is dose dependent and is the dose limiting 
toxicity. Peripheral blood 
 
 counts should be monitored frequently during treatment and until recovery is 
achieved  
 
8.1.2.3 Carboplatin can induce emesis which can be more severe in patients 
previously receiving emetogenic therapy.  The incidence and intensity of 
emesis have been reduced by using premedication with antiemetics 
 
8.1.2.4 Although peripheral neurotoxicity is infrequent, its incidence is increased 
in patients older than 65 years and in patients previously treated with 
cisplatin 
  
8.1.2.5 Allergic reactions to carboplatin have been reported.  These may occur 
within minutes of administration and should be managed with appropriate 
supportive therapy. There is increased risk of allergic reactions including 
anaphylaxis in patients previously exposed to platinum therapy 
 
8.1.2.6 Carboplatin injection may cause fetal harm when administered to a 
pregnant woman.  If this drug is used during pregnancy, or if the patient 
becomes pregnant while receiving the drug, the patient should be 
apprised of the potential hazard to the fetus.  Women of childbearing 
potential should be advised to avoid becoming pregnant 
8.1.3 
Interaction with other medications 
 
8.1.3.1 The renal effects of nephrotoxic compounds may be potentiated by 
carboplatin 
8.1.4 
Adverse Reactions 
 
8.1.4.1 The most common adverse reactions (incidence ≥ 10%) are bone marrow 
suppression (anemia, thrombocytopenia, and/or neutropenia), nausea, 
vomiting, mild elevations in alkaline phosphatase, and mild decreases in 
serum electrolyte values 
 
8.1.4.2 Hypersensitivity to carboplatin has been reported in 2% of patients. 
These allergic reactions have been similar in nature and severity to those 
reported with other platinum containing compounds and have been 
successfully managed with standard epinephrine, corticosteroid, and 
antihistamine therapy 
 
 
8.2 
Experimental Therapy with Palbociclib 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 
8.2.1 
Contraindications 
 
 
 
 
8.2.1.1 There are no known contraindications 
 
8.2.2 
Special Warnings and Precautions for Use 
 


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8.2.2.1 Neutropenia- Monitor CBC prior to start of palbociclib therapy and at the 
beginning of each cycle, and as clinically indicated 
 
8.2.2.2 Pulmonary embolism- Monitor patients for signs and symptoms of 
pulmonary embolism and treat as medically appropriate 
 
8.2.2.3 Embryo-Fetal toxicity- Can Cause fetal harm. Advise patients of potential 
risk to a fetus and to use effective contraception 
 
 
 
 
8.2.3 
Adverse Reactions 
 
8.2.4.1 The most common adverse reactions (incidence ≥ 10%) are neutropenia, 
leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, 
diarrhea, thrombocytopenia, constipation, alopecia, vomiting, rash, and 
decreased appetite 
 
 
8.2 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Data on adverse events will be collected from 
the time of the initial study treatment administration through 30 days after the last dose of 
study treatment. Any serious adverse event that occurs more than 30 days after the last 
study treatment and is considered related to the study treatment must also be reported. 
Serious Adverse Events (SAEs) will continue to be followed until: 
• 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
• 
There is satisfactory explanation other than the study treatment for the changes 
observed; or  
• 
Death. 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration is considered to be pre-existing in nature. Any known pre-
existing conditions that are ongoing at time of study entry should be considered medical 
history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, 
occurring from the initial study treatment administration through 30 days following the last 
dose of the study treatment must be recorded as an adverse event in the patient’s source 
documents and on the CRF regardless of frequency, severity (grade) or assessed 
relationship to the study treatment. All serious adverse events (SAEs) and unanticipated 
problems (UPs), regardless of causality to study drug, will be reported to the Principal 
Investigator and also to the Coordinating Center. In addition, SAEs should be submitted 
to the Coordinating Center and PI any time after the administration of the last dose of 
palbociclib if the Investigator suspects a causal relationship between the palbociclib and 
the SAE. 


UMCC 2017.054 
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In addition to new events, any increase in the frequency or severity (i.e., toxicity 
grade) of a pre-existing condition that occurs after the patient begins study treatment 
is also considered an adverse event. 
8.3 
Definitions 
8.3.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention.  
 
• 
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) 
procedures will not be reported as adverse events. However, the medical 
condition for which the procedure was performed must be reported if it meets 
the definition of an adverse event unless it is a pre-existing (prior to protocol 
treatment) condition. 
 
• 
Abnormal laboratory values or test results constitute adverse events if they 
induce clinical signs or symptoms or require therapy. They are to be captured 
under the signs, symptoms or diagnoses associated with them. 
8.3.2 Serious Adverse Event 
An adverse event is considered “serious” if, in the view of either the investigator 
or sponsor-investigator, it results in any of the following outcomes: 
  
o 
Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
o 
A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of either the 
investigator [or sponsor-investigator], its occurrence places the patient or 
subject at immediate risk of death. It does not include an adverse event that, 
had it occurred in a more severe form, might have caused death.  
 
o 
Inpatient hospitalization or prolongation of existing hospitalization for > 24 
hours. 
 
o 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
o 
A congenital anomaly/birth defect 
 
o 
Important medical event 
Any event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition 
of “Serious Adverse Event”. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse. 


UMCC 2017.054 
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Previously planned (prior to signing the informed consent form) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened 
during the course of the study. Preplanned hospitalizations or procedures for 
preexisting conditions that are already recorded in the patient’s medical history at 
the time of study enrollment should not be considered SAEs. Hospitalization or 
prolongation of hospitalization without a precipitating clinical AE (for example, for 
the administration of study therapy or other protocol-required procedure) should 
not be considered SAEs. However, if the preexisting condition worsened during 
the course of the study, it should be reported as an SAE. 
 
8.3.3 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
• 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label).  
• 
For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochure.  
• 
In clinical research studies, information on expected adverse events is 
also summarized in the protocol and in the consent document.  See 
section 9.1 for the list of expected adverse events related to the drug 
under study. 
8.3.4 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the 
Package Insert, Investigator’s Brochure, in published medical literature, in the 
protocol, or in the informed consent document.  
8.4 
Adverse Event Characteristics 
8.4.1 CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.03. A copy of the CTCAE version 4.03 can be 
down loaded from the CTEP web site. (http://ctep.cancer.gov) 
8.4.2 Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.5 
Serious Adverse Event Reporting Guidelines 
All SAEs and UPs must be reported to the Coordinating Center within 24 hours of 
first awareness of the event.  Events should be reported using the Coordinating 
Center SAE form.  A copy of the Coordinating Center SAE form should be sent to the 
Coordinating Center via fax at 734-232-0744 or via email to CTSU-Oncology-
Multisite@med.umich.edu within 24 hours of the site’s knowledge of the event.   
Contact information for Principal Investigator SAE Reporting:  


UMCC 2017.054 
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Paul L. Swiecicki, M.D. 
 
 
 
 
University of Michigan Rogel Cancer Center 
 
 
 
 
N13A23 North Ingalls Building, 300 North Ingalls St., SPC 5419 
 
 
 
 
Ann Arbor MI 48109 
 
 
 
 
Phone: 734-647-1017, Fax: 734-647-9480 
 
 pswiecic@med.umich.edu 
Follow-up information must also be reported within 24 hours of receipt of the 
information by the investigator.   
All SAEs and UPs will be reported to the local IRBs per current institutional 
standards.  
The Coordinating Center will disseminate information regarding SAEs and UPs to the 
participating sites within 5 days of review of the information by the Coordinating 
Center’s Principal Investigator (or designee in the event of extended absence) only in 
the case that the event(s) is believed to be related (i.e., possibly, probably, or 
definitely) to the study drug.  
The Coordinating Center will be responsible for reporting to Pfizer by facsimile any 
Serious Adverse Event that occur during the SAE reporting period.  The coordinating 
center will report the SAE within 24 hours of first awareness of the event 
(immediately if the event is fatal or life-threatening). 
The Multi-site team will coordinate with the Sponsor-Investigator and the Michigan 
Institute for Clinical and Health Research (MICHR) IND/IDE Investigator Assistance 
Program (MIAP) office for the reporting of any and all IND safety reports to the FDA 
as per the requirements outlined in 21 CFR 312.32.  A summary of all non-expedited 
safety reports will be submitted in the annual report. 
In addition to new events, any increase in the frequency or severity (i.e., toxicity 
grade) of a pre-existing condition that occurs after the patient begins study treatment 
is also considered an adverse event. 
 
8.6 
Routine Reporting 
All other adverse events- such as those that are expected, or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data 
submission. 
8.7 
Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the conduct of 
human subjects research that represent unanticipated problems but are not considered 
adverse events. For example, some unanticipated problems involve social or economic 
harm instead of the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased risk of harm, 
but no harm occurs. 
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem, the investigator should assess 
whether the incident, experience, or outcome represents an unanticipated problem. The 
incident, experience or outcomes is considered unanticipated if it meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 


UMCC 2017.054 
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3. Suggests that the research places subjects or others at a greater risk of harm 
than was previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB according to the local 
IRB reporting requirements. 
9.0 
DRUG INFORMATION 
9.1 
Carboplatin 
• 
Other names for the drug: Carboplatin (Paraplatin ®) 
 
• 
Description: IV Medication. Vial sizes of 50 mg/5 mL, 150 mg/15 mL, 450 mg/45 mL, 
600 mg/60 mL all in individually packaged multi-dose vials.  
 
• 
Classification - type of agent: Cytotoxic/Alkylating-Like Compound 
 
• 
Mode of action: Carboplatin produces interstrand DNA cross-links which in turn 
interfere with mitosis.  DNA damage leads to attempts at DNA repair however, when 
repair is not possible apoptosis is activated, especially in the case of double strand 
DNA breaks. 
 
• 
Pharmacokinetics: Carboplatin exhibits linear pharmacokinetics with Cmax and AUC 
increasing linearly with dose. 
 
• 
Half-life- Plasma levels of intact carboplatin decay in a biphasic manner with a 
half-life of 2.6-5.9 hours. 
 
• 
Elimination- The major route of elimination is renal excretion. The primary 
determinant of carboplatin clearance is glomerular filtration rate 
 
• 
Metabolism- Minimally hepatic to aquated and hydroxylated compounds 
 
• 
Side effects: 
 
• 
The most common adverse reactions (incidence ≥ 10%) are bone marrow 
suppression (anemia, thrombocytopenia, and/or neutropenia), nausea, vomiting, 
mild elevations in alkaline phosphatase, and mild decreases in serum electrolyte 
values 
• 
Hypersensitivity to carboplatin has been reported in 2% of patients. These 
allergic reactions have been similar in nature and severity to those reported with 
other platinum containing compounds and have been successfully managed with 
standard epinephrine, corticosteroid, and antihistamine therapy 
• 
Please refer to the package insert for a comprehensive list of adverse events. 
  
• 
Drug Interactions: 
 
• 
Fosphenytoin/Phenytoin- Carboplatin may decrease serum concentrations of 
these drugs hence monitor therapy 
 
• 
Storage and stability:  
 
• 
Unopened vials of carboplatin are stable to the expiration date indicated on the 


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package when stored at 25°C (77°F); excursions permitted from 15°C-30°C (59°-
86°F). Protect from light 
• 
Multidose vials maintain microbial, chemical, and physical stability for up to 14 
days at 25°C following multiple needle entries 
• 
Parenteral drug products should be visually inspected for particulate matter and 
discoloration prior to administration. Solutions for infusion should be discarded 8 
hours after preparation  
 
• 
Administration:  
 
• 
Needles or intravenous administration sets containing aluminum parts that may 
come in contact with carboplatin should not be used for the preparation or 
administration of the drug as aluminum can react with carboplatin causing 
precipitate formation and loss of potency 
 
• 
Availability: Commercially available. Will be purchased from commercial sources and 
billed to patients or their insurers 
9.2 
Palbociclib 
• 
Other names for the drug: Palbociclib (Ibrance ®) 
 
• 
Description: Oral Medication. Supplied as capsules which must be swallowed or 
solution which may be swallowed or administered via feeding tube (ie nasogastric 
tube or PEG).  Capsules are supplied in 125 mg, 100 mg, 75 mg doses.  Bottles 
consist of 21 tablets.  Solution is supplied at a concentration of 25 mg/mL and 112 
mL are in each bottle 
 
• 
Classification - type of agent: Cyclin-dependent kinase (CDK) 4 and 6 inhibitor 
 
• 
Mode of action: Palbociclib is an inhibitor of CDK 4/6.  Cyclin D1, CDK 4, and CKD 6 
are downstream signaling pathways which lead to cellular proliferation. In vitro, 
palbociclib reduced cellular proliferation of estrogen receptor-positive breast cancer 
cee lines by blocking the progression of the cell from G1 into S phase of the cell 
cycle.  
 
• 
Pharmacokinetics: 
 
• 
Absorption- The mean time to reach maximum concentration (Tmax) is between 
6-12 hours following oral administration. The mean bioavailability of palbociclib 
after an oral 125 mg dose is 46% and in the dosing range of 25-225 mg the AUC 
and Cmax increased proportionally with dose in general.  Steady state was 
achieved within 8 days following repeated once daily dosing.  In studies utilizing 
capsules, food intake reduced the intersubject variability of palbociclib exposure 
therefore the palociclib capsules should be taken with food.  Pharmacokinetic 
studies of the solution demonstrate no change in the variability of palbociclib 
exposure with food administration.  Therefore, palbociclib solution may be taken 
with or without food. 
 
• 
Half-life- The plasma elimination half-life is 29 (+/- 5) hours in patients with 
advanced breast cancer 
 
• 
Metabolism- Palbociclib undergoes hepatic metabolism in humans.  The primary 
metabolic pathways for palbociclib involve oxidation and sulfonation. CYP3A and 


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SULT2A1 are mainly involved in the metabolism of palbociclib.  Palbociclib is a 
weak time-dependent inhibitor of CYP3A following daily dosing to steady state. 
 
• 
Elimination- Fecal elimination is the major route of excretion (74.1%) with an 
additional 17.5% recovered in urine.  The majority of excreted materials were 
metabolites 
 
• 
Side effects:  
 
• 
The most common adverse reactions (incidence ≥ 10%) are neutropenia, 
leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, 
thrombocytopenia, constipation, alopecia, vomiting, rash, and decreased appetite 
 
• 
Drug Interactions:  
 
• 
None applicable 
 
• 
Storage and stability:  
 
• 
Store at 20° C -25° C (68° F-77° F), excursions permitted between 15° C-30° C 
(59° F-86° F) 
• 
Palbociclib must be stored in a secure, limited access area.   
 
• 
Preparation and Dispensing: 
• 
How Supplied:  Supplied as capsules which must be swallowed or solution 
which may be swallowed or administered enterally via feeding tubes (ie 
nasogastric tube or gastric tube). 
 
Capsules are supplied in 125 mg, 100 mg, 75 mg doses.  Bottles consist of 
21 tablets. 
 
Oral solution is supplied at a concentration of 25 mg/mL and 112 mL are in 
each bottle Oral solution (25 mg/mL) will be supplied in HDPE packaged 
bottles with a PIBA (push in bottle adapter) and a reusable oral syringe for 
dosing. Labeling will occur according to local regulatory requirements. Each 
clinical site will be provided the oral solution product manual which contains 
the detailed dosage and administration instructions for preparation of the oral 
solution.  Please note the oral solution product manual is sponsor-provided 
and utilized for multiple studies.  All references to placebo formulation do not 
apply for this protocol and should be disregarded. 
• 
Note:  Capsules should not be repackaged after they are dispensed.  Capsules 
should not be opened or emptied into another vehicle for oral delivery.  Similarly, 
oral solution should not be transferred into any other container. 
 
• 
Administration:  
• 
Palbociclib Capsules 
• 
Take once daily by mouth at approximately the same time each day. 
• 
Palbociclib should be taken orally with food 
• 
Patients should be instructed that if they vomit any time after taking a dose, 
that they must not “make it up” with an extra dose, but instead resume 
subsequent doses as prescribed. Missed doses may be taken late, up to 6 
hours after the scheduled dose, otherwise should be skipped and reported to 
the investigators. 
• 
Palbociclib Solution 
• 
Will be available for patients who are unable to swallow capsules or develop 


UMCC 2017.054 
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an inability to swallow capsules during the study. 
• 
Will be administered using an oral syringe at volumes corresponding to the 
dose prescribed by the investigator (125 mg dose = 5mL, 100 mg dose = 4 
mL, and 75 gm dose = 3 mL). Detailed instructions patient administration 
directions using syringe are detailed in Pfizer Approved ‘Administration 
Instruction’ Handouts (Appendix C- Administration Instructions for Oral Dose 
Using Syringe and Appendix D- Administration Instructions for Each Dose via 
NG Tubes) 
• 
Take once daily at approximately the same time each day 
• 
Solution does not need to be taken with food 
• 
May be taken by mouth or by administration via feeding tube  
 
• 
The patients will be asked to bring medication bottles to each follow-up visit, 
and remaining pills in bottle will be counted at each visit to document 
compliance. This information will be recorded in each patient’s data file. 
• 
If patients are being treated with oral solution, they will be asked to return the 
bottles in clear ziplock bag.  For drug accountability research staff may use a 
best approximation as to the remaining solution as they may be unable to 
open HDPE bottles. 
• 
Drug administration will be provided by the Coordinating Center to record 
compliance with study drug administration, route of administration (by mouth or 
feeding tube) as well as document dose adjustments. 
 
• 
Availability: Provided by sponsor free of charge. 
 
• 
Under no circumstance will the study medication palbociclib be used other than 
as directed by the protocol. 
 
• 
Do Not Use Commercially Available Product. 
 
• 
Drug Accountability: 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of the drug, 
palbobciclib.   The drug accountability records will capture drug receipt, drug 
dispensing, drug return and final disposition. 
10.0 
CORRELATIVES/SPECIAL STUDIES 
10.1 
Sample Collection Guidelines 
 
We plan on collecting and banking serial saliva and serum samples as well as tumor tissue. 
 
10.1.1 Serum and Saliva Samples 
 
10.1.1.1 These samples are mandatory.  They will be obtained at Day 1 Cycle 1, 
Day 8 (+/- 4 days) Cycle 1, and Day 1 (+/- 4 days) of each subsequent 
Cycle while on therapy (see section 6.1). 
 
 
10.1.1.4 Sample Transportation 
- 
Whenever as specimen has been obtained (i.e. after a procedure, 
blood draw, oral rinse in clinic), sample will be labeled with the 
subject’s de-identified study number and collection date, and the 


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study coordinator will transport the sample directly to the Brenner 
laboratory.  
 
10.1.2 Tumor Samples 
 
10.1.2.1 We plan on obtaining tumor samples at screening, at Cycle 2 Day 1, and 
at progression. 
- 
Screening biopsy sample is mandatory.  This must be obtained within 
the 56 days prior to study treatment. No systemic therapy (i.e. 
immunotherapy) may have been administered since obtaining the 
biopsy, if so, a new biopsy is needed.     
- 
Interim Biopsy at Cycle 2, Day 1 (+/- 7 days) is optional and will be 
offered if safe and clinically feasible 
- 
Biopsy at the time of progression is mandatory however if the treating 
physician deems biopsy to be either unsafe or not clinically feasible, 
this must be documented and patient may forego repeat biopsy 
- 
FFPE core biopsy is preferred, However, if not clinically feasible or 
safe to obtain a core biopsy, contact coordinating site PIs (P.S. and 
F.W.) as a block made from several FNA passes is acceptable.  
10.1.3 Brenner lab will receive and process samples.  See Lab Manual for details  
10.2 
Assay Methodology 
 
 
Hypothesis 1. Specific genetic networks will correlate with response to Palbociclib-based 
therapy including patients with alterations in CDKN2A, CyclinD1, CDK4/6, RB and/or 
human papilloma virus. Thus, developing genetic biomarkers that predict response to this 
therapy will help identify the patients that would most benefit from early advancement to 
precision medicine trials.     
 
Experimental design: We will perform integrative targeted sequencing of all available 
tumor specimens to identify the distribution of lesions co-incident with commonly 
deregulated genes (e.g. CyclinD1 and CDKN2A and their modifying genes) as well as the 
transcriptional programs deregulated in these tumors. We will utilize the knowledge 
gained from existing publicly available sequencing studies10,11,27-32 to perform targeted 
DNA and RNA sequencing in our cohort using our 250 gene MiOTOseq panel. We will 
also perform targeted RNA-Seq to assess the expression of genes used to classify 
tumors into immunogenic, classical, mesenchymal, basal or atypical molecular subtypes. 
The co-incidence of events will be correlated with immunohistochemical stains for 
established HNSCC biomarkers and correlations established between molecular events 
and clinical data.   
 
1i. Preparation of biopsy specimens for targeted DNA and RNA sequencing. Collaborator 
Dr. McHugh is a board certified pathologist and will identify representative FFPE sections 
with >50% tumor content, he has extensive experience in tissue specimen evaluation for 
molecular analysis33-45. We will use macrodissection to enrich for tumor content as 
needed. At least 3x10um sections per case will be cut for simultaneous DNA/RNA 
extraction using the Qiagen Allprep FFPE DNA/RNA kit and protocols optimized by our 
group to isolate assayable DNA (median 1.5 ug) and RNA (median 5.3 ug). As little as 
9x10um sections from a single needle biopsy core yield sufficient DNA and RNA for the 
studies proposed herein. DNA and RNA will be quantified using the Qubit fluorometer.  
 


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1ii. Targeted next generation 
sequencing (NGS). Targeted, 
capture based NGS will be 
performed as shown in our 
preliminary data to the left 
using Ion Torrent or Illumina 
based sequencing (as in Fig 
11). Briefly, barcoded libraries 
will be generated from 40ng 
of DNA per sample using our 
HNSCC-gene enriched 
custom Ion AmpliSeq panel, 
and the Ion Ampliseq Library 
Kit 2.0 with barcode 
incorporation. Templates will 
be prepared using the PGM 
Template OT2 Kitv2 on the 
Ion One Touch2; all protocols 
will be performed according 
to the manufacturer’s 
instructions. Sequencing of 
multiplexed templates will be 
performed on Ion 318 chips 
using the Ion PGM 200 
Sequencing Kitv2, sequenced to an average depth >100x. We routinely generate 
between 400-500 million aligned bases per 318 chip, yielding ~300-500x coverage for 
~4-6 Oncomine Cancer Panel prepared templates. Mutation analysis will be performed in 
Torrent Suite 3.6, with alignment by TMAP using default parameters, and variant calling 
using the Torrent Variant Caller plugin using default low-stringency somatic variant 
settings. Variants will be annotated using ANNOVAR46. Called variants will be filtered to 
prioritize likely candidate somatic drivers by removing the following variants: synonymous 
variants, those with frequencies >0.001 in ESP6500 or 1000 genomes, those with flow 
corrected read depths (FDP) <20, flow variant allele containing reads (FAO) <5 or variant 
allele fractions (FAO/FDP) <0.05. Copy number alterations will be identified as 
described34,47 (24, 39) using normalized read counts per amplicon with GC content 
correction and comparison to distributions from multiple unrelated normal FFPE derived 
genomic DNA samples. Gene-level copy number estimates will be determined by taking 
the coverage-weighted mean of the per-probe ratios, with expected error determined by 
the probe-to-probe variance; genes with |Z|>2.5 with respect to both the normal pool and 
the internal error will be considered as gained or lost. Our team has established robust 
protocols for Ion Torrent sequencing, and has used the above methodology to 
characterize >600 tissue specimens. Alterations will be advanced for potential as HPV+ 
co-dependent drivers and correlated with RNA pathway alterations based on known roles 
in oncogenesis and H&N cancer, comparison to Oncomine (including TCGA and publicly 
available data) and COSMIC mutational data, and comparison to in house databases of 
driving lesions. Sanger sequencing, FISH, or qPCR will be performed to confirm 
prioritized alterations.  
 
Fig 11: Targeted DNA-SEQ to molecularly characterize HPV negative H&N tumors. A) 
(Upper) Plot shows relative DNA copy number from AmpliSEQ analysis of an FFPE tumor 
sample. Top panel shows genes assessed across the genome. Chr1 shown on left and ChrX 
on the right. Bottom panel shows zoomed in Chr8 and FGFR1 copy number increase. (Below) 
FISH was performed with FGFR1 and Centromere8 probes to confirm amplification. A 
representative image is shown taken with a 40x objective lens. B) Plot shows relative aberration 
status from 42 FFPE isolated DNA samples from HNSCC tumors that were profiled using the 
Ampliseq method and the Oncomine Cancer panel (OCP). Alignment and variant calling were 
performed using standard plugins in the Torrent Server Suite (v3.6) and variants were filtered 
through a pipeline to remove low confidence calls, sequencing errors, germline variants and 
common polymorphisms 1. Results were compared to known mutations in COSMIC, the


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1iii. Targeted RNA-SEQ for molecular subtyping, gene fusion identification and pathway 
activity. Reverse transcription will be performed on 300ng of isolated RNA from each 
tissue sample using gene specific priming 
with subsequent targeted RNA-SEQ using 
FFPE optimized assays as in Fig12. 
Genes have been selected to assess 
critical HNSCC pathways including HPV 
signaling status (including both E6 and E7 
genes), deregulated CDK4/6 pathway 
genes, known HNSCC cancer fusions 
(through 5’ and 3’ assays for FGFR-
TACC348 and EGFR-ADACM (TCGA-CV-
6941), R-spondin 49, potential therapeutic 
targets in other malignancies (ie. 5’ and 3’ 
assays for ALK and RET overexpression), 
and housekeeping genes. Our team has 
extensive experience in RNA-SEQ, 
transcriptome evaluations and statistical 
analysis and will determine the 
frequencies of RNA signatures with DNA 
lesions as described33-40,50-58.     
 
1iv. Determination of protein expression 
and validation of sequencing data. We will 
create a tissue microarray of excess FFPE 
tissue from samples sequenced for this 
Aim. Gene fusions and copy number 
alterations will be confirmed by 
fluorescence in situ hybridization (FISH) 
and critical targets advanced from 
sequencing studies will also be assessed by immunohistochemistry (IHC) if IHC grade 
antibodies are available. Staining and scoring will be completed as we described59-61 with 
prioritization beginning with proteins found in the CDK4/6 pathway (e.g. CDK4, CDK6, 
RB, CyclinD1, etc.). We will leverage this data by integrating it with the sequencing data 
generated here to identify correlations between copy number, mutation and expression 
as well as HPV status using statistical methods described above.  
 
Pitfalls, alternative strategies and future directions.  We do not anticipate significant 
obstacles as we have extensive experience in tissue examination, NGS and integrative 
statistical analysis of molecular data in cancer as well as modeling of 
disease34,40,41,43,44,51,62. Additionally, Dr. Brenner is involved in several protocols that are 
sequencing tissue specimens as part of clinical trials or protocols, including the 
MiOncoseq-SU2C program48,63. The cohort size is based on conservative statistical 
estimates as noted to reach independent correlative endpoints. Targeted sequencing has 
been proposed to enable a focused analysis of tumors with limited DNA/RNA yields. 
However, we have had success sequencing whole exomes from FFPE tissues from large 
quantities of DNA using multiple platforms and may implement these if the technology 
becomes robust enough during the course of the proposal for smaller quantities of DNA. 
Similarly, we are currently evaluating whole transcriptome analysis as an alternative to 
targeted RNA-SEQ from FFPE in samples with sufficient RNA yield.  Overall, we expect 
that completion of this Aim will identify the co-incident frequency of commonly 
deregulated pathways on the DNA and RNA levels that will predict response to standard 
therapy. Importantly, we will create a molecularly characterized TMA of specimens from 
this clinical trial to assess correlations between genetic and protein expression status. 
Taken together, this Aim will provide a wealth of data and resources for future studies 
Fig 12. Example of targeted RNA-seq from FFPE isolated 
RNA. A) Reverse transcription and targeted multiplexed PCR 
(Ampliseq) was performed on 20ng FFPE isolated RNA per 
sample on a cohort of macrodissected benign urothelium, non-
invasive urothelial carcinoma (pTa) and invasive urothelial 
carcinoma (>pTa). Technical and biological replicates are 
indicated, as well as unique components isolated from the same 
case. For each sample, the log2 total reads for each target gene 
(n=103) was normalized to the average log2 total reads for 8 
housekeeping genes. Median centered normalized target gene 
expression and samples were clustered using centroid linkage 
clustering and visualized as a heatmap. B) Scatter plot of target 
gene expression (log2 normalizd gene expression) for two 
biological replicates of normal urothelium (BL193A and 
BL193B, macrodissected from separate blocks).  (R2=0.8986).    


UMCC 2017.054 
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and provide a comprehensive data set correlating genetic aberrations with clinical 
outcome in this trial setting.  
 
Hypothesis 2:  Cancer response to therapy can be detected in saliva and serum 
biospecimens collected at routine interval time points and will identify tumor response 
earlier than interim imaging. 
 
Correlative Justification 
 
Less than 40% have a response (SD, PR, CR) to chemotherapy in R/M which currently 
only be identified by interval imaging after approximately 8-12 weeks of therapy.  As 
patients are at risk for treatment failure, a non-invasive biomarker for detecting response 
earlier in therapy is of extreme importance.  The measurement of serum and saliva 
circulating tumor ctDNA as a biomarker for recurrence may be an important, noninvasive 
method to detect treatment responses. Our group and others have identified HPV and 
mutant ctDNA in both the blood and saliva samples of patients with advance or recurrent 
HNSCC, suggesting this noninvasive biomarker as a way to measure disease response 
to therapy.  Finally, using data generated from the targeted next generation sequencing 
on tumor specimens from above, we can prioritize evaluable somatic mutations in ctDNA 
from both the blood and saliva of each patient for targeted sequencing studies as well as 
monitor for the occurrence of mutations common in tumors that become resistant to 
Palbociclib treatment. Therefore, our goal is to collect longitudinal samples of saliva and 
serum as a part of our trial to determine if serum and saliva biomarkers can predict 
response to therapy and also identify emergence of resistant clones.   
 
10.3 
Specimen Banking 
Patient samples collected for this study will be retained at the Brenner lab. Specimens 
will be stored indefinitely or until they are used up. If future use is denied or withdrawn by 
the patient, best efforts will be made to stop any additional studies and to destroy the 
specimens. 
 
Specimens being stored long-term for potential use not outlined in the protocol are 
subject to University Policy Governing Tissue Sample Collection, Ownership, Usage, and 
Disposition within all UMMS Research Repositories. 
 
11.0 
STATISTICAL CONSIDERATIONS 
11.1 
Study Design/Study Endpoints 
 
This is an open-label multi-institution single arm Phase II study with a two-stage design.  
We will power this study to detect a 20% improvement in disease control rate (DCR) with 
the addition of palbociclib.  Based on historical data, the DCR in R/M HNSCC with single 
agent platinum therapy is 40%4,64.  We hypothesize that addition of Palbociclib to 
carboplatin will increase the DCR at 12 weeks to 60%. We anticipate no loss to followup 
for this endpoint.  The primary clinical objective of this trial is to estimate disease control 
rate (DCR) at 12 weeks in patients with metastatic head and neck squamous cell cancer 
treated with carboplatin and palbociclib.  Response will be assessed after every two 
cycles. DCR will be defined as either CR, PR or SD at 12 weeks. The regimen will be 
considered promising if the true disease control rate is 60% or better.  Conversely, if the 
DCR is 40% or lower, there would be little interest in pursuing this therapy in further 
studies.  In this case, we would like to terminate the trial early and consider a new 
therapy.  The optimal two-stage accrual design has been adopted65. 
 


U M C C 2 0 1 7. 0 5 4  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
P a g e 4 2  of 5 5  
 
I n t h e fir st st a ge, w e will a c cr u e 1 8  r e s p o n s e-e v al u a bl e p ati e nt s  a s d efi n e d  i n s e cti o n 
7. 1. 1. If 8 or l e s s s u bj e ct s ar e c o n si d er e d D C R at 1 2  w e e k s, t h e tri al will b e st o p p e d a n d 
w e will c o n cl u d e t h at t h e t h er a p y i s i n eff e cti v e.  If w e o b s er v e 9 or m or e wit h di s e a s e 
c o ntr ol ( C R, P R, or S D) at 1 2 w e e k s, tri al will c o nti n u e t o t h e s e c o n d st a g e a n d a n 
a d diti o n al 2 2 r e s p o n s e-e v al u a bl e p ati e nt s will b e e nt er e d.  B a s e d o n all 4 0 s u bj e ct s, if 2 1  
or m or e p ati e nt s h a v e a c hi e v e d di s e a s e c o ntr ol, t h e t h er a p y will b e c o n si d er e d 
pr o mi s i n g. If f e w er t h a n 2 1 e v al u a bl e s u bj e ct s a c hi e v e D C R at 1 2  w e e k s, w e will 
c o n si d er t h e t h er a p y t o b e i n eff e cti v e.  
 
E arl y t er mi n ati o n or m o difi c ati o n f or t o xi cit y  
At t h e i niti al st a g e, aft er 1 0 p ati e nt s h a v e b e e n e v al u at e d, if m or e t h a n 7 0 % e x p eri e n c e d 
gr a d e 3 or 4 t o xi cit y e v e nt s, t h e tri al will b e h alt e d f or f urt h er s af et y r e vi e w a n d t h e 
i n v e sti g at or s will c o n si d er t er mi n ati n g t h e st u d y or a dj u sti n g t h e d o s e s. T hr o u g h o ut t h e 
st u d y if m or e t h a n 7 0 % of p ati e nt’ s  e x p eri e n c e gr a d e 4 t o xi cit y , t h e n t h e st u d y will b e 
h alt e d f or c o n si d er ati o n of f urt h er a dj u st m e nt s t o d o si n g . 
 
1 1. 2  
S a m pl e Si z e a n d A c cr u al  
W e will b e u si n g a t w o-st a g e d e si g n. T hi s d e si g n yi el d s a t y p e I err or r at e of 0. 0 5 9 a n d 
p o w er of 0. 8 0 w h e n t h e tr u e r e s p o n s e r at e i s 0. 6 0.  T h e al p h a l e v el will b e 0 . 0 5. T h e t w o-
st a g e s a m pl e si z e c al c ul ati o n s w er e c arri e d o ut a s s u mi n g a n ull D C R pr o b a bilit y of 0. 4 0.  
 
1 1. 3  
D at a A n al y s e s Pl a n s  
Di s e a s e c o ntr ol will b e  d efi n e d b y R E CI S T  v 1. 1  crit eri a at 1 2  w e e k s. C R, P R or S D will 
b e c o n si d er e d di s e a s e c o ntr ol.  T h e i niti al D C R  r at e wit h 9 5 % c o nfi d e n c e i nt er v al ( CI) will 
b e r e p ort e d t o gi v e a p oi nt e sti m at e a n d pr e ci si o n of t h e e sti m at e  at t h e c o n cl u si o n of t h e 
tri al. T h e n u m b er a n d pr o p orti o n of a d v er s e e v e nt s will b e r e p ort e d b y gr a d e a c c or di n g t o 
C T C A E v er si o n 4. 0 3  g ui d eli n e s . Pr o gr e s si o n fr e e a n d o v er all s ur vi v al ti m e will b e 
e sti m at e d u si n g a K a pl a n -M ei er a n al y si s.  
 
1 2. 0  
D A T A A N D S A F E T Y M O NI T O RI N G  
 
T h e D at a a n d S af et y M o nit ori n g C o m mitt e e ( D S M C) of T h e U ni v er sit y of Mi c hi g a n R o g el C a n c er 
C e nt er  i s t h e D S M C f or t hi s st u d y.  T hi s c o m mitt e e i s r e s p o n si bl e f or m o nit ori n g t h e s af et y a n d 
d at a i nt e grit y of t h e tri al.  
 
At e a c h sit e t h e st u d y t e a m i s r e q uir e d t o m e et q u art erl y t o di s c u s s m att er s r el at e d t o:  
 
 
E nr oll m e nt r at e r el ati v e t o e x p e ct ati o n s, c h ar a ct eri sti c s of p arti ci p a nt s  
 
S af et y of st u d y p arti ci p a nt s ( S eri o u s A d v er s e E v e nt & A d v er s e E v e nt r e p orti n g)  
 
A d h er e n c e t o pr ot o c ol ( pr ot o c ol d e vi ati o n s)  
 
C o m pl et e n e s s, v ali dit y a n d i nt e grit y of st u d y d at a  
 
R et e nti o n of st u d y p arti ci p a nt s  
 
T h e s e m e eti n g s ar e t o b e d o c u m e nt e d b y t h e sit e d at a m a n a g er or st u d y c o or di n at or u si n g t h e 
Pr ot o c ol S p e cifi c D at a a n d S af et y M o nit ori n g R e p ort ( D S M R), si g n e d b y t h e sit e pri n ci p al 
i n v e sti g at or or c o-i n v e sti g at or.  E a c h sit e i s r e q uir e d t o s u b mit t h e c o m pl et e d D S M R t o t h e M ulti-
Si t e C o or di n at or at t h e U ni v er sit y of Mi c hi g a n C o or di n ati n g C e nt er o n a q u art erl y b a si s t o g et h er 
wit h ot h er p erti n e nt d o c u m e nt s.  
 
Si mil arl y, pr ot o c ol d e vi ati o n s ar e t o b e d o c u m e nt e d u si n g t h e N oti c e of Pr ot o c ol D e vi ati o n F or m 
a n d r e q uir e s t h e si g n at ur e s of b ot h t h e sit e s d at a m a n a g er or st u d y c o or di n at or a n d t h e sit e 


U M C C 2 0 1 7. 0 5 4  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
P a g e 4 3  of 5 5  
 
pri n ci p al i n v e sti g at or or c o -i n v e sti g at or. T h e s e r e p ort s ar e t o b e s e nt t o t h e U ni v er sit y of Mi c hi g a n 
C o or di n ati n g C e nt er wit hi n 7 c al e n d ar d a y s of a w ar e n e s s of t h e e v e nt a n d o n a q u art erl y b a si s  
wit h t h e Pr ot o c ol S p e cifi c D at a a n d S af et y M o nit ori n g R e p ort.  
1 3. 0  
Q U A LI T Y A S S U R A N C E A N D A U DI T S  
D at a a n d S af et y M o nit ori n g C o m mitt e e c a n r e q u e st a ‘f or c a u s e’ q u alit y a s s ur a n c e a u dit of t h e 
tri al if t h e c o m mitt e e i d e ntifi e s a n e e d f or a m or e ri g or o u s e v al u ati o n of st u d y-r el at e d i s s u e s. A 
r e g ul at or y a ut h orit y ( e. g. F D A) m a y al s o wi s h t o c o n d u ct a n i n s p e cti o n of t h e st u d y, d uri n g it s 
c o n d u ct or e v e n aft er it s c o m pl eti o n. If a n i n s p e cti o n h a s b e e n r e q u e st e d b y a r e g ul at or y 
a ut h orit y, t h e sit e i n v e sti g at or m u st i m m e di at el y i nf or m t h e C o or di n ati n g C e nt er t h at s u c h a 
r e q u e st h a s b e e n m a d e. 
1 4. 0  
C LI NI C A L M O NI T O RI N G P R O C E D U R E S  
Cli ni c al st u di e s c o or di n at e d b y T h e U ni v er sit y of Mi c hi g a n R o g el  C a n c er C e nt er  m u st b e 
c o n d u ct e d i n a c c or d a n c e wit h t h e et hi c al pri n ci pl e s t h at ar e c o n si st e nt wit h G o o d Cli ni c al 
Pr a cti c e s ( G C P) a n d i n c o m pli a n c e wit h ot h er a p pli c a bl e r e g ul at or y r e q uir e m e nt s.  
 
T hi s st u d y will b e m o nit or e d b y a r e pr e s e nt ati v e of t h e C o or di n ati n g C e nt er of t h e U ni v er sit y of 
Mi c hi g a n R o g el C a n c er C e nt er . M o nit ori n g vi sit s will b e m a d e d uri n g t h e c o n d u ct of t h e st u d y a n d 
at st u d y cl o s e -o ut.  
 
Pri or t o s u bj e ct r e cr uit m e nt, a p arti ci p ati n g sit e will u n d er g o sit e i niti ati o n m e eti n g t o b e c o n d u ct e d 
b y t h e C o or di n ati n g C e nt er. T hi s will b e d o n e a s a n a ct u al sit e vi sit; t el e c o nf er e n c e, 
vi d e o c o nf er e n c e, or w e b -b a s e d m e eti n g aft er t h e sit e h a s b e e n gi v e n a c c e s s t o t h e st u d y 
d at a b a s e a n d a s s e m bl e d a st u d y r ef er e n c e bi n d er.  T h e sit e’ s pri n ci p al i n v e sti g at or a n d hi s st u d y 
st aff s h o ul d m a k e e v er y eff ort i n att e n di n g t h e sit e i niti ati o n m e eti n g. St u d y – r el at e d q u e sti o n s or 
i s s u e s i d e ntifi e d d uri n g t h e sit e i niti ati o n m e eti n g will b e f oll o w e d-u p b y t h e a p pr o pri at e 
C o or di n ati n g C e nt er  p er s o n n el u ntil t h e y h a v e b e e n a n s w er e d a n d r e s ol v e d.  
 
M o nit ori n g of t hi s st u d y will i n cl u d e b ot h ‘ C e ntr ali z e d M o nit ori n g’, t h e r e vi e w of s o ur c e d o c u m e nt s 
at t h e C o or di n ati n g C e nt er a n d ‘ O n -sit e M o nit ori n g’, a n a ct u al sit e vi sit.  T h e fir st ‘ C e ntr ali z e d’ 
vi sit s h o ul d o c c ur aft er t h e fir st s u bj e ct e nr oll e d c o m pl et e s fir st tr e at m e nt c y cl e .  T h e st u d y sit e 
will s e n d t h e d e -i d e ntifi e d s o ur c e d o c u m e nt s t o t h e C o or di n ati n g C e nt er f or m o nit ori n g.  
‘ C e ntr ali z e d’ m o nit ori n g m a y b e r e q u e st e d b y t h e C o or di n ati n g C e nt er if a n a m e n d m e nt r e q uir e s 
c h a n g e s t o t h e pr ot o c ol pr o c e d ur e s. T h e sit e will s e n d i n p erti n e nt d e -i d e ntifi e d s o ur c e 
d o c u m e nt s, a s d efi n e d b y t h e C o or di n ati n g C e nt er f or m o nit ori n g.  
 
T h e fir st a n n u al ‘ O n -sit e’ m o nit ori n g vi sit s h o ul d o c c ur aft er t h e fir st fi v e st u d y p arti ci p a nt s ar e 
e nr oll e d or t w el v e m o nt h s aft er a st u d y o p e n s, w hi c h e v er o c c ur s fir st.  T h e a n n u al vi sit m a y b e 
c o n d u ct e d a s a ‘ C e ntr ali z e d’ vi sit if l e s s t h a n t hr e e s u bj e ct s h a v e e nr oll e d at t h e st u d y sit e.  T h e 
t y p e of vi sit i s at t h e di s cr eti o n of t h e C o or di n ati n g C e nt er.  At a mi ni m u m, a r o uti n e m o nit ori n g 
vi sit wil l b e d o n e at l e a st o n c e a y e ar, or o n c e d uri n g t h e c o ur s e of t h e st u d y if t h e st u d y d ur ati o n 
i s l e s s t h a n 1 2 m o nt h s. T h e p ur p o s e of t h e s e vi sit s i s t o v erif y: 
 
 
A d h er e n c e t o t h e pr ot o c ol  
 
C o m pl et e n e s s a n d a c c ur a c y of st u d y d at a a n d s a m pl e s c oll e ct e d  
 
Pr o p er st or a g e, di s p e n si n g a n d i n v e nt or y of st u d y m e di c ati o n  
 
C o m pli a n c e wit h r e g ul ati o n s  
 
D uri n g a m o nit ori n g vi sit t o a sit e, a c c e s s t o r el e v a nt h o s pit al a n d cli ni c al r e c or d s m u st b e gi v e n 
b y t h e sit e i n v e sti g at or t o t h e C o or di n ati n g C e nt er r e pr e s e nt ati v e  c o n d u cti n g t h e m o nit ori n g vi sit 
t o v erif y c o n si st e n c y of d at a c oll e ct e d o n t h e C R F s wit h t h e ori gi n al s o ur c e d at a.  W hil e m o st 
p ati e nt c a s e s will b e s el e ct e d fr o m p ati e nt s a c cr u e d si n c e t h e pr e vi o u s m o nit ori n g vi sit, a n y 
p ati e nt c a s e h a s t h e p ot e nti al f or  r e vi e w.  At l e a st o n e or m or e u n a n n o u n c e d c a s e s will b e 
r e vi e w e d, if t h e t ot al a c cr u al s w arr a nt s el e cti o n of u n a n n o u n c e d c a s e s.  


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The Coordinating Center expects the relevant investigational staff to be available to facilitate the 
conduct of the visit, that source documents are available at the time of the visit, and that a 
suitable environment will be provided for review of study-related documents. Any issues identified 
during these visits will be communicated to the site and are expected to be resolved by the site in 
a timely manner.  For review of study-related documents at the Coordinating Center, the site will 
be required to ship or fax documents to be reviewed.   
 
Participating site will also undergo a site close-out upon completion, termination or cancellation of 
a study to ensure fulfillment of study obligations during the conduct of the study, and that the site 
Investigator is aware of his/her ongoing responsibilities. In general, a site close-out is conducted 
during a site visit; however, site close-out can occur without a site visit. 
 
15.0 
APPENDICES 
 
Appendix A- ECOG Performance Status 
 
Grade 
ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of sedentary nature (e.g. light house work, office work) 
2 
Ambulatory and capable of all self care but unable to carry our any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited self care; confined to bed or chair more than 50% of waking 
day 
4 
Completely disabled, cannot carry on any self care; totally confined to bed or chair 
5 
Dead 
 
 
 


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Appendix B- FACT Head and Neck Questionnaire  
 
 
 


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Appendix C- Administration Instructions for Oral Dose Using Syringe 
 


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Appendix D- Administration Instructions for Each Dose via NG Tubes  
 


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