Conditions: Head and Neck Squamous Cell Carcinoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 6
Healthy volunteers: no

Brief summary:
In phase I of the trial, the investigators aim to explore the safety and feasibility of abemaciclib in combination with nivolumab in patients with recurrent/metatstatic head and neck squamous cell carcinoma (RM-HNSCC). A dose de-escalation study design will be used to determine the recommended phase II dose (RP2D) of abemaciclib given with the standard dose of nivolumab.

In phase II of the trial, the investigators aim to determine if abemaciclib and nivolumab will improve the one year survival from 36% (historical comparison with nivolumab) to 60% (abemaciclib + nivolumab) in patients with RM-HNSCC that had progressed or recurred within six months after platinum-based chemotherapy. Patients will be treated with abemaciclib at the recommended phase 2 dose (RP2D) in combination with standard doses of nivolumab. If this aim is met, genome sequencing, bulk and single cell RNAseq, and selected protein expression and deep cellular phenotyping will be performed on tumor tissue and blood obtained before and during treatment with abemaciclib and nivolumab. These biomarker data will be correlated with survival and tumor response to abemaciclib and nivolumab.

Detailed description:

Arms:
arm 1: * Abemaciclib (150 mg) will be administered orally twice per day (with or without food) on Days 1 through 28 of every 4-week cycle
* Nivolumab 480 mg will be given intravenously (IV) over 30 minutes on Day 1 of every 4-week cycle. arm 2: * Phase II Lead-in: Patients will be treated with abemaciclib monotherapy at the recommended phase II dose (150 mg) on Day -7 through Day -1 prior to starting Cycle 1 with the combination of abemaciclib and nivolumab. Patients will proceed directly from Day -1 to Cycle 1 Day 1 of combination abemaciclib + nivolumab, there is not a Day 0.
* Patients will be treated with abemaciclib at the RP2D (150 mg) (Days 1 through 28) + nivolumab (480 mg, Day 1) of each 4-week cycle.

Interventions: intervention 1: Abemaciclib intervention 2: Nivolumab intervention 3: Tumor biopsy intervention 4: Peripheral blood intervention 5: EORTC QLQ-30
Intervention descriptions: intervention 1: Abemaciclib is an investigational agent for this trial and will be supplied by Lilly Oncology, free of charge to the patient. intervention 2: Nivolumab is commercially available intervention 3: * Phase II patients only
* If the patient consents, fresh tumor tissue will be collected at baseline and then during Cycle 2 (between days 8-22) of abemaciclib and nivolumab. intervention 4: * Phase II patients only
* Peripheral blood will be collected at baseline, at the end of the Lead In (cycle 1 day 1 prior to treatment), during cycle 2 (between days 8-22), and during cycle 3 (between days 21-28). If patient does not have progression after cycle 3, patient will also have peripheral blood collected at time of progression. intervention 5: * Phase II patients only
* Screening , Cycle 2 D1, Cycle 4 D1, and End of treatment (EOT)

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version: 09/10/2019 
 
Page 1 of 50 
 
 
A Prospective Phase I and II Trial of Abemaciclib + Nivolumab in Patients with 
Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma that Progressed 
or Recurred within Six Months after Platinum-based Chemotherapy 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201810019  
Version Date: 09/10/2019 
 
Principal Investigator: 
Douglas R. Adkins, MD 
(314) 747-8475 
dadkins@wustl.edu 
 
 
Sub-Investigators  
 
 
Modality 
Miriam Jacobs, MD  
 
 
Medical Oncology 
Peter Oppelt, MD 
 
 
 
Medical Oncology 
Todd Fehniger, MD, PhD  
 
Medical Oncology 
Kevin Palka, MD 
 
 
 
Medical Oncology 
Esther Lu, PhD 
 
 
 
Biostatistics  
Jessica Ley, BS 
 
 
 
Clinical Research Specialist 
Sid Puram, MD 
 
 
 
Otolaryngology/Head and Neck Surgery        
 
 
Study Drug(s): 
 
Abemaciclib (Verzenio) 
Nivolumab (Opdivo) 
                                            
 
 
IND #: 
141105 (EXEMPT)  
ClinicalTrials.gov #: 
NCT03655444 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent 
necessary to obtain informed consent, may not be disclosed to another party unless law or 
regulations require such disclosure.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them 


Protocol Version: 09/10/2019 
 
Page 2 of 50 
SCHEMA 
 
 
 
 
*Phase I: Abemaciclib De-Escalation Schedule 
Dose Level 
Abemaciclib Dose 
1(Starting Dose) 
150 mg bid 
2 
100 mg bid 
3 
50 mg bid 
Three patients will be treated at each dose level. De-escalation to the next dose level will occur if 2 or more 
patients experience DLTs attributable to abemaciclib during cycle 1. 
 
**RP2D: recommended phase 2 dose. 
 
 
 
PHASE I TRIAL: 
Baseline Evaluations
Physical Exam
CT Scans
Bloodwork
(n= 3-12 pts)
Abemaciclib po (Days 1-28) 
Dose De-escalation* 
+ 
Nivolumab IV (480 mg, Day 1)
q 4 week cycles
Scans every 3 cycles
Treatment Until Progression
Primary Objective: Establish the RP2D**
of Abemaciclib.


Protocol Version: 09/10/2019 
 
Page 3 of 50 
 
PHASE II TRIAL (n=23 pts): 
Baseline Evaluations
Physical Exam
CT Scans
Bloodwork + Tumor Biopsy
LEAD IN
Abemaciclib po RP2D
Day -7 to Day -1
Blood at Day -1 or Day 1 prior to 
treatment 
Abemaciclib po (Days 1-28) 
RP2D
+ 
Nivolumab IV (480 mg, Day 1)
q 4 week cycles
Scans every 3 cycles
Blood + Tumor Biopsy cycle 2, between 
days 8-22 or at time of progression
Treatment Until Progression
Primary Objective: Establish the one 
year Overall Survival.


Protocol Version: 09/10/2019 
 
Page 4 of 50 
Table of Contents 
 
SCHEMA ........................................................................................................................................ 2 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 6 
1.1 
Head and Neck Squamous Cell Carcinoma ..................................................................... 6 
1.2 
Nivolumab in Platin-Refractory RM-HNSCC ................................................................. 6 
1.3 
CDK4/6 Inhibition is an Effective Therapeutic Strategy in RM-HNSCC ....................... 7 
1.4 
Selective CDK4/6 Inhibition with Abemaciclib .............................................................. 7 
1.5 
Rationale for the Combination of Abemaciclib and Nivolumab: “CDK4/6 Inhibition 
Triggers Anti-Tumor Immunity” ................................................................................................ 8 
2.0 
OBJECTIVES ...................................................................................................................... 9 
2.1 
Primary Objectives ........................................................................................................... 9 
2.2 
Secondary Objectives ....................................................................................................... 9 
2.3 
Exploratory Objectives ..................................................................................................... 9 
3.0 
PATIENT SELECTION ...................................................................................................... 9 
3.1 
Inclusion Criteria ............................................................................................................ 10 
3.2 
Exclusion Criteria ........................................................................................................... 10 
4.0 
REGISTRATION PROCEDURES ................................................................................... 12 
4.1 
Confirmation of Patient Eligibility ................................................................................. 12 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 12 
4.3 
Assignment of UPN ....................................................................................................... 12 
5.0 
TREATMENT PLAN ........................................................................................................ 12 
5.1 
Phase I: Dose De-Escalation .......................................................................................... 12 
5.2 
Phase II ........................................................................................................................... 14 
5.3 
Definitions of Evaluability ............................................................................................. 14 
5.4 
Concomitant Medications .............................................................................................. 15 
5.5 
Radiotherapy in Combination with Abemaciclib is NOT Permitted. ............................ 16 
5.6 
Women of Childbearing Potential .................................................................................. 16 
5.7 
Duration of Therapy ....................................................................................................... 16 
5.8 
Duration of Follow-up .................................................................................................... 17 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS/TREATMENT OF AEs ............................. 17 
6.1 
Abemaciclib ................................................................................................................... 17 
6.2 
Nivolumab ...................................................................................................................... 21 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 21 
7.1 
Definitions ...................................................................................................................... 22 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
24 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 24 
7.4 
Reporting to the FDA ..................................................................................................... 24 
7.5 
Reporting to Lilly Oncology .......................................................................................... 25 
7.6 
Timeframe for Reporting Required Events .................................................................... 26 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 26 
8.1 
Abemaciclib (Verzenio) ................................................................................................. 26 
8.2 
Nivolumab (Opdivo) ...................................................................................................... 28 
9.0 
CORRELATIVE STUDIES .............................................................................................. 30 


Protocol Version: 09/10/2019 
 
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9.1 
Tumor Tissue (Phase II patients only) ........................................................................... 30 
9.2 
Peripheral Blood (Phase II patients only) ...................................................................... 31 
9.3 
Quality of Life (Phase II patients only) .......................................................................... 32 
10.0 STUDY CALENDAR ....................................................................................................... 33 
11.0 DATA SUBMISSION SCHEDULE ................................................................................. 34 
12.0 MEASUREMENT OF EFFECT........................................................................................ 34 
12.1 Antitumor Effect – Solid Tumors................................................................................... 34 
12.2 Disease Parameters ......................................................................................................... 34 
12.3 Methods for Evaluation of Measurable Disease ............................................................ 35 
12.4 Response Criteria ........................................................................................................... 37 
13.0 DATA AND SAFETY MONITORING ............................................................................ 40 
14.0 STATISTICAL CONSIDERATIONS............................................................................... 40 
14.1 Study Design .................................................................................................................. 41 
14.2 Study Endpoints ............................................................................................................. 41 
14.3 Study Population ............................................................................................................ 41 
14.4 Accrual ........................................................................................................................... 41 
14.5 Power Analysis ............................................................................................................... 41 
14.6 Data Analysis ................................................................................................................. 41 
14.7 Stopping Rules (Phase I) ................................................................................................ 42 
15.0 REFERENCES .................................................................................................................. 43 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 44 
APPENDIX B: EORTC QLQ-C30 ............................................................................................... 45 
APPENDIX C: FACT-H&N......................................................................................................... 47 
APPENDIX D: Medication Diary (for Lead In week, block out Days 8-28) ............................... 50 
 
 
 


Protocol Version: 09/10/2019 
 
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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Head and Neck Squamous Cell Carcinoma 
 
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common 
cancer. Most patients (80%) present with locally advanced disease, and 50% of 
these patients are cured. However, 50% of these patients develop 
recurrent/metastatic (RM) disease within 18 months of completion of initial therapy. 
The magnitude of the problem of RM-HNSCC is significant: in the USA alone, 
over 20,000 new cases of RM-HNSCC occur each year, while in the world, 
over 240,000 new cases of RM-HNSCC occur each year. 
 
Outcomes are poor for those patients who are not cured with initial therapy. The 
median overall survival (OS) of patients with RM-HNSCC treated with first line 
platin-based chemotherapy and cetuximab is 10 months1. Median OS for patients 
with platinum-refractory RM-HNSCC is 5 months and one year survival is only 
17%. Novel effective therapies are needed for patients with RM-HNSCC.  
 
1.2 
Nivolumab in Platin-Refractory RM-HNSCC  
 
Checkmate 141 was a randomized phase III trial that compared outcomes of 
patients with RM-HNSCC that had progressed or recurred within six months after 
platinum-based chemotherapy who were treated with nivolumab (anti-PD-1 
antibody) or investigator’s choice (IC) of chemotherapy (docetaxel, methotrexate 
or cetuximab)2. Median OS was 7.5 months in the nivolumab group and 5.1 months 
in the IC group (p=0.01). One-year survival was 36% in the nivolumab group 
and 17% in the IC group. Median progression-free survival (PFS) was not 
significantly different between the two groups (2.0 vs 2.3 months, respectively, 
p=0.32). Tumor response rate was 13% in the nivolumab group and 6% in the IC 
group. 
 
 


Protocol Version: 09/10/2019 
 
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This trial established nivolumab as the new standard therapy for patients with RM-
HNSCC that had progressed or recurred within six months after platinum-based 
chemotherapy. However, the one year survival of only 36% with nivolumab 
emphasizes the need to develop strategies to improve these results. 
 
1.3 
CDK4/6 Inhibition is an Effective Therapeutic Strategy in RM-HNSCC 
 
Because the genetics of HNSCC suggest a crucial role for CDK4/cyclin D in this 
disease3, we performed a phase I trial to determine the dose limiting toxicity (DLT) 
and the maximum tolerated dose (MTD) of palbociclib combined with standard 
weekly doses of cetuximab in patients with RM-HNSCC4. We built upon the 
cetuximab platform because palbociclib targets a pathway associated with 
resistance to EGFR inhibitors. 
 
A phase I trial using 3+3 design was performed to determine the DLT and MTD of 
palbociclib with standard dose weekly cetuximab. Palbociclib was administered 
orally days 1-21 every 28 days: dose level 1 (100 mg/d) and 2 (125 mg/d). Tumor 
response was assessed using RECIST 1.1. 
 
Nine patients were enrolled across dose levels 1 (n=3) and 2 (n=6) and none 
experienced a DLT. The MTD of palbociclib was not reached. Six of nine patients 
had cetuximab-resistant and four of nine had platinum-resistant disease. Disease 
control (DC) occurred in 89% of patients, including partial response (PR) in two 
(22%) and stable disease in six (67%) patients. Five patients (56%) had 
measurable decreases in tumor target lesions. In platinum-resistant HNSCC, best 
tumor response was PR in 1 and DC in 3 patients. In cetuximab-resistant HNSCC, 
best tumor response was PR in 1 and DC in 5 patients. 
 
This trial, the first to evaluate a CDK4/6 inhibitor in HNSCC, determined that 
palbociclib is an active agent in RM-HNSCC, even in platinum-resistant 
disease. Tumor responses in cetuximab-resistant disease suggest that 
monotherapy with a CDK4/6 inhibitor would result in tumor responses in this 
disease. 
 
1.4 
Selective CDK4/6 Inhibition with Abemaciclib 
 
Abemaciclib is an oral selective CDK4/6 inhibitor administered on a continuous 
schedule5-7. Abemaciclib results in cell cycle arrest at the G1 checkpoint and 
inhibits cell growth. Continuous inhibition of CDK4/6 results in sustained growth 
arrest and initiation of apoptosis or senescence8. Abemaciclib is 14 times more 
potent than palbociclib or ribociclib against cyclin D1/CDK4 than cycle D3/CDK6 
in enzymatic assays6-10. Compared to palbociclib, abemaciclib has greater 
potency as a CDK4/6 inhibitor and is administered on a continuous schedule. 
These advantages make abemaciclib an attractive option to inhibit CDK4/6 
in HNSCC and could translate into improved and more durable tumor 
responses compared to palbociclib. 


Protocol Version: 09/10/2019 
 
Page 8 of 50 
 
In a phase I trial, the DLT of abemaciclib was fatigue6. Other (grade 3) toxicities 
included diarrhea (5%) and hematologic (10%). Tumor responses were seen in 
breast cancer, NSCLC and melanoma. In hormone-receptor positive breast 
cancer, the tumor response rate was 31%. The phase II MONARCH 1 trial 
confirmed the single agent activity of abemaciclib in refractory hormone-receptor 
positive breast cancer with a tumor response rate of 19.7%8. The phase III 
MONARCH 2 trial showed a significantly longer median PFS (16.4 vs 9.3 months) 
and better tumor response rate (48.1% vs 21.3%) with abemaciclib and fulvestrant 
compared to placebo and fulvestrant in refractory hormone-receptor positive 
breast cancer11. Diarrhea, neutropenia, nausea and fatigue were more common in 
the abemaciclib arm. 
 
1.5 
Rationale for the Combination of Abemaciclib and Nivolumab: 
“CDK4/6 Inhibition Triggers Anti-Tumor Immunity” 
 
Abemaciclib, a CDK4/6 inhibitor, increases tumor immunogenicity by enhancing 
tumor antigen presentation and suppressing proliferation of regulatory T cells12. 
These effects are mediated by decreased expression of DNMT1. The functional 
significance of these effects include promotion of CD8 T cell mediated killing 
of tumor cells which is enhanced by the addition of PD-1 antibody. 
 
1.6      Study Synopsis and Aims 
 
Nivolumab monotherapy is the current standard FDA approved therapy to treat 
RM-HNSCC that has progressed or recurred within six months after platinum-
based chemotherapy; however, the benefit is modest. One year survival was only 
36%, and median PFS 2.0 months and tumor response 13%. CDK4/6 inhibition is 
an effective therapeutic strategy in RM-HNSCC, and abemaciclib promotes CD8 
T cell mediated killing of tumor cells which is enhanced by the addition of 
PD-L1 antibody. Based on these observations, we hypothesize that the 
combination of abemaciclib and nivolumab will increase the one year survival of 
patients with RM-HNSCC that had progressed or recurred within six months after 
platinum-based chemotherapy, compared to historical data with nivolumab 
monotherapy.  
 
In phase I of the trial, we aim to explore the safety and feasibility of 
abemaciclib in combination with nivolumab in patients with RM-HNSCC. A 
dose de-escalation study design will be used to determine the recommended 
phase II dose (RP2D) of abemaciclib given with the standard dose of nivolumab.  
In phase II of the trial, we aim to determine if abemaciclib and nivolumab will 
improve the one year survival from 36% (historical comparison with 
nivolumab) to 60% (abemaciclib + nivolumab) in patients with RM-HNSCC 
that had progressed or recurred within six months after platinum-based 
chemotherapy. Patients will be treated with abemaciclib at the RP2D in 
combination with standard doses of nivolumab. If this aim is met, genome 


Protocol Version: 09/10/2019 
 
Page 9 of 50 
sequencing, bulk and single cell RNAseq, and selected protein expression and 
deep cellular phenotyping will be performed on tumor tissue and blood obtained 
before and during treatment with abemaciclib and nivolumab. These biomarker 
data will be correlated with survival and tumor response to abemaciclib and 
nivolumab. 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
1) Phase I: Determine the RP2D of abemaciclib combined with a fixed dose of 
nivolumab in patients with RM-HNSCC. 
 
2) Phase II: Determine the OS of patients with RM-HNSCC that progressed or 
recurred within six months of platinum-based therapy who are treated with 
abemaciclib and nivolumab. 
 
2.2 
Secondary Objectives 
 
1) Phase II: Determine the best tumor response rate for patients with RM-HNSCC 
who are treated with abemaciclib and nivolumab. 
 
2) Phase II: Determine the duration of tumor response for patients with RM-
HNSCC who are treated with abemaciclib and nivolumab. 
 
3) Phase II: Determine the progression-free survival (PFS) for patients with RM-
HNSCC who are treated with abemaciclib and nivolumab. 
 
4) Phase II: Determine the adverse events (AEs) associated with the combination 
of abemaciclib and nivolumab. 
 
5) Phase II-Lead In: Characterize the changes in peripheral blood lymphocyte 
subsets before and after one week of abemaciclib monotherapy.  
 
2.3 
Exploratory Objectives 
 
1) Phase II: Collect and store pre-treatment and on-treatment tissue and blood 
specimens from patients for correlative studies, including studies of tumor 
heterogeneity that may define the malignant, stromal, and immune response 
with treatment. 
 
2) Phase II: Monitor quality of life (QOL) as documented by QOL measurements 
using the FACT H&N and EORTC QLQ-C30 assessment tools. 
 
3.0 
PATIENT SELECTION 
 


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3.1 
Inclusion Criteria 
 
1. Incurable RM-HNSCC, defined as disease not amenable to cure by surgery 
and/or radiation therapy (or patient declines or is ineligible for surgery and/or 
radiation therapy).  
 
2. Disease Evaluation: 
a. Phase I: evaluable or measurable disease.  
b. Phase II: measurable disease, defined as lesions that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 
10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm by clinical 
exam.  
 
3. Prior Treatment: 
a. Phase I: any number of lines of prior therapy for RM-HNSCC.  
b. Phase I: prior therapy with inhibitors of CDK4/6 or PD-L1/PD-1 is 
acceptable. 
c. Phase II: RM-HNSCC that progressed or recurred within six months of 
platinum-based therapy (given for curable or incurable disease).  
d. Phase II: prior therapy with inhibitors of CDK4/6 or PD-L1/PD-1 is not 
acceptable. 
 
4. 18 years of age or older. 
 
5. Performance status 0-1 (ECOG: Appendix 1). 
 
6. Adequate blood and organ function as defined: 
a. Absolute neutrophil count ≥ 1,500/mcL 
b. Platelets ≥ 100,000/mcL 
c. Hemoglobin ≥ 8.0 g/dL 
d. Total bilirubin ≤ 1.5 x ULN 
e. AST(SGOT) ≤ 3 x IULN and ALT(SGPT) ≤ 3 x IULN 
f. Creatinine ≤ 2 x ULN OR creatinine clearance ≥ 40 mL/min/1.73 m2 
g. INR ≤ 1.5 x ULN and PTT ≤ 1.5 x ULN (Patients are allowed to be on 
anticoagulation) 
 
7. Able to swallow oral medication. 
 
8. Women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control, abstinence) 
beginning 14 days prior to first dose of abemaciclib, through the dosing period, 
and for at least 28 days after. 
 
9. Signed IRB approved written informed consent document. 
 
3.2 
Exclusion Criteria 


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1. Phase II: prior inhibitors of CDK4/6 or PD-L1/PD-1 for treatment of incurable 
HNSCC. 
 
2. Radiation within 14 days of treatment start (patients who received radiotherapy 
must have completed and fully recovered from the acute effects of 
radiotherapy); Chemotherapy, targeted or investigational therapy within 21 
days of treatment start.  
 
3. History of other malignancy ≤ 1 year prior to consent with the exception of 
completely resected skin carcinoma or other cancers with a low risk of 
recurrence. 
 
4. Ongoing toxicity attributed to prior anti-cancer therapy that is > grade 1, except 
alopecia or peripheral neuropathy. 
 
5. Active central nervous system metastases: defined as currently receiving 
radiation therapy to metastatic CNS disease. Once radiation therapy is 
completed, patients with CNS disease are eligible if they meet all other criteria 
for enrollment. 
 
6. History of severe allergic reactions attributed to agents used in the study. 
 
7. Serious uncontrolled inter-current illness within the 3 months prior to study 
entry or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
8. Serious and/or uncontrolled preexisting medical condition(s) that, in the 
judgment of the investigator, would preclude participation in this study (i.e., 
interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, 
severe renal impairment [e.g. estimated creatinine clearance <30ml/min], 
history of major surgical resection involving the stomach or small bowel,  or 
preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic 
condition resulting in baseline Grade 2 or higher diarrhea). 
 
9. Active systemic bacterial infection (requiring intravenous [IV] antibiotics at time 
of initiating study treatment), fungal infection, or detectable viral infection (such 
as known human immunodeficiency virus positivity or with known active 
hepatitis B or C [for example, hepatitis B surface antigen positive].  Screening 
is not required for enrollment. 
 
10. History of any of the following conditions: syncope of cardiovascular etiology, 
ventricular arrhythmia of pathological origin (including, but not limited to, 
ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. 
 


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11. Pregnant and/or breastfeeding. Patient must have a negative serum pregnancy 
test within 7 days of first dose of treatment. 
 
12. Active serious autoimmune disease requiring systemic immunosuppression 
(biologics, prednisone equivalent dose > 20 mg/day). 
 
13. Current use of strong CYP3A inhibitors or inducers.     
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the 
Siteman Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study 
team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore 
database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  
All data will be recorded with this identification number on the appropriate CRFs. 
 
5.0 
TREATMENT PLAN 
 
5.1 
Phase I: Dose De-Escalation 
             


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Abemaciclib will be administered po bid (with or without food) on Days 1 through 
28 of every 4-week cycle. Patients will be asked to complete a drug diary 
Nivolumab 480 mg will be given intravenously (IV) over 30 minutes on Day 1 of 
every 4-week cycle. Abemaciclib dose levels are shown in the table below.  
Nivolumab dosing will not change. 
 
5.1.1 Phase I Abemaciclib Dose De-Escalation Plan 
 
Dose  
Level 
Dose (mg bid) 
1 (Starting Dose) 
150 
-1 
100 
-2 
50 
 
Starting at dose level 1, three patients will be treated. De-escalation to the 
next lowest dose level will occur if 2 or more patients experience dose-
limiting toxicities (DLTs) attributable to abemaciclib. Dose de-escalation will 
not occur until all patients in the cohort have completed the first cycle of 
therapy and the Principal Investigator has been able to review all toxicities. 
If 1 or fewer patients experience a DLT within a dose level, that dose level 
will be considered the RP2D of abemaciclib given with nivolumab.  
 
5.1.2 Definition of RP2D and DLT 
 
5.1.2.1 
Definition of RP2D of Abemaciclib 
 
The RP2D of abemaciclib is defined as the highest dose level at 
which fewer than 2 patients of a cohort of three patients experience 
a DLT during the first cycle. Dose de-escalations will proceed until 
the RP2D has been reached.  If no more than one DLT in three 
patients is experienced in dose level 1, this will be considered the 
RP2D and there will be no dose de-escalation.  
 
5.1.2.2 
Dose Limiting Toxicities (DLTs) 
 
DLTs will only be assessed during Cycle 1 of the phase I portion 
of the study.  
 
Hematologic DLT is defined as neutropenia (grade 4) or 
thrombocytopenia (grades 4). Hematologic toxicity is not a known AE 
of nivolumab.  
 
Non-hematologic DLT is defined as any possibly, probably, or 
definitely abemaciclib-related grade 3 or grade 4 toxicity occurring 
during the first cycle except: 
 


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• Grade 3 or 4 nausea, vomiting or diarrhea that occurs without 
maximal antiemetic/antidiarrheal prophylaxis 
• Grade 3 or 4 hypertension that is adequately controlled by 
medication 
• Grade 3 or 4 venous thromboembolism (they can receive 
anticoagulation) 
• Any grade: anorexia, fatigue, alopecia, or lymphopenia 
 
5.2 
Phase II 
 
5.2.1 Lead In: Abemaciclib Monotherapy 
 
Patients will be treated with abemaciclib monotherapy at the RP2D on Day 
-7 through Day -1 prior to starting Cycle 1 with the combination of 
abemaciclib and nivolumab. Patients will proceed directly from Day -1 to 
Cycle 1 Day 1 of combination abemaciclib + nivolumab, there is not a Day 
0. 
  
5.2.2 Abemaciclib + Nivolumab 
 
Patients will be treated with abemaciclib at the RP2D (Days 1 through 28) 
+ nivolumab (480 mg, Day 1) of each 4-week cycle. Tumor response 
assessment will be performed after every three cycles (12 weeks). If either 
drug is stopped for reasons other than disease progression, the other drug 
will continue and the patient will remain on the protocol. Patients will remain 
on study therapy until disease progression, intolerance, or patient decision 
to stop therapy. Study treatment will be stopped when disease progression 
is documented, after which patients will be followed for OS. 
 
5.2.3 Toxicity and Tumor Response Evaluations 
 
All patients who receive any study treatment are evaluable for toxicity.  
Patients are evaluated from first receiving study treatment until a 30-day 
follow up after the conclusion of treatment or death. 
 
All patients who have received at least one dose of abemaciclib will be 
evaluable for disease response (including patients who discontinue 
abemaciclib early but continue to receive nivolumab), unless they come off 
study entirely due to treatment related adverse events(s) prior to completion 
of Cycle 1 and have not had any disease assessment. CT scans of the neck 
and chest will be performed at baseline and after every 12 weeks (3 cycles) 
of therapy. 
 
5.3 
Definitions of Evaluability 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients 


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are evaluated from first receiving study treatment until a 28-day follow up after the 
conclusion of treatment or death.  
 
All patients who received at least one dose of abemaciclib will be evaluable for 
disease response (including patients who discontinue abemaciclib early but 
continue to receive nivolumab), unless they come off study entirely and have not 
had any disease assessment. CT scans of the neck and chest will be performed 
at baseline and after every 12 weeks (three cycles) of therapy. 
 
A patient is evaluable for DLT assessment only during Cycle 1 of treatment, and 
only if enrolled in Phase I of the study.  If the patient is not able to be treated on 
Day 1 of Cycle 2, then s/he is still considered in Cycle 1 active treatment and can 
experience a DLT.  Once the patient has been treated in Cycle 2, s/he will no 
longer be evaluated for DLTs in subsequent cycles.   
 
5.4 
Concomitant Medications 
 
5.4.1 CYP3A inhibitors 
 
Abemaciclib is predominantly cleared by oxidative metabolism via CYP3A4.  
Clinical drug interaction studies with a CYP3A inhibitor and CYP3A inducer 
significantly altered the PK of abemaciclib and its circulating major 
metabolites. Therefore, drugs that are strong and moderate inducers of 
CYP3A and/or strong inhibitors of CYP3A should be avoided or substituted 
if necessary.  
 
If concomitant use cannot be avoided, abemaciclib dose adjustments may 
be required:  
• Patients who must take CYP3A inhibitors such as clarithromycin, 
diltiazem, or verapamil should reduce the abemaciclib dose to 
100 mg twice daily.  
• Patients who must take itraconazole should reduce the abemaciclib 
dose to 50 mg twice daily.  
• Patients who must take ketoconazole should reduce the abemaciclib 
dose to 50 mg twice daily.  
• Patients should avoid grapefruit or grapefruit juice. 
 
5.4.2 CYP3A inducers 
 
Avoid concomitant use of strong CYP3A inducers. Consider alternative 
agents without CYP3A induction. 
 
If a CYP3A inhibitor is discontinued, increase the abemaciclib dose (after 3-
5 half-lives of the inhibitor) to the dose that was used before starting the 
inhibitor. *Communicate with the PI and receive PI approval before doing 
this* 


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5.5 
Radiotherapy in Combination with Abemaciclib is NOT Permitted. 
 
 
5.6 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women 
with amenorrhea, women with irregular cycles, women using a contraceptive 
method that precludes withdrawal bleeding, and women who have had a tubal 
ligation) are required to have a negative pregnancy test within 7 days prior to the 
first dose of abemaciclib.   
 
Female and male patients (along with their female partners) are required to use 
two forms of acceptable contraception, including one barrier method, during 
participation in the study and for 3 months following the last dose of either study 
drug. Contraceptive methods may include an intrauterine device [IUD] or barrier 
method. If condoms are used as a barrier method, a spermicidal agent should be 
added as a double barrier protection. 
 
If a patient is suspected to be pregnant, both study drugs should be immediately 
discontinued.  In addition a positive urine test must be confirmed by a serum 
pregnancy test.  If it is confirmed that the patient is not pregnant, the patient may 
resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during 
therapy or within 3 months after the last dose of either study drug, the investigator 
must be notified in order to facilitate outcome follow-up. Data on fetal outcome and 
breast-feeding are to be collected for regulatory reporting and drug safety 
evaluation. 
 
5.7 
Duration of Therapy  
 
If at any time the constraints of this protocol are considered to be detrimental to 
the patient’s health and/or the patient no longer wishes to continue protocol 
therapy, the protocol therapy should be discontinued and the reason(s) for 
discontinuation documented in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue 
indefinitely or until one of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe 
or permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 


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• Suspected pregnancy 
• Serious noncompliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
If either drug is stopped for reasons other than disease progression, the other drug 
will continue and the patient will remain on the protocol. Patients will remain on 
study therapy until one of the above criteria is met. Study treatment will be stopped 
when disease progression is documented, after which patients will be followed for 
OS. 
 
5.8 
Duration of Follow-up 
 
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  Patients will be followed for 28 
days after last dose of therapy for adverse events, and until death for OS objective.   
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS/TREATMENT OF AEs 
 
6.1 
Abemaciclib  
 
6.1.1 Dose Levels for Abemaciclib 
 
Starting dose for Phase II will be determined by results of Phase I. Dose 
escalations are not permitted. Only dose reductions are permitted. 
 
Dose Level 
Abemaciclib Dose 
Starting Dose 150 mg twice daily 
-1 
100 mg twice daily 
-2 
50 mg twice daily 
 
6.1.2 Dose Modification and Management – Hematologic Toxicities 
 
Monitor complete blood counts prior to the start of abemaciclib therapy, 
every 2 weeks for the first 2 months, monthly for the next 2 months, and as 
clinically indicated. 
CTCAE v5.0 Grade Abemaciclib Dose Modifications 
Grade 1 or 2 
No dose modification is required 
Grade 3 
Suspend dose until toxicity resolves to ≤Grade 2  


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Dose reduction is not required. 
Grade 3 recurrent, 
or Grade 4 
Suspend dose until toxicity resolves to ≤Grade 2. 
Resume at next lower dose 
Patient requires 
administration of a 
blood cell growth 
factor 
 
Suspend abemaciclib dose for at least 48 hours after 
the last dose of blood cell growth factor and until 
toxicity resolves to ≤Grade 2. 
Resume abemaciclib at next lower dose unless the 
dose was already reduced for the toxicity that led to 
the use of the growth factor 
 
6.1.3 Dose Modification and Management – Diarrhea 
 
At enrollment, patients should receive instructions on the prompt 
management of diarrhea.  In the event of diarrhea, supportive care 
measures should be initiated as early as possible.  
 
At the first sign of loose stools, start treatment with antidiarrheal agents, 
such as loperamide, and notify the PI for further instructions and 
appropriate follow-up. Site personnel should assess response within 24 
hours. 
 
Patients should be encouraged to drink fluids (e.g., 8-10 glasses of clear 
liquids/day) 
CTCAE v5.0 Grade 
Abemaciclib Dose Modifications 
Grade 1 
No dose modification is required 
Grade 2 
If toxicity does not resolve within 24 hours 
to ≤Grade 1, suspend dose until 
resolution. Dose reduction is not required 
Grade 2 that persists or 
recurs after resuming the 
same dose despite maximal 
supportive measures 
Suspend dose until toxicity resolves to 
≤Grade 1 
Resume at next lower dose 
Grade 3 or 4 or requires 
hospitalization 
 
Dose level reductions should be made in 50 mg increments. For example, 
if the starting dose of abemaciclib for the study is 150 mg q12 hours, dose 
reduction 1 would be 100 mg q12 hours, dose reduction 2 would be 50 mg 
q12 hours. 
 
6.1.4 Dose Modification and Management – Interstitial Lung Disease 
(ILD)/Pneumonitis Events 
 
Patients should be asked to report any new or worsening pulmonary 
symptoms such as hypoxia, cough, dyspnea, cough and fever; these 
symptoms should be investigated and treated as per SOC guidelines 


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(including corticosteroids as appropriate). Infectious, neoplastic, and other 
causes for such symptoms should be excluded by means of appropriate 
investigations. Imaging such as high resolution computer tomography 
(HRCT), broncheoalveolar lavage (BAL), and biopsy as clinically 
indicated.  
 
 
CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 or 2 
No dose modification is required. 
Persistent or recurrent Grade 2 
toxicity that does not resolve with 
maximal supportive measures 
within 7 days to baseline or Grade 1 
Suspend dose until toxicity resolves 
to baseline or Grade 1. 
Resume at next lower dose. 
Grade 3 or 4 
Discontinue abemaciclib. 
 
 
6.1.5 Dose Modification and Management – Increased ALT 
Screening CMP will be used for C1D1 of abemaciclib & nivolumab 
treatment 
 
CTCAE v5.0 Grade 
Abemaciclib Dose Modifications 
Grade 1 (>ULN-3.0 × ULN) 
Grade 2 (>3.0-5.0 × ULN) 
No dose modification is required 
Persistent 
or 
Recurrent 
Grade 2, or Grade 3 (>5.0-
20.0 × ULN) that does not 
resolve 
with 
maximal 
supportive measures within 7 
days to baseline or Grade 1 
Suspend dose until toxicity resolves to 
baseline or Grade 1. 
Resume at next lower dose. 
Grade 3 (>5.0 x ULN) with 
total bilirubin > 2 x ULN, in the 
absence of cholestasis 
Discontinue abemaciclib 
Grade 4 (>20.0 × ULN) 
Discontinue abemaciclib 
Abbreviations: ALT = alanine aminotransferase; ULN = upper limit of normal. 
 
Details for hepatic monitoring depend upon the severity and persistence of 
observed laboratory test abnormalities. To ensure patient safety the 
investigator should collect specific recommended clinical information 
and follow-up laboratory tests as shown in the table below.  
 
Details for hepatic monitoring depend upon the severity and persistence of 
observed laboratory test abnormalities. If a study patient experiences 
elevated ALT 5×ULN and elevated TBL 2×ULN, or ALT 8×ULN, liver tests, 
including ALT, AST, TBL, direct bilirubin, gamma-glutamyl transferase 
(GGT), and creatine phosphokinase (CPK), should be repeated within 3 to 


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5 days to confirm the abnormality and to determine if it is increasing or 
decreasing.  If the abnormality persists or worsens, clinical and laboratory 
monitoring should be initiated by the investigator, based on the hepatic 
monitoring tests below.  
 
Hepatic Monitoring Tests for a Hepatic Treatment Emergent 
Abnormality. 
 
Hepatic Hematology 
Haptoglobin 
Hemoglobin 
 
Hematocrit 
Hepatic Coagulation 
RBC 
Prothrombin Time 
WBC 
Prothrombin Time, INR 
Neutrophils, segmented and bands 
 
Lymphocytes 
Hepatic Serologiesa 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
 
Hepatitis B Core antibody 
Hepatic Chemistry 
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Direct bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Anti-nuclear antibody 
AST 
Anti-actin antibody 
GGT 
CPK  
Anti-smooth muscle antibody 
 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CPK = creatine phosphokinase; GGT = gamma-glutamyl transferase; 
Ig = immunoglobulin; INR = international normalized ratio; RBC = red blood cells; 
WBC = white blood cells. 
a Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
 
 


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6.1.6 Dose Modification and Management – Nonhematologic        
           Toxicities 
Excluding 
Diarrhea, 
ALT 
Increased, 
and 
ILD/Pneumonitis 
 
CTCAE v5.0 Grade 
Abemaciclib Dose Modifications 
Grade 1 or 2 
No dose modification is required 
Persistent or recurrent Grade 2 
toxicity that does not resolve with 
maximal supportive measures 
within 7 days to baseline or Grade 1 
Suspend dose until toxicity resolves 
to baseline or Grade 1 
Resume at next lower dose 
Grade 3 or 4 
 
6.1.7 General Guidance for Increases in Serum Creatinine and 
Assessment of Renal Insufficiency 
 
Elevation of serum creatinine is observed with abemaciclib, and is due to a 
pharmacological inhibitory effect of abemaciclib on renal tubular 
transporters without affecting glomerular function. The rise in serum 
creatinine (mean increase, 0.2 mg/dL) occurs within the first 28-day cycle 
of abemaciclib, and remains elevated but stable throughout the treatment 
period, and were reversible upon treatment discontinuation. Alternative 
markers (such as BUN, cystatin C level, or cystatin C calculated GFR) which 
are not based on creatinine, may be considered to determine whether renal 
function is impaired.  
 
6.2 
Nivolumab 
 
Guidance for dose modifications or delays and treatment of AEs attributed to 
nivolumab will be guided based on the package insert. If nivolumab is omitted or 
stopped, patients will continue to receive abemaciclib. If abemaciclib is omitted or 
stopped, patients will continue to receive nivolumab. 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require 
reporting as outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all 
events meeting the definition of unanticipated problem or serious noncompliance be 
reported as outlined in Section 7.2. 
 
The FDA requires that all serious and unexpected adverse events be reported as outlined 
in Section 7.4.  In addition, any fatal or life-threatening adverse experiences where there 
is a reasonable possibility of relationship to study intervention must be reported. 
 


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Eli Lilly requires that all events be reported as outlined in Section 7.5. 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject 
including any abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will 
be utilized for all toxicity reporting.  A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the 
definitions for the terms listed that should be used are those provided by the 
Department of Health and Human Services’ Office for Human Research 
Protections (OHRP).  A copy of this guidance can be found on OHRP’s 
website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results 
in any of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which 
is not consistent with the current investigator brochure (or risk information, 
if an IB is not required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA.  
 


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7.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view 
of the investigator) at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
 
Life-threatening adverse experiences must be reported to the FDA. 
 
7.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the 
subject population being studied; 
• related or possibly related to participation in the research (in this 
guidance document, possibly related means there is a reasonable 
possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• suggests that the research places subjects or others at a greater risk 
of harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized. 
 
7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies 
that govern human subjects research or failure to follow the determinations 
of the IRB.  Noncompliance may occur due to lack of knowledge or due to 
deliberate choice to ignore regulations, institutional policies, or 
determinations of the IRB. 
 
7.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in 
substantial harm to subjects or others, or that materially compromises the 
rights or welfare of participants. 
 
7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under 
the research team’s control. Exceptions apply only to a single participant or 
a singular situation. 
 


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Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which 
occur at WU, any BJH or SLCH institution, or that impacts participants or 
the conduct of the study. 
• Noncompliance with federal regulations or the requirements or 
determinations of the IRB. 
• Receipt of new information that may impact the willingness of participants 
to participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the 
occurrence of the event or notification to the PI of the event.  The death of a 
research participant that qualifies as a reportable event should be reported within 
1 working day of the occurrence of the event or notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at 
WU or any BJH or SLCH institution that has been reported to and acknowledged 
by HRPO as reportable.  (Unanticipated problems reported to HRPO and 
withdrawn during the review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to a QASMC auditor. 
 
7.4 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the investigator to report any unanticipated problem to the FDA as 
follows: 
 
• Report any unexpected fatal or life-threatening adverse experiences 
(Section 7.1.4) associated with use of the drug (i.e., there is a reasonable 
possibility that the experience may have been caused by the drug) by 
telephone or fax no later than 7 calendar days after initial receipt of the 
information.   
• Report any serious, unexpected adverse experiences (Section 7.1.2), as 
well as results from animal studies that suggest significant clinical risk within 


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15 calendar days after initial receipt of this information.   
 
All MedWatch forms will be sent by the investigator or investigator’s team to the 
FDA at the following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
7.5 
Reporting to Lilly Oncology 
 
A serious adverse event is an undesirable sign, symptom or medical condition 
which: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition (specify what this includes) 
• elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the 
start of study drug 
• treatment on an emergency outpatient basis for an event not fulfilling 
any of the definitions of a SAE given above and not resulting in hospital 
admission 
• social reasons and respite care in the absence of any deterioration in 
the patient definitions of a SAE 
• is medically significant, i.e., defined as an event that jeopardizes the patient 
or may require medical or surgical intervention to prevent one of the 
outcomes listed above 
 
The principal investigator has the obligation to report all serious adverse events to 
the FDA, IRB, and Lilly. 
 
All events reported to the FDA by the investigator are to be filed utilizing the Form 
FDA 3500A (MedWatch Form).  
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
• after the patient has provided informed consent and until at least 30 days 
after the patient has stopped study treatment/participation 
• after protocol-specified procedures begin (e.g., placebo run-in, washout 
period, double-blind treatment, etc.) and 30 days after the patient has 


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stopped study treatment 
• after the start of any period in which the study protocol interferes with the 
standard medical treatment given to a patient (e.g., treatment withdrawal 
during washout period, change in treatment to a fixed dose of concomitant 
medication) and until 30 days after the patient has stopped study treatment 
 
All events must be reported to Lilly within 15 days of learning of its occurrence.  
Information about all SAEs is collected and recorded on a Serious Adverse Event 
Report Form; all applicable sections of the form must be completed in order to 
provide a clinically thorough report. The investigator must assess and record the 
relationship of each SAE to each specific study treatment (if there is more than 
one study treatment), complete the SAE Report Form in English, and submit the 
form via the electronic SAE reporting portal within 24 hours to Lilly. 
 
This includes serious, related, labeled (expected) and serious, related, unlabeled 
(unexpected) adverse experiences. All deaths during treatment or within 30 days 
following completion of active protocol therapy must be reported within 5 working 
days. 
 
Any SAEs experienced after this 30 days period should only be reported to Lilly if 
the investigator suspects a causal relationship to the study drug. Recurrent 
episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode within 24 hours of the investigator receiving the 
follow-up information. A SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one should be reported 
separately as a new event.  The end date of the first event must be provided. 
 
The original copy of the SAE Report and the fax confirmation sheet must be kept 
within the Trial Master File at the study site. 
 
Follow-up information is sent to the same fax number as the original SAE Report 
Form was sent, using a new fax cover sheet, stating that this is a follow-up to the 
previously reported SAE, and giving the date of the original report. Each re-
occurrence, complication, or progression of the original event should be reported 
as a follow-up to that event regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, if and how it was 
treated, whether the blind was broken or not (if applicable), and whether the patient 
continued or withdrew from study participation. 
 
7.6 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked for 28 days following the last day of study treatment. 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Abemaciclib (Verzenio) 


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8.1.1 Abemaciclib Description 
 
Abemaciclib is a kinase inhibitor indicated: 
• in combination with fulvestrant for the treatment of women with HR-
positive, HER2-negative advanced or metastatic breast cancer with 
disease progression following endocrine therapy 
• as monotherapy for the treatment of adult patients with HR-positive, 
HER2-negative advanced or metastatic breast cancer with disease 
progression following endocrine therapy and prior chemotherapy in 
the metastatic setting 
 
It is a white to yellow powder with the empirical formula C27H32F2N8 and a 
molecular weight 506.59.  The chemical name for abemaciclib is 2-
Pyrimidinamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-
[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-. 
 
8.1.2 Clinical Pharmacology 
 
Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and 
CDK6). These kinases are activated upon binding to D-cyclins. In estrogen 
receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 
promote phosphorylation of the retinoblastoma protein (Rb), cell cycle 
progression, and cell proliferation. In vitro, continuous exposure to 
abemaciclib inhibited Rb phosphorylation and blocked progression from G1 
into S phase of the cell cycle, resulting in senescence and apoptosis. In 
breast cancer xenograft models, abemaciclib dosed daily without 
interruption as a single agent or in combination with antiestrogens resulted 
in reduction of tumor size. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
Following single and repeated twice daily dosing of 50 mg (0.3 times the 
approved recommended 150 mg dosage) to 200 mg of abemaciclib, the 
increase in plasma exposure (AUC) and Cmax was approximately dose 
proportional. Steady state was achieved within 5 days following repeated 
twice daily dosing, and the estimated geometric mean accumulation ratio 
was 2.3 (50% CV) and 3.2 (59% CV) based on Cmax and AUC, 
respectively. 
 
Hepatic metabolism is the main route of clearance for abemaciclib. 
Abemaciclib is metabolized to several metabolites primarily by cytochrome 
P450 (CYP) 3A4, with formation of N-desethylabemaciclib (M2) 
representing the major metabolism pathway. Additional metabolites include 
hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an 
oxidative metabolite (M1). M2, M18, and M20 are equipotent to abemaciclib 


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and their AUCs accounted for 25%, 13%, and 26% of the total circulating 
analytes in plasma, respectively. 
 
After a single 150 mg oral dose of radiolabeled abemaciclib, approximately 
81% of the dose was recovered in feces and approximately 3% recovered 
in urine. The majority of the dose eliminated in feces was metabolites. 
 
8.1.4 Supplier 
  
Abemaciclib is an investigational agent for this trial and will be supplied by 
Lilly Oncology, free of charge to the patient. 
 
8.1.5 Dosage Form and Preparation 
 
Abemaciclib is available in 50 mg tablets. 
 
8.1.6 Storage and Stability 
 
Abemaciclib must be stored at room temperature. For specific storage, 
instructions refer to the product label. 
 
8.1.7 Administration 
 
Abemaciclib will be taken by mouth twice daily at the assigned dose. 
 
8.2 
Nivolumab (Opdivo) 
 
8.2.1 Nivolumab Description 
 
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody 
indicated for the treatment of patients with: 
• BRAF V600 wild-type unresectable or metastatic melanoma, as a 
single agent 
• BRAF V600 mutation positive unresectable or metastatic melanoma, 
as a single agent 
• Unresectable or metastatic melanoma, in combination with 
ipilimumab 
• Metastatic non-small cell lung cancer and progression on or after 
platinum-based chemotherapy 
• Advanced renal cell carcinoma who have received prior anti-
angiogenic therapy 
• Classical Hodgkin lymphoma that has relapsed or progressed after 
autologous hematopoietic stem cell transplantation and post-
transplantation brentuximab vedotin 
• Recurrent or metastatic squamous cell carcinoma of the head and 
neck with disease progression on or after a platinum-based therapy 


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It is a human monoclonal antibody that blocks the interaction between PD-
1 and its ligands, PD-L1 and PD-L2.  Nivolumab is an IgG4 kappa 
immunoglobulin that has a calculated molecular mass of 146 kDa. 
 
8.2.2 Clinical Pharmacology 
 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found 
on T cells, inhibits T-cell proliferation and cytokine production. Upregulation 
of PD-1 ligands occurs in some tumors and signaling through this pathway 
can contribute to inhibition of active T-cell immune surveillance of tumors. 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that 
binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, 
releasing PD-1 pathway-mediated inhibition of the immune response, 
including the anti-tumor immune response. In syngeneic mouse tumor 
models, blocking PD-1 activity resulted in decreased tumor growth. 
 
8.2.3 Pharmacokinetics and Drug Metabolism 
 
The pharmacokinetics (PK) of nivolumab was studied in patients over a 
dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple 
doses of nivolumab every 2 or 3 weeks. Nivolumab clearance decreases 
over time, with a mean maximal reduction (% coefficient of variation [CV%]) 
from baseline values of approximately 24.5% (47.6%) resulting in a 
geometric mean steady state clearance (CLss) (CV%) of 8.2 mL/h (53.9%); 
the decrease in CLss is not considered clinically relevant. The geometric 
mean volume of distribution at steady state (Vss) (CV%) is 6.8 L (27.3%), 
and geometric mean elimination half-life is 25 days (77.5%).  Steady-state 
concentrations of nivolumab were reached by 12 weeks when administered 
at 3 mg/kg every 2 weeks, and systemic accumulation was approximately 
3-fold. The exposure to nivolumab increased dose proportionally over the 
dose range of 0.1 to 10 mg/kg administered every 2 weeks. 
 
8.2.4 Supplier 
 
Nivolumab is commercially available and is listed in the compendia and 
NCCN Practice Guidelines as indicated for the therapy of RM-HNSCC. 
 
8.2.5 Dosage Form and Preparation 
 
Nivolumab will be provided as a 100 mg/10 mL (10 mg/mL) solution in a 
single-use vial. 
 
• Withdraw the required volume of nivolumab and transfer into an 
intravenous container. 


Protocol Version: 09/10/2019 
 
Page 30 of 50 
• Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 
5% Dextrose Injection, USP, to prepare an infusion with a final 
concentration ranging from 1 mg/mL to 10 mg/mL. 
• Mix diluted solution by gentle inversion. Do not shake. 
• Discard partially used vials or empty vials of nivolumab. 
 
8.2.6 Storage and Stability 
 
The product does not contain a preservative. 
 
After preparation, store the nivolumab infusion either: 
• at room temperature for no more than 8 hours from the time of 
preparation. This includes room temperature storage of the infusion 
in the IV container and time for administration of the infusion or 
• under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 
hours from the time of infusion preparation. 
 
Do not freeze. 
 
8.2.7 Administration 
 
Administer the infusion over 30 minutes through an intravenous line 
containing a sterile, nonpyrogenic, low protein binding in-line filter (pore size 
of 0.2 micrometer to 1.2 micrometer). 
 
Do not coadminister other drugs through the same intravenous line. 
 
Flush the intravenous line at end of infusion. 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Tumor Tissue (Phase II patients only) 
 
9.1.1 Collection of Specimens 
 
Archived tumor tissue (10 to 15 slides; preferably from the relapsed setting) 
will be collected at baseline. 
 
If the patient consents, fresh tumor tissue will be collected at baseline and 
then during Cycle 2 (between days 8-22) of abemaciclib and nivolumab. 
Tumor tissue should be preferentially collected from the primary tumor site 
or regional neck nodes if possible, but a distant metastatic deposit is an 
alternative. If possible, the same site should be biopsied at baseline and 
during cycle 2. The biopsy should consist of a minimum of 4 needle cores 
(14-18 gauge is preferred) or 2 (each 4 x 4 x4 mm) pieces of tumor. 
 


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9.1.2 Storage of Specimens 
 
Fresh tumor tissue will be transported immediately to the Puram Lab, 
Monday-Friday, 8AM-6PM.  Please notify the Puram lab, the Fehniger lab 
and Dr. Miriam Jacobs prior to submission. Sample collections that are 
outside those hours should be directly discussed with Dr. Jacobs at least 
72 hours in advance.   
 
Attention: Puram Lab / Ashley Reeb Schappe  
WU-Genetics 6th floor, Couch Research Building 
4515 McKinley Ave 
St. Louis, MO 63110  
Lab PI: (617) 721-6744 
 
For some assays, cells will be isolated and used immediately for single cell 
or single nuclei isolation and preparation, with library generation using the 
droplet-based 10X genomics platform. Tissues will be de-identified with no 
PHI included on sample vials. Single cell preparations will then undergo 
library preparation and sequencing at the McGovern Genome Institute, with 
analysis by investigators at MGI.  These single cell preparations may also 
be stored for future research as new scientific methods arise in the field. 
In other assays, samples will be isolated, cryopreserved and stored in the 
Fehniger Lab (6th floor southwest tower building) in liquid nitrogen or -70oC 
freezers for future batch analysis.  Serum cytokine measurements, NK and 
T 
cell 
function 
(degranulation, 
cytotoxicity, 
cytokine-production, 
proliferation, survival) are planned. These cryopreserved samples may also 
be stored for future research as new scientific findings arise in the field. 
 
9.1.3 Analysis of Specimens  
 
Tumor biopsies (core or excisional/incisional) will be used to perform whole 
exome sequencing (WES), RNAseq, p16INK4a expression, Ki-67 by IHC, 
total and phospho-Rb by IHC, Cyclin D1 by IHC, Cyclin E by IHC, Cyclin A 
by IHC, cdk2 by IHC, p53 by IHC, p21 by IHC, p27 by IHC, and TUNEL 
assay. Deep phenotyping of tumor immune microenvironment with mass 
spectrometry (CyTOF) and IHC to determine potential markers to predict 
response to therapy and/or resistance mechanisms. Reverse phase protein 
array (RPPA) will be performed. RPPA is a high-throughput antibody-based 
technique developed for Functional Proteomics studies to evaluate protein 
activities in signaling networks.  Additional analyses of other potential 
biomarkers may be performed as they emerge from the scientific 
understanding of abemaciclib and nivolumab activity. 
 
9.2 
Peripheral Blood (Phase II patients only) 
 
9.2.1 Collection of Specimens 


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Peripheral blood will be collected at baseline, at the end of the Lead In 
(Cycle 1 Day 1 prior to treatment),during cycle 2 (between days 8-22), and 
during cycle 3 (between days 21-28), on all patients. If patient does not have 
progression after cycle 3, patient will also have peripheral blood collected 
at time of progression. Peripheral blood will be collected by standard venous 
phlebotomy. At each timepoint mentioned above, sixty mL of anti-
coagulated blood will be collected in 3 sodium heparin green top tubes 
(45mL), one red top tube (5mL) and 1 streck (tiger top) tube (10 mL).   
 
9.2.2 Storage and Processing of Specimens 
 
Peripheral blood will be transported immediately to the Fehniger Lab, 
Monday-Friday, 8AM-6PM.  Please notify the Fehninger lab and Dr. Miriam 
Jacobs prior to submission. Sample collections that are outside those hours 
should be directly discussed with Dr. Jacobs at least 72 hours in advance.   
 
Attention: Fehniger Lab / Michelle Becker-Hapak or Tim Schappe  
WU-Oncology 7th floor, Southwest Tower Building, Room 724  
4940 Parkview Place  
St. Louis, MO 63110  
Lab: (314) 273-0156 / Secondary: (314) 747-1547 / Tertiary: (314) 747-1385 
or (314) 510-2397 (pager)  
Fax: (314) 362-9333 
 
For some assays, cells will be isolated and used immediately.  In other 
assays, samples will be isolated, cryopreserved and stored in the Fehniger 
Lab (7th floor southwest tower building) in liquid nitrogen or -70oC freezers 
for future batch analysis.  No PHI is included on the sample vials.  Serum 
cytokine measurements, NK and T cell function (degranulation, cytotoxicity, 
cytokine-production, proliferation, survival) are planned. These samples 
may also be stored for future research as new scientific findings arise in the 
field. 
 
9.3 
Quality of Life (Phase II patients only) 
 
The EORTC QLQ-30 (Appendix B) and FACT H&N (Appendix C) will be given at 
the following time-points: 
• Screening  
• Cycle 2 D1 
• Cycle 4 D1 
• End of treatment (EOT) 
 
 


Protocol Version: 09/10/2019 
 
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10.0 STUDY CALENDAR 
 
Screening evaluations and baseline procedures are to be conducted within 21 days prior 
to date of enrollment, with the exception of scans which can be within 28 days prior to 
date of enrollment.   
 
Screening 
Baseline 
 
Lead-In 
Cycle 1: 
Day 1  
 (+/- 2 days) 
Cycle 1: 
Day 15 
 (+/- 2 days) 
Cycle  2+: 
Day 1  
(+/- 2 days) 
EOT 
F/Ui 
Physical exam 
X 
 
X 
X 
X 
X 
X 
 
Vitals signs 
X 
 
X 
X 
X 
X 
X 
 
Performance status 
X 
 
X 
X 
X 
X 
X 
 
AE assessment  
X 
 
X 
X 
X 
X 
X 
 
CBC 
X 
 
X 
X 
X 
Xj 
X 
 
Chemistry panela, LFTsb 
X 
 
 
* 
X 
X 
X 
 
Pregnancy test 
X 
 
 
 
 
 
X 
 
PT/INR; PTT 
X 
 
 
 
 
 
 
 
Research blood 
 
X 
 
Xc 
 
Xc 
X 
 
QOLs 
 
X 
 
 
 
Xg 
X 
 
Archival tissue 
 
X 
 
 
 
 
 
 
Biopsy 
 
Xd 
 
 
 
Xd 
 
 
Tumor assessment 
X 
 
 
 
 
Xh 
X 
 
Abemaciclib 
 
 
Xe 
Xf 
Xf 
Xf 
 
 
Nivolumab 
 
 
 
X 
 
X 
 
 
* Screening CMP will be used for C1D1 of abemaciclib & nivolumab treatment 
a Chemistry includes Ca, Mg, K, Na, glucose, albumin, urea, and creatinine. 
b LFTs include ALT, AST, alkaline phosphatase, and total bilirubin. 
c Peripheral blood (5 tubes, see correlatives section) to be collected at baseline, Cycle 1 Day 1 prior to 
treatment, C2 D8-22, C3 D21-28, and EOT. 
d Optional. If patient consents, collect at baseline and C2 D8-22. 
e Lead In. Will be administered po on Day -7 through Day -1. 
f Will be administered po on Days 1-28  
g Cycle 2 day 1 and Cycle 4 Day 1 only. 
fhTumor assessments with CT will be performed at screening and every 12 weeks (3 cycles). All patients 
must have neck and chest CT; patients with liver metastases also require abdominal CT.  Confirmatory 
scans should also be obtained not less than 4 weeks following initial documentation of objective response.   
i Patients will be followed for 28 days post treatment for AEs and until death for OS objective. 
j CBC at Cycle 2 Day 15. 
 
 


Protocol Version: 09/10/2019 
 
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11.0 DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to 
the schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
28-day follow-up 
Tumor Measurement Form 
Baseline, end of every 4th cycle, and end of treatment 
Research Specimen Form 
Baseline, if patient consents – Cycle 2 
QOL Form 
Baseline, C2, C4 EOT 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
 
12.0 MEASUREMENT OF EFFECT 
 
12.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 
12 weeks.  In addition to a baseline scan, confirmatory scans should also be 
obtained not less than 4 weeks following initial documentation of objective 
response. 
 
Response and progression will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in Solid 
Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes 
in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
 
12.2 Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 
as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with ruler or 
calipers by clinical exam.  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 >15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 


Protocol Version: 09/10/2019 
 
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Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
 
12.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 


Protocol Version: 09/10/2019 
 
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Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm 
diameter as assessed using ruler or calipers (e.g., skin nodules).  In the case of 
skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, CT is 
preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  If 
CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in 
certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved 
in MRI, which greatly impact image quality, lesion conspicuity, and measurement.  
Furthermore, the availability of MRI is variable globally.  As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease.  Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline 
and the lesions should be measured/assessed on the same pulse sequence.  It is 
beyond the scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases.  Ideally, the same 
type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT performed 
as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET 
portion of the CT introduces additional data which may bias an investigator if it is 
not routinely or serially performed.   
 
Cytology, Histology:  These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 


Protocol Version: 09/10/2019 
 
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lesions in tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
 
12.4 Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new 
lesions is also considered progressions).  Please note that disease 
progression will be determined using CT imaging and not PET imaging.  
That is, if a CT scan shows progression by RECIST criteria, the patient will 
be determined to have progressed regardless of the results of the PET 
scan; however, if a PET scan shows disease progression while a CT scan 
does not, the patient’s disease will be determined to have progressed only 
if there are physical examinations signs or symptoms that are consisted with 
disease progression as judged by the treating physician and principal 
investigator. 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 


Protocol Version: 09/10/2019 
 
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maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion 
increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and 
the progression status should be confirmed at a later time by the review 
panel (or Principal Investigator). 
 
12.4.3 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. 
    
   For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
                        
 


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
12.4.4 Definition of Modified Partial Response 
 
In the phase I trial of pazopanib and cetuximab, 39% of patients developed 
cavitation of target and non-target lesions while on therapy. In these cases, 
FDG-PET/CT showed findings consistent with mPR or mCR by PERCIST50. 
Cavitation only occurred in pulmonary sites of disease. The cavitating 
lesions usually did not decrease in dimensions but clearly decreased in 
tumor volume. Although these cases were scored as stable disease by 
RECIST, they correlated with prolonged PFS as did cases of PRs by 
RECIST.  
 
As such, patients on this trial who develop cavitation of pulmonary 
metastases without decrease in measurement will be scored as modified 
PR and summed with other cases of PRs by RECIST as long as no new 
target or non-target lesions appear and as long as the cavitating lesion does 
not enlarge by > 20%. A confirmatory tumor response assessment will be 
required, as noted earlier for PR by RECIST.  
 
12.4.5 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 progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the treatment started, including 
the baseline measurements.  
 
 


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13.0 DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring 
Plan, the Principal Investigator will provide a Data and Safety Monitoring (DSM) report to 
the Washington University Quality Assurance and Safety Monitoring Committee 
(QASMC) semi-annually beginning six months after accrual has opened (if at least five 
patients have been enrolled) or one year after accrual has opened (if fewer than five 
patients have been enrolled at the six-month mark). 
 
During phase I, the Principal Investigator will review all patient data at least monthly (or 
before each dose de-escalation if occurring sooner than monthly), and provide a semi-
annual report to the Quality Assurance and Safety Monitoring Committee (QASMC).  
During phase II, the Principal Investigator will review all patient data at least every six 
months, and provide a semi-annual report to the QASMC. This report will include: 
 
• HRPO protocol number, protocol title, Principal Investigator name, data 
coordinator name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO 
approval/revision, date of HRPO expiration, date of most recent QA audit, study 
status, and phase of study 
• History of study including summary of substantive amendments; summary of 
accrual suspensions including start/stop dates and reason; and summary of 
protocol exceptions, error, or breach of confidentiality including start/stop dates 
and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who 
have met the early stopping rules 
• Summary of toxicities separated by cohorts with the number of dose-limiting 
toxicities indicated 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient 
Coordinator becomes aware of an adverse event, the AE will be reported to the HRPO 
and QASMC according to institutional guidelines. 
 
 
14.0 STATISTICAL CONSIDERATIONS 
 


Protocol Version: 09/10/2019 
 
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14.1 Study Design 
 
This is an open-label, single center, one arm, Phase I/II study.  The aim is to 
investigate the safety and efficacy of combining abemaciclib + nivolumab in 
patients with RM-HNSCC. In Phase I, a dose de-escalation design will be applied. 
In Phase 2, the one-year OS of the study group will be compared to a known 
historical control (i.e., null hypothesis).  
 
14.2 Study Endpoints 
 
Primary endpoints are (a) Phase I: safety as measured by establishment of DLT, 
MTD and RP2D and (b) Phase II: OS. Secondary endpoints include best tumor 
response, duration of tumor response, AEs, and PFS.  The exploratory endpoint 
includes QOL scores.  
 
14.3 Study Population 
 
Patients with RM-HNSCC will be enrolled and will receive abemaciclib + 
nivolumab. The Phase I trial will enroll up to 9 patients. For the Phase II trial, a total 
of 23 patients with be enrolled.  
 
14.4 Accrual 
 
Based on historical experience at this institution, we expect to accrue 4 patients 
per month to phase I and 1-2 patients per month to phase II, completing accrual to 
phase I in 3 months, and completing accrual to phase II in 18 months.  
 
14.5 Power Analysis 
 
Power analysis is not applicable for the Phase I trial.  
 
Phase II: The primary endpoint is OS and the secondary endpoints include best 
tumor response rate, duration of tumor response, AEs, PFS and QOL scores. The 
sample size calculation is based on the primary endpoint only. Prior data suggests 
one-year survival probability for the patients treated with nivolumab is 36%2. With 
an accrual interval of 18 months and additional follow-up of 18 months after the 
accrual interval, 18 patients will have 80% power to detect the survival difference 
if one-year survival probability for the patients treated with abemaciclib plus 
nivolumab is 60% using a one-sided test at the type I error of 5%13. An additional 
5 patients will be accrued for a total of 23 patients to address patients who enroll 
but either do not proceed on study, complete less than one cycle of therapy due to 
causes other than disease progression or adverse events, or are lost to follow-up.  
 
14.6 Data Analysis 
 


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All data will be evaluated as observed, and no imputation method for missing 
values will be used.  
 
Descriptive statistics will be used to summarize the trial results, i.e., statistics for 
continuous variables may include means, medians, ranges and appropriate 
measures of variability. Qualitative variables will be summarized by counts and 
percentages. The uncertainty of estimates will be assessed by confidence intervals 
(CIs).  
 
OS is defined as the time from the date of treatment to the date of death, censored 
at the last follow-up otherwise. PFS is defined as the time from treatment to the 
date of progression or death, whichever occurs first. The alive patients without 
progression is censored at the last follow-up. The Kaplan-Meier method will be 
used to calculate the probability of OS and PFS at specific time points, e.g. one-
year. Best rumor response rate and associated 95% confidence intervals will be 
calculated assuming a binomial distribution. Duration of response will be 
summarized by dose using the minimum, 25th percentile, median, 75th percentile, 
and maximum values. AEs and SAEs occurring during each cycle will be 
summarized by patient, dose, type and grade with 95% CIs. Frequencies for the 
full treatment period will be summarized in the same manner. Descriptive statistics 
will be used to report tissue and blood specimens. In phase II, the QOL 
assessment tools (EORTC QLQ-C30 and FACT-H&N) will be performed at 
baseline and after cycle 3 of therapy. Scoring of each tool will be performed using 
the published guidelines established for each tool. Median scores for each item 
and domain will be reported at each time point. Reporting will be descriptive and 
will not test a specific QOL hypothesis.   
 
14.7 Stopping Rules (Phase I) 
 
For Phase I, using the dose de-escalation design, three patients will be initially 
enrolled into the highest dose cohort (i.e., abemaciclib starting dose). If there are 
no patients or only one patient experiencing DLTs, the RDP2 is established and 
enrollment to phase I stops. If two or more patients experience DLTs, de-escalation 
to the next lower dose level will occur. Phase I will be halted if two or more patients 
experience DLTs at the lowest dose level. Twelve is the maximum number of 
patients that could be enrolled in Phase I.  
 
 
 


Protocol Version: 09/10/2019 
 
Page 43 of 50 
15.0 REFERENCES 
 
1. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus 
Cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116-27. 
2. Ferris RL, Blumenschein Jr. G, Fayette J, et al. Nivolumab for recurrent 
squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375:1856-
67. 
3. Network CGA. Comprehensive genomic characterization of head and neck 
squamous cell carcinomas. Nature. 2015;517(7536):576-582. 
4. Michel L, Ley J, Wildes TM, et al. Phase I trial of Palbociclib, a selective cyclin 
dependent kKinase 4/6 inhibitor, in combination with Cetuximab in patients with 
recurrent/metastatic head and neck squamous cell carcinoma. Oral Oncol. 
2016;58:41-8. 
5. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH1: Results from a phase II 
study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients 
with HR+/HER2- breast cancer, after chemotherapy for advanced disease. J Clin 
Oncol. 2016;34:supplement abstract 510. 
6. Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of abemaciclib, an 
inhibitor of CDK4 and CDK6, for patients with breast cancer, non–small cell lung 
cancer, and other solid tumors. Cancer Discov. 2016;6:740-53. 
7. Gelbert LM, Cai S, Lin X, et al. Preclinical characterization of the CDK4/6 
inhibitor LY2835219: In-vivo cell cycle-dependent/independent anti-tumor 
activities alone/in combination with gemcitabine. Invest New Drugs. 2014;32:825-
37. 
8. Lallena MJ, Boehnke K, Torres R, et al. In-vitro characterization of abemaciclib 
pharmacology in ER+ breast cancer cell lines. Cancer Res. 2015;75:suppl 
abstract nr3101. 
9. Pfizer: Ibrance package insert. 
http://labeling.pfizer.com/ShowLabeling.aspx?id=2191 
10. Novartis Pharmaceuticals: Kisquali package insert. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209092s000lbl.pdf 
11. Sledge Jr. GW, Toi M, Neven P, Sohn J, et al. MONARCH2: Abemaciclib in 
combination with fulvestrant in women with HR+/HER2- Advanced breast cancer 
who had progressed while receiving endocrine therapy. J Clin Oncol. 
2017;35(25):2875-84. 
12. Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 inhibition triggers anti-tumor 
immunity. Nature. 2017;548(7668):471-5. 
13. Lawless, JF. Statistical Models and Methods for Lifetime Data. 2nd ed. John Wiley 
& Sons, 2003. 
 
 
 
 
 
 


Protocol Version: 09/10/2019 
 
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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-
care, but unable to carry out any work activities.  Up and about 
more than 50% of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


Protocol Version: 09/10/2019 
 
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APPENDIX B: EORTC QLQ-C30 
 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" 
answers. The information that you provide will remain strictly confidential. 
 
 
Not 
at 
All 
A 
Little 
Quite a 
bit 
Very 
Much 
1. Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
4. Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not 
at 
All 
A 
Little 
Quite a 
Bit 
Very 
Much 
6. Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
7. Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. Were you short of breath? 
1 
2 
3 
4 
9. Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
During the past week: 
Not 
at 
All 
A 
Little 
Quite a 
Bit 
Very 
Much 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 


Protocol Version: 09/10/2019 
 
Page 46 of 50 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
For the following questions please circle the number between 1 and 7 that 
best applies to you 
29. How would you rate your overall health during the past week? 
1 
2 
3 
4 
5 
6 
7 
Very Poor 
 
 
 
 
 
Excellent 
30. How would you rate your overall quality of life during the past week? 
1 
2 
3 
4 
5 
6 
7 
Very Poor 
 
 
 
 
 
Excellent 
 
 
 


Protocol Version: 09/10/2019 
 
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APPENDIX C: FACT-H&N 
 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 7 days. 
Not 
PHYSICAL WELL-BEING 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of energy ....................................................... 
0 
1 
2 
3 
4 
GP2 
I have nausea ...................................................................... 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family ......................................... 
0 
1 
2 
3 
4 
GP4 
I have pain .......................................................................... 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment ......................... 
0 
1 
2 
3 
4 
GP6 
I feel ill ............................................................................... 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ........................................ 
0 
1 
2 
3 
4 
SOCIAL/FAMILY WELL-BEING 
Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
GS1 
I feel close to my friends .................................................... 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................ 
0 
1 
2 
3 
4 
GS3 
I get support from my friends............................................. 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness .................................... 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness.................................................................................. 
0 
1 
2 
3 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) .............................................................................. 
0 
1 
2 
3 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box 
and go to the next section. 
GS7 
I am satisfied with my sex life ............................................ 
0 
1 
2 
3 
4 
 


Protocol Version: 09/10/2019 
 
Page 48 of 50 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days  
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
GE1 
I feel sad ............................................................................. 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness......... 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness................. 
0 
1 
2 
3 
4 
GE4 
I feel nervous ...................................................................... 
0 
1 
2 
3 
4 
GE5 
I worry about dying ............................................................ 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ........................... 
0 
1 
2 
3 
4 
 
FUNCTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
GF1 
I am able to work (include work at home) ......................... 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling.................... 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life......................................................... 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness.................................................. 
0 
1 
2 
3 
4 
GF5 
I am sleeping well .............................................................. 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ..................... 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now............. 
0 
1 
2 
3 
4 
 
 
 


Protocol Version: 09/10/2019 
 
Page 49 of 50 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
ADDITIONAL CONCERNS 
Not at 
all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
H&N1 
I am able to eat the foods that I like ................................... 
0 
1 
2 
3 
4 
H&N2 
My mouth is dry ................................................................. 
0 
1 
2 
3 
4 
H&N3 
I have trouble breathing ..................................................... 
0 
1 
2 
3 
4 
H&N4 
My voice has its usual quality and strength ....................... 
0 
1 
2 
3 
4 
H&N5 
I am able to eat as much food as I want ............................. 
0 
1 
2 
3 
4 
H&N6 
I am unhappy with how my face and neck look................. 
0 
1 
2 
3 
4 
H&N7 
I can swallow naturally and easily ..................................... 
0 
1 
2 
3 
4 
H&N8 
I smoke cigarettes or other tobacco products ..................... 
0 
1 
2 
3 
4 
H&N9 
I drink alcohol (e.g. beer, wine, etc.).................................. 
0 
1 
2 
3 
4 
H&N 
10 
I am able to communicate with others ............................... 
0 
1 
2 
3 
4 
H&N 
11 
I can eat solid foods............................................................ 
0 
1 
2 
3 
4 
H&N 
12 
I have pain in my mouth, throat or neck ............................ 
0 
1 
2 
3 
4 
 
 
 


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APPENDIX D: Medication Diary (for Lead In week, block out Days 8-28) 
 
Today’s Date:    
 
 
Agent:  abemaciclib 
Cycle:    
 
Study ID#:   
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take _____mg of abemaciclib at approximately the same times each day 
with or without food. Swallow the capsules whole and do not chew them. 
2. Record the date, the number of capsules taken, and when you took them. 
3. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit. 
4. Please return the forms to your physician or your study coordinator when you go to your next appointment.  
Please bring your unused study medications and/or empty bottles with you to each clinic visit so that a pill count 
can be done. 
5. Avoid St. John’s Wort, Seville oranges, grapefruit, grapefruit juice, grapefruit hybrids, pummelos, and exotic 
citrus fruits from 7 days before you start taking abemaciclib and throughout the entire study.   
Day 
Date 
What time was dose 
taken? 
# of capsules taken, if 
applicable 
Comments 
AM dose 
PM dose 
AM dose 
PM dose 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28