Conditions: Sarcoma Liposarcoma
Keywords: soft tissue Palbociclib (PD0332991) 10-094
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 90
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out what effects, good and/or bad, Palbociclib (Ibrance) (formerly known as PD0332991) has on the patient and on the liposarcoma.

Palbociclib is an investigational drug. An investigational drug is a medication that has not been approved for marketing by the Food and Drug Administration (FDA). Palbociclib blocks a protein called CDK4 which is part of a pathway in liposarcoma cells that is over-active. The investigators hope that blocking CDK4 will shut down this pathway in the liposarcoma cells and stop tumors from growing. Palbociclib is an oral medication.

Detailed description:

Arms:
arm 1: This is a phase II study of Palbociclib in patients with advanced / metastatic liposarcoma. A one-stage design is used to determine whether patients treated with Palbociclib achieved a PFS rate of ≥ 40% at 12 weeks. arm 2: This is a phase II study of Palbociclib in patients with advanced / metastatic liposarcoma. A one-stage design is used to determine whether patients treated with Palbociclib achieved a PFS rate of ≥ 40% at 12 weeks.

Interventions: intervention 1: Palbociclib 200mg intervention 2: Palbociclib 125mg
Intervention descriptions: intervention 1: Schedule 2/1: Palbociclib 200mg given once daily by mouth for 14 consecutive days, followed by 7 days of rest. A cycle will be defined as 21 days. intervention 2: Schedule 3/1: Palbociclib 125mg given once daily by mouth for 21 consecutive days, followed by 7 days of rest. A cycle will be defined as 28 days. Following the positive results of the study, a new Expansion Cohort has been added to permit enrollment of up to 20 additional patients.

Expansion Cohort: Dosed as per Schedule 3/1. Capsules should be taken with food.

Protocol document:
Prot_SAP_000.pdf: 
 
 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-094 A(18) 
 
 
A Phase II Study Of PD0332991 (Palbociclib) in Patients with Advanced or Metastatic 
Liposarcoma 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Mark A. Dickson, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
William Tap, MD 
Medicine 
Investigator(s)/Department: 
Mrinal M. Gounder, MD 
Mary Louise Keohan, MD 
Sandra D’Angelo, MD 
Ping Chi, MD, PhD 
Cristina Antonescu, MD 
Jonathan Landa, DO 
Li-Xuan Qin, PhD 
Medicine 
Medicine 
Medicine 
Medicine 
Pathology 
Radiology 
Biostatistics 
Consenting Professional(s)/Department: 
Mark A. Dickson, MD 
Mrinal M. Gounder, MD 
Mary Louise Keohan, MD 
William Tap, MD 
Sandra D’Angelo, MD 
Ping Chi, MD, PhD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amended: 13-OCT-2015 
 
 
 
Page 1 of 41 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
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20.0 APPENDICES ...................................................................................................................... 36 
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Page 2 of 41 
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 3 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 3 
 
2.1 Primary Objectives................................................................................................................... 3 
2.2 Secondary Objectives .............................................................................................................. 3 
3.0 
BACKGROUND AND RATIONALE ....................................................................................... 4 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION................................................................ 8 
 
4.1 
Design................................................................................................................................. 8 
4.2 
Intervention ......................................................................................................................... 9 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................... 9 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................. 10 
 
6.1 
Subject Inclusion Criteria................................................................................................... 10 
6.2 
Subject Exclusion Criteria ................................................................................................. 11 
7.0 
RECRUITMENT PLAN ......................................................................................................... 12 
 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 12 
 
9.0 
TREATMENT/INTERVENTION PLAN.................................................................................. 13 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 13 
 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................... 19 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 21 
 
12.2 Parameters of Response – RECIST (version 1.1) ............................................................. 21 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 26 
 
14.0 BIOSTATISTICS .................................................................................................................. 26 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES... 27 
 
15.1 Research Participant Registration ..................................................................................... 27 
15.2 Randomization .................................................................................................................. 28 
16.0 DATA MANAGEMENT ISSUES ........................................................................................... 28 
 
16.1 Quality Assurance ............................................................................................................. 28 
16.2 Data and Safety Monitoring ............................................................................................... 28 
17.0 PROTECTION OF HUMAN SUBJECTS .............................................................................. 29 
 
17.1 Privacy .............................................................................................................................. 29 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................... 29 
17.2.1 ....................................................................................................................................... 30 
 
18.0 INFORMED CONSENT PROCEDURES .............................................................................. 35 
 
19.0 REFERENCES ..................................................................................................................... 35 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
A phase II study of Palbociclib in patients with advanced or metastatic liposarcoma 
 
This is a phase II study of Palbociclib in patients with advanced / metastatic liposarcoma. 
The primary endpoint is the progression-free survival rate at 12 weeks.  Eligible patients 
must have Rb gene expression by IHC and CDK4 amplification by FISH. 
 
Patients will receive  one of two dose schedules: 
 
Schedule 2/1: Palbociclib 200mg given once daily by mouth for 14 consecutive days, 
followed by 7 days of rest.  A cycle will be defined as 21 days. 
 
Schedule 3/1:  Palbociclib 125mg given once daily by mouth for 21 consecutive days, 
followed by 7 days of rest.  A cycle will be defined as 28 days. 
 
Re-staging scans will be performed every 6 weeks.  Patients continue on study until 
unacceptable toxicity or disease progression by RECIST. 
 
Following the positive results of the study, a new Expansion Cohort has been added to 
permit enrollment of up to 20 additional patients. Patients enrolled to this cohort do not 
require prior treatment with other systemic therapy and do not require Rb expression and 
CDK4 amplification to be eligible. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 Primary Objectives 
The primary endpoint of this study is to determine the proportion of patients with 
advanced/metastatic liposarcoma who are progression-free at 12 weeks (PFS, defined as 
RECIST 1.1 CR + PR + SD) when treated with Palbociclib 
 
2.2 Secondary Objectives 
Secondary endpoints include determination of: 
(1) Overall response rate (defined as CR + PR) 
(2) Overall survival 
(3) Clinical benefit rate (CR + PR + SD) 


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3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Targeting CDK4 in Liposarcoma 
 
Sarcomas are malignant tumors of mesenchymal origin.  Approximately 13,000 cases of soft tissue 
and bone are diagnosed annually in the US.  Liposarcoma, a tumor originating from adipocytes, 
accounts for more than 20% of soft-tissue sarcoma in adults.  Liposarcoma may occur anywhere in 
the body, but the retroperitoneum and the thigh are the most common sites.  Surgery, often with 
adjuvant radiation therapy for larger tumors, is the mainstay of treatment. Despite primary combined 
modality therapy, between 30-80% of patients develop recurrent and/or metastatic disease. 
 
The standard of care for metastatic disease for many years has been doxorubicin or a doxorubicin 
combination.  Response rates, however, are low.  A recent phase III trial by the EORTC compared 
doxorubicin to two schedule of ifosfamide in 1st line treatment of metastatic soft tissue sarcomas. 
This 450-patient trial demonstrated a response rate of just 12% for doxorubicin and 8% for 
ifosfamide (Lorigan et al., JCO 2007).  Another chemotherapy option for metastatic disease is 
gemcitabine with docetaxel (Maki et al., JCO 2007). This combination shows some activity in other 
sarcoma subtypes such as malignant fibrous histiocytoma and leiomyosarcoma, but very few 
patients with liposarcoma respond.  Recent phase II studies of the targeted agents imatinib, 
sunitinib, and sorafenib have shown no responses in liposarcoma. Thus, there is a dearth of active 
agents for liposarcoma and an unmet medical need. 
 
Palbociclib is an inhibitor of CDK4, a target that is important in the development of well- 
differentiated and de-differentiated liposarcomas.  CDK4 is amplified in 90% of liposarcomas 
(Sirvent et al., Am J Surg Pathol 2007). Our published gene array data indicates that liposarcomas 
exhibit an 11.6-fold increase in expression of CDK4 when compared to normal fat (Singer et al., 
Cancer Research 2007).  This makes it one of the highest expressed genes in this tumor type.   In 
liposarcoma cell lines with amplified CDK4 we have shown that shRNAs induce significant 
apoptosis, suggesting an “oncogenic” addition to this pathway (manuscript in preparation). We have 
also observed clinical benefit and minor radiological responses in patients with liposarcoma treated 
on the phase I study of Palbociclib .  In particular, we have two patients with metastatic liposarcoma 
who have had stable disease for 3.1 years (225 mg daily) and 2.3 years (200 mg daily).  Notably, the 
first patient had previously had progression of disease on single agent sorafenib before starting this 
clinical trial. 
 
Thus the current study is a phase II trial of Palbociclib in patients with liposarcoma.  Patients will be 
followed for time to progression, with the primary endpoint the proportion of patients progression- 
free at 12 weeks.  All patients must have CDK4 amplification by fluorescence in situ hybridization 
(FISH) on pre-treatment archival tumor tissue.  Since intact Rb is required for CDK4 inhibition to be 
effective, the presence of detectable Rb protein by IHC is also a requirement for study entry.  Prior 
series have shown that the majority of liposarcomas express Rb (eg. 83% in Karpeh et al., Br J 
Cancer 1995). 


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Patients will be treated at the MTD determined by the Phase I study of Palbociclib (O’Dwyer, 2007). 
Of note, clinical activity was also seen in Rb-expressing germ cell tumors in this study (Vaughn et al, 
NEJM 2009).  Of patients with growing teratoma syndrome, two had prolonged stable disease and 
one had a partial response. 
 
 
3.2 
Preclinical data on PD 0332991 
 
 
Palbociclib is an orally administered potent and highly selective reversible inhibitor of Cdk4/6. 
The compound prevents cellular DNA synthesis by prohibiting progression of the cell cycle from 
G1 into the S phase, as demonstrated in laboratory models. Palbociclib preclinical data indicate 
that it may be expected to have direct cytotoxic activity as well as potential for growth arrest. 
Arrest in the G1 phase is known to cause cell death in some tumor types, as demonstrated by this 
and other G1 arresting agents (eg, Tamoxifen). Moreover, CDK inhibitors like Palbociclib have 
the potential to enhance the effects of conventional therapies. 
 
 
Treatment of cultured tumor cells with Palbociclib causes growth arrest that is accompanied by 
the conversion of phosphorylated Rb to its hypophosphorylated form. Residues serine-780 and 
-795 of Rb are specifically phosphorylated by Cdk4/6. Consequently, the phosphorylation status 
of these sites serves as specific biomarkers of Cdk4/6 inhibition byPalbociclib . The IC50 
values for reduction of Rb phosphorylation at serine-780 and -795 in MDA-MB-435 breast 
FDUFLQRPD FHOOV ZHUH 0.066 DQG 0.063 ȝ0. UHVSHF WLYH Oy. Similar effects on serine-780 and -795 
phosphorylation were obtained in Colo-205 colon carcinoma cells. The IC50 values for reduction 
of Rb phosphorylation are similar to the IC50 values of inhibition of thymidine incorporation 
across a range of cultured tumor and normal cells. 
 
In MDA-MB-453 breast carcinoma cells exposed for 24 hours to varying concentrations of 
Palbociclib , the percentage of cells in G1 began to increase in the presence of as little as 
0.04 ȝ0 Palbociclib with a concomitant decrease in other phases of the cell cycle. Maximum 
HIIHF WV ZHUH D WWDLQHG D W 0.08 ȝ0. 
 
 
These data indicate that the 3 biological parameters that are expected for a CDK4/6 inhibitor, 
growth inhibition, Rb-dephosphorylation, and G1 arrest, all occur in drug-treated cells at 
comparable concentrations of Palbociclib . This correlation suggests that these biochemical 
readouts are related and a result of the same mechanism of action (ie, specific inhibition of 
CDK 4/6). 
 
Time-course experiments indicate that the reduction of Rb phosphorylation begins to occur as 
quickly as 4 hours after exposure to Palbociclib and reaches a maximum at 16 hours with 
continued exposure. The inhibition is completely reversible. After removal of the drug, 
phosphorylation on serine-780 and -795 begins to return in 2 hours and is complete within 
16 hours. Active cellular proliferation returns concurrently with Rb phosphorylation. While this 
suggests that Palbociclib will be most efficacious using continuous daily dosing, intermittent 
dosing using a variety of schedules has proven as efficacious as continuous daily dosing in 
animal xenograft models. Tumor regrowth is observed following discontinuation of therapy. 


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This provides the basis for chronic intermittent dosing, which allows the integration of other 
agents as well as a period for recovery from anticipated toxicities, eg, myelosuppression. 
To determine whether tumors that regressed following discontinuation of Palbociclib remained 
sensitive to further Palbociclib  treatment or whether they had acquired resistance, Colo-205 
colon tumors that regressed post Palbociclib treatment were harvested and reimplanted into 
naïve mice. Following Palbociclib treatment at a dose and schedule identical to the original 
experiment, the tumors responded with equal sensitivity to the drug and fully regressed, 
indicating that no resistance had developed during the initial treatment. 
 
Palbociclib exhibits significant antitumor efficacy, including tumor regressions, against multiple 
human tumor xenograft models in nude mice. In the MDA-MB-435 breast carcinoma PRG H O. WKH 
2 GRVH OHYHOV WKDW UHVXOWHG LQ •s0% WXPR U JURZ WK LQKLEL WLRQ VXSSUHVVHG phosphorylation on 
serine-780 over the full 24-hour prior between doses. At 2 lower doses, ZKLFK GLG  QRW SURGXFH 
•s0% WXPR U JURZ WK inhibition, phosphorylation returned over the 24-hour prior before the next 
dose. Similar experiments with the highly sensitive Colo-205 colon carcinoma model show that 
complete suppression of phosphorylation on serine-780 is not necessary to produce growth 
inhibition. However, complete suppression of phosphorylation between doses is necessary for 
tumor regression. 
To ensure that Palbociclib acts exclusively by inhibition of Rb phosphorylation, Palbociclib was 
tested on Rb-negative tumor cells, the MDA-MB-468 human breast carcinoma and the H2009 
human NSCLC, both of which have deleted Rb. Palbociclib had no antiproliferative DFWLYL W\ RQ 
WKHVH FHOOV  D W WKH KLJKHVW FRQ FH Q W UD WLRQ WHVWHG (3 ȝ0). ZKLFK LV 1 WR 2 RUGH UV RI magnitude 
higher than the concentration necessary to inhibit Rb-positive tumor cells. Further evidence that 
the antitumor activity observed for Rb-positive tumors is due to inhibition of Cdk4/6 was 
obtained by testing Palbociclib in Rb-negative human tumor xenograft models, the MDA-MB-
468 human breast carcinoma and the DU-145 human prostate tumor. Neither tumor responded 
to Palbociclib . 
 
These findings indicate that Palbociclib is not expected to have an antitumor effect in tumors 
that do not express Rb, and that only patients with tumor types that express Rb should be 
included in a clinical trial of Palbociclib . 
 
3.3 
Preclinical Toxicity Data 
Palbociclib has been examined in various genetic toxicology and safety pharmacology 
(cardiovascular, neurofunctional, and pulmonary) studies. General toxicology (acute, escalating 
dose, and 2-week dose range-finding) studies were conducted in rats and dogs. Pivotal 
toxicology studies were conducted in both species with Palbociclib administered once daily 
(QD) by gavage for 3 weeks followed by a 1-month reversal period. 
 
The primary Palbociclib toxicities in preclinical studies are to the bone marrow, lymphoid tissues, 
and testes. These toxicities occurred in both rats and dogs, and are consistent with cell cycle 
inhibition induced by the intended pharmacology of the drug. Bone marrow suppression resulted 
in decreases in various hematology parameters; however, the changes were reversible following 
cessation of dosing. Reversible myelosuppression is anticipated to be dose limiting in man. 
Palbociclib demonstrated a potential for clastogenicity in the in vitro and in vivo 


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micronucleus assays. 
 
 
Acute intravenous administration of Palbociclib to dogs anesthetized with propofol (a CNS 
depressant with known respiratory depressant effects) resulted in significant pulmonary effects, 
including apnea, which were reversible. The effects were transient, appeared related to peak 
plasma concentrations, and were consistent with centrally-mediated respiratory depression. No 
changes in pulmonary function occurred in dogs following oral administration of drug. 
Pulmonary changes were also observed in rats administered Palbociclib orally. The clinical 
relevance of these effects, which included rales, dyspnea, and atrophy of tracheal epithelium, is 
unknown. 
Results of the Purkinje fiber and HERG in vitro assays, and cardiovascular study in dogs have 
indicated a potential for prolongation of the QT interval. 
 
3.4 
Clinical toxicity data 
A first-in-patient, phase 1, dose-finding study of Palbociclib was conducted in patients with Rb- 
positive solid tumors or non-Hodgkin’s lymphoma (NHL). The primary objective of this trial was to 
establish the safety profile of Palbociclib and to identify the recommended phase 2 dose of two 
different treatment schedules.  The 3/1 schedule consisted of daily dosing for 21 days followed by 7 
days off. The 2/1 schedule consisted of daily dosing for 14 days followed by 7 days off treatment. 
 
A total of 74 patients were enrolled in the study at three sites in the United States and received at 
least one dose of Palbociclib. The median patient age was 58 years (range 22–78), and the most 
common primary tumor types were melanoma (n=10; 14%), liposarcoma (n=10; 14%) and colon 
(n=9; 12%). All but one patient (n=73; 99%) had received any prior therapy, including surgery (n=66; 
90%), chemotherapy (n=61; 84%). 
 
In total, 41 patients received Palbociclib on the 3/1 schedule in six different cohorts, with doses 
ranging from 25 mg QD to 150 mg QD. An additional 33 patients received treatment on the 2/1 
schedule in four different cohorts, with doses ranging from 100 mg QD to 225 mg QD. 
 
The MTD for the 3/1 schedule was identified as 125 mg QD and the MTD for the 2/1 schedule was 
200 mg QD. The MTD was expanded to 22 patients in the 3/1 schedule and 20 patients in the 2/1 
schedule 
 
Myelosuppression was the primary DLT associated with Palbociclib administration. The frequency 
and severity of myelosuppression for patients treated on both schedules is described in the table 
below. 
 
Hematologic 
abnormalities, 
n (%)* 
Palbociclib 
Schedule 3/1 (n=41)  
 Schedule 2/1 (n=33) Grade 1/2
 
Grade 3/4 
Grade 1/2 
Grade 3/4 
 
Hemoglobin 
22 (55) 
 3 (8) 
21 (64) 
  1 (3) 
Lymphocytes 
14 (36) 
14 (36) 
 8 (24) 
12 (36) 
Neutrophils 
21 (54) 
 8 (21) 
14 (42) 
 8 (24) 


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Platelets 
18 (45) 
0 
19 (58) 
3 (9) 
Leukocytes 
27 (68) 
9 (23) 
22 (67) 
7 (21) 
 
 
The most common treatment-related non-hematologic AEs were fatigue, nausea and diarrhea. 
Overall, the majority of AEs were mild to moderate in severity (grades 1/2). Nausea was the only 
grade 3, treatment-related, non-hematologic AE reported on schedule 3/1 (1/41; 2%). Non- 
hematologic grade 3 events on schedule 2/1 comprised nausea (n=1/33, 3%), vomiting (n=1/33, 
3%), hyperglycemia (n=1/33, 3%) and hyponatremia (n=1/33, 3%). No clinically significant ECG 
changes were observed, and there was no correlation between QTc interval and Palbociclib dose or 
plasma concentration. 
 
The 2/1 schedule was selected for this phase II trial based on the observed clinical benefit in 
patients with liposarcoma treated on that schedule (see section 3.1 above). 
 
Preliminary results of the first 20 patients treated on this protocol show that 13 reached 12 weeks 
without evidence of progression. Thus, the trial met its primary endpoint with an estimated 12-week 
PFS of 65%, exceeding the 40% required for a positive study.  As expected, myelosuppression was 
the principal toxicity.  Of the first 27 patients evaluable for toxicity, the rates of grade 3-4 toxicity 
were 37% for neutropenia, 15% for anemia, and 33% for thrombocytopenia. 
 
Based on these results, the trial will be expanded to test the 3/1 schedule in patients with 
liposarcoma.  Understanding if there is comparable efficacy will enable the prioritization of which 
dose/schedule to initially move forward in this indication. 
 
3.5 
Pharmacokinetics 
 
 
Following repeated daily dosing to steady-state Palbociclib was absorbed with a median Tmax of 
~4 hours. The mean PD 0332991 Vz/F was 3103 L, which is significantly greater than total body 
water (42 L), indicating that Palbociclib extensively penetrates into peripheral tissues. Palbociclib 
was eliminated slowly; the mean t½ was 26.5 hours and the mean CL/F was 86.1 L/hour. Palbociclib 
accumulated following repeated dosing with a median Rac of 2.4, which is consistent with a half-life 
of ~27 hours. 
 
The major clearance mechanism for Palbociclib is oxidative metabolism catalyzed by CYP3A 
enzymes.  Renal excretion was < 1% of unchanged drug and thus appears to be a minor route of 
elimination. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is a phase II study of Palbociclib in patients with advanced / metastatic liposarcoma. 
The primary endpoint will be the progression-free survival rate at 12 weeks.  Eligible patients 
must have Rb gene expression by IHC and CDK4 amplification by FISH (except for patients 
treated in the Expansion Cohort).  A one-stage design is used to determine whether patients 
treated with Palbociclib DFKLHYHG D 3)6 UDWH RI • 40% at 12 weeks. 


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4.2 
Intervention 
 
Patients will receive Palbociclib at one of two doses and schedules: 
Schedule 2/1:  200 mg PO daily x 14 days, every 21 days 
Schedule 3/1:  125 mg PO daily x 21 days, every 28 days 
Expansion Cohort:  Dosed as per Schedule 3/1 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Palbociclib (Ibrance) will be supplied commercially by Pfizer, the study sponsor. 
 
 
5.1 
Formulation and Packaging 
 
 
Palbociclib is formulated in free-based capsules. These capsules come in three strengths and sizes, 
and all strengths come in 23 count bottles. The sizes and strengths are listed below: 
 
125mg. 0 size capsules – Caramel 
100mg. 1 size capsules – Yellow/Caramel 
75mg.  2 size capsules – Yellow 
 
 
Palbociclib may be stored at room temperature and must be protected from light. 
 
 
5.2 
Preparation and Dispensing 
 
 
Palbociclib is a cytotoxic agent that must be handled and administered with care. Inhalation of drug 
powder or drug contact with skin and mucous membranes, especially those of the eyes, must be 
avoided. Should accidental eye contact occur, copious irrigation with water should be instituted 
immediately followed by prompt ophthalmologic consultation. Should accidental skin contact occur, 
the exposed area should be irrigated immediately with copious amounts of water for at least 15 
minutes. As with other cytotoxic antineoplastic agents, appropriate precautions should be followed in 
accordance with local guidelines. 
 
5.3 
Administration 
 
 
Oral Palbociclib is administered once daily. On clinic visit days, the patient should wait to take that 
day’s dose until continued treatment on the protocol is approved by the physician.  Capsules must 
be swallowed intact. Due to the lack of stability data and possible hazards associated with topical 
and environmental exposure to cytotoxic agents, capsules must not be opened and emptied into any 
vehicle for oral ingestion. Capsules should be taken with food. The absorption and exposure of 
Palbociclib was very low in approximately 13% of the population under the fasted condition with 
administration of the free base capsule formulation.  Patients should be encouraged to take their 
dose at approximately the same time each day. However, a variance of up to 12 hours either way is 


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allowed for any given dose, rather than miss a day’s dose. If a patient misses a days dose entirely, 
they must be instructed not to “make it up” the next day. If a patient vomits anytime after taking a 
dose, they must be instructed not to “make it up,” but to resume subsequent doses the next day as 
prescribed. If a patient inadvertently takes 1 extra dose during a day, the patient should not take the 
next day’s dose of Palbociclib. A study medication diary is to be completed for each dose of 
Palbociclib. 
 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
6.1.1 A diagnosis of liposarcoma confirmed at MSKCC. Because myxoid / round cell 
liposarcoma does not have significant CDK4 amplification, patients with this 
subtype are not eligible. 
 
6.1.2 Metastatic and/or locally advanced or locally recurrent disease that is not 
surgically resectable, with evidence of disease progression, either clinically or 
radiographically, as determined by the investigator 
 
6.1.3 All patients must have measurable disease as defined by RECIST 1.1. 
Measurable disease is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded). Each 
lesion must be >10 mm when measured by CT, MRI or caliper measurement by 
clinical exam; or >20 mm when measured by chest x-ray. Lymph nodes must be > 
15 mm in short axis when measured by CT or MRI. 
 
 
 
6.1.4 A minimum of 1 prior systemic regimen for recurrent/metastatic disease.  Note: 
This requirement does not apply to patients enrolled in the Expansion Cohort. 
The last dose of systemic therapy (include targeted therapies) must have been 
given at least 2 weeks prior to initiation of therapy.  Patients receiving BCNU or 
mitomycin C must have received their last dose of such therapy at least 6 weeks 
prior to initiation of therapy. 
 
6.1.5 Patients with brain metastasis that have been treated with definitive surgery or 
radiation and have been clinically stable for 3 months are eligible. 
 
6.1.6 Age >18 years. 
 
6.1.7 ECOG performance status 0 or 1 (Please see Appendix C for ECOG/KPS 
conversion table). 
 
6.1.8 Adequate organ and marrow function as defined below (ULN indicates 
institutional upper limit of normal): 
 
Absolute neutrophil count 
• 1.su109/L 


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Hemoglobin 
• 9.0 g/dL 
WBC 
• 3.0u109/L 
Platelets 
• 100u109/L 
Total bilirubin 
” 1.s u ULN except for patients with known 
Gilbert syndrome 
 
AST(SGOT)/ALT(SGPT) 
” 3 u institutional ULN 
 
Serum creatinine 
” 1.s u ULN or Creatinine Clearance > 50 
mL/min (calculated by Cockcroft-Gault method) 
 
QTc interval 
” 470 msec 
 
6.1.9 Patients must not have current evidence of another malignancy that requires 
treatment. 
 
6.1.10 The effects of Palbociclib on the developing human fetus at the recommended 
therapeutic dose are unknown. Women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence). Women must not breast feed while on study. 
 
 
 
6.1.11 Ability to understand and the willingness to sign a written informed consent 
document. 
 
6.1.12 Ability to swallow intact Palbociclib capsules 
 
6.1.13 Patients’ tumors must express Rb, as assessed using an historical biopsy sample 
if available or a newO\ REWDLQHG WXPR U VDPSOH. 6DPSOHV PXVW GHPRQVWUDWH •1+ 
staining for Rb (see Section 8.0).  Patients' tumors must also have evidence of 
CDK4 amplification by FISH (see Section 8.0).  Note: This does not apply to 
patients enrolled in the Expansion Cohort. 
 
6.2 
Subject Exclusion Criteria 
 
6.2.1.  Patients who have not recovered from adverse events of prior therapy to ” 1&, 
CTCAEv4.0 Grade 1. 
 
6.2.2 Patients receiving any other investigational agents. 
 
6.2.3 Patients who have received prior treatment with a selective CDK4 inhibitor 
 
6.2.4 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to Palbociclib. 


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6.2.5 Uncontrolled intercurrent illness including, but not limited to, known ongoing or 
active infection, including HIV, active hepatitis B or C, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia (specifically, atrial 
fibrillation or ventricular dysrhythmias except ventricular premature contractions), 
or psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
6.2.6 Pregnant women and women who are breast-feeding. 
 
6.2.7 Patients with a history of long-QT syndrome or documented family history of long- 
QT syndrome.  Patients who must remain on drugs that prolong the QT interval. 
 
6.2.8 Palbociclib is a substrate of CYP3A. Caution should be exercised when dosing 
Palbociclib concurrently with CYP3A inducers or inhibitors.  Furthermore, patients 
who are taking concurrent medications that are strong inducers/inhibitors or 
substrates of CYP3A4 should be switched to alternative medications to minimize 
any potential risk.  A list of CYP3A4 substrates, inducers and/or inhibitors is 
provided in Appendix B.  The following medications with strong potential for 
interaction are not allowed: 
 
indinavir 
nelfinavir 
ritonavir 
clarithromycin 
itraconazole 
ketoconazole 
nefazodone 
saquinavir 
telithromycin 
carbamazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St. John's wort 
Troglitazone 
 
 
7.0 
RECRUITMENT PLAN 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
The clinical trial will be listed on the clinicaltrials.gov website as well as on the MSKCC 
website.  Patients will not be paid for participation in this study. 
 
8.0 
PRETREATMENT EVALUATION 


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An existing tumor biopsy sample or a freshly obtained tumor sample will be used to assess 
for Rb expression and CDK4 amplification.  Both are required for protocol entryNote: This 
requirement is waived for patients in the Expansion Cohort because our data havs shown 
that CDK4 amplification is nearly universal, and a future phase 3 study will plan to enroll 
patients with liposarcoma without requiring CDK4 amplification.  CDK4 amplification testing 
by FISH will be performed in the laboratory of Cristina Antonescu, MD, MSKCC.  Rb 
expression will be determined by immunohistochemistry.  Patients’ tumors must express Rb 
DV DVVHVVHG E\ ,+& VWDLQLQJ D W D OHYH O • 1+.  $ 1+ VWDLQLQJ OHYHO LV HTXLYD OHQW WR D PLQLPD O  
intensity level that is nonetheless determined to be above background.  Rb staining by IHC 
will be performed by Alan Meeker, PhD, Johns Hopkins Oncology. 
 
Pretreatment evaluations include: 
 
x    Tumor assessment (either archival tissue or fresh biopsy if necessary) to evaluate for 
Rb expression and CDK4 amplification 
x    Medical history 
x    Physical exam 
x    CBC w/ plt, diff 
x    Serum chemistry 
x    Radiologic evaluation (CT or MRI) 
x    EKG 
x    Blood pregnancy test (for women of child-bearing potential) 
 
 
Baseline assessments including radiologic evaluation but excluding tumor assessment for Rb 
expression and CDK4 amplification must be done within 3 weeks of starting protocol therapy. 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Treatment will consist of either: 
 
Schedule 2/1: Palbociclib 200mg given once daily by mouth for 14 consecutive days, 
followed by 7 days of rest.  A cycle will be defined as 21 days. 
 
Schedule 3/1:  Palbociclib 125mg given once daily by mouth for 21 consecutive days, 
followed by 7 days of rest.  A cycle will be defined as 28 days. 
 
Patients may deviate from the study schedule at the Principal Investigator’s discretion as 
long as patient safety is not compromised. 
 
Treatment will be administered on an outpatient basis.  Appropriate dose modifications for 
Palbociclib are described in Section 11.4. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
Schedule 2/1: 


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Cycle 1, Week 1 
x 
Physical Exam 
x 
CBC with platelets, differential 
x 
Serum chemistry 
Cycle 1, Week 2 
x 
CBC with platelets, differential 
x 
Serum chemistry 
Cycle 1, Week 3 
x 
CBC with platelets, differential 
x 
Serum chemistry 
Cycle 2 – 12 
x 
Physical exam at the start of every cycle 
x 
CBC with platelets, differential at the start of every cycle 
x 
Serum chemistry at the start of every cycle 
x 
EKG at the start of every cycle (after Cycle 8 , at the start of every other cycle) 
x 
CT or MRI every 6 weeks (starting with Cycle 3 Week 1) 
Cycle 13+ 
x 
Physical exam at the start of every other cycle 
x 
EKG at the start of every other cycle 
x 
CBC with platelets, differential at the start of every cycle 
x 
Serum chemistry at the start of every cycle 
x 
CT or MRI every 12 weeks (3 cycles) 
 
 
Start of each cycle: 
x 
Adverse events 
x 
Concurrent medications 
 
 
 
Off study: 3-4 weeks after last dose 
x 
Physical Exam 
x 
CBC with platelets, differential 
x 
Serum chemistry 
x 
EKG 
 
 
Schedule 3/1: 
Cycle 1, Week 1 
x 
Physical Exam 
x 
CBC with platelets, differential 
x 
Serum chemistry 
Cycle 1, Week 2 
x 
CBC with platelets, differential 
x 
Serum chemistry 
Cycle 1, Week 3 


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x 
CBC with platelets, differential 
x 
Serum chemistry 
Cycle 1, Week 4 
x 
CBC with platelets, differential 
x 
Serum chemistry 
Cycle 2 – 9 
x 
Physical exam at the start of every cycle 
x 
CBC with platelets, differential at the start of every cycle 
x 
Serum chemistry at the start of every cycle 
x 
EKG at the start of every cycle (after Cycle 8 , at the start of every other cycle) 
x 
CT or MRI every 6 weeks 
Cycle 10+ 
x 
Physical exam at the start of every other cycle 
x 
EKG at the start of every other cycle 
x 
CBC with platelets, differential at the start of every cycle 
x 
Serum chemistry at the start of every cycle 
x 
CT or MRI every 12 weeks 
 
 
Start of each cycle: 
x 
Adverse events 
x 
Concurrent medications 
Off study: 3-4 weeks after last dose 
x 
Physical Exam (May be performed by a physician not affiliated with the protocol if 
patient is unable to return to MSKCC) 
x 
CBC with platelets, differential 
x 
Serum chemistry 
x 
EKG 
Any study assessments may be performed + / - 3 days from the scheduled time. 
 
 
Pre- and post-treatment biopsies may be obtained in at least 10 patients on the study. The biopsy 
will be used to assess total Rb, phospho-Rb to confirm CDK4 inhibition, induction of apoptosis 
(781(/ DQG FOHDYHG FDVSDVH 3). DQG PDUNH UV RI FHOOXODU  VHQHVFHQFH (VHQHVFHQFH ȕ-galactosidase) 
and proliferation (Ki67).   Other biomarkers may also be explored.  In addition, a third biopsy may be 
performed in patients who are removed from the study for disease progression. This will enable us 
to better understand mechanisms of resistance to CDK4 inhibition.  All biopsies are optional for 
patients. 
 
Collection of Specimen(s) 
The pre-treatment biopsy will be collected within 2 weeks of the first dose. The post-treatment 
biopsy will be collected after at least 3 weeks of treatment (i.e., after completion of cycle 1). The 
exact timing of the biopsy is at the discretion of the Principal Investigator. 
 
Patients will also have the option of having a second biopsy within 14 days following removal from 
study for disease progression. 


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Handling of Specimens(s) 
For each sample indicate the unique subject ID number, histology diagnosis, and the date of the 
specimen. 
 
Shipping of Specimen(s): Tumors will be sent to: 
 
 
Grazia Ambrosini, Ph.D. 
Memorial Sloan-Kettering Cancer Center 
Sarcoma Laboratory, Z-1841 
1275 York Ave 
New York, NY 10065 
Tel: 646-888-2183 
Fax: 646-422-0631 
Email: ambrosig@mskcc.org 


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Patients will undergo evaluation on treatment according to the tables below. 
 
SCHEDULE 2/1 
Pre- 
Study 
Cy cle1 
Wk 1 
Cy cle1 
Wk 2 
Cy cle1 
Wk 3 
Cy cle2 
Wk 1 
Cy cle2 
Wk 2 
Cy cle2 
Wk 3 
Cy cle3 
Wk 1 
Cy cle3 
Wk 2 
Cy cle3 
Wk 3 
Cy cle4 
Wk 1 + 
Off 
Study d 
Palbocicliba 
X 
X 
X 
X 
X 
X 
X 
Tumor for RB and 
CDK4 
X 
Informed consent 
X 
Medical history 
X 
Concurrent meds 
X 
X 
X 
X 
X 
Physical examf 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryb 
X 
X 
X 
X 
X 
X 
X 
X 
EKG 
X 
X 
X 
X 
X 
Adverse event 
evaluation 
X 
X 
X 
X 
X 
Radiologic evaluatione 
X 
Radiologic measurements should be performed every 6 weeks. 
B-HCG 
Xc 
Tumor Biopsyg 
Xg 
Xg 
a: 
Palbociclib 200mg PO daily x 14 days, every 21 days. 
b: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total 
protein, SGOT[AST], SGPT[ALT], sodium. 
c: 
Serum pregnancy test (women of childbearing potential). 
d: 
Off-study evaluation 3-4 weeks after last dose. 
e:    CT and/or MRI as appropriate based on location of disease.  After 36 weeks, radiologic evaluation will be performed every 12 
weeks. 
f: 
After Cycle 13, physical exam will be performed at every other cycle. After Cycle 8, EKGs will be performed at every other 
cycle. 
g: 
Both post treatment and off study tumor biopsies are optional. 


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Page  18 of 41 
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SCHEDULE 3/1 
Pre- 
Study 
Cy cle1 
Wk 1 
Cy cle1 
Wk 2 
Cy cle1 
Wk 3 
Cy cle1 
Wk 4 
Cy cle2 
Wk 1 
Cy cle2 
Wk 2 
Cy cle2 
Wk 3 
Cy cle2 
Wk 4 
Cy cle4 
Wk 1 + 
Off 
Study d 
Palbocicliba 
X 
X 
X 
X 
X 
X 
X 
Tumor for RB and 
CDK4 
X 
Informed consent 
X 
Medical history 
X 
Concurrent meds 
X 
X 
X 
X 
Physical examf 
X 
X 
X 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryb 
X 
X 
X 
X 
X 
X 
X 
X 
EKG 
X 
X 
X 
X 
Adverse event 
evaluation 
X 
X 
X 
X 
Radiologic evaluatione 
X 
Radiologic measurements should be performed every 6 weeks. 
B-HCG 
Xc 
Tumor Biopsyg 
Xg 
Xg 
Xg 
a: 
Palbociclib 125mg PO daily x 21 days, every 28 days. 
b: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total 
protein, SGOT[AST], SGPT[ALT], sodium. 
c: 
Serum pregnancy test (women of childbearing potential). 
d: 
Off-study evaluation 3-4 weeks after last dose. 
e:    CT and/or MRI as appropriate based on location of disease.  After 36 weeks, radiologic evaluation will be performed every 12 
weeks. 
f: 
After Cycle 10, physical exam will be performed at every other cycle. After Cycle 8, EKGs will be performed at every other 
cycle. 
g: 
 Pretreatment biopsy to be collected within 2 weeks of first dose.   Both post treatment and off study tumor biopsies are 
optional. 
 


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• DLT (Section 11.1); 
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Page 19 of 41 
 
 
 
 
 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
Expected toxicities include 
x 
Myelosuppression (anemia, thrombocytopenia, leukopenia, lymphopenia, neutropenia) 
x 
Nausea 
x 
Vomiting 
x 
Hyperglycemia 
x 
Hyponatremia 
The severity and frequency observed in the phase I trial of Palbociclib are summarized in section 3.4 
above. 
 
11.1 
Dose modification for toxicity 
Patients who experience dose-limiting toxicity (DLT) may have their dose modified. 
A DLT is an adverse event occurring after the initiation of Palbociclib treatment that meets 
any of the following criteria within a given cycle: 
DLT is defined as: 
1. 
*UDGH 4 KHPDWR ORJLF WR[L FL W\ (LQF OX GLQ J SODWHOH WV <2s.000/ȝ/. DEVROXWH QHXWURSKLO 
count >$1&@ <s00/ȝ/. KHPRJORELQ <6.5 g/dL); 
2. 
$1& <1000/ȝ/ (*UDGH 3 QHXW URSHQLD) DVVRFL D WH G ZLWK D GRFXPHQWHG LQIHFWLRQ RU 
fever •38.sƒ&; 
3. 
•*UDGH 3 QRQKHPD WRORJLF WUHDWPHQW-related toxicity, except those that have not been 
maximally treated (eg, nausea, vomiting, diarrhea) or that the patient considers 
tolerable, such as skin rash. In an asymptomatic patient, Grade 3 QTc prolongation 
(QTc >500 msec) will first require repeat testing, manual over-read to exclude 
confounding factors such as U wave or other abnormal wave forms, and correction of 
reversible causes such as electrolyte abnormalities or hypoxia for confirmation. If, 
after correction of any reversible causes, the Grade 3 QTc prolongation persists, then 
the event should be considered a DLT. 
4. 
 Inability to receive the next dose of PD 0332991 within 1 week (±1 day) of the last 
cycle due WR  ODFN RI KHPD WR ORJLF UHFRYH U\ (S ODWH OH W V <s0.000/ȝ/. $1& <1.000/ȝ/. 
DQG hemoglobin <8.0 J/G/); RU GXH WR S URORQJHG QRQKHPDWRORJLF WR[LFL WLHV RI 
•*UDGH 3 severity. 
 
The occurrence of a DLT necessitates immediate interruption of the scheduled study treatment. 
Resumption of study treatment for patients experiencing DLTs is permitted, contingent on the 
criteria defined in Section 11.3. For QTc-related DLTs, a risk/benefit assessment by 
investigator and sponsor will determine whether or not to continue study drug at a reduced dose 
following return of the QTc interval to baseline. 
 
 
11.2 Treatment Interruption 
Treatment is to be interrupted under the following circumstances: 


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a treatment-related toxicity within 21 days OR they experience agent related adverse events 
Amended: 13-OCT-2015 
Page 20 of 41 
 
 
• •*UDGH 3 QRQKHPDWR ORJLF R U KHPD WR ORJLF WR[LFLW\ (LQF OXGLQJ SOD WHOHWV <s0.000/ȝ/. $1& 
<1.000/ȝ/. DQG KHPRJORELQ <8.0 J/G/) LQ WKH ILUV W F\F OH; IR U VXEVHTXHQW F\FOHV. DQFL O O DU\ 
supportive medications such as anti-diarrhea agents should be used in order to maintain full 
dose; 
• Dosing may be interrupted or discontinued for serious AEs (SAEs) at the investigator’s 
discretion. 
 
 
11.3   Recovery Requirements Following Treatment Interruption 
 
 
Delay retreatment following treatment interruption for toxicity until all of the following 
conditions have been met: 
‡ 3ODWHOHW  FRXQW •s0.000/ȝ/; 
‡ $1& •1000/ȝ/; 
‡ +HPRJORELQ •8.0 J/G/; 
• Treatment-UHO DWHG QRQKHPD WRORJLF $(V KDYH UHFRYH UHG WR ”*UDGH 1 R U WR EDVH OLQH. ZL WK WKH 
exception of alopecia; 
If treatment interruption results from decline in hematologic parameters, the frequency of blood 
count assessments should be increased as indicated clinically. 
 
11.4. Dose Adjustments Following Treatment Interruption for Toxicity 
 
 
Patients who have experienced a DLT must have any subsequent doses reduced once they meet 
recovery requirements (Section 11.3). Patients who had a dose interruption for an AE that did not 
meet DLT criteria (eg, Grade 3 hematologic toxicity) are to continue at the same dose of PD 
0332991 as administered in the previous cycle. 
 
 
Schedule 2/1: 
 
 
Patients resuming treatment following DLT are to have their dose reduced to 150mg. 
If patients require a second dose modification, the dose should be reduced to 100mg. 
Schedule 3/1: 
 
 
Patients resuming treatment following DLT are to have their dose reduced to 100mg. 
If patients require a second dose modification, the dose should be reduced to 75mg. 
The maximum number of dose reductions is 2. The maximum delay for any reason, including 
toxicities, is 3 weeks. If study drug is withheld for more than 3 continuous weeks due to a treatment- 
related toxicity that does not resolve, the patient will be withdrawn from the study. 
 
Subjects will be withdrawn from the study if they fail to recover to CTCAE v4.0 Grade 0-1 or 
tolerable grade 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) from 


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requiring dose modification despite two previous dose reductions (i.e. would require a 3rd dose 
reduction) unless the investigator believes that the subject should remain in the study because of 
evidence that the patient is/may continue deriving benefit from continuing study treatment.  Patients 
requiring dose reductions should not have the dose re-escalated with subsequent treatments. 
 
 
 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1 
Measurement of antitumor effect 
 
Patients should be reevaluated for response every 6 weeks (by the clock, not at the end of a 
specific cycle). After 36 weeks, patients should be re-evaluated for response every 12 weeks.  
Again, the scans should be performed on schedule, not according to the number of 
cycles administered. Patients who achieve a complete or partial response should continue to 
have follow-up scans on schedule to document the duration of the response. 
 
12.2 
Parameters of Response – RECIST (version 1.1) 
Please refer to the following reference for complete details:  Eisenhauer EA, Therasse P, 
Bogarerts J, et al.  New response evaluation criteria in solid tumours:  Revised RECIST 
guideline (version 1.1). European Journal of Cancer 2009; 45:228-247. 
 
12.2.1 Measurable disease (“Target”) is defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded).  Each 
lesion must be t 10 mm when measured by CT (CT scan slice thickness no greater than 
5 mm*); > 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable); and > 20 mm 
by chest x-ray. 
 
*If CT scan with slice thickness > 5 mm is used, the minimum lesion size must have a 
longest dimension twice the actual slice thickness. 
 
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. 
 
Clinical lesions will only be considered measureable when they are superficial and > 10 
mm diameter as assessed using calipers (e.g. skin nodules). When lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should be undertaken 
since it is more objective and my also be reviewed at the end of the study. 
 
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment.  MRI may be substituted for contrast enhanced CT for some sites 
(e.g. for abdomen and/or pelvis), but NOT lung. The minimum size for measurability is the 
same as for CT (10 mm) as long as the scans are performed with slice thickness of 


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5 mm and no gap.  In the event the MRI is performed with thicker slices, the size of a 
measurable lesion at baseline should be two times the slice thickness. 
 
Tumors within a previously irradiated field will be designated as “non- target” lesions 
unless progression is documented or a biopsy is obtained to confirm persistence at least 
90 days following completion of radiation therapy. 
 
 
 
 
 
 
Bone lesions: 
 
x Bone scan, PET scan or plain films are NOT considered adequate imaging 
techniques to measure bone lesions. 
x Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques 
such as CT or MRI can be considered as measurable if the soft tissue 
component meets the definition of measurability described above. 
x Blastic bone lesions are non-measurable. 
Cystic lesions: 
 
x Lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor 
non-measurable). 
x Cystic lesions thought to represent cystic metastases can be considered 
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. 
 
 
12.2.2 Non-measurable disease (“Non-Target”) is defined as all other lesions, including 
small lesions (<10 mm or pathological lymph nodes with > 10 to < 15 mm short axis) as 
well as truly non-measurable lesions. 
 
Lesions considered truly non-measurable include: 
 
x Leptomeningeal disease 
x Ascites 
x Pleural or pericardial effusion 
x 
Inflammatory breast disease 
x 
Lymphangitic involvement of skin or lung 
x 
Abdominal masses/abdominal organomegaly indentified by physical 
exam that is not measureable by reproducible imaging techniques 
12.2.3 Baseline documentation of “Target” and “Non-Target” lesions 
 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two 
lesions per organ) 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 


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organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  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. The baseline sum diameters will be used as reference to further characterize 
the objective tumor response of the measurable dimension of the disease. 
 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements are not required and these lesions 
should be followed as “present” or “absent”. It is possible to record multiple non-target 
lesions involving the same organ as a single item on the D2M form (e.g. ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases”). 
 
All baseline evaluations of disease status should be performed as close as possible to 
the start of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging based evaluation should ALWAYS be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
exam. 
 
12.2.4 Response Criteria 
 
12.2.4.1 Complete Response (CR):  Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
 
12.2.4.2 Partial Response (PR):  At least a 30% decrease in the sum of diameters 
of target lesions, taking into reference the baseline sum diameters. 
 
12.2.4.3 Progressive Disease (PD):  At least a 20% increase in the sum of 
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 progression.  Guidance on when a lesion is to be considered 
new is provided in the above cited reference).  Unequivocal progression of 
existing non-target lesions is also considered progression (a detailed 
description and examples of unequivocal progression of existing non-target 
lesions is provided in the above cited reference). 
 
For equivocal findings of progression (e.g. very small and uncertain new 
lesions; cystic changes or necrosis in existing lesions), treatment may 
continue until the next scheduled assessment.  If at the next scheduled 
assessment, progression is confirmed, the date of progression should be 
the earlier date when progression was suspected. 


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12.2.4.4 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. 
 
12.2.4.5 Not evaluable (NE) is when no imaging/measurement is done at all at a 
particular time point. The patient is not evaluable (NE) at that time point. 
 
12.2.4.6 Early death is defined as having NO repeat tumor assessments following 
initiation of study therapy resulting from the death of the patient due to disease or 
treatment. 
 
 
 
Patients with global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time will be recorded as 
‘symptomatic deterioration’.  Every effort should be made to document objective 
progression even after discontinuation of treatment. 
 
Confirmation of response (for both CR and PR):  Complete or partial response may 
only be claimed if the criteria for each are met at a subsequent time point (> 4 weeks 
later) in studies with a primary endpoint that includes response rate. When response rate 
is a secondary endpoint (e.g. randomized phase II or III studies with progression-free 
survival or overall survival as primary endpoint) confirmation is NOT required. 
 
Special note on lymph nodes:  Lymph nodes identified as target lesions should always 
have the actual short axis measurement recorded (measured in the same anatomical 
plane as the baseline examination), even if the nodes regress to below 10 mm on study. 
This means that when lymph nodes are included as target lesions, the ‘sum’ of lesions 
may not be zero even if complete response criteria are met, since a normal lymph node is 
defined as having a short axis of < 10 mm.  For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
 
Special note on target lesions that become ‘too small to measure’: While on study, 
all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 2 
mm).  However, sometimes lesions or lymph nodes which are recorded as target lesions 
at baseline become so faint on CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being ‘too small to measure’. When 
this occurs it is important that a value be recorded on the D2M form. If it is the opinion of 
the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm.  If the lesion is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned (Note:  It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size when normal 
and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph 
node is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned in this circumstance as well). 


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Page 25 of 41 
 
 
12.2.5 Evaluation of best overall response is according to table below: 
 
Time point response: patients with target (+/– non-target) disease 
 
Target lesions 
Non-target lesions 
New 
lesions 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
*If a CR is truly met at first time point, then any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, makes the disease PD at that point 
(since disease must have reappeared after CR). However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact 
the patient had PR or SD, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR or SD and the best response is PR or SD. 
 
12.2.6 Duration of response is defined as the time measurement criteria are first met for 
CR/PR until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurement recorded on 
study). 


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be evaluated using a one-stage design. Given the high PFS rate observed on the 2/1 
Amended: 13-OCT-2015 
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12.2.7 Duration of stable disease is measured from the start of the treatment (in 
randomized trials, from the date of randomization) until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, 
this is the reference for calculation of PD). 
 
12.2.8 Progression-Free Survival is the period from study entry until recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurement recorded on study), death or date of last contact. 
 
12.2.9 Survival is the observed length of life from entry into the study to death or the date 
of last contact. 
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient develops progressive disease he/she will be taken off study and 
referred for alternative therapy. 
If at any time the patient develops unacceptable toxicity he/she will be removed from study. 
If the patient is unable to follow the requirements of the protocol for treatment or evaluation 
he/she will be removed from study. 
 
14.0 
BIOSTATISTICS 
 
The primary endpoint of this study is to determine the progression-free survival at 12 weeks 
for patients with liposarcoma treated with Palbociclib.  Progression includes both disease 
progression (as defined by RECIST 1.1) and death from any cause.  Based on historical 
controls (Van Glabbeke et al. Eur J. Cancer 2002; 39:543-549), a PFS of > 40% at 3 months 
is considered promising for second-line therapy, and a PFS of < 20% is considered not 
promising. 
 
A one-stage design will be used.  Accrual will continue until 28 evaluable patients have been 
treated. The study will be claimed to be positive if there are 9 or more who are progression- 
free at 12 weeks. This design has a type I error rate of 0.09 and a type II error rate of 0.15. 
The probability of claiming the study positive given various true rates of 12-week PFS is 
given as follows. 
 
True Rate of PFS at 12 weeks Probability of Claiming the Study Positive 
0.2 
0.09 
0.3 
0.47 
0.4 
0.85 
0.5 
0.98 
0.6 
>0.99 
 
The study met its primary endpoint for patients treated on the 2/1 schedule. The estimated 
PFS at 12 weeks is 66% (Dickson et al., JCO 2013, in press). The study was expanded to 
enroll an additional 28 patients to be treated on the 3/1 schedule. The 3/1 schedule will also 


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Consent Procedures. 
Amended: 13-OCT-2015 
Page 27 of 41 
 
 
schedule, the 3/1 schedule will be held to a higher standard.  An acceptable 12 weeks PFS 
rate will be 60% and an unacceptable rate will be 35%. The 3/1 schedule will be claimed 
positive if there are 14 or more who are progression free at 12 weeks. This design has a 
type I error rate of 0.07 and a type II error rate of 0.10. The probability of claiming the study 
positive given various true rates of 12-week PFS is given as follows. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
True Rate of PFS at 12 weeks Probability of Claiming the Study Positive 
0.3 
0.02 
0.35 
0.07 
0.4 
0.19 
0.5 
0.57 
0.6 
0.90 
0.65 
0.97 
0.7 
0.99 
The 3/1 schedule also met its primary endpoint (to be reported at ASCO 2013).  Based on 
these results, a phase 3 study of the 3/1 schedule is planned. In the interim, the current 
study will be expand to include up to 20 additional patients in the Expansion Cohort.  No 
formal statistical hypothesis is being tested in the Expansion Cohort however the outcomes 
will be reported with descriptive statistics as described in the next paragraph. 
 
Secondary endpoints include determination of RECIST overall response rate (CR + PR), 
clinical benefit rate (CR+PR+SD) and overall survival. Response rate and clinical benefit rate 
will be estimated with the confidence interval provided. PFS and the overall survival 
probabilities will be estimated using the Kaplan-Meier method. 
 
Expected accrual is estimated at 2 patient/month with total duration of the study estimated 38 
months. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 


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and quality.  There are institutional processes in place for quality assurance (e.g., protocol 
Amended: 13-OCT-2015 
Page 28 of 41 
 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploadedvia the PPR Electronic Registration System. 
 
15.2 
Randomization 
 
N/A 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. 
 
The data collected for this study will be entered into a secure database.  Source 
documentation will be available to support the computerized patient record. 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data.  Routine data quality reports will be generated to assess missing data and 
inconsistencies.  Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated.. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html.  The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet: 
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 


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x 
The intervention 
Amended: 13-OCT-2015 
Page 29 of 41 
 
 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control,  plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials,  report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for it’s 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
17.1 
Privacy 
 
Informed consent will be obtained from all research subjects. The informed consent 
document will explain to the subjects the risks, benefits, toxicities/side effects, 
alternatives/options for treatment, and financial costs/burdens.  Participation in the study is 
voluntary.  The study drug will be provided commercially by Pfizer at no cost to the patient. 
Patients will be billed for patient care services. 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at  sae@mskcc.org. The report should contain the following 
information: 
 
Fields populated from CRDB: 
x Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
x Medical record number 
x Disease/histology (if applicable) 
x Protocol number and title 
 
Data needing to be entered: 
x The date the adverse event occurred 
x The adverse event 
x Relationship of the adverse event to the treatment (drug, device, or intervention) 
x If the AE was expected 
x The severity of the AE 


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x Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
 
 
 
17.2.1 Adverse Event Reporting 
 
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following sections. 
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event (see Section 17.2.2 requiring immediate notification to 
Pfizer or its designated representative.) For all adverse events, sufficient information should be 
obtained by the investigator to determine the causality of the adverse event. The investigator is 
required to assess causality. For adverse events with a causal relationship to the investigational 
product, follow-up by the investigator is required until the event or its sequelae resolve or stabilize at 
a level acceptable to the investigator, and Pfizer concurs with that assessment. 
Serious adverse events require immediate notification to Pfizer or its designated representative 
beginning from the time that the subject provides informed consent, which is obtained prior to the 
subject’s participation in the clinical trial, ie, prior to undergoing any trial-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product. Any serious adverse event occurring any time after the 
reporting period must be promptly reported if a causal relationship to investigational product is 
suspected. 
Adverse events serious and non-serious) should be recorded on the CRF from the time the subject 
has taken at least one dose of trial treatment through last subject visit. If a patient begins a new 
anticancer therapy, the adverse event reporting period for non-serious adverse events ends at the 
time the new treatment is started. Death must be reported if it occurs during the serious adverse 
event reporting period after the last dose of investigational product, irrespective of any intervening 
treatment. 
 
Serious Adverse Event Contact Information 
 
All serious adverse events regardless of treatment group or suspected relationship to study drug 
must be reported immediately by fax to the number listed below: 


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Page  31 of 41 
 
 
 
17.2.2 Definition of an Adverse Event 
 
 
An adverse event is any untoward medical occurrence in a clinical investigation subject administered 
a product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage. Examples of adverse events include but are not limited to: 
• Abnormal test findings; 
• Clinically significant symptoms and signs; 
• Changes in physical examination findings; 
• Hypersensitivity; 
Additionally, they may include the signs or symptoms resulting from: 
• Drug overdose; 
• Drug withdrawal; 
• Drug abuse; 
• Drug misuse; 
• Drug interactions; 
• Drug dependency; 
• Extravasation; 
• Exposure in utero. 
 
 
Worsening of signs and symptoms of the malignancy under trial should be reported as adverse 
events in the appropriate section of the CRF. Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as adverse events. 
 
The criteria for determining whether an abnormal objective test finding should be reported as an 
adverse event are as follows: 
• Test result is associated with accompanying symptoms, and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
• Test result leads to a change in trial dosing or discontinuation from the trial, significant 
additional concomitant drug treatment, or other therapy, and/or 
• Test result is considered to be an adverse event by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event. Any abnormal test result that is determined to be an error does not 
require reporting as an adverse event. 
A serious adverse event or serious adverse drug reaction is any untoward medical occurrence that: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 
• Results in congenital anomaly/birth defect. 
 
 
Progression of the malignancy under study should not be reported as a serious adverse event (SAE) 
unless the outcome is fatal within the safety reporting period. If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death must be 


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Page  32 of 41 
 
 
recorded as an adverse event and as a SAE with CTCAE grade 5.  Hospitalizations clearly due to 
signs and symptoms of disease progression should not be reported as SAEs. 
 
Medical and scientific judgment should be exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or result in 
death or hospitalization. However, if it is determined that the event may jeopardize the subject 
and/or may require intervention to prevent one of the other outcomes listed in the definition above, 
the important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
 
Adverse events reported from clinical trials associated with hospitalization or prolongation of 
hospitalization are considered serious. Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria. Admission also includes transfer within the hospital to an 
acute/intensive care unit (eg, from the psychiatric wing to a medical floor, medical floor to a coronary 
care unit, neurological floor to a tuberculosis unit). 
Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 
• Respite care (eg, caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• Routine emergency room admissions; 
• Same day surgeries (as outpatient/same day/ambulatory procedures). 
 
 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical adverse 
event is not in itself a serious adverse event. Examples include: 
• Admission for treatment of a preexisting condition not associated with the development of a 
new adverse event or with a worsening of the preexisting condition (eg, for work-up of 
persistent pre-treatment lab abnormality); 
• Social admission (e.g., subject has no place to sleep); 
• Administrative admission (e.g., for yearly physical exam); 
• Protocol-specified admission during a clinical trial (e.g., for a procedure required by the trial 
protocol); 
• Optional admission not associated with a precipitating clinical adverse event (e.g., for elective 
cosmetic surgery); 
• Pre-planned treatments or surgical procedures should be noted in the baseline documentation 
for the entire protocol and/or for the individual subject. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as adverse events. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an adverse event. For example, an acute appendicitis 
that begins during the adverse event reporting period should be reported as the adverse event, and 
the resulting appendectomy should be recorded as treatment of the adverse event. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
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environmental exposure to a Pfizer product in a pregnant woman (e.g. a nurse reports that she is 
Amended: 13-OCT-2015 
Page 33 of 41 
 
 
If required on the adverse event case report forms, the investigator will use the following definitions 
of severity in accordance with National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0 to describe the maximum intensity of the adverse event. If the event is 
serious, the CTCAE grade reported in the adverse event CRF must be consistent with the 
description of CTCAE grade included in the narrative section of the serious adverse event report. 
 
GRADE Clinical Description of Severity 
0 
No Change from Normal or Reference Range (This grade is not included in 
the Version 3.0 document but may be used in certain circumstances.) 
1 
MILD Adverse Event 
2 
MODERATE Adverse Event 
3 
SEVERE Adverse Event 
4 
LIFE-THREATENING OR DISABLING Adverse Event 
5 
DEATH RELATED TO Adverse Event 
 
 
Note the distinction between the severity and the seriousness of an adverse event. A severe event is 
not necessarily a serious event. For example, a headache may be severe (interferes significantly 
with subject's usual function) but would not be classified as serious unless it met one of the criteria 
for serious adverse events, listed above. 
 
The investigator’s assessment of causality must be provided for all adverse events (serious and non-
serious). An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an adverse event. If 
the investigator’s final determination of causality is unknown and the investigator does not know 
whether or not investigational product caused the event, then the event will be handled as “related to 
investigational product” for reporting purposes. If the investigator's causality assessment is 
"unknown but not related to investigational product", this should be clearly documented on trial 
records.  In addition, if the investigator determines a serious adverse event is associated with trial 
procedures, the investigator must record this causal relationship in the source documents and CRF, 
as appropriate, and report such an assessment in accordance with the serious adverse event 
reporting requirements, if applicable. 
 
For investigational products within clinical trials and for marketed products, an exposure in-utero 
(EIU) occurs if: 
1) a female becomes, or is found to be, pregnant either while receiving or having been directly 
exposed to (e.g., environmental exposure) the investigational product, or the female becomes, or is 
found to be, pregnant after discontinuing and/or being directly exposed to the investigational product 
(maternal exposure); 
2) a male has been exposed, either due to treatment or environmental, to the investigational product 
prior to or around the time of conception and/or is exposed during the partner pregnancy (paternal 
exposure). 
If any trial subject or trial subject’s partner becomes or is found to be pregnant during the trial 
subject’s treatment with the investigational product, the investigator must submit this information to 
Pfizer on an Exposure in Utero Form. In addition, the investigator must submit information regarding 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
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Information on other possible causes of the event, such as concomitant medications and illnesses 
Amended: 13-OCT-2015 
Page 34 of 41 
 
 
pregnant and has been exposed to a cytotoxic product by inhalation or adverse event has occurred 
and within 24 hours of awareness of the pregnancy. The information submitted should include the 
anticipated date of delivery (see below for information related to induced termination of pregnancy). 
Follow-up is conducted to obtain pregnancy outcome information on all Exposure in Utero reports 
with an unknown outcome. The investigator will follow the pregnancy until completion or until 
pregnancy termination (ie, induced abortion) and then notify Pfizer of the outcome. The investigator 
will provide this information as a follow up to the initial Exposure in Utero Form. The reason(s) for an 
induced abortion should be specified. An EIU report is not created when an ectopic pregnancy report 
is received since this pregnancy is not usually viable. Rather, a serious adverse event case is 
created with the event of ectopic pregnancy. 
 
 
Withdrawal due to adverse event should be distinguished from withdrawal due to insufficient 
response, according to the definition of adverse event noted earlier, and recorded on the appropriate 
adverse event CRF page. When a subject withdraws due to a serious adverse event, the serious 
adverse event must be reported in accordance with the reporting requirements defined below. 
 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial subject. In addition, each trial subject will be questioned about 
adverse events. 
 
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse event. 
If a serious adverse event occurs, expedited reporting will follow local regulations, as appropriate. All 
adverse events will be reported on the adverse event page(s) of the CRF. It should be noted that the 
form for collection of serious adverse event information is not the same as the adverse event CRF. 
Where the same data are collected, the forms must be completed in a consistent manner. For 
example, the same adverse event term should be used on both forms. Adverse events should be 
reported using concise medical terminology on the CRFs as well as on the form for collection of 
serious adverse event information. 
 
If a serious adverse event occurs, Pfizer is to be notified within 24 hours of awareness of the event 
by the investigator. In particular, if the serious adverse event is fatal or life-threatening, notification to 
Pfizer must be made immediately, irrespective of the extent of available adverse event information. 
This timeframe also applies to additional new information (follow-up) on previously forwarded 
serious adverse event reports. In the rare event that the investigator does not become aware of the 
occurrence of a serious adverse event immediately (eg, if an outpatient trial subject initially seeks 
treatment elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event. 
 
For all serious adverse events, the investigator is obligated to pursue and provide information to 
Pfizer in accordance with the timeframes for reporting specified above. In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an expedited 
fashion. This information may be more detailed than that captured on the adverse event case report 
form. In general, this will include a description of the adverse event in sufficient detail to allow for a 
complete medical assessment of the case and independent determination of possible causality. 


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ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue 
Amended: 13-OCT-2015 
Page 35 of 41 
 
 
must be provided. In the case of a subject death, a summary of available autopsy findings must be 
submitted as soon as possible to Pfizer or its designated representative. 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
For tumor screening testing, the patient may consent by fax and, if found eligible, will re- 
consent in person prior to trial initiation. 
 
 
19.0 
REFERENCES 
 
Dickson, MA, Tap WD, Keohan MK, et al.  Phase II Trial of the CDK4 inhibitor PD0332991 in 
Patients with Advanced CDK4-amplified Well-Differentiated or Dedifferentiated 
Liposarcoma.  J Clin Onc, 2013, in press. 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. 
 
Karpeh MS, Brennan MF, Cance WG, et al. Altered patterns of retinoblastoma gene product 
expression in adult soft-tissue sarcomas. Br J Cancer. 1995;72:986-991. 
 
Lorigan P, Verweij J, Papai Z, et al. Phase III trial of two investigational schedules of 


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Page  36 of 41 
 
 
sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and 
Bone Sarcoma Group Study. J Clin Oncol. 2007;25:3144-3150. 
 
Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and 
docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: 
results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin 
Oncol. 2007;25:2755-2763. 
 
O’Dwyer P, LoRusso P, DeMichele A, et al. A phase I dose escalation trial of a daily oral 
CDK 4/6 inhibitor PD-0332991 J Clin Oncol 2007;25:Abstr 3550. 
 
Singer S, Socci ND, Ambrosini G, et al. Gene expression profiling of liposarcoma identifies 
distinct biological types/subtypes and potential therapeutic targets in well-differentiated and 
dedifferentiated liposarcoma. Cancer Res. 2007;67:6626-6636. 
 
Sirvent N, Coindre JM, Maire G, et al. Detection of MDM2-CDK4 amplification by 
fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in 
diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time 
PCR. Am J Surg Pathol. 2007;31:1476-1489. 
 
Van Glabbeke M, Verweij J, Judson I, Nielsen OS. Progression-free rate as the principal 
end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer. 2002;38:543-549. 
 
Vaughn DJ, Flaherty K, Lal P, et al. Treatment of growing teratoma syn 
drome. N Engl J Med. 2009;360:423-424. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20.0 
APPENDICES 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-094 A(18) 
Amended: 13-OCT-2015 
Page  37 of 41 
 
 
10-094: A Phase II Study of Palbociclib in Patients with Advanced or Metastatic 
Liposarcoma 
 
PATIENT MEDICATION LOG FOR Palbociclib   2/1 schedule 
 
NAME:  
  MRN:  
CYCLE:  
WEEK:  
 
 
Number of Pills given: 
Number of Pills Returned: 
 
Pill Bottle (s) returned: Circle   Yes   or  No 
Total Daily Dose:   
 
 
Day # 
Date 
Time Dose Taken 
Taken with 
food 
(Yes or No) 
Please 
Circle One 
# of 
Capsules 
Taken 
1 
A.M  P.M 
2 
A.M  P.M 
3 
A.M  P.M 
4 
A.M  P.M 
5 
A.M  P.M 
6 
A.M  P.M 
7 
A.M  P.M 
8 
A.M  P.M 
9 
A.M  P.M 
10 
A.M  P.M 
11 
A.M  P.M 
12 
A.M  P.M 
13 
A.M  P.M 
14 
A.M  P.M 
INSTRUCTIONS: Please remember to take medication with food. This log should be filled in 
each time you take any medication at home and returned upon your next clinic visit or when the 
form is completed. 
 
Patient Signature: 
  
 
 
Date:   
_ 
*The patient states he/she has taken the medication as documented above. 
 
Consenting Professional/RN Signature:   
_   Date:   
 
 
Consenting Professional/RN Comments: 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-094 A(18) 
Amended: 13-OCT-2015 
Page  38 of 41 
 
 
10-094: A Phase II Study of Palbociclib in Patients with Advanced or Metastatic 
Liposarcoma 
 
PATIENT MEDICATION LOG FOR Palbociclib 
3/1 schedule 
 
 
 
NAME:  
  MRN: 
CYCLE: 
WEEK:  
 
 
Number of Pills given: 
Number of Pills Returned: 
 
Pill Bottle (s) returned: Circle   Yes   or  No 
Total Daily Dose:   
 
 
 
 
Day # 
Date 
Time Dose Taken 
Taken with 
food 
(Yes or No) 
Please 
Circle One 
# of 
Capsules 
Taken 
1 
A.M  P.M 
2 
A.M  P.M 
3 
A.M  P.M 
4 
A.M  P.M 
5 
A.M  P.M 
6 
A.M  P.M 
7 
A.M  P.M 
8 
A.M  P.M 
9 
A.M  P.M 
10 
A.M  P.M 
11 
A.M  P.M 
12 
A.M  P.M 
13 
A.M  P.M 
14 
A.M  P.M 
15 
A.M  P.M 
16 
A.M  P.M 
17 
A.M  P.M 
18 
A.M  P.M 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-094 A(18) 
Amended: 13-OCT-2015 
Page  39 of 41 
 
 
Day # 
Date 
Time Dose Taken 
Taken with 
food 
(Yes or No) 
Please 
Circle One 
# of 
Capsules 
Taken 
19 
A.M  P.M 
20 
A.M  P.M 
21 
A.M  P.M 
 
 
INSTRUCTIONS: Please remember to take medication with food.  This log should be filled in 
each time you take any medication at home and returned upon your next clinic visit or when the 
form is completed. 
 
Patient Signature: 
  
 
 
Date:   
_ 
*The patient states he/she has taken the medication as documented above. 
 
Consenting Professional/RN Signature:   
_   Date:   
 
 
Consenting Professional/RN Comments: 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-094 A(18) 
Amended: 13-OCT-2015 
Page  40 of 41 
 
 
APPENDIX B 
LIST OF CYP3A4 INHIBITORS AND INDUCERS 
CYP3A4 Inhibitors 
 
Acetominophen 
Acetazolamide 
Amiodarone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffeine 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetidine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dasatinib (1) 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice (2) 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Ranolazine 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Voriconazole 
Zafirlukast 
Ziprasidone 
 
CYP3A4 Inducers 
 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin 
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin 
Rifapentine 
St. John’s wort (3) 
 
When Palbociclib is co-administered with compounds classified as ‘inhibitors’, increased plasma concentrations of Palbociclib 
is the potential outcome. The co-administration of ‘inducers’ would potentially lower plasma Palbociclib concentrations. 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, Goldman MP, 
Lance LL eds. Drug Information  Handbook 15
TH ed. Hudson, OH; LexiComp Inc. 2007: 1899-1912. 
Only major substrates and effective inducers are listed. 
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at 
http://medicine.iupui.edu/flockhart/. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-094 A(18) 
Amended: 13-OCT-2015 
Page  41 of 41 
 
 
 
 
Appendix C 
 
ECOG 
KARNOFSKY 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (e.g., light housework, 
office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional 
assistance, but is able to care 
for most of his/her needs. 
50 
Requires considerable 
assistance and frequent 
medical care. 
3 
In bed >50% of the time. 
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special 
care and assistance. 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not 
imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead 
0 
Dead