CDK4/6 Inhibition in Locally Advanced/Metastatic Chordoma (NCT-PMO-1601)
Phase: PHASE2
Conditions: Chordoma
Sponsor: University Hospital Heidelberg

 
 
 
 
 
Clinical Trial Protocol 
 
 
CDK4/6 inhibition in locally advanced/metastatic 
chordoma 
NCT-PMO-1601 
 
 
 
 
 
Clinical Trial Code: 
NCT-2016-415 / Chordoma 
EudraCT No.: 
2016-004660-19 
Clinical Phase: 
Therapeutic exploratory (Phase II)  
Version and date: 
Version 2.0, 16.11.2020 
Sponsor: 
Heidelberg University Hospital 
 
represented in law by its acting Commercial Director 
 
Katrin Erk 
 
Im Neuenheimer Feld 672, 69120 Heidelberg, Germany 
 
Phone +49 (0)6221 56 7000 
 
Fax: +49 (0)6221 56 4888 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL: This protocol contains confidential information and is intended solely for the guidance of 
the clinical investigation. This protocol may not be disclosed to parties not associated with the clinical 
investigation or used for any purpose without the prior written consent of the Principal Investigator/  
Coordinating Investigator. 

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Responsibilities  
 
Coordinating Investigator (Leiter der 
klinischen Prüfung*) 
Sponsor 
Prof. Dr. Richard F. Schlenk 
National Center for Tumor Diseases (NCT) 
 
Im Neuenheimer Feld 460 
69120 Heidelberg, Germany 
Phone: +49 / 6221 / 56-6228 
Fax: +49 / 6221 / 56-5863 
E-Mail: richard.schlenk@nct-heidelberg.de  
  
Heidelberg University Hospital 
represented in law by its Commercial 
Director Ms. Katrin Erk 
Im Neuenheimer Feld 672 
69120 Heidelberg, Germany  
Phone: +49 (0)6221 56 7000 
Fax: +49 (0)6221 56 4888 
E-mail: kaufmaennische-
direktorin@med.uni-heidelberg.de 
* According to § 40 German Drug Law (AMG) 
 
 
 
Scientific Coordinator  
Co-Coordinating Investigator 
Prof. Dr. Stefan Fröhling 
National Center for Tumor Diseases (NCT) 
Im Neuenheimer Feld 460 
69120 Heidelberg, Germany  
Dr. med. Christoph E. Heilig 
National Center for Tumor Diseases (NCT) 
Im Neuenheimer Feld 460 
69120 Heidelberg, Germany  
Phone: +49 (0)6221 56-35212 
Fax: +49 (0)6221 56-5389 
E-Mail: stefan.froehling@nct-heidelberg.de 
Phone: +49 (0)6221 56 32613 
Fax: +49 (0)6221 56 33548 
E-Mail: christoph.heilig@nct-
heidelberg.de 
 
 
 
Trial Coordination 
Data Management  
NCT Trial Center 
Im Neuenheimer Feld 130/3 
69120 Heidelberg, Germany 
NCT Trial Center 
Im Neuenheimer Feld 130/3 
69120 Heidelberg, Germany 
Phone: +49 (0)6221 56 6294 
Fax: +49 (0)6221 56 5863 
E-Mail: studienzentrale@nct-heidelberg.de 
Phone: +49 (0)6221 56-6294 
Fax: +49 (0)6221 56-5861 
E-Mail: studienzentrale_dm@nct-
heidelberg.de  
 
 
Biometrics 
Clinical Monitoring and 
Pharmacovigilance 
Lisa-Marie Rother 
NCT Trial Center 
Im Neuenheimer Feld 130/3 
69120 Heidelberg, Germany 
 
Coordination Centre for Clinical Trials 
(KKS)  
Heidelberg University Hospital 
Im Neuenheimer Feld 130/3 
69120 Heidelberg, Germany 
Phone: +49 (0)6221 56 6085 
Fax: +49 (0)6221 56 5863 
E-Mail: lisa-marie.rother@nct-heidelberg.de 
Phone:+49 (0)6221 56-34500 
Fax: +49 (0)6221 56-33508 

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E-Mail: 
V-KKS.SAE@med.uni-
heidelberg.de 
 
 
Patient reported outcomes Prof. Dr. Karen 
Steindorf 
Central Reference Pathology 
Division of Physical Activity, Prevention and 
CancerGerman Cancer Research Center 
Im Neuenheimer Feld 460 
D-69120 Heidelberg 
Phone: +49 (0)6221 42 2351  
E-Mail: k.steindorf@dkfz.de 
Prof. Dr. med. Thomas F.E. Barth 
Institute of Pathology, M23 
University of Ulm 
Albert-Einstein-Allee 11 
89075 Ulm  
Phone: +49 (0)731 / 500-56340  
Fax: +49 (0)731 / 500-56384 
Email: thomas.barth@uniklinik-ulm.de 
 
 
Summary 
Chordoma is a rare bone tumor with slow growth. The standard treatment is en bloc excision, but 
the site of origin of the disease often prevents complete resection. For these patients, debulking 
surgery followed by radiation therapy (RT) or high-dose RT alone can be an alternative. However, 
local relapses or more rarely metastatic disease frequently occur, and there is no efficient 
standard systemic therapy available. Only very limited responses are seen with chemotherapy or 
targeted agents, such as imatinib and lapatinib. In chordoma cell lines and patient biopsies, the 
p16 (cyclin-dependent kinase Inhibitor 2a, CDKN2A) tumor suppressor is consistently deleted. 
Thus, chordomas are an example of a tumor with universal activation of the cyclin-dependent 
kinases 4 and 6 (CDK4/6) pathway, and experiments with patient-derived chordoma cell lines 
demonstrate aberrant CDK4/6 activity downstream of p16 loss can be efficiently inhibited by the 
CDK4/6 inhibitor palbociclib, resulting in reduced proliferation and growth of neoplastic cells. We 
aim to conduct a phase II clinical trial to evaluate the efficacy of the small-molecule CDK4/6 
inhibitor palbociclib in patients with locally advanced/metastatic chordoma who are not candidates 
for standard therapy. The primary objective is disease control in patients with chordoma treated 
with palbociclib as single agent. The study design of this phase-II study is based on a Simon two-
stage design. Correlative laboratory investigations includes extensive molecular screening at 
study entry, systematic biobanking, and correlative studies in primary samples and cell lines. 
Together, this trial establishes whether the overreliance of chordomas on the activation of the 
CDK4/6-Retinoblastoma 1 (RB1) pathway can be exploited for therapeutic benefit. Based on 
previous experience with 125 mg palbociclib once daily for 21 days followed by 7 days of rest in 
patients with breast cancer, liposarcoma, non-small cell lung cancer, hepatocellular carcinoma, 
ovarian cancer, mantle-cell lymphoma, and glioblastoma, this regimen is chosen. Based on a 
Simon optimal two-stage design, the disease control rate (DCR) is  the primary endpoint, whereby 
response is defined as complete response (CR), partial response (PR), or stable disease (SD) 
according to RECIST v1.1 criteria after six cycles. For sample size calculation, we estimate a poor 
response with 10% and a good response with 25% (power, 80%; alpha, 5%) leading to a first 
stage of 18 patients and, if three or more patients responded, to a second stage with additional 
25 patients (total n=43). 
 
 
 

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Zusammenfassung 
Chordome werden zu den Knochentumoren gezählt, obwohl sie nicht aus Knochengewebe 
stammen. Sie leiten sich aus Resten der Chorda dorsalis her und treten deshalb präferentiell an 
Schädelbasis und Steißbein an den Enden der Wirbelsäule auf. Die Standardtherapie ist eine 
chirurgische en bloc Resektion; wenn diese aufgrund der Lokalisation nicht möglich ist, dann ist 
ein chirurgisches Debulking gefolgt von Strahlentherapie eine alternative Therapieoption. 
Allerdings treten häufig lokale Rezidive und gelegentlich eine Metastasierung der Erkrankung auf. 
In diesem Stadium der Erkrankung steht aktuell keine Standardtherapie zur Verfügung. 
Therapeutische Ansätze mit zytostatischer Chemotherapie oder zielgerichteten Ansätzen mit 
Imatinib oder Lapatinib führen zu insgesamt niedrigen Ansprechraten. In Chordomzelllinien und 
primärem Tumormaterial ist der Tumorsuppressor p16 (Cyclin-dependent kinase Inhibitor 2a, 
CDKN2A) regelhaft deletiert. Somit sind Chordome eine beispielhafte Tumorentität mit einer 
universellen CDK4/6-Aktivierung. Experimente mit aus Patienten gewonnenen Chordom-
Zelllinien zeigen, dass die aberrante CDK4/6-Aktivität „downstream“ von p16 mit dem 
spezifischen CDK4/6-Inhibitor Palbociclib gehemmt werden kann, mit einer deutlich reduzierten 
Proliferationsrate. Unser Ziel ist eine Phase-II Studie mit dem CDK4/6 Inhibitor Palbociclib bei 
Patienten mit lokal fortgeschrittenen bzw. metastasierten Chordomen, die nicht mit einer 
Standardtherapie behandelt werden können, durchzuführen. Das Studiendesign dieser Phase-II 
Studie fußt auf dem Simon two-stage design mit dem primären Endpunkt Ansprechen, welcher 
die Grade komplette Remission (CR), partielle Remission (PR), sowie stabile Erkrankung (SD) 
umfasst. 
Begleituntersuchungen 
mit 
molekularem 
Profiling 
bei 
Studieneinschluss, 
systematisches Biobanking, und korrelative Untersuchungen an Primärmaterial und Zelllinien 
sind vorgesehen. Diese Studie wird zeigen, ob die Abhängigkeit von Chordomen vom CDK4/6-
Retinoblastoma 1 (RB1) Signalweg therapeutisch nutzbar ist. Basierend auf vorhergehenden 
klinischen Studien wird die Dosis von 125 mg Palbociclib einmal täglich über 21 Tage gefolgt von 
7 Tagen Therapiepause wie bereits bei Patienten mit Brustkrebs, Liposarkomen, kleinzelligem 
Lungenkarzinom, hepatozellulärem Karzinom, Ovarialkarzinom, Mantelzell-Lymphom und 
Glioblastom eingesetzt, als sicher eingeschätzt. Der primäre Endpunkt wird in Abwesenheit eines 
klinisch offensichtlichen Progresses nach 6 Monaten überprüft. Für die Fallzahlkalkulation wurde 
eine schlechte Ansprechrate mit 10% und eine gute Ansprechrate mit 25% (power, 80%; alpha, 
5%) definiert. Dies führt zu einer Fallzahl von 18 Patienten in der ersten Stufe und, bei 
Ansprechen von 3 oder mehr Patienten, zu weiteren 25 Patienten in der zweiten Stufe (Gesamt 
n=43). 
 

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Table of Contents 
RESPONSIBILITIES .................................................................................................................. 2 
SUMMARY ................................................................................................................................. 3 
ZUSAMMENFASSUNG ............................................................................................................. 4 
TABLE OF CONTENTS ............................................................................................................. 5 
PROTOCOL SYNOPSIS ............................................................................................................ 8 
ABBREVIATIONS .................................................................................................................... 15 
1 INTRODUCTION ................................................................................................................... 17 
1.1 
SCIENTIFIC BACKGROUND .............................................................................................. 17 
1.1.1 Palbociclib ................................................................................................................. 17 
1.1.2 Chordomas ............................................................................................................... 18 
1.2 TRIAL RATIONALE/BENEFIT-RISK ASSESSMENT ................................................................... 18 
1.2.1 Trial Rationale ........................................................................................................... 18 
1.2.2 Benefit-Risk Assessment .......................................................................................... 18 
1.4 REFERENCE COMMITTEES ................................................................................................. 19 
1.4.1 Independent Data Monitoring Committee (IDMC) ...................................................... 19 
2 TRIAL OBJECTIVES ............................................................................................................ 19 
2.1 PRIMARY OBJECTIVE ......................................................................................................... 19 
2.2 SECONDARY OBJECTIVES .................................................................................................. 19 
3 TRIAL DESIGN ..................................................................................................................... 20 
4 TRIAL DURATION AND SCHEDULE ................................................................................... 20 
5 SELECTION OF PATIENTS ................................................................................................. 20 
5.1 NUMBER OF PATIENTS AND RECRUITMENT .......................................................................... 20 
5.2 GENERAL CRITERIA FOR PATIENT SELECTION ..................................................................... 21 
5.3 INCLUSION CRITERIA ......................................................................................................... 21 
5.4 EXCLUSION CRITERIA ........................................................................................................ 21 
5.5 CRITERIA FOR WITHDRAWAL .............................................................................................. 22 
5.5.1 Withdrawal of Patients .............................................................................................. 22 
5.5.2 Handling of Withdrawals ............................................................................................ 22 
5.5.3 Replacement of Patients ........................................................................................... 23 
5.5.4 Premature Closure of the Clinical Trial or a Single Center ......................................... 23 
5.6 PRIOR AND CONCOMITANT ILLNESSES ................................................................................ 23 
5.7 BACKGROUND MEDICATION ............................................................................................... 23 
5.8 PRIOR AND CONCOMITANT MEDICATION ............................................................................. 23 
5.8.1 Supportive Care ........................................................................................................ 23 
5.8.2 Other Permitted Concomitant Medications ................................................................ 24 
5.8.3 Prohibited Medications During Therapy With Palbociclib and Interactions With Strong 
Inhibitors/Inducers of Cytochrome P450-3A4 ..................................................................... 24 
6 INVESTIGATIONAL MEDICINAL PRODUCT/-S .................................................................. 24 
6.1 GENERAL INFORMATION ABOUT INVESTIGATIONAL MEDICINAL PRODUCT/-S .......................... 24 
6.2 THERAPEUTIC/DIAGNOSTIC EFFECTS ................................................................................. 25 
6.3 KNOWN SIDE EFFECTS ...................................................................................................... 25 
6.4 DOSAGE SCHEDULE .......................................................................................................... 26 
6.4.1 Dosage ..................................................................................................................... 26 
6.4.2 Dosage Adjustment ................................................................................................... 26 
6.5 TREATMENT ASSIGNMENT .................................................................................................. 26 
6.6 RANDOMIZATION AND BLINDING ......................................................................................... 26 
6.7 PACKAGING AND LABELING ................................................................................................ 27 
6.8 SUPPLIES AND ACCOUNTABILITY ........................................................................................ 27 
6.9 COMPLIANCE .................................................................................................................... 27 
7 TRIAL METHODS ................................................................................................................. 27 
7.1 DESCRIPTION OF STUDY VISITS.......................................................................................... 27 
7.2 METHODS OF DATA AND SAMPLE COLLECTION .................................................................... 31 
7.2.1 Data Collection and Handling .................................................................................... 31 

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7.2.2 Sample Collection and Handling ............................................................................... 31 
7.3 MEASUREMENT OF EFFICACY PARAMETERS........................................................................ 31 
7.3.1. 
Tumor Response................................................................................................... 31 
7.4 MEASUREMENT OF SAFETY PARAMETERS ........................................................................... 32 
7.5 MEASUREMENT OF FURTHER PARAMETERS ........................................................................ 33 
8 ANCILLARY AND POST TRIAL CARE ................................................................................ 33 
9 ASSESSMENT OF SAFETY ................................................................................................. 34 
9.1 SPECIFICATION OF SAFETY PARAMETERS ........................................................................... 34 
9.1.1 Adverse Events ......................................................................................................... 34 
9.1.2 Serious Adverse Event .............................................................................................. 34 
9.1.3 Expectedness, Reference Safety Information (RSI) .................................................. 34 
9.1.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) .................................... 34 
9.2 PERIOD OF OBSERVATION AND DOCUMENTATION ................................................................ 35 
9.2.1 Grading of AEs .......................................................................................................... 35 
9.2.2 Coherence between AEs and the IMP ....................................................................... 35 
9.2.3 Outcome of AEs ........................................................................................................ 36 
9.2.4 Action taken with the IMP .......................................................................................... 36 
9.2.5 Treatment of SAE...................................................................................................... 36 
9.3 REPORTING OF SERIOUS ADVERSE EVENTS BY INVESTIGATOR ............................................ 37 
9.4 EXPEDITED REPORTING ..................................................................................................... 37 
9.5 EMERGENCY TREATMENT .................................................................................................. 37 
9.6 REPORTING REQUIREMENTS FOR PREGNANCIES ................................................................. 37 
9.6.1 
Pregnancies in Female Patients ............................................................................ 37 
9.6.2 Pregnancies in Female Partners of Male Patients ..................................................... 38 
10 STATISTICAL CONSIDERATIONS .................................................................................... 38 
10.1 STUDY DESIGN AND RESEARCH HYPOTHESIS ................................................................... 38 
10.2 SAMPLE SIZE CALCULATION ............................................................................................. 38 
10.3 ANALYSIS VARIABLES ...................................................................................................... 39 
10.3.1 Primary analysis ...................................................................................................... 39 
10.3.2 Secondary analyses ................................................................................................ 39 
10.3.3 Safety ...................................................................................................................... 39 
10.3.4 Patient Reported Outcomes (PROs) including Health-related quality of life (QoL) ... 39 
10.4 ANALYSIS POPULATIONS .................................................................................................. 40 
10.4.1 Full Analysis Population .......................................................................................... 40 
10.4.2 Per Protocol Population ........................................................................................... 40 
10.4.3 Safety Population .................................................................................................... 40 
10.5 STATISTICAL METHODS ................................................................................................... 40 
10.5.1 General Considerations........................................................................................... 40 
10.5.2 Demographic and other Baseline Characteristics .................................................... 40 
10.5.3 Study Therapy, Treatment Compliance, and Follow-up ........................................... 41 
10.5.4 Analysis of the Primary Endpoint ............................................................................. 41 
10.5.5 Analysis of the Secondary Endpoints ...................................................................... 41 
10.5.6 Handling of Missing Data ........................................................................................ 42 
10.6 INTERIM ANALYSES ......................................................................................................... 42 
10.7 SAFETY MONITORING ...................................................................................................... 42 
11 DATA MANAGEMENT ....................................................................................................... 42 
11.1 DATA COLLECTION .......................................................................................................... 42 
DATA COLLECTION CAN ONLY BE DONE BY AUTHORIZED PERSONS. ALL STUDY DATA ARE PASSWORD-
PROTECTED. THE ELECTRONIC CRF PROVIDES SEVERAL CHECKS FOR COMPLETENESS AND 
CONSISTENCY. EACH ENTRY OR CHANGE OF DATA IS TRACKED WITH NAME AND EXACT DATE. THE 
INVESTIGATOR  SIGNS THE CRF ELECTRONICALLY AS PER AGREED PROJECT PROCESS. A COPY OF 
THE ELECTRONIC CRF IS ARCHIVED AT THE STUDY SITE. ........................................................... 42 
11.2 DATA HANDLING .............................................................................................................. 42 
11.3 STORAGE AND ARCHIVING OF DATA ................................................................................. 43 
12 ETHICAL AND LEGAL ASPECTS ..................................................................................... 43 
12.1 GOOD CLINICAL PRACTICE ............................................................................................... 43 

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12.2 PATIENT INFORMATION AND INFORMED CONSENT.............................................................. 43 
12.3 CONFIDENTIALITY ............................................................................................................ 43 
12.4 RESPONSIBILITIES OF INVESTIGATOR ................................................................................ 44 
12.5 APPROVAL OF TRIAL PROTOCOL AND AMENDMENTS .......................................................... 44 
12.6 CONTINUOUS INFORMATION TO INDEPENDENT ETHICS COMMITTEE .................................... 44 
12.7 NOTIFICATION OF REGULATORY AUTHORITIES................................................................... 44 
12.8 REGISTRATION OF THE TRIAL ........................................................................................... 44 
12.9 INSURANCE ..................................................................................................................... 45 
13 QUALITY ASSURANCE ..................................................................................................... 45 
13.1 MONITORING ................................................................................................................... 45 
13.2 INSPECTIONS/ AUDITS ..................................................................................................... 45 
14 AGREEMENTS ................................................................................................................... 45 
14.1 
 FINANCING OF THE TRIAL ........................................................................................... 45 
14.2 
 DECLARATION OF INTERESTS ..................................................................................... 45 
14.3 
DISSEMINATION POLICY .............................................................................................. 46 
14.3.1 Access to data ........................................................................................................ 46 
14.3.2 Reports ................................................................................................................... 46 
15 SIGNATURES ..................................................................................................................... 47 
16 
DECLARATION OF INVESTIGATOR ............................................................................ 48 
17 
REFERENCES ............................................................................................................... 49 
 
 
 

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Protocol Synopsis 
Title 
CDK4/6 inhibition in locally advanced/metastatic chordoma   
 
Phase 
Phase II 
 
Sponsor 
Heidelberg University Hospital 
represented in law by its acting Commercial Director 
Katrin Erk 
Im Neuenheimer Feld 672, 69120 Heidelberg, Germany 
 
Coordinating Investigator (CI, LKP) 
Prof. Dr. med. Richard F. Schlenk 
 
Financing/ Status of the Sponsor  
The trial is financed by funds of Pfizer Pharma GmbH and DKFZ Heidelberg. 
Study drug is provided free-of-charge by Pfizer Pharma GmbH. 
 
Indication 
Chordoma (ICD-classification code: C41.0)  
 
Trial Population 
Inclusion Criteria 
1. Patients with locally advanced or metastatic chordoma with confirmed diagnosis in a 
reference pathology (with immunohistology for epithelial membrane antigen, S100, 
Brachyury, INI-1) not amenable to curative treatment with surgery or radiotherapy. 
2. At least one measurable tumor lesion according to RECIST 1.1 criteria 
3. Loss of p16 determined immunohistochemically or CDKN2A/B genomically, presence 
of CDK4/6 and RB1 determined immunohistochemically or by RNA sequencing. 
4. Age ≥ 18 years, no upper age limit 
5. Availability of tissue blocks preferably not older than 12 months for immunohistologic 
assessment (if no adequate material is available, re-biopsy should be considered 
before entering the study) 
6. Non-pregnant and non-nursing. Women of child-bearing potential must have a 
negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 
72 hours prior to registration (WOCBP is defined as a sexually active mature woman 
who has not undergone a hysterectomy or who has had menses at any time in the 
preceding 24 months). 
7. Women of child-bearing potential must either commit to continued abstinence from 
heterosexual intercourse or use a highly effective method of birth control (e.g. double 
barrier contraceptive method (IUD, condome), tubal ligation, or partner’s vasectomy) 
while on therapy and for 14 weeks after the last dose of therapy. Hormonal 
contraception alone is an inadequate method of birth control. Female patients must 

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agree not to donate lactation during treatment and until 14 weeks after end of 
treatment. 
8. Men must agree not to father a child and must use a latex condom during any sexual 
contact with WOCBP while receiving therapy and for 14 weeks after therapy is 
stopped, even if they have undergone successful vasectomy. Sperm donation is not 
permitted for the same time interval. 
9. Signed written informed consent  
10. Performance status ≤ 2 according to ECOG/WHO criteria 
11. Ability of patient to understand the character and individual consequences of clinical 
trial 
 
Exclusion Criteria 
1. Prior treatment with palbociclib or known intolerance/allergy to the compound or any 
ingredient (acquired or hereditary). 
2. Prior treatment with other CDK4/6 inhibitors  
3. Co-therapy with strong/potent CYP3A inducers and/or inhibitors, (e.g., clarithromycin, 
indinavir, 
itraconazol, 
ketoconazol, 
lopinavir/ritonavir, 
nefazodon, 
nelfinavir, 
posaconazol, saquinavir, telaprevir, telithromycin, voriconazol, and St. John’s Wort 
[Hypericum perforatum]) while on treatment with study drug 
4. Co-therapy with corticosteroids above 7.5 mg prednisolone/prednisone equivalent  
5. Anticancer treatment less than 2 weeks prior to study treatment 
6. Organ insufficiency: creatinine clearance <30 ml/min; total bilirubin >1.5x upper 
normal serum level; AST > upper normal serum level; abnormal blood counts; heart 
failure (New York Heart Association (NYHA) III/IV); uncontrolled hypertension; 
unstable angina; serious cardiac arrhythmia; severe obstructive or restrictive 
ventilation disorder 
7. Clinical signs of active infection (>Grade 2 according to CTCAE version 5.0) 
8. Patients with a “currently active” second malignancy other than non-melanoma skin 
cancer. Patients are not considered to have a “currently active” malignancy if they 
have completed therapy and are considered by their physician to be at less than 30% 
risk of relapse within one year. 
9. Severe neurologic or psychiatric disorder interfering with ability of giving informed 
consent 
10. Known or suspected active alcohol or drug abuse 
11. Known positivity for HIV, active HAV, HBV, or HCV infection 
12. Cytopenia: platelets <100 G/l, neutrophils <1.0 G/l, hemoglobin <10.0 g/dl 
13. Corrected QT interval (QTcB) >470 msec (based on the mean value of triplicate 
ECGs), family or personal history of long or short QT syndrome, Brugada syndrome, 
or known history of QTcB prolongation or Torsade de Pointes 
14. Uncontrolled electrolyte disorders that can aggravate the effects of a QTcB-prolonging 
drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia) 
15. Participation in other ongoing interventional clinical trials (according to AMG) within 4 
weeks prior to study treatment.  
 
Objectives 
Primary objective of this phase II trial is to gain first evidence of antitumor activity of palbociclib 
in adult patients with (locally) advanced or metastasized chordoma not amenable to curative 
treatment with surgery or radiotherapy. 
 

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The primary endpoint is the disease control rate (DCR) after six cycles of palbociclib, which 
is defined as the presence of complete response (CR) or partial response (PR) or stable 
disease (SD) according to RECIST version 1.1. 
   
Secondary Objectives include: 
1. Tumor response rate (TRR) according to RECIST version 1.1 
2. Progression-free survival (PFS) 
3. Overall survival (OS) 
4. Safety/tolerability 
5. Patient reported outcome including Quality of life  
 
Trial Design 
Non-randomized, single-arm, open-label, multicenter phase II trial, designed to gain first 
evidence of antitumor activity of palbociclib in adult patients with (locally) advanced or 
metastatic chordoma. A total of 18 (stage I) or 43 patients (stages I+II) evaluable for the 
primary outcome (DCR) need to be treated guided by Simon's optimal two-stage design. 
 
Investigational Medicinal Product(s) 
Palbociclib (Ibrance®) 125 mg, 100 mg or 75 mg Capsule/Tablet 
Sample Size  
18 in the first stage  
25 in the second stage (only if first stage was positive) 
Total sample size: minimum 18 patients; maximum 43 patients 
 
Statistical Analysis 
The study is a phase II trial with a standard palbociclib dose of 125 mg once daily for 21 days 
in a 28-day cycle.  
 
The study needs 43 patients evaluable for the primary endpoint to complete. The sample size 
and power calculations were based on Simon's optimal two-stage design (Simon, 1989). The 
type I error was set at  = 0.05, the type II error at  = 0.2. Here, the null hypothesis that the 
true response rate is less or equal to p0 = 0.1 is tested against a one-sided alternative, where 
the desirable level of response is 0.25.  
 
In the first stage, n1 = 18 patients are accrued. If there are r1 = 2 or fewer responses in these 
18 patients, the study is stopped. Otherwise, 25 additional patients are accrued for a total of 
n = 43 patients. In the final analysis the null hypothesis is rejected and the drug recommended 
for further development if 8 or more responses are observed in 43 patients. 
 
Trial Duration and Dates 
Total trial duration: 
66 months 
Duration of the clinical phase: 
54 months 
First patient first visit (FPFV): 
4 Quarter 2017 
Last patient first visit (LPFV): 
2 Quarter 2021 
Last patient last visit (LPLV):  
2 Quarter 2022 
Trial Report completed: 
2 Quarter 2023 
 

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Protocol Activities 
and Forms to be completed 
Baseline 
On Treatment Cycles  
(1 cycle = 28 days) 
Primary 
efficacy 
assessment 
Extended 
treatment period 
(ExT)1 
Follow-Up Period1, 
Follow-Up after stop of 
treatment 
Survival 
follow-up 
Cycle 
 28 days 
1 
1 
1 
1 
2 
2 
3 
4 
5 
6 
Day 29 of last 
(6th) cycle  
or when 
applicable 
before 
day 1 of each cycle; 
until 
progression/EOT 
 
3 month 
after stop 
of study 
treatment 
 
6 month 
after stopf 
of study 
tretament 
Every 3 
month 
Visit description  
On treatment: +/- 2 days 
During follow up: +/- 1 week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ExT-X 
F-UP-3 
F-UP-6 
SF-UP-X 
Day 
Baseline 
0 
7 
14 
21 
28 
42 
56 
84 
112 140 
169 
 
 
 
 
Informed consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General medical and 
Oncologic history4a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In- and Exclusion Criteria 4b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signs/symptoms5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs6 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Physical examination6 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Signs and symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG8 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory and Clinical Assessments 
 
 
 
Hematology (local lab)9  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Blood chemistry (local lab)10a 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Coagulation (local lab)10b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (local lab)11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HAV, HBV, HCV, HIV-1 
testing (local lab)12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test and 
counseling as well as 
counseling in cryo-
preservation of oocyte or 
sperm (local lab)13 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Pathology, 
immunohistochemistry14  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging (local assessment)15  
X 
 
 
 
 
 
 
 
X 
 
 
X 
 X 
 every 12 weeks after 
X 
X 
 

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V11 
Samples for biobanking 
(central lab Heidelberg)16  
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
every 3 treatment 
cycles 
 
 
 
Enrollment17  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
Distribution of Palbociclib18 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X  
in case of 
benefit 
X 
 
 
 
Assessment of Concomitant 
medications19 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AE assessments20 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
PRO  assessment21 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
every 3 treatment 
cycles 
X 
X 
 
Survival Follow up 
assessments22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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Footnotes for schedule of events: 
1. 
Observation time for all patients is expected to be at least 12 months after entry into the study. Patients  
receive palbociclib for 6 cycles. At day 29 of the 6th cycle Primary efficacy assessment  takes place. In 
case of clinical benefit patients may continue with palbociclib therapy and are  followed until progression 
or end of trial (Extended Treatment Period). There is a regular follow-up of 6 months after end of 
treatment. During follow-up every 3 months patient reported outcomes including quality of life are  
assessed and the investigator should make an assessment on tumor development. All Patients with 
ongoing drug-related toxicities must be followed until all drug-related toxicities are resolved.  
2. 
Informed consent and patient assignment: every patient must sign the informed consent to participate in 
this trial before starting any trial-related procedures. After signature, the patient study ID is  assigned 
automatically when a data set of a new patient is created in eCRF. 
3. 
Demographics: gender, year of birth, ethnicity 
4. 
a) General Medical and oncologic history: date of first diagnosis, detailed information on pretreatment 
including type and composition of prior therapy as well as response to prior therapy, , detailed information 
on disease progression according to RECIST v1.1 criteria over the last 6 months prior to study inclusion, 
family history, additional medical history on concomitant diseases, prior exposure to toxic agents, prior 
malignancy including therapy, information on smoking; tumor staging according to UICC (TNM) 
b) Inclusion / Exclusion Criteria:  
    At Baseline, all inclusion/ Exclusion criteria as defined in chapter 5.3 and 5.4 are assessed. 
5. 
Signs/symptoms: chordoma-related and unrelated signs and symptoms 
6. 
Vital signs: At baseline and at the start of every new cycle: weight (in kg), WHO performance status, 
temperature (in grade centigrade), blood pressure/pulse; at baseline additionally height (in cm).  
Physical examination at baseline and at the start of every new cycle: inspection, abdominal, cardiac and 
lung auscultation, palpation of the abdomen and lymph node sites, neurological examination  
7. 
ECHO: at baseline and thereafter at investigator’s discretion. If abnormal at baseline, ejection fraction 
(EF) to be quantified, and thereafter in case of of abnormal findings. EF should be specified according to 
Simpson.  
8. 
ECG: 12-lead study, at baseline, during the first treatment cycle every week, and thereafter at 
investigator’s discretion 
9. 
Hematology (local lab): hemoglobin, RBC, PLT, WBC. Differential cell counts should be performed at 
baseline, weekly during the first treatment cycle, on Day 1 and Day 14 (+/- 2 days) of second cycle, in 
each first week during following cycles, at Primary efficacy assessment, and in the first week of each 
cycle during Extended Treatment Period. Clinical status and laboratory parameters are to be followed 
using individual institutional guidelines and the best clinical judgment of the responsible physician, which 
can involve more frequent testing, especially in neutropenic/aplastic patients. It is expected that patients 
on this protocol are cared for by physicians experienced in the treatment and supportive care. 
10. a) Blood chemistry (local lab): BUN, creatinine, albumin, AST/SGOT, ALT/SGPT, total bilirubin, AP, LDH, 
sodium, potassium, magnesium, calcium, serum uric acid: at baseline and then once a week during the 
first treatment cycle, in each first week during following cycles, at Primary efficacy assessment, and in 
each first week during Extended Treatment Period, or to be followed using individual institutional 
guidelines and the best clinical judgment of the responsible physician, which can involve more frequent 
testing.  
b) Coagulation: Prothrombin time , aPTT and fibrinogen are  measured at baseline and at investigator’s 
discretion during treatment. 
11. Urinalysis (local lab): pH, glucose, proteins (qualitative, dipstick accepted): at baseline and at 
investigator’s discretion during treatment 
12. HAV, HBV, HCV, and HIV-1 testing: at baseline and thereafter at investigator’s discretion 
13. Serum/urine pregnancy test (local lab, sensitivity of at least 25 mIU/mL): in WOCBP, a pregnancy test 
must be performed at baseline ( 72h prior to patient registration). In addition, WOCBP and male patients 
must be counseled to avoid getting pregnant or to father a child within three months after the last 
application of therapy. 
Serum/urine pregnancy test must be repeated at cycle 3 and at the end of  the 6th cycle. 
14. Pathology and Immunohistochemistry at baseline: tissue blocks preferably not older than 12 months are 
requested either from initial diagnosis or from biopsies of locally advanced disease or metastatic sites. 
Re-biopsy should be performed in any case if no adequate material is available. Samples must be 
shipped to Central Pathology Ulm.  

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15. Imaging/ Local assessment: MRI/CT should be available at the time of study entry. MRI/CT scan should 
not be older than 2 weeks and include all known chordoma manifestations. Tumor imaging is part of the 
clinical routine (for assessment details see 7.3.1). The choice of either MRI or CT depends on tumor 
localization and is at investigator’s discretion. For chordoma of the axial skeleton, including sacral or 
clival tumors, MRI is recommended. The imaging method should not be changed after study entry. 
During study treatment imaging should be performed on day 1 (+/- 2 days) of cycle 4, day 1 (+/- 2 days) 
after cycle 6 (primary efficacy assessment) or when progression/relapse occurs. During extended 
treatment Imaging should be performed every 12 (+ max. 4) weeks and during follow-up 3 month after 
stop of study treatmend (+/- 1 week) as well as 6 months after stop of study treatment.  
16. Procurement of Samples for Biobanking at NCT Heidelberg: 40 ml blood (for details see sample 
shipping instructions) should be sent at baseline, at the beginning of each treatment cycle, every three 
treatment cycles in responding patients (Extended Treatment Period) and at relapse (if CR or PR was 
achieved)  
17. Enrollment: at the end of baseline visit the investigator verifies inclusion and exclusion criteria and 
confirms patient enrollment with his signature. 
18. Palbociclib is  taken orally by the patient on days 1-21 of each treatment cycle (28 days). 
19. Concomitant medications should be reported in the relevant case report form (CRF) pages, including 
supportive care drugs, prophylaxis with antiemetics, and drugs used for treating AEs or chronic diseases. 
20. AE assessments: Events should be documented and recorded continuously. Patients must be followed 
for AEs from first palbociclib administration up to 28 days after last study drug administration or until all 
drug-related toxicities have been resolved, whichever is later, or until the investigator assesses AEs as 
“chronic” or “stable”. However, if the patient commences alternative anti-cancer therapy < 28 days after 
the last dose of study drug administration, the AE reporting period  ends at the time the new treatment is 
started. Each AE must be reported once per cycle, indicating the worst CTCAE (Version 5.0) grade. If an 
event stops and later restarts within the same cycle, all occurrences must be reported. A specific 
procedure for definition and reporting of SAEs is described in protocol section 9.3. 
21. Patient reported Outcomes (PRO) including Quality of life (QoL):  assessed by questionnaires of the 
EORTC Quality of Life Item Library (core questionnaire QLQ-C30, fatigue module QLQ-FA12, and 
selected symptom items), as well as the Pittsburgh Sleep Quality Index (PSQI), the Patient Health 
Questionnaire for Anxiety and Depression (PHQ-4), and the Functional Assessment of Cancer Therapy 
- cognitive function scale (FACT-cog). In addition, patient-reported information on personal traits and 
experiences are collected at baseline. Assessments are performed  at the beginning of the 2nd cycle, 
and after the sixth cycle, during follow-up every 3 months, and every three treatment cycles in 
responding patients (Extended Treatment Period). 
22. Follow-up assessment: further oncological treatment e.g. chemotheraphy and radiotherapy, vital status 
and disease status according to RECIST 1.1 criteria. 
 

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Abbreviations 
AE 
 
 
Adverse Event 
ALT  
 
 
Alanine Amino Transferase, also known as SGPT 
AST   
 
Aspartate Amino Transferase, also known as SGOT 
AP 
 
 
Alkaline Phosphatase   
AMG  
 
German Drug Law (Deutsches Arzneimittelgesetz) 
BfArM  
 
Bundesinstitut für Arzneimittel und Medizinprodukte 
BUN 
 
 
Blood Urea Nitrogen 
CDK 
 
 
Cyclin-dependent kinase 
CDKN2  
 
Cyclin-dependent kinase Inhibitor 2 
CI 
 
 
Coordinating Investigator (LKP) 
CNS 
 
 
Central nervous system 
CR 
 
 
Complete Response 
CRF 
 
 
Case Report Form 
CRO  
 
Contract Research Organisation  
CTCAE 
 
Common Toxicity Criteria for Adverse Events 
DCR  
 
Disease Control Rate 
DKFZ  
 
Deutsches Krebsforschungszentrum (German Cancer Research Center) 
IDMC  
 
Independent Data Monitoring Committee 
EC 
 
 
Ethics Committee 
ECG  
 
Electrocardiogram 
ECOG  
 
Eastern Cooperative Oncology Group 
EMA  
 
European Medicines Agency 
EORTC 
 
European Organization for Research an Treatment of Cancer 
EOT   
 
End of Treatment 
ExT 
 
 
Extended treatment period 
FDA 
 
 
US Food and Drug Administration 
FPI 
 
 
First Patient In 
GCP  
 
Good Clinical Practice 
GCP-V 
 
Good Clinical Practice Ordinance (GCP-Verordnung) 
HAV 
 
 
Hepatitis A Virus 
HBV 
 
 
Hepatitis B Virus 
HCV 
 
 
Hepatitis C Virus 
HIV 
 
 
Human Immunodeficiency Virus 
IB 
 
 
Investigator´s Brochure 
IC 
 
 
Informed Consent 
ICH 
 
 
International Conference on Harmonization of Technical Requirements for 
 
 
 
Registration of Pharmaceuticals for Human Use 
ICD  
 
 
International Classification of Disease  
IIT 
 
 
Investigator Initiated Trial 
IMP 
 
 
Investigational Medicinal Product 
IMPD  
 
Investigational Medicinal Product Dossier 
INI-1  
 
Integrase interactor 1 
INN 
 
 
International Nonproprietary Name 
INR 
 
 
International Normalized Ratio 

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ISF 
 
 
Investigator Site File 
IUD 
 
 
Intrauterine device 
LDH 
 
 
Lactatdehydrogenase 
LKP 
 
 
Coordinating Investigator according to AMG (Leiter der Klinischen  
 
 
 
Prüfung) 
LPI 
 
 
Last Patient In 
LPLV  
 
Last Patient Last Visit 
n.a. 
 
 
Not applicable 
NCT 
 
 
National Center for Tumor Diseases Heidelberg 
NYHA  
 
New York Heart Association 
OS  
 
 
Overall Survival 
PD 
 
 
Progessive Disease 
PET 
 
 
Probability for Early Termination 
PFS 
 
 
Progression-free Survival 
PHQ-4  
 
Patient Health Questionnaire for Anxiety and Depression 
p.o. 
 
 
per os/ per oral/ orally 
PR 
 
 
Partial Response 
PRO  
 
Patient Reported Outcomes 
PSQI  
 
Pittsburgh Sleep Quality Index 
PTT 
 
 
Partial Thromboplastine Time 
QoL 
 
 
Quality of Life 
QTcB   
 
Corrected QT interval (Bazett's formula) 
RBC   
 
Red Blood Cell 
RB1 
 
 
Retinoblastoma 1 
RDE 
 
 
Remote Data Entry 
RECIST 
 
Response Evaluation Criteria in Solid Tumors 
RSI 
 
 
Reference Safety Information 
RT 
 
 
Radio therapy 
SAE 
 
 
Serious Adverse Event 
SAS 
 
 
Statistical Analysis Systems 
SD 
 
 
Stable Disease 
SDV 
 
 
Source Data Verification 
SGPT  
 
Serum Glutamic-Pyruvat Transaminase, also known as ALT 
SGOT  
 
Serum Glutamic-Oxaloacetic Transaminase, also known as AST 
SOP 
 
 
Standard Operating Procedure 
SPC 
 
 
Summary of Product Characteristics 
SUSAR 
 
Suspected Unexpected Serious Adverse Reaction 
TMF 
 
 
Trial Master File 
TNM  
 
TNM Classification of Malignant Tumors 
TRR 
 
 
Tumor Response Rate 
UICC  
 
Union for International Cancer Control 
WBC  
 
White Blood Cell 
WHO  
 
World Health Organization 
WOCBP 
 
Women of Childbearing Potential 

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1 Introduction 
1.1 Scientific Background 
1.1.1 Palbociclib 
Palbociclib, an orally available pyridopyrimidine, is a highly selective, reversible inhibitor of cyclin-
dependent kinases 4 and 6 (CDK4/6) that is being studied for use in cancer treatment. The 
compound prevents cellular DNA synthesis by blocking progression from the G1 to the S phase 
of the cell cycle, as demonstrated in laboratory models and early clinical trials.  
Palbociclib inhibits purified CDK4-catalyzed phosphorylation of retinoblastoma (Rb) protein with 
an IC50 of less than 20 nM. Palbociclib prevents Rb phosphorylation at serine 780 and 795, 
inducing a G1 arrest. Estimated steady-state plasma concentrations of 1,000 ng/mL resulted in 
80% to 90% inhibition of phospho-Rb formation and 50% reduction of tumor growth. Reduction in 
phospho-Rb was rapidly reversible as plasma palbociclib concentrations declined. CDK6, another 
enzyme that also complexes with cyclin-D subunits, is also commonly expressed in mammalian 
cells and tumors. CDK6 is highly homologous to CDK4 and can perform the same function by 
phosphorylating Rb, thus potentially creating a redundant mechanism to promote cell cycle 
progression. Palbociclib inhibits purified CDK6 with an IC50 of 15 nM.1 
In humans, the primary routes of metabolic clearance for [14C]-palbociclib include multiple 
oxidative pathways and a single conjugative pathway (sulfonation). Minor primary routes of 
metabolism include glucuronidation and acylation (acetylation and formylation) pathways. Based 
on the sum of radioactivity in peaks from feces and urine that can be ascribed exclusively to 
primary and secondary oxidative metabolites, greater than 50% of the clearance mechanism can 
be assigned to oxidative pathways, while primary conjugative processes (sulfonation and 
glucuronidation) contribute approximately 26% and 2%, respectively, to the overall clearance, 
with acylation (formyl and acetyl) pathways contributing less than 3%.1 
A study in 26 healthy women of non-childbearing potential evaluated drug-drug interaction with 
midazolam. This pharmacokinetic study was conducted to evaluate the potential of palbociclib to 
act as a time-dependent inhibitor of CYP3A4/5 at steady-state. Plasma midazolam Cmax and 
AUCinf values increased 1.37 and 1.61-fold, respectively, when single oral doses of midazolam 
were co-administered with multiple doses of palbociclib as compared to its administration alone. 
This is consistent with weak time-dependent CYP3A4/5 inhibition mediated by palbociclib at 
steady-state following daily 125 mg dosing.1 
Two completed phase I studies have established dosing regimens of 200 mg daily for two weeks 
of three, or 125 mg daily for three weeks in a four-week cycle.2, 3 Following repeated daily dosing 
to day 14 and day 21 (assumed to be steady-state), palbociclib was absorbed with a median Tmax 
of approximately four hours. The mean palbociclib Vz/F was 3,103 L, which is significantly greater 
than total body water (42 L), indicating that palbociclib extensively penetrates into peripheral 
tissues. Palbociclib was eliminated slowly with a mean t½ of 27 hours. Renal excretion of 
palbociclib is the minor route of elimination with ~1.7% of the drug excreted unchanged in urine 
over the 10-hour collection period after dosing with 125 mg and 200 mg. The mean renal 
clearance (CLR) is ~6.6 L/hour. 
In all clinical studies, neutropenia has been the most frequently reported adverse event. In each 
case, neutropenia was the dose-limiting toxicity and the one-week break was required for 
neutrophil recovery. This toxicity profile is likely to be a result of transient growth arrest in 
hematopoietic precursor cells.4 Gastrointestinal toxicity, alopecia, mucositis, neutropenic fever, or 
infection were rare. 
Palbociclib was tested in CDK4-amplified liposarcoma and promising results have been 
reported.5, 6 Similarly, palbociclib has also shown promising activity in mantle-cell lymphoma.7  
The development of palbociclib in breast cancer is most advanced; it has broad activity in breast 
cancer cells in vitro, especially the estrogen receptor-positive luminal type.8 Several clinical 
studies from phase I to phase III showed  impressive prolongation of progression-free survival by 

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palbociclib when given in combination with letrozole9 which led to marketing approval in US on 
03Feb2015. FDA approved IBRANCE® (palbociclib) capsules in combination with letrozole for 
the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal 
growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based 
therapy for their metastatic disease. 
The resent investigation in vivo with patient-derived chordoma cell lines demonstrated that 
downstream machinary of p16 can be efficiently inhibited by the CDK4/6 inhibitor palbociclib, 
resulting in reduced proliferation and growth of neoplastic cells10. 
1.1.2 Chordomas 
Chordomas are rare tumors considered to arise from persistent notochordal remnants along in 
the vertebral bodies10. Because of their slow growth, there is no efficient standard chemotherapy: 
therapy of choice is surgery followed by radiotherapy. After surgical therapy of this orphan 
disease, chordoma recurs in up to 50% of patients and metastasizes in 20% an more10. Only a 
minority is cured by surgery, the disease-free survival is generally short10. The median survival is 
6 to 7 years after diagnosis, although the range varies from months to 25 years. High-dose 
radiotherapy is administered for residual or recurrent disease10. Patients who have metastases 
and have inoperable recurrent disease are not eligible for further radiotherapy. Therefore, there 
is a strong unmet need for systemic pharmacologic therapy. Aggressive chemotherapy has been 
described to be effective in rare cases of dedifferentiated chordomas10. Only limited response is 
seen by therapy with alkylating agents (ifosfamid), anthracyclines (doxorubicin), and cisplatin10. 
In the first prospective phase II study with 9-nitrocamptothecin, one patient out of 15 achieved a 
partial response10. Recently, new targeted therapy options using erlotinib, cetuximab, gefitinib, 
sunitinib, thalidomide, and lapatinib have been published10. An activated platelet-derived growth 
factor receptor b (PDGFRb) was described as a basis for therapy with imatinib in patients with 
progressive disease7, 8. Because of the rarity of this tumor and only a few well characterized 
chordoma cell lines, there is limited experience with preclinical models10. Recently, systematic 
pharmacologic screening of our first published two chordoma cell lines U-CH1 and U-CH2 
chordoma cell lines, we found that the tumor suppressor p16 (CDKN2A) is deleted and that p16 
protein is not expressed in these cell lines. This deletion has been described in the majority of 
chordomas10. The downstream machinery of p16 can be efficiently inhibited by CDK4/6 inhibitors 
such as palbociclib10. Inhibition of this pathway by palbociclib is a defined mechanism to reduce 
the proliferation and growth of neoplastic cells10. 
 
1.2 Trial Rationale/Benefit-Risk Assessment  
1.2.1 Trial Rationale 
The aim of this phase II study is to gain first evidence of antitumor activity of palbociclib in patients 
with locally advanced or metastasized chordoma not amenable to surgery or radiotherapy. 
Currently, no standard treatment is available in this clinical situation and tumor control rates in 
published experimental approaches are low (<50%). Thus, there is a clear unmet medical need 
to evaluate new treatment approaches based on solid preclinical data.  
1.2.2 Benefit-Risk Assessment 
Chordoma is a rare bone tumor. The standard treatment is en bloc excision, but the site of origin 
of the disease often prevents complete surgery. For these patients, debulking surgery followed 
by radiation therapy (RT) or exclusive high-dose RT can be an alternative. However, local 
relapses occur in >50% of cases, while metastases affect >20% of patients. Systemic therapy is 
needed in patients not amenable to surgery or RT11.  
Only very limited responses are seen with chemotherapy or targeted agents, such as imatinib and 
lapatinib. However, no active drugs are approved to date11. In chordoma cell lines and patient 
biopsies, the p16 (CDKN2A) tumor suppressor is consistently deleted. Thus, chordomas are an 
example of a tumor with universal activation of the CDK4/6 pathway, and experiments with 

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patient-derived chordoma cell lines demonstrate aberrant CDK4/6 activity downstream of p16 loss 
can be efficiently inhibited by the CDK4/6 inhibitor palbociclib, resulting in reduced proliferation 
and growth of neoplastic cells. 
Palbociclib, an orally available pyridopyrimidine, is a highly selective, reversible inhibitor of CDK4 
and 6 that is being studied for use in the treatment of cancer. The most common side effects of 
palbociclib are reversible neutropenia, thrombocytopenia, anemia, fatigue, constipation, nausea, 
and diarrhea. Taking into the consideration beneficial safety profile, palbociclib may offer these 
patients a more specific and effective treatment option.  
 
1.4 Reference Committees  
1.4.1 Independent Data Monitoring Committee (IDMC) 
An IDMC is assembled. The IDMC is composed of two independent experts, assessing the 
progress and safety data. The mission of the IDMC is to ensure the ethical conduct of the trial 
and to protect the safety interests of patients in this trial. 
The IDMC meets virtually after 18 patients have finished at least one cycle of study treatment. 
Based on its review, the IDMC provides the sponsor with recommendations regarding trial 
modification, continuation or termination.  
Further details including IDMC members are specified in the IDMC charter. 
2 Trial Objectives  
2.1 Primary Objective  
Primary objective of this phase II trial is to gain first evidence of antitumor activity of palbociclib in 
adult patients with (locally) advanced or metastasized chordoma not amenable to to curative 
treatment with surgery or radiotherapy. 
 
The primary endpoint is the disease control rate (DCR) after six cycles of palbociclib, which is 
defined as the presence of complete response (CR) or partial response (PR) or stable disease 
(SD) according to RECIST version 1.1 (compare Section 7.3.1 for definitions).  
 
2.2 Secondary Objectives  
Secondary objectives include further efficacy (clinical response, survival), safety and quality of 
life analyses. 
 
Secondary endpoints: 
 
Tumor response rate (TRR), defined as the sum of complete response (CR) and partial 
response (PR) according to RECIST version 1.1 after six cycles of study medication 
(compare Section 7.3.1 for definitions). 
 Progression-free survival (PFS), defined as the time from first administration of the IMP 
to progression of disease or death from any cause, whichever occurs first. Patients without 
the event are censored on the last date of follow-up. [time frame: up to LPLV] 
 
Overall survival (OS), defined as the time from first administration of the IMP to time of 
death from any cause. Patients without the event are censored on the last date of follow-
up. [time frame: up to LPLV] 
 
Safety (toxicity, tolerability); Toxic effects are graded according to CTCAE v5.0.  
 
 Patient reported outcomes (PRO) including QoL is assessed by questionnaires of the 
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Item Library (core questionnaire QLQ-C30, fatigue module QLQ-FA12, and selected 

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symptom items), as well as the Pittsburgh Sleep Quality Index (PSQI), the Patient Health 
Questionnaire for Anxiety and Depression (PHQ-4), and the Functional Assessment of 
Cancer Therapy - cognitive function scale (FACT-cog). 
3 Trial Design  
Non-randomized, single-arm, open-label, multicenter phase II trial, designed to gain first evidence 
of antitumor activity of palbociclib in adult patients with (locally) advanced or metastatic chordoma. 
A total of 18 (stage I) or 43 patients (stages I+II) evaluable for the primary outcome (DCR) need 
to be treated guided by Simon's optimal two-stage design. 
4 Trial Duration and Schedule 
The duration of the trial for each patient is expected to be 12 months, including 6 treatment cycles 
and 6 months of follow-up. In case of clinical benefit, it will be longer.  
Each patient  remains on treatment until disease progression or other reasons for withdrawal. 
Conditions leading to patient withdrawal from the study are detailed in Section 5.5 Criteria for 
Withdrawal. Treatment response is assessed every 12 weeks according to RECIST version 1.1 
criteria. In case of progressive disease, study therapy will be stopped. In patients showing 
response or stable disease, therapy within the study is intended until progression or LPLV. After 
6 treatment cycles, primary efficacy assessment takes place. Patients are followed for 6 months 
after discontinuation of study medication. There is no further follow-up in all patients under 
treatment with palbociclib at LPLV. LPLV is 12 months after LPFV at the latest. 
Recruitment of minimally 18 and maximally 43 patients evaluable for the primary endpoint  takes 
place at 3 investigator sites in Germany. 
A recruitment period of approximately 4 years and an overall study duration of approximately 6 
years is anticipated. 
The treatment duration for an individual patient is estimated to be 2-6 months, but may be 
prolonged in patients with sustained response (“case-by-case decision”).  
After finishing all study-relevant procedures, therapy, and follow-up period, the patient is followed 
in terms of routine care and treated if necessary by the primary responsible hematology/oncology 
center. 
 
Total trial duration: 
66 months 
Duration of the clinical phase: 
54 months 
First patient first visit (FPFV): 
4 Quarter 2017 
Last patient first visit (LPFV): 
2 Quarter 2021 
Last patient last visit (LPLV):  
2 Quarter 2022 
Trial Report completed: 
2 Quarter 2023 
5 Selection of Patients 
5.1 Number of Patients and Recruitment 
As described in Section 10.2, a minimum of 18 (stage I) or 43 (stage II) patients are to be enrolled 
in the clinical trial. Expecting a number of 15 eligible patients per year with a consent rate of 
> 90%, approximately 4 years are required to recruit the intended number of patients. 
Recruitment and treatment of patients should be performed in 3 trial centers.  

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5.2 General Criteria for Patient Selection 
This clinical trial can fulfill its objectives only if appropriate patients are enrolled. The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate. All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular patient. Any questions regarding a 
patient’s eligibility should be discussed with the Coordinating Investigator or the Scientific 
Coordinator. 
5.3 Inclusion Criteria 
Both female and male patients are included in this clinical trial as the occurrence of chordoma is 
independent of gender. Patients must meet all of the following inclusion criteria to be eligible for 
enrollment into the study: 
1. Patients with locally advanced or metastatic chordoma with confirmed diagnosis in a 
reference pathology (with immunohistology for epithelial membrane antigen, S100, 
Brachyury, INI-1) not amenable to curative treatment with surgery or radiotherapy 
2. At least one measurable tumor lesion according to RECIST 1.1 criteria. 
3. Loss of p16 determined immunohistochemically or CDKN2A/B genomically, presence of 
CDK4/6 and RB1 determined immunohistochemically or by RNA sequencing.  
4. Age ≥ 18 years, no upper age limit 
5. Availability of tissue blocks preferably not older than 12 months for immunohistologic 
assessment (if no adequate material is available, re-biopsy should be considered before 
entering the study) 
6. Non-pregnant and non-nursing. Women of child-bearing potential must have a negative 
serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 72 hours prior 
to registration (WOCBP is defined as a sexually active mature woman who has not 
undergone a hysterectomy or who has had menses at any time in the preceding 24 
months). 
7. Women of child-bearing potential must either commit to continued abstinence from 
heterosexual intercourse or use a highly effective method of birth control (double barrier 
contraceptive method (IUD, condome), tubal ligation, or partner’s vasectomy) while on 
therapy and for 14 weeks after the last dose of therapy. Hormonal contraception alone is 
an inadequate method of birth control. Female patients must agree not to donate lactation 
during treatment and until 14 weeks after end of treatment. 
8. Men must agree not to father a child and must use a latex condom during any sexual 
contact with WOCBP while receiving therapy and for 14 weeks after therapy is stopped, 
even if they have undergone successful vasectomy. Sperm donation is not permitted for 
the same time interval. 
9. Signed written informed consent  
10. Performance status ≤ 2 according to ECOG/WHO criteria 
11. Ability of patient to understand the character and individual consequences of clinical trial 
 
5.4 Exclusion Criteria 
Patients fulfilling any of the following criteria cannot be included in the trial: 
1. Prior treatment with palbociclib or known intolerance/allergy to the compound or any 
ingredient (acquired or hereditary). 
2. Prior treatment with other CDK4/6 inhibitors  
3. Co-therapy with strong/potent CYP3A inducers and/or inhibitors, (e.g., Clarithromycin, 
Indinavir, 
Itraconazol, 
Ketoconazol, 
Lopinavir/Ritonavir, 
Nefazodon, 
Nelfinavir, 
Posaconazol, Saquinavir, Telaprevir, Telithromycin, Voriconazol, and St. John’s Wort 
[Hypericum perforatum])) while on treatment with study drug. 
4. Co-therapy with corticosteroids above 7.5 mg Prednisolone/Prednisone equivalent 

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5. Anticancer treatment less than 2 weeks prior to study treatment 
6. Organ insufficiency: creatinine clearance <30ml/min; total bilirubin > 1.5x upper normal 
serum level; AST > upper normal serum level ; abnormal blood counts; heart failure (New 
York Heart Association (NYHA) III/IV); uncontrolled hypertension; unstable angina; 
serious cardiac arrhythmia; severe obstructive or restrictive ventilation disorder 
7. Clinical signs of active infection (>Grade 2 according to CTCAE version 5.0) 
8. Patients with a “currently active” second malignancy other than non-melanoma skin 
cancer. Patients are not considered to have a “currently active” malignancy if they have 
completed therapy and are considered by their physician to be at less than 30% risk of 
relapse within one year. 
9. Severe neurologic or psychiatric disorder interfering with ability of giving informed consent 
10. Known or suspected active alcohol or drug abuse 
11. Known positivity for HIV, active HAV, HBV, or HCV infection 
12. Cytopenia: platelets <100 G/l, neutrophils <1.0 G/l, hemoglobin <10.0 g/dl 
13. Corrected QT interval (QTcB) >470 msec (based on the mean value of triplicate ECGs), 
family or personal history of long or short QT syndrome, Brugada syndrome, or known 
history of QTcB prolongation or Torsade de Pointes 
14. Uncontrolled electrolyte disorders that can aggravate the effects of a QTcB-prolonging 
drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia) 
15. Participation in other ongoing interventional clinical trials (according to AMG) within 4 
weeks prior to study treatment.  
No patient is  allowed to enroll in this trial more than once. 
 
5.5 Criteria for Withdrawal 
5.5.1 Withdrawal of Patients  
A patient must be withdrawn from the trial treatment or/and all trial-related procedures for the 
following reasons: 
 
At any time at their own request. Withdrawal of patient’s consent to continue therapy. 
Unresolved AEs should be followed. 
 
Unacceptable toxicity dictating cessation of treatment 
 
Changes in medical status of the patient such that the investigator believes that patient safety 
is compromised or that it would be in the best interest of the patient to stop treatment 
 
Pregnancy 
 
Non-compliance by the patient with protocol requirements 
 
Patient is lost to follow-up. If a patient does not return for scheduled visits, every effort should 
be made to re-establish contact. In any circumstance, every effort should be made to 
document patient outcome if possible. 
If the patient withdraws from the trial and also withdraws consent for disclosure of future 
information (e.g. follow-up visits), no further evaluations are allowed to be performed and no 
additional data can be collected. The sponsor may retain and continue to use any data collected 
before such withdrawal of consent. 
5.5.2 Handling of Withdrawals 
In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in the 
patient’s medical records. In case of withdrawal of a patient at his/ her own request, the reason 
should be asked for as extensively as possible and documented.  

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5.5.3 Replacement of Patients 
Patients are replaced to meet the goal of 43 patients evaluable for the primary endpoint. 
Patients who go off study due to adverse events before final staging at 6 months are considered 
treatment failures, receive reponse status = PD (progressive disease), and are not be replaced.  
Patients going off study for other reasons (drop-outs; e.g. lost-to-follow-up, death unrelated to 
disease/treatment, retracted IC, etc. without assessment of the primary outcome are replaced 
until the goal of 18 or 43 patients (as the case may be) is met. 
5.5.4 Premature Closure of the Clinical Trial or a Single Center 
The trial can be prematurely closed or suspended by the Sponsor after consulting the 
Coordinating Investigator. The Ethics Committee (EC) and the competent regulatory authorities 
must then be informed. Furthermore, the Ethics Committee(s) and competent regulatory 
authorities themselves may decide to stop or suspend the trial.  
Should the trial be closed prematurely, all trial material (completed, partially completed, and blank 
CRFs, investigational medicinal product and other material) must be returned to the Sponsor in 
Heidelberg or treated according Sponsor notice. 
All involved investigators have to be informed immediately about a cessation/ suspension of the 
trial. The decision is binding to all trial centers and investigators.  
 
The Sponsor after consulting the Coordinating Investigator has the right to close a center, at any 
time, in case of: 
 
Non-compliance with the protocol 
 
Poor data quality  
 
No recruitment  
5.6 Prior and Concomitant Illnesses 
Relevant additional illnesses present at the time of informed consent are regarded as concomitant 
illnesses and are documented on the appropriate pages of the CRF. Included are conditions that 
are seasonal, cyclic, or intermittent (e.g. seasonal allergies; intermittent headache). 
Abnormalities which appear for the first time or worsen (intensity, frequency) during the trial are 
adverse events (AEs) and must be documented on the appropriate pages of the CRF. 
5.7 Background Medication 
Not applicable. 
5.8 Prior and Concomitant Medication 
Relevant additional treatments administered to the patients on entry to the trial or at any time 
during the trial are regarded as concomitant treatments and must be documented on the 
appropriate pages of the CRF. 
Directives for supportive care are outlined below. 
 
5.8.1 Supportive Care 
Antiemetics support: emesis prophylaxis is mandatory and is administered at the investigator’s 
discretion using institutional or DGHO guidelines taking into account potential interactions (e.g. 
CYP3A4 inhibition/induction). 
Antidiarrheal support: infectious work-up is left at the investigator’s discretion using institutional 
guidelines. Treatment with antidiarrheal drugs is recommended once the earliest signs of diarrhea 
are present. Patients should be instructed to refer immediately to the center in case of such 
symptoms, and treatment should proceed according to institutional or DGHO guidelines. 
Hematopoietic support: RBC and PLT transfusions should be administered as indicated. 

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Granulocyte-colony stimulating factor: primary prophylactic use of G-CSF is not permitted, but G-
CSF may be used to treat therapy-related neutropenia in patients with response, including PR, 
CR, and SD, in subsequent treatment cycles. If neutropenic complications are observed in a 
previous cycle, CSFs may be given at the discretion of the investigator, but only if dose reduction 
or delay of palbociclib are not considered reasonable alternatives. 
Antibiotic treatment: patients with neutropenic fever or systemic infection should be hospitalized 
promptly for i.v. antibiotic therapy. 
Pain relief: analgesics can be administered as needed. 
 
5.8.2 Other Permitted Concomitant Medications 
Therapies considered necessary for the patient’s well-being may be given at the discretion of the 
investigator, such as chronic treatments for concomitant medical conditions as well as agents 
required for life-threatening medical problems, analgesics, etc. Patients should be advised to 
contact their physician before starting any new drug. 
 
5.8.3 Prohibited Medications During Therapy With Palbociclib and Interactions 
With Strong Inhibitors/Inducers of Cytochrome P450-3A4 
Strong CYP3A inhibitors/inducers: palbociclib is metabolized to multiple metabolites in a 
qualitatively similar manner in rat, dog, and human liver microsomes. In vitro, palbociclib is 
primarily metabolized by CYP3A4 enzymes. Co-administration with drugs that are CYP3A 
inhibitors or inducers may change the plasma concentrations of palbociclib in humans. The 
concurrent use of potent CYP3A inhibitors, including but not limited to aprepitant, 
amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, 
erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, 
miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice are not allowed. 
The concurrent use of potent CYP3A inducers, including but not limited to carbamazepine, 
felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, 
and St. John’s Wort is not allowed. Refer to the following website for additional information on 
CYP3A4 inhibitors, inducers, and substrates: http://medicine.iupui.edu/flockhart/table.htm 
Based on in vitro data, palbociclib is predicted to inhibit intestinal P-glycoprotein (P-gp) and breast 
cancer resistance protein (BCRP) mediated transport. Therefore, administration of palbociclib 
with medicinal products that are substrates of P-gp (e.g., digoxin, dabigatran, colchicine) or BCRP 
(e.g., pravastatin, rosuvastatin, sulfasalazine) may increase their therapeutic effect and adverse 
reactions.   
  
Based on in vitro data, palbociclib may inhibit the uptake transporter organic cationic transporter 
OCT1 and then may increase the exposure of medical product substrates of this transporter (e.g., 
metformin). 
 
In addition, co-medication with corticosteroids above 7.5 mg prednisolone/prednisone 
equivalent during the study period is prohibited to avoid masking of infections. 
 
6 Investigational Medicinal Product/-s 
6.1 General Information about Investigational Medicinal Product/-s 
 
Investigational medicinal product 1: 
 
Drug Code: 
PD-0332991-00 
Trade name: 
IBRANCE 

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ATC code, if officially registered: 
L01XE33 
Pharmaceutical formulation: 
75 mg/100 mg/125 mg capsules 
Route of administration: 
oral 
Storage conditions: 
At room temperature 
Manufacturer / Importer: 
Pfizer Pharma GmbH 
 
 
Investigational medicinal product 2: 
 
Drug Code: 
PD-0332991-00 
Trade name: 
IBRANCE 
ATC code, if officially registered: 
L01XE33 
Pharmaceutical formulation: 
75 mg/100 mg/125 mg tablets 
Route of administration: 
oral 
Storage conditions: 
At room temperature 
Manufacturer / Importer: 
Pfizer Pharma GmbH 
 
The pharmaceutical manufacturer Pfizer Pharma GmbH switches the formulation of palbociclib 
from capsules to tablets during the NCT-PMO-1601 trial. While there are no safety issues tablets 
are more convenient allowing intake with or without food. The active ingredient, dosage strength 
and administration schedule are the same. Bioequivalence is given. Patients in the NCT-PMO-
1601 trial are treated with capsules from the beginning and will be switched to tablets upon 
availibility. Instructions in this protocol are valid without change. 
 
6.2 Therapeutic/Diagnostic Effects 
Palbociclib, an orally available pyridopyrimidine, is a highly selective, reversible inhibitor of cyclin-
dependent kinases 4 and 6 (CDK4/6) that is being studied for use in cancer treatment. The 
compound prevents cellular DNA synthesis by blocking progression from the G1 to the S phase 
of the cell cycle, as demonstrated in laboratory models and early clinical trials.  
6.3 Known Side Effects 
The most common side effects of palbociclib are reversible neutropenia, thrombocytopenia, 
anemia, fatigue, constipation, nausea, and diarrhea. 
Serious adverse events considered to be related to palbociclib included febrile neutropenia, 
unstable angina, diarrhea, ischemic colitis, pneumonia and bronchopneumonia, dehydration and 
metabolic acidosis, allergic alveolitis, and attempted suicide. 
In vitro data indicate that palbociclib is primarily metabolized by CYP3A4. Potent CYP3A4 
inhibitors (e.g., ketoconazole, miconazole, itraconazole, posaconazole, clarithromycin, 
erythromycin, tilithromycin, nefazodone, diltiazem, verapamil, indinavir, saquinavir, ritonavir, 
nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, and grapefruit juice) are thought to 
represent the most significant potential for drug interaction with palbociclib. In addition, 
concomitant administration of agents that are strong CYP3A inducers (such as phenobarbital, 
rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, and St. John’s Wort) may 
reduce the exposure to palbociclib and are thus not recommended. For further information, please 
refer to the summary of product characteristics (SPC). 
 

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6.4 Dosage Schedule 
Palbociclib is given orally once per day for 21 days in a 28-day cycle. 
6.4.1 Dosage 
Maximum duration of treatment: in responding patients until disease progression or LPLV. 
Maximum dose allowed: 125 mg/day for 21 days in a 28 days cycle 
 
Dose level  
 
Palbociclib for 3 out of 4 weeks 
Starting dose   
125 mg/d 
-1  
 
 
100 mg/d 
-2  
 
 
75 mg/d 
Palbociclib dose reduction below 75 mg/d is not intended. 
 
6.4.2 Dosage Adjustment 
 
Toxicity 
Action 
Grade 4 neutropenia (ANC < 0.5 G/l) 
Hold palbociclib treatment until ANC recovery to 
≥ 1 G/l 
Reintroduce palbociclib at next lower dose level 
Grade 4 thrombocytopenia (PLT count < 25 G/l) 
Hold palbociclib treatment until PLT recovery to ≥ 
50 G/l 
Reintroduce palbociclib at next lower dose level 
Grade 3 neutropenia (ANC < 1 G/l) associated 
with documented infection or fever ≥ 38.5°C 
Hold palbociclib treatment until ANC recovery to 
≥ 1 G/l and no fever 
Reintroduce palbociclib at next lower dose level 
Uncomplicated grade 3 neutropenia (ANC < 1 
G/l) 
Hold palbociclib treatment until ANC recovery to 
≥ 1 G/l 
Reintroduce palbociclib at same dose level 
Grade 3 thrombocytopenia (PLT count < 50 G/l) 
Hold palbociclib treatment until PLT recovery to ≥ 
75 G/l 
Reintroduce palbociclib at same dose level 
Grade ≥ 3 non-hematologic toxicity, including 
nausea, vomiting, diarrhea, and hypertension 
only if persisting despite optimal medical 
treatment 
Hold palbociclib treatment until recovery to grade 
≤ 1, baseline, or, at the investigator’s discretion, 
grade ≤ 2 if not considered a safety risk for the 
patient  
Reintroduce palbociclib at next lower dose level 
 
No specific dose adjustments are recommended for grade 1/2 treatment-related toxicity. 
However, physicians should always manage patients according to their medical judgment based 
on the particular clinical circumstances. 
6.5 Treatment Assignment 
The trial medication is administered only to patients included in this trial. It is administered 
following the patient medication diary. 
Patients withdrawn from the trial retain their identification codes.   
6.6 Randomization and Blinding  
Not applicable. 

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6.7 Packaging and Labeling 
The trial medication is not labeled according to § 5 (8) of GCP-V. Pfizer Pharma GmbH provides 
palbociclib free of charge.  
Supplies have to be obtained by sending an order form to Pfizer and the NCT Trial Center. The 
required amount of investigational medicinal product is shipped to the local pharmacies of the 
study sites by Pfizer Pharma GmbH. A pre-requisite for shipment is the full regulatory approval of 
the study site. 
6.8 Supplies and Accountability 
The investigators keep an account of the trial medication and acknowledge the receipt of all 
shipments of the trial medication. All trial medication must be kept in a locked area with access 
restricted to designated trial staff. The trial medication must be stored dry and in accordance with 
manufacturer’s instructions at room temperature. The investigator also keeps accurate records of 
the quantities of trial medication dispensed, used, and returned by each patient. The 
documentation has to include date of dispensary, patient identification, batch/serial numbers or 
other identification of trial medication. After examination by the monitor, all unused trial medication 
and all medication containers are destroyed and this process is documented. It is assured that a 
final report of the drug accountability is prepared and maintained by the investigator in the 
Investigator’s site file. 
6.9 Compliance 
Trial medication is dispensed/applied to the patients by the investigator or another authorized 
study physician. Patients are instructed to bring all trial medication to the trial site at every visit. 
Compliance is assessed by count of capsules/tablets. Details are recorded on the Drug 
Accountability Form.  
7 Trial Methods 
7.1 Description of Study Visits 
Overviews of the course of the trial and all diagnostic and therapeutic measures are given in the 
trial schedule at protocol synopsis.  
Baseline 
 
Prior to any trial specific invasive procedures, all patients provide written informed consent 
to participate in the study. 
 
A patient ID is assigned 
 
Assessment of general inclusion and exclusion criteria 
 
Assessment demographics (year of birth, gender, ethnic group) 
 
Assessment of general medical and oncologic history: date of first diagnosis detailed 
information on pretreatment including type and composition of prior therapy, response to 
prior therapy, date of relapse/refractory disease, detailed information on disease 
progression according to RECIST v1.1 criteria over the last 6 months prior to study 
inclusion, family history, additional medical history on concomitant diseases, prior 
exposure to toxic agents, prior malignancy including therapy, information on smoking; 
tumor staging according to UICC (TNM). 
 
Assessment of vital signs: height (in cm), weight (in kg), WHO performance status, 
temperature (in grade centigrade), blood pressure/pulse 
 
Assessment of child bearing potential and/or pregnancy blood test (women) 
 
Physical examination (inspection, abdominal, cardiac and lung auscultation, palpation of 
the abdomen and lymph node sites, neurological examination) 
 
Assessment of signs/symptoms: chordoma-related and unrelated signs and symptoms  
 
Assessment of Concomitant medications  

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 
Assessment of PRO including Quality of Life assessed by questionnaires of the EORTC 
Quality of Life Item Library (core questionnaire QLQ-C30; fatigue module QLQ-FA12, and 
selected symptom items), as well as the Pittsburgh Sleep Qualitiy Index (PSQI), the 
Patient Health Questionnaire for Anxiety and Depression (PHQ-4), and the Functional 
Assessment of Cancer Therapy – cognitive function scale (FACT-cog). In addition, 
patient-reported information on personal traits and experiences are collected.  
 
ECHO and ECG 
 
Hematology (local lab): hemoglobin, RBC, PLT, WBC and differential cell counts 
 
Blood chemistry (local lab): BUN, creatinine, albumin, AST/SGOT, ALT/SGPT, total 
bilirubin, AP, LDH, sodium, potassium, magnesium, calcium, serum uric acid 
 
Coagulation: Prothrombin time, aPTT and fibrinogen 
 
Urinalysis (local lab): pH, glucose, proteins (qualitative, dipstick accepted) 
 
HAV, HBV, HCV, and HIV-1 testing (local lab) 
 
Checking of tumor status on basis of CT/MRI scan not older than 2 weeks  
 
Sample shipment to Central Pathology Ulm for pathology and immunohistochemistry 
 
Taking samples for biological characterization (40 ml blood; for details see sample 
shipping-manual) and shipment to Heidelberg  
 
Visit 1 - Start of Therapy 
 
Assessment of vital signs: weight, WHO performance status, temperature (in grade 
centigrade), blood pressure/pulse 
 
Physical examination (inspection, abdominal, cardiac and lung auscultation, palpation of 
the abdomen and lymph node sites, neurological examination) 
 
ECG 
 
Assessment of Concomitant medications  
 
Hematology (local lab): hemoglobin, RBC, PLT, WBC and differential cell counts 
 
Blood chemistry (local lab): BUN, creatinine, albumin, AST/SGOT, ALT/SGPT, total 
bilirubin, AP, LDH, sodium, potassium, magnesium, calcium, serum uric acid 
 
Distribution of palbociclib to patient 
 
Taking samples for biological characterization (40 ml blood; for details see sample 
shipping-manual) and shipment to Heidelberg 
 
Visit 2-4, weekly in first treatment cycle 
 
ECG 
 
Assessment of concomitant medications  
 
Assessment of AEs  
 
Hematology (local lab): hemoglobin, RBC, PLT, WBC and differential cell counts 
 
Blood chemistry (local lab): BUN, creatinine, albumin, AST/SGOT, ALT/SGPT, total 
bilirubin, AP, LDH, sodium, potassium, magnesium, calcium, serum uric acid 
 
Visit 5, Day 1 (+/- 2 Days) of 2nd treatment cycle 
 
Assessment of vital signs weight, WHO performance status, temperature (in grade 
centigrade), blood pressure/pulse 
 
Physical examination (inspection, abdominal, cardiac and lung auscultation, palpation of 
the abdomen and lymph node sites, neurological examination) 
 
Assessment of Concomitant medications  
 
Assessment of AEs  
 
Assessment of PRO including Quality of Life 
 
Hematology (local lab): hemoglobin, RBC, PLT, WBC and differential cell counts 
 
Blood chemistry (local lab): BUN, creatinine, albumin, AST/SGOT, ALT/SGPT, total 
bilirubin, AP, LDH, sodium, potassium, magnesium, calcium, serum uric acid 

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 
Taking samples for biological characterization (40 ml blood; for details see sample 
shipping-manual)  and shipment to NCT Heidelberg 
 
If applicable, distribution of palbociclib to patient 
 
Visit 6, Day 14 (+/- 2 Days) of 2nd treatment cycle 
 
Assessment of Concomitant medications  
 
Assessment of AEs  
 
Hematology (local lab): hemoglobin, RBC, PLT, WBC and differential cell counts 
 
 
Visit 7, Day 1 (+/- 2 Days) of 3rd treatment cycle 
 
Assessment of vital signs: weight, WHO performance status, temperature (in grade 
centigrade), blood pressure/pulse 
 
Physical examination (inspection, abdominal, cardiac and lung auscultation, palpation of 
the abdomen and lymph node sites, neurological examination) 
 
Assessment of Concomitant medications  
 
Assessment of AEs  
 
Hematology (local lab): hemoglobin, RBC, PLT, WBC and differential cell counts 
 
Blood chemistry (local lab): BUN, creatinine, albumin, AST/SGOT, ALT/SGPT, total 
bilirubin, AP, LDH, sodium, potassium, magnesium, calcium, serum uric acid 
 
Taking samples for biological characterization (40 ml blood; for details see sample 
shipping-manual) and shipment to NCT Heidelberg  
 
If applicable, distribution of palbociclib to patient 
 
Assessment of child bearing potential and/or pregnancy blood test (women) 
 
 
Visit 8 Day 1 (+/- 2 Days) of 4th treatment cycle 
 
Assessment of vital signs: weight, WHO performance status, temperature (in grade 
centigrade), blood pressure/pulse 
 
Physical examination (inspection, abdominal, cardiac and lung auscultation, palpation of 
the abdomen and lymph node sites, neurological examination) 
 
Assessment of Concomitant medications  
 
Assessment of AEs  
 
Hematology (local lab): hemoglobin, RBC, PLT, WBC and differential cell counts 
 
Blood chemistry (local lab): BUN, creatinine, albumin, AST/SGOT, ALT/SGPT, total 
bilirubin, AP, LDH, sodium, potassium, magnesium, calcium, serum uric acid 
 
Taking samples for biological characterization (40 ml blood; for details see sample 
shipping-manual) and shipment to NCT Heidelberg 
 
MRI/CT 
 
If applicable, distribution of palbociclib to patient 
 
 
Visit 9 / 10 Day 1 (+/- 2 Days) of 5th / 6th treatment cycle 
 
Assessment of vital signs: weight, WHO performance status, temperature (in grade 
centigrade), blood pressure/pulse 
 
Physical examination (inspection, abdominal, cardiac and lung auscultation, palpation of 
the abdomen and lymph node sites, neurological examination) 
 
Assessment of Concomitant medications  
 
Assessment of AEs  
 
Hematology (local lab): hemoglobin, RBC, PLT, WBC and differential cell counts 

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 
Blood chemistry (local lab): BUN, creatinine, albumin, AST/SGOT, ALT/SGPT, total 
bilirubin, AP, LDH, sodium, potassium, magnesium, calcium, serum uric acid 
 
Taking samples for biological characterization (40 ml blood; for details see sample 
shipping-manual) and shipment to NCT Heidelberg 
 
If applicable, distribution of palbociclib to patient 
 
Visit 11 Day 1 (+/- 2 Days) after 6th treatment cycle - Primary efficacy assessment 
or whenever applicable before in case of premature end of study treatment 
 
Assessment of vital signs: weight, WHO performance status, temperature (in grade 
centigrade), blood pressure/pulse 
 
Physical examination (inspection, abdominal, cardiac and lung auscultation, palpation of 
the abdomen and lymph node sites, neurological examination) 
 
Assessment of Concomitant medications  
 
Assessment of AEs  
 
Assessment of PRO including Quality of Life 
 
Hematology (local lab): hemoglobin, RBC, PLT, WBC and differential cell counts 
 
Blood chemistry (local lab): BUN, creatinine, albumin, AST/SGOT, ALT/SGPT, total 
bilirubin, AP, LDH, sodium, potassium, magnesium, calcium, serum uric acid 
 
Taking samples for biological characterization (40 ml blood; for details see sample 
shipping-manual) and shipment to NCT Heidelberg 
 
MRI/CT 
 
If the patient benefits from treatment, this is the starting day of the next treatment cycle 
and beginning of the “Extended Treatment Period” 
 
In case of clinical benefit distribution of palbociclib to patient 
 
Assessment of child bearing potential and/or pregnancy blood test (women) 
 
If patient continus treatment with study medication: Extended Treatment Period 
Visit 10+X Day 1 (+/- 2 Days) of each treatment cycle after Primary efficacy 
assessment 
 
Assessment of vital signs: weight, WHO performance status, temperature (in grade 
centigrade), blood pressure/pulse 
 
Physical examination (inspection, abdominal, cardiac and lung auscultation, palpation of 
the abdomen and lymph node sites, neurological examination) 
 
Assessment of Concomitant medications  
 
Assessment of AEs  
 
Hematology (local lab): hemoglobin, RBC, PLT, WBC and differential cell counts 
 
Blood chemistry (local lab): BUN, creatinine, albumin, AST/SGOT, ALT/SGPT, total 
bilirubin, AP, LDH, sodium, potassium, magnesium, calcium, serum uric acid 
 
Taking samples for biological characterization (40 ml blood; for details see sample 
shipping-manual) and shipment to NCT Heidelberg every 12 weeks (= every three 
treatment cycles) 
 
Assessment of PRO including Quality of Life every 12 weeks (= every three treatment 
cycles) 
 
MRI/CT every 12 weeks (+ 4 weeks) 
 
Visit F-UP-3: 3 months after stop of study treatment (+/- 1 Week) – Follow-up  
 
Assessment of PRO including quality of life  
 
Assessment of tumor status with MRI/CT 
 
 

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Visit F-UP-6: 6 months after stop of study treatment (+/- 1 Week) – End of follow-up 
 
Assessment of PRO including quality of life  
 
Assessment of tumor status with MRI/CT 
 
Visit SF-UP-X: Survival Follow-up 
Patients are followed until death every 3 months by phone, unless they are seen in the center 
regularly anyway. Survival-Follow-up is continued until end of clinical trial (LPLV). 
 
7.2 Methods of Data and Sample Collection  
7.2.1 Data Collection and Handling 
All findings including clinical and laboratory data are  documented by the investigator or an 
authorized member of the study team in the patient's medical record and in the case report form 
(CRF). The investigator at the clinical site is responsible for ensuring that all sections of the CRF 
are completed correctly and that entries can be verified against source data. The CRF has to be 
filled out according to the specified CRF Completion Guidelines. The correctness of entries in the 
CRF is confirmed by dated signature of the responsible investigator. 
All data is  reported pseudonymized. 
7.2.2 Sample Collection and Handling 
Tumor biopsy 
Tissue blocks preferably not older than 12 months are requested either from initial diagnosis or 
from biopsies of locally advanced disease or metastatic sites. A corresponding pathology report 
should be included along with the archival sample. 
In case of re-biopsies before study entry, also fresh material could be send by courier in provided 
standard medium to the central pathology lab.  
Biopsies are analyzed for p16 (CDKN2A) tumor suppressor expression level at: 
 
Institute of Pathology, M23 
University of Ulm 
Albert-Einstein-Allee 11 
89075 Ulm 
 
Blood samples 
Blood samples of 40 ml blood (for details see sample shipping-manual) taken at every dedicated 
visit are used for biobanking. 
Blood samples for biobanking are sent to: 
 
Biobank des Nationalen Centrums für Tumorerkrankungen (NCT) Heidelberg 
Im Neuenheimer Feld 460 
69120 Heidelberg  
 
7.3 Measurement of Efficacy Parameters 
7.3.1. Tumor Response  
Tumor assessment is evaluated by MRI or CT and progression or response is based on RECIST 
v1.1 criteria12 as well as Choi criteria13. Tumor imaging is done according to clinical routine. The 
first measurement is performed during study entry and subsequent scans are performed on the 

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first day of the 4th cycle, at primary efficacy assessment, every 12 weeks (+ 4 weeks variance) in 
the extended treatment phase and in F-up-3 and F-up-6.  All lesions are assessed locally and 
reported at each scheduled scan. The same imaging technique used to characterize each 
identified and reported lesion at baseline is employed in the following tumor assessments.  
 
Target Lesions 
Complete response (CR) is defined as the disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
Partial response (PR) is defined as a ≥30% decrease in the sum of the longest dimensions of 
the target lesions taking as a reference the baseline sum longest dimensions. 
Progressive disease (PD) is defined as a ≥20% increase in the sum of the longest dimensions 
of the target lesions taking as a reference the smallest sum of the longest dimensions recorded 
while on study, or the appearance of one or more new lesions. In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as a reference the smallest sum of the longest dimensions since 
the treatment started. 
Non-Target Lesions 
Complete response (CR) is defined as the disappearance of all non-target lesions. All lymph 
nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD is defined as a persistence of 1 or more non-target lesions. 
Progressive disease (PD) is defined as unequivocal progression of existing non-target lesions, or 
the appearance of 1 or more new lesion. 
7.4 Measurement of Safety Parameters 
The following laboratory parameters are used to monitor safety: 
Hematology (local lab): hemoglobin, RBC, PLT, WBC and differential cell counts should be 
performed at baseline, weekly during the first treatment cycle, in each first week during following 
cycles (including ExT), Visit 6 and 11. Clinical status and laboratory parameters are to be followed 
using individual institutional guidelines and the best clinical judgment of the responsible physician, 
which can involve more frequent testing, especially in neutropenic/aplastic patients. It is expected 
that patients on this protocol are cared for by physicians experienced in the treatment and 
supportive care of patients with acute leukemia. 
Blood chemistry (local lab): including creatinine, albumin, BUN, AP, AST/SGOT, ALT/SGPT, 
serum uric acid, total bilirubin, sodium, potassium, magnesium, calcium, and LDH, are performed 
at baseline and then once a week during the first treatment cycle, in each first week during 
following cycles (including ExT), at primary efficacy assessment, and during follow-up while 
ongoing treatment, or following individual institutional guidelines and the best clinical judgment of 
the responsible physician, which can be more often. 
Prothrombin time, aPTT, and fibrinogen are measured at baseline and at appropriate times during 
treatment cycles at the investigator’s discretion. 
Urinalysis (local lab), pH, glucose, proteins [qualitative, dipstick accepted] are performed at 
baseline and at appropriate times during treatment cycles at the investigator’s discretion. 

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Serum/urine pregnancy test (local lab, sensitivity of at least 25 mIU/mL) is performed at baseline 
( 72 hours prior to patient registration), at day 1 cycle 3, at the end of study treatment and 
repeated if clinically indicated. 
Hepatitis A, B, and C as well as HIV-1 testing (local lab) is performed at baseline and thereafter 
at the investigator’s discretion. 
 
7.5 Measurement of Further Parameters 
Vital signs 
Height, weight, temperature, WHO performance status, and blood pressure/ pulse are  collected. 
Height (in cm) is measured at baseline only. Weight (in kg), WHO performance status, 
temperature (in grade centigrade), and blood pressure/pulse are measured at baseline and before 
the start of every new cycle. 
Echocardiography 
Cardiac ultrasound is performed at baseline as safety assessment and thereafter at the 
investigator’s discretion. Ejection fraction must be specified in case of abnormalities and 
quantified. 
 
Electrocardiogram (ECG) 
A 12-lead ECG is performed at baseline and during the first treatment cycle every week as well 
as additionally at the investigator’s discretion. 
For the purpose of this study, QTcB intervals are calculated according to the formula of Bazett: 
  
For QTcB intervals > 450 ms and ≤ 470 ms, check magnesium and potassium levels and correct 
any abnormalities. If possible, stop any medication that may prolong the QTcB interval. Continue 
palbociclib. 
For QTcB intervals > 470ms and ≤ 500 ms, check magnesium and potassium levels and correct 
any abnormalities. If possible, stop any medication that may prolong the QTcB interval. Reduce 
palbociclib to the next lower dose level or, if the lowest dose level is reached, discontinue 
palbociclib. 
For QTcB intervals > 500 ms, immediately stop palbociclib, check magnesium and potassium 
levels and correct any abnormalities. If possible, stop any medication that may prolong the QTcB 
interval. Re-start palbociclib if the QTcB interval is < 470ms. If QTcB interval is not improved (QTcB 
remains > 470 ms for more than three weeks), discontinue palbociclib until QTcB improves to < 
470 ms, then resume palbociclib. Missed doses of palbociclib are not  made up. 
8 Ancillary and Post Trial Care  
After the end of the 6 months follow-up phase, patients are routinely followed-up usually including 
visits every 3 months, and treated regarding standard of care according to the discretion of the 
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9 Assessment of Safety 
9.1 Specification of Safety Parameters 
9.1.1 Adverse Events 
According to GCP, an adverse event (AE) is defined as follows: Any untoward medical occurrence 
in a patient administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
An AE may be: 
 
New symptoms/ medical conditions 
 
New diagnosis 
 
Changes of laboratory parameters 
 
Intercurrent diseases and accidents 
 
Worsening of medical conditions/ diseases existing before inclusion into the trial 
 
Recurrence of disease 
 
Increase of frequency or intensity of episodical diseases. 
A pre-existing disease or symptom is not  considered an adverse event unless there is an 
untoward change in its intensity, frequency or quality. This change is documented by an 
investigator. 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical trial protocol and the condition(s) leading to these measures 
are not AEs, if the condition leading to the measure was present prior to inclusion into the trial. 
AEs are classified as "non-serious" or "serious". 
9.1.2 Serious Adverse Event 
A serious adverse event (SAE) is one that at any dose: 
 
Results in death 
 
Is life-threatening (the term life-threatening refers to an event in which the patient was at 
risk of death at the time of event and not to an event which hypothetically might have 
cause death if it was more severe)  
 
Requires patient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity or 
 
Results in a congenital anomaly/ birth defect 
 
Any other important medical event may be considered serious when, based upon medical 
judgement, it may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed above. 
 
9.1.3 Expectedness, Reference Safety Information (RSI) 
An ‘unexpected’ adverse event is one the nature or severity of which is not consistent with the 
applicable reference safety information (RSI) included in the Investigator’s Brochure (IB) or 
Summary of Product Characteristics (SPC). In this trial the current version of the SPC is 
considered RSI.  
Furthermore, reports which add significant information on specificity or severity of a known 
adverse reaction may be counted as ‘unexpected’ events (cf. 9.4 Expedited Reporting).  
9.1.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
SAEs that are both suspected, i.e. possibly related to IMP, and ‘unexpected’, i.e. the nature and/ 
or severity of which is not consistent with the RSI are to be classified as Suspected Unexpected 
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In case if either the investigator, who primarily reported the SAE, or the second assessor classify 
the SAE as ‘suspected’ (i.e. as ‘definitely’, ‘probably’, ‘possibly’ related to IMP) and the SAE is 
also ‘unexpected’, it is categorized as a SUSAR. 
All SUSARs are subject to an expedited reporting to the responsible ethics committee(s), the 
competent higher federal authority (BfArM), and to all participating investigators. 
9.2 Period of Observation and Documentation 
All AEs reported by the patient or detected by the investigator are collected during the trial, and 
must be documented on the appropriate pages of the CRF. AEs must also be documented in the 
patient’s medical records. 
In this trial, all AEs that occur after first administration of the IMP are documented on the pages 
provided in the CRF. The individual period of observation ends 28 days after the last dose of the 
IMP for chordoma. All patients who have AEs, whether considered associated with the use of the 
trial medication or not, must be monitored to determine the outcome. The clinical course of the 
AE is followed up until resolution or normalization of changed laboratory parameters or until it has 
changed to a stable condition. 
9.2.1 Grading of AEs 
The grading of AEs in this trial is carried out on the basis of the 5-grade scale defined in the 
CTCAE v5.0. 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL* 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
Grade 4: 
Life-threatening consequences; urgent intervention indicated.  
Grade 5: 
Death related to AE 
 
A Semi-colon indicates ‘or’ within the description of the grade. 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 
The grading of all AEs listed in the CTCAE v5.0 is based on the information contained therein. 
The grading of all other AEs, i.e. those which are not listed in the CTCAE v5.0 are  performed by 
a responsible investigator, based on  definitions of CTCAE v5.0 shown in the table above. 
9.2.2 Coherence between AEs and the IMP 
The investigator evaluates each AE that occurred after administration of investigational medicinal 
product regarding the coherency with the administration of the investigational medicinal product 
according to the definitions of the WHO: 
 
Definitely related: 
There is a reasonable possibility that the event may have been 
caused by IMP. A certain event has a strong temporal 
relationship and an alternative cause is unlikely. 
Probably related 
An AE that has a reasonable possibility that the event is likely 
to have been caused by IMP. The AE has a timely relationship 
and follows a known pattern of response, but a potential 
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Possibly related: 
An AE that has a reasonable possibility that the event may 
have been caused by IMP. The AE has a timely relationship to 
the IMP; however, the pattern of response is atypical, and 
another cause seems more likely. 
Unlikely related: 
Only a remote connection exists between the IMP and the 
reported adverse event. Other conditions including concurrent 
illness, progression or expression of the disease state or 
reaction of the concomitant medication appear to explain the 
reported adverse event. 
Not related: 
 
 
An AE that does not follow a reasonable temporal sequence 
related to IMP and is likely to have been produced by the 
patient’s clinical state, other modes of therapy or other known 
etiology. 
Unassessable/Unclassified: A report suggesting an AE which cannot be judged because of 
insufficient or contradictory information, or a report which 
cannot be supplemented or verified. 
9.2.3 Outcome of AEs 
The outcome of an AE at the time of the last observation is classified as: 
Recovered/ resolved 
All signs and symptoms of an AE disappeared without any 
sequels at the time of the last interrogation. 
Recovering/ resolving 
The intensity of signs and symptoms has been diminishing 
and/or their clinical pattern has been changing up to the time of 
the last interrogation in a way typical for its resolution. 
Not recovered/ not resolved 
Signs and symptoms of an AE are mostly unchanged at the time 
of the last interrogation. 
Recovered/ resolved with 
sequel 
Actual signs and symptoms of an AE disappeared but there are 
sequels related to the AE. 
Fatal 
Resulting in death. If there are more than one AE only the 
adverse event leading to death (possibly related) is 
characterized as ‘fatal‘. 
Unknown 
The outcome is unknown or implausible and the information 
cannot be supplemented or verified.  
 
9.2.4 Action taken with the IMP 
The action taken with IMP is assigned to one of the following categories: 
Dose not changed 
No change in the dose of IMP. 
Dose reduced 
Reduction in the dose of IMP. 
Temporary discontinuation  
Temporary discontinuation of IMP. 
Drug withdrawn 
Discontinuation of IMP. 
Unknown 
The information is unknown or implausible and it cannot be 
supplemented or verified. 
Not applicable 
The question is implausible (e.g. the patient is dead). 
 
9.2.5 Treatment of SAE 
The term ‘Treatment of SAE’ refers to the specific actions taken to treat or alleviate adverse 
events or to avoid their sequelae. The following categories are used to categorize this treatment: 
None 
No action taken 

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Drug treatment 
Newly-prescribed medication or change in dose of a 
medication 
Others 
Other countermeasures, e.g. an operative procedure   
 
9.3 Reporting of Serious Adverse Events by Investigator 
All SAEs must be reported by the investigator to the KKS Heidelberg within 24 hours after the 
SAE becomes known using the "Serious Adverse Event" (SAE)-form. The initial report must be 
as complete as possible, including details of the (serious) adverse event as well as an assessment 
of the causal relationship between the event and the trial medication. The reporting is performed 
by faxing of a completed ‘SAE Form’ to the KKS Heidelberg.  
 
 
 
 
Fax-number: + 49 (0)6221 56 33687 
9.4 Expedited Reporting 
SUSARs are to be reported to the ethics committee(s), regulatory authorities (BfArM) and to all 
participating investigators within regulative defined timelines, i.e. they are subject to an expedited 
reporting.  
All SAEs are forwarded by e-mail immediately (not later than 24 hours after receipt) by the 
responsible person at KKS Heidelberg to the coordinating investigator or the scientific coordinator 
in order to perform a second assessment. The coordinating investigator or the scientific 
coordinator  fills out a ‘Second Assessment Form’ for each SAE and returns it by e-mail to the 
KKS Heidelberg within 48 hours. 
 
 
 
 
E-mail: V-KKS.SAE@med.uni-heidelberg.de 
 
The ‘Second Assessment Form’ contains the following information:  
 
I) 
Assessment of relationship between SAE and IMP  
 
II) 
Assessment of expectedness of SAE (derived from IB which serves as RSI)  
III) 
Statement if the benefit/ risk assessment for the trial did change as a result of SAE, 
and 
 
The expedited reporting is  carried out by a responsible person of KKS Heidelberg. Only SUSARs 
occurring after administration of IMP undergo expedited reporting.  
9.5 Emergency Treatment 
During and following a patient’s participation in the trial, the investigator should ensure that 
adequate medical care is provided to a patient for any AE, including clinically significant laboratory 
values. The investigator should inform a patient when medical care is needed for intercurrent 
illness(es) of which the investigator becomes aware. 
9.6 Reporting Requirements for Pregnancies  
9.6.1 Pregnancies in Female Patients 
Female patients of childbearing potential are instructed to immediately inform the investigator if 
they become pregnant during the study. A pregnancy should primarily be reported using an SAE-
form. The investigator has to send the SAE-form immediately (i.e. no more than 24 hours after 
learning of the pregnancy).  
 
 
 
Fax-number: + 49 (0)6221 56 33 687 
The investigator should discontinue study drug and counsel the patient, discussing the risks of 
the pregnancy and the possible effects on the fetus. Medical monitoring of the patient should 
continue until conclusion of the pregnancy. Any SAEs associated with the pregnancy (e.g., an 

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event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event CRF and additionally 
in accordance with the requirements defined for all other SAEs (see above).  
9.6.2 Pregnancies in Female Partners of Male Patients 
Male patients are instructed through the Informed Consent Form to immediately inform the 
investigator if their partner becomes pregnant during the study or within 28 days after the last 
dose of study drug. The SAE-form has to be completed by the investigator immediately (i.e. within 
24 hours after becoming aware of the pregnancy) and submitted to KKS Heidelberg. Attempts 
should be made to collect and report details of the course and outcome of any pregnancy in the 
partner of a male patient exposed to study drug. The pregnant partner  needs to sign an 
authorization for use and disclosure of pregnancy health information to allow for follow-up on her 
pregnancy. Once the authorization has been signed, the investigator  updates the information on 
the course and outcome of the pregnancy. An investigator who is contacted by the male patient 
or his pregnant partner may provide information on the risks of the pregnancy and the possible 
effects on the fetus, to support an informed decision. 
10 Statistical Considerations 
10.1 Study Design and Research Hypothesis 
Non-randomized, single-arm, open-label, multicenter phase II trial, designed to gain first evidence 
of antitumor activity of palbociclib in adult patients with (locally) advanced or metastatic chordoma. 
The primary endpoint is the disease control rate (DCR) after six cycles of palbociclib.   
 
Formally, the null hypothesis that the true response rate p is less or equal to a reference rate p0 
is tested against a one-sided alternative: 
 
H0: p  p0    vs.   H1: p  p1 
 
where p is the true response probability, p0, the (uninteresting) reference response rate, and p1 
the (desirable) target level.  
 
10.2 Sample Size Calculation 
The sample size and power calculations were based on Simon's optimal two-stage design14, 
which minimizes the expected sample size under the null hypothesis subject to the error 
probability constraints. The type I error was set at  = 0.05, the type II error at  = 0.2. Here, the 
null hypothesis that the true response rate is less or equal to p0 = 0.1 is tested against a one-
sided alternative, where the desirable level of response is 0.25.  
 
The study needs 43 patients evaluable for the primary endpoint to complete. In the first stage, n1 
= 18 patients are accrued. If there are r1 = 2 or fewer responses in these 18 patients, the study is  
stopped and the drug rejected. This occurs with a probability of early termination under H0 of 
PET(p0) = 0.73. Otherwise, 25 additional patients are  accrued for a total of n = 43 patients. In the 
final analysis the null hypothesis is  rejected and the drug recommended for further development 
if 8 or more responses are observed in 43 patients. This design yields a type I error rate of  0.05 
and power of  80% when the true response rate is p = 0.25. 
 
Impact on Secondary Analyses 
A sample size of 43 patients is deemed adequate for all secondary/exploratory analyses. 
 

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Replacements  
Patients who go off study due to adverse events before final staging at 6 months are considered 
treatment failures,  receive response status = PD (progressive disease) and are not  replaced. 
Patients going off study for other reasons (drop-outs, e. g. lost-to-follow-up, death unrelated to 
disease/treatment, retracted IC, etc.) without assessment of the primary outcome are replaced 
until the goal of 43 is met.  
 
Drop-outs 
The rate of patient drop-out is estimated at 5%. 
 
10.3 Analysis Variables 
10.3.1 Primary analysis 
The primary endpoint is the disease control rate (DCR) after six cycles of palbociclib, which is 
defined as the presence of at least one confirmed complete response (CR) or confirmed partial 
response (PR) or stable disease (SD) according to RECIST version 1.1. 
 
10.3.2 Secondary analyses 
Tumor response rate (TRR) 
The TRR is defined as the presence of at least one complete response (CR) or partial response 
(PR) according to RECIST version 1.1 after six cycles of study medication. 
 
Progression-free survival (PFS) 
PFS is defined as the time from first administration of the IMP to progression of disease or death 
from any cause, whichever occurs first. Patients without the event are censored on the last date 
of follow-up. [time frame: up to LPLV] 
 
Overall survival (OS) 
OS is defined as the time from first administration of the IMP to time of death from any cause. 
Patients without the event are censored on the last date of follow-up. [time frame: up to LPLV] 
 
10.3.3 Safety 
This endpoint includes all AEs, their severity, SAEs, the relation of AEs to the study treatment, 
dose modifications for toxicity and discontinuation of study treatment during the trial phase. Toxic 
effects are graded according to the National Cancer Institute Common Toxicity Criteria (CTCAE) 
version 5.0.  
 
10.3.4 Patient Reported Outcomes (PROs) including Health-related quality of life 
(QoL) 
o 
Patient Reported Outcomes (PROs) are calculated as the new EORTC QLQ-C30 
Summary Score recommended by the EORTC Quality of Life Group, which has been 
recently developed and and evaluated.15 In addition, the EORTC QLQ function and 
symptom scores are calculated according to the actual EORTC Scoring Manual.16 
o 
Fatigue is calculated from the EORTC QLQ-FA12 according to the EORTC Scoring 
Manual.16 
o 
Sleep problems are calculated from the PSQI according to the corresponding scoring 
guidelines.17 

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o 
Perceived cognitive impairments and impact of cognitive changes are calculated 
from the FACT-cog according to the corresponding scoring manual. 
o 
Anxiety is calculated from the PHQ-4 according to the corresponding scoring manual.18  
o 
Depression is calculated from the PHQ-4 according to the corresponding scoring 
manual.18 
PROs are assessed using questionnaires (EORTC QLQ-C30, EORTC QLQ-FA12, PSQI, FACT-
cog, PHQ-4)  at baseline, at the beginning of the second and after the sixth 28-day treatment 
cycle, every 3 treatment cycles during the extended treatment period. 
 
10.4 Analysis Populations 
10.4.1 Full Analysis Population 
All enrolled patients who have finished at least one cycle of the study medication and who are 
evaluable for the primary endpoint are  included in the full analysis set under the ITT principle. 
Untreated patients are identified and described separately.  
 
10.4.2 Per Protocol Population 
No per protocol analysis is planned for the present study. 
 
10.4.3 Safety Population 
All enrolled patients who have received any amount of the study medication are subject to the 
safety analysis. 
Patients’ disposition and reasons for ending the study are presented in frequency distribution 
tables and individual data listing. Patients not meeting the eligibility criteria and who are 
considered protocol violations are also  described. Descriptive statistics of the baseline 
characteristics are generated across all treated patients. Frequency distributions are presented 
for the categorical categorized variables. Summary statistics including mean, standard deviation, 
median, minimum, maximum, and the number of assessed patients is calculated, as appropriate, 
for the quantitative variables. Individual data are  presented in listings. 
 
10.5 Statistical Methods 
10.5.1 General Considerations 
The statistical analysis is carried out by the responsible biostatistician at the National Center for 
Tumor diseases (NCT) Heidelberg using SAS statistical software (SAS Insitute Inc., Cary, NC, 
USA). The details of the analysis are specified in the statistical analysis plan (SAP), which is 
finalized and approved prior to the database lock. 
 
10.5.2 Demographic and other Baseline Characteristics 
Categorical baseline characteristics, like sex, age, detailed history of cancer, performance status 
(ECOG), relevant previous anticancer treatment, tumor staging according to UICC (TNM), 
concomitant illness at trial initiation, and concomitant treatment maintained, are summarized by 
frequency tables. Summary statistics are provided for quantitative variables like age, weight, 
laboratory values. 
 

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10.5.3 Study Therapy, Treatment Compliance, and Follow-up 
Summary statistics are presented for the dosage of palbociclib received at each cycle, dose 
modifications for toxicity, discontinuation and withdrawal from study treatment, as well as drop-
out from the follow-up during the post-study phase. 
The number of cycles administered, actual and total doses administered, dose modifications, 
delays and omissions, as well as reasons for deviation from planned therapy and overall duration 
of treatment, are described.  
 
10.5.4 Analysis of the Primary Endpoint  
Descriptive statistics and patient data listing are used for the presentation of all response data. 
Treatment efficacy is evaluated considering the disease control rate (DCR) and best overall 
response achieved according to RECIST criteria, for which an unbiased estimate and exact 95% 
CI is computed. Exploratory efficacy analyses may be performed if deemed of clinical relevance. 
 
10.5.5 Analysis of the Secondary Endpoints 
Tumor response 
Descriptive statistics and patient data listing are used for the presentation of all response data. 
Treatment efficacy is evaluated considering the tumor response rate (TRR), for which an unbiased 
estimate and exact 95% CI is computed. Exploratory efficacy analyses may be performed if 
deemed of clinical relevance. 
 
Survival Analysis 
Standard methods for right-censored data are used for analyzing PFS and OS. Cox Proportional 
Hazards Regression is used to examine the influence of covariates on PFS/OS if deemed 
clinically relevant. 
 
Safety Analysis 
The assessment of safety is based mainly on the frequency of adverse events (see Section 9) 
and on the number of laboratory values that fall outside of pre-determined ranges and/or show 
prominent worsening from baseline during the study phase (up to cycle 6 + 4 weeks). Adverse 
events are summarized by presenting the number and percentage of patients having any adverse 
events or serious adverse events, and having each individual adverse event, and by determining 
and summarizing the maximum individual toxicity grade (over all forms of toxicity) for each 
treatment cycle during the study phase. Furthermore, the most common AEs (those occurring in 
at least 10% of the treatment group) are  determined. Any other information collected (e.g. severity 
or relatedness to study drug) is summarized as appropriate. Laboratory data is summarized by 
presenting shift tables using normal ranges (baseline to most extreme post-baseline value) and 
by presenting summary statistics of raw data and change from baseline values (means, medians, 
standard deviations, ranges). All proportions are  given along with exact Pearson-Clopper 95% 
confidence intervals. 
 
Patient Reported Outcomes Analysis 
The scales are scored and analyzed according to the corresponding EORTC guidelines. The 
Quality of Life subscales and single item sub-scores are summarized by the mean, standard 
deviation, median, minimum and maximum, and plotted by time. The change from baseline for all 
domains is examined descriptively. 
 
Other Analyses 
Patients Disposition is tabulated. In addition, the number of patients who withdrew from the study 
and reasons for discontinuation are summarized. The number and percentage of patients with 

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normal and abnormal ECG results are summarized. Summary statistics for baseline values and 
Follow-up are displayed for QT and QTcB correction methods. 
 
10.5.6 Handling of Missing Data 
Missing values are not replaced or imputed. For patients with incomplete follow-up, time to last 
follow-up date is used as the censoring time in the analysis of time-to-event data. 
 
10.6 Interim Analyses 
As defined in section 10.2, one interim analysis of efficacy is performed at the end of the first 
stage. After accrual of 18 patients, recruitment is interrupted, if necessary, until a decision 
according to the first stage of Simon's design has been reached. Evaluation  takes place after 
response evaluation of the last patient of the first stage is available. 
The objective of the interim analysis is  to allow the early stopping of the trial in case of an 
insufficient number of responders (2). 
 
10.7 Safety Monitoring 
Safety monitoring is performed by the IDMC after 18 patients have finished at least one cycle of 
the study treatment. Safety assessments consist of evaluating AEs and SAEs. The IDMC provides 
the sponsor with recommendations regarding trial modification, continuation or termination. 
11 Data Management 
11.1 Data Collection 
As used in this protocol, the term Case Report Form (CRF) should be understood to refer to an 
electronic data record. 
All findings including clinical and laboratory data are documented by the investigator or an 
authorized member of the study team in the patient's medical record and in the CRF except the 
data on PRO. The investigator is responsible for ensuring that all sections of the CRF are 
completed correctly and  entries can be verified by source data. The CRF has to be filled out 
according to the specified CRF Completion Guidelines.  
Data collection can only be done by authorized persons. All study data are password-protected. 
The electronic CRF provides several checks for completeness and consistency. Each entry or 
change of data is tracked with name and exact date. The investigator  signs the CRF electronically 
as per agreed project process. A copy of the electronic CRF is archived at the study site. 
 
PRO questionnaires, which are paper-based, are completed by the patient and serve as source 
data. Upon completion the questionnaires are sent by the trial site to the NCT trial centre for 
tracking. Thereafter, they are forwarded to the central unit responsible for Patient-Reported 
Outcomes. The questionnaires are recorded using the TELEFORM® system (Cardiff) and 
undergo a computer assisted manual verification. 
 
11.2 Data Handling 
Data entries  undergo an automatic online check for plausibility and consistency.  
Further checks for plausibility, consistency, and completeness of data are performed after 
completion of the study. Queries are generated on the basis of these checks, combined with a 
visual control by a responsible monitor/data manager. 
The investigator has to resolve and clarify all queries. 

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All data management activities are done according to the current Standard Operating Procedures 
(SOPs) of the NCT Trial Center. 
 
11.3 Storage and Archiving of Data 
According to §13 of the German GCP-Regulation all important trial documents (e.g. CRFs)  are  
archived for at least 10 years after the trial termination. 
The CI is responsible for archiving the TMF including protocol, CRFs, report etc. 
The investigator(s)  archives all trial data (source data and Investigator Site File (ISF) including 
Patient Identification List and relevant correspondence) according to the section 4.9 of the ICH 
Consolidated Guideline on GCP (E6) and to local law or regulations. The Patient Identification 
List is  archived for at least 15 years after trial termination. 
If the investigator relocates, retires, or for any reason withdraws from the study, the NCT Trial 
Center should be prospectively notified. The study records must be transferred to an acceptable 
designee, such as another investigator, another institution, or to the NCT Trial Center. The 
investigator must obtain CIs written permission before disposing of any records, even if archiving 
requirements have been met. 
12 Ethical and Legal Aspects 
12.1 Good Clinical Practice 
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and 
documentation of this trial, are designed to ensure that all persons involved in the trial abide by 
Good Clinical Practice (GCP) and the ethical principles described in the current version of the 
Declaration of Helsinki. The trial is carried out in keeping with local legal and regulatory 
requirements. 
12.2 Patient Information and Informed Consent 
Before being admitted to the clinical trial, the patient must consent in written form to participate 
after the nature, scope, and possible consequences of the clinical trial have been explained in a 
form understandable to him or her. The original personally signed and dated Informed Consent 
Form must be kept on file by the investigator(s), and documented in the case report form. 
A copy of the signed informed consent document must be given to the patient. The documents 
must be in a language easily understandable to the patient and must clearly state who informed 
the patient, which is confirmed by the dated signature of the responsible investigator 
If new safety information results in significant changes in the risk/benefit assessment, or if 
changes are made in the protocol, the consent form should be reviewed and updated if necessary. 
All patients (including those already being treated) should be informed of the new information and 
must give their written informed consent to continue the study.  
12.3 Confidentiality 
The data obtained in the course of the trial is treated pursuant to the applicable Data Protection 
Law as well as § 40 (2a) AMG. 
During the clinical trial, patients are identified solely by means of an individual identification code 
(Patient ID). Storage of trial findings on a computer is done in accordance with local data 
protection law and is handled in strictest confidence. For protection of these data, organizational 
procedures are implemented to prevent distribution of data to unauthorized persons. The 
appropriate regulations of local data legislation are fulfilled in its entirety. 
The patient consents in writing to relieve the investigator from his/her professional discretion in 
so far as to allow inspection of original data for monitoring purposes by health authorities and 
authorized persons (inspectors, monitors, auditors). Authorized persons (clinical monitors, 

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auditors, inspectors) may inspect the patient-related data collected during the trial, ensuring the 
data protection law. 
The investigator maintains a patient identification list (Patient IDs with the corresponding patient 
names) to enable records to be identified. 
Patients who did not consent to circulate their pseudonymized data are not included into the trial. 
12.4 Responsibilities of Investigator 
The Principal Investigator should ensure that all persons assisting with the trial are adequately 
informed about the protocol and any amendments, the trial treatments, and their trial-related 
duties and functions. 
The Principal Investigator should maintain a list of investigators and other appropriately qualified 
persons to whom he or she has delegated significant trial-related duties (Log of Staff). 
The investigator(s) should support monitoring, auditing and inspections as described in sections 
13.1 and 13.2. 
12.5 Approval of Trial Protocol and Amendments 
Before the start of the trial, the trial protocol, informed consent document, and any other 
appropriate documents are submitted to the independent Ethics Committee (EC) as well as to the 
competent federal authority (BfArM). A written favourable vote of the EC and an (implicit) approval 
by the competent higher federal authority are a prerequisite for initiation of the clinical trial. The 
statement of EC should contain the title of the trial, the trial code, the trial site, and a list of 
reviewed documents. It must mention the date on which the decision was made and must be 
officially signed by a committee member.  
Before the first patient is enrolled in the trial, all ethical and legal requirements must be met. All 
planned substantial changes (see §10, (1) of German GCP-Regulation) are submitted to EC and 
the competent higher federal authority in writing as amendments. They have to be approved by 
the EC and the competent higher federal authority.  
The Coordinating Investigator or the NCT Trial Center, and if applicable the investigator(s)  keep 
a record of all communication with the EC and the regulatory authorities. 
12.6 Continuous Information to Independent Ethics Committee 
Pursuant to the German Drug Law (AMG) and the GCP Regulation, the EC and the competent 
higher federal authority are informed of all suspected serious unexpected adverse reactions 
(SUSARs). Both institutions are informed in case the benefit-risk assessment did change or any 
others new and significant hazards for patients’ safety or welfare did occur. Furthermore, a report 
on all observed serious adverse events (SAEs) is submitted once a year (Development Safety 
Update Report (DSUR)). 
The EC and the regulatory authorities must be informed of the end of the trial. They are provided 
with a summary of trial results within one year after the end of clinical phase (LPLV). 
12.7 Notification of Regulatory Authorities 
The local regulatory authorities as responsible for each particular investigator and the competent 
higher federal authority are informed before the beginning, during and at the end of the trial 
according to §67 AMG and §13 GCP-V. Each investigator is obliged to notify his/ her local 
regulatory authority and the competent higher federal authority according §67 AMG and §12 (1, 
2, 6) GCP-V.  
12.8 Registration of the Trial 
Prior to the beginning of the clinical phase (FPI) the coordinating / principal investigator registers 
the trial at a public accessible clinical trial register having the status of a primary register according 
to the International Clinical Trials Registry Platform (ICTRP) and correspondingly is listed at the 
International Clinical Trials Registry Platform of the World Health Organization (WHO, 

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http://www.who.int/ictrp/en/). The requirements are fulfilled by the European Clinical Trials 
Register and submission of EMA Module 1 (Clinical Trial Application Form). 
The registration is a prerequisite for a publication in many peer-reviewed journals (see Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals by the International Committee 
of Medical Journal Editors; (http://www.icmje.org/ publishing_10register.html). 
12.9 Insurance 
According to § 40 AMG, the sponsor has to subscribe to an insurance policy which covers in its 
terms and provisions its legal liability for injuries caused to participating persons. The insurance 
policy also covers any damage done to the patient, even if the harm done arises out of strictly 
following the procedures described in this protocol and abiding as applicable law and professional 
standards. The insurance was taken out at HDI Global SE (insurance number: 57 010310 03018, 
maximum limit: € 500.000 per participating person). 
Any impairment of health which might occur in consequence of trial participation must be notified 
to the insurance company. The patient is responsible for notification. The insured person must 
agree to help clarify the cause and the extent of damage with all appropriate measures. He is also 
obliged to take measures himself to reduce damage as much as possible.  During the conduct of 
the trial, the patient must not undergo other clinical treatment except for cases of emergency. The 
patient is bound to inform the investigator immediately about any adverse events and additionally 
drugs taken. The terms and conditions of the insurance must be delivered to the patient. 
The insurance company has to be informed about all amendments that could affect patients’ 
safety, and must also receive the actual version of the informed consent. 
13 Quality Assurance 
13.1 Monitoring  
Monitoring is done by personal visits from a clinical monitor and by centralized monitoring. The 
investigator must allow the monitor to verify all essential documents and must provide support at 
all times to the monitor. Monitoring is done in a risk based manner. 
By frequent communications (e-mails, letters, telephone, fax), the site monitor a ensure that the 
trial is conducted according to the protocol and to regulatory requirements. 
13.2 Inspections/ Audits  
Regulatory authorities and an auditor authorized by the sponsor may request access to all source 
documents, CRF, and other trial documentation. Direct access to these documents must be 
guaranteed by the investigator, who must provide support at all times for these activities. 
14 Agreements 
14.1  Financing of the Trial 
The trial is financed using funds of Pfizer Pharma GmbH and DKFZ. 
 The study drug is provided free-of-charge by Pfizer Pharma GmbH. 
14.2  Declaration of Interests  
Before the start of the trial, the investigator discloses to the sponsor any proprietary or financial 
interests he or she might hold in the sponsors/ a funding company, in the investigational 
product(s), or any commercial organisation being involved in the clinical trial. The investigator has 
also to confirm that he/she has not entered into any financial arrangement whereby the value of 
compensation paid could affect the outcome of the clinical trial. 
The investigator agrees to update this information in case of significant changes.  

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14.3 Dissemination Policy 
Trial results are published in medical journals, and via the chordoma foundation 
(https://www.chordomafoundation.org/). 
14.3.1 Access to data  
After the trial  has been completed and published, it is planned to make the trial available for re- 
and meta-analyses. An appropriate repository is defined at the end of the trial.19 
14.3.2 Reports 
The biostatistician  prepares the final trial report together with the Coordinating Investigator within 
12 months after the end of the study (database lock). 
Interim safety reports (DSURs) are prepared by the pharmacovigilance officer together with the 
Coordinating Investigator in accordance with legally required timeframes; data reconciliation is  
carried out where necessary and possible together with the data management of the NCT Trial 
Center based on already available CRF-AE data.  
14.3.3 Publication 
All information concerning the trial is confidential before publication. Trial results are  published 
in medical journals.  

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15 Signatures 
The present trial protocol was subject to critical review and has been approved in the present 
version by the persons undersigned. The information contained is consistent with: 
 
The current benefit-risk assessment of the investigational medicinal product 
 
Moral, ethical, and scientific principles governing clinical research as set out the 
principles of GCP and in the applicable version of Declaration of Helsinki. 
The investigator is supplied with details of any significant or new finding, including relevant safety 
information relating to treatment with the investigational medicinal product. 
 
 
 
 
 
 
Date: 
 
___________________ 
Signature:  
 
 
_________________________________ 
 
 
Prof. Dr. Richard F. Schlenk 
Function: Coordinating Investigator 
 
 
 
 
 
 
 
 
 
 
Date: 
 
___________________ 
Signature:  
 
 
_________________________________ 
 
 
Lisa-Marie Rother 
Function: Biostatistician 
 

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16 
Declaration of Investigator 
I have read the above trial protocol and confirm that it contains all information to conduct the 
clinical trial. I pledge to conduct the clinical trial according to the protocol. 
I will enrol the first patient only after all ethical and regulatory requirements are fulfilled. I pledge 
to obtain written consent for trial participation from all patients before enrolment. 
I know the requirements for accurate reporting of serious adverse events, and I pledge to 
document and notify such events as described in the protocol. 
I pledge to retain all trial-related documents and source data as described.  
 
Date:  
 
___________________ 
Signature: 
 
___________________________ 
 
Name (block letters): 
 
___________________________ 
 
Trial Center (address): 
 
___________________________ 
 
___________________________ 
 
___________________________ 

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17 
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von Witzleben A, Goerttler LT, Marienfeld R, et al. Preclinical Characterization of Novel 
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Giesinger JM, Kieffer JM, Fayers PM, et al. Replication and validation of higher order 
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Fayers P, Aaronson NK, Bjordal K, et al. EORTC QLQ-C30 Scoring Manual. European 
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Buysse DJ, Reynolds CF, Monk TH, et al. Pittsburgh Sleep Quality Index., in APA task 
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18 
Patient Health Questionnaire (PHQ) Screeners. INSTRUCTION MANUAL Instructions 
for Patient Health Questionnaire (PHQ) and GAD-7 Measures. 
 
19 
Warren E. Strengthening Research through Data Sharing. N Engl J Med 2016; 375:401-
403.