Clinical trial NCT02611037
Conditions: Malignant Pleural Mesothelioma Mesothelioma
Keywords: MPM Unresectable Respiratory Intrathoracic Transarterial Chemoperfusion
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2016-03-04; Completion date: 2024-01-26
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine whether the transarterial chemoperfusion treatment with cisplatin, methotrexate and gemcitabine is safe and effective in adults with malignant pleural mesothelioma (MPM).

Detailed description:
This is an open-label, single arm, phase 2 study with a lead in safety cohort to evaluate the safety and efficacy of transarterial chemoperfusion treatment with cisplatin (35 mg/m2\^), methotrexate (100 mg/m\^2) and gemcitabine (1000 mg/m\^2) in patients with unresectable MPM. During the lead in phase of the study, 3 patients will be treated with 50% reduced dose of methotrexate (50 mg/m\^2) and regular doses of cisplatin (35 mg/m\^2 body surface area (BSA)) and gemcitabine (1000 mg/m\^2 BSA).

Arms: arm 1: Transarterial Chemoperfusion treatment with cisplatin (35 mg/m\^2), methotrexate (100 mg/m\^2) and gemcitabine (1000 mg/m\^2).

Patients undergo angiogram and transarterial chemoperfusion treatment in every 4 weeks (3-6 weeks interval allowed) when cisplatin, methotrexate and gemcitabine will be administered into the thoracic aorta and/or the internal mammary artery on the side of the disease.

Quality of life will be assessed using the modified version of the Lung Cancer Symptom Scale for Mesothelioma questionnaire.
Interventions: intervention 1: Cisplatin intervention 2: Methotrexate intervention 3: Gemcitabine intervention 4: Lung Cancer Symptom Scale for Mesothelioma Questionnaire
Intervention descriptions: intervention 1: The recommended dose of cisplatin for transarterial chemoperfusion in this study is 35 mg/m\^2 body surface area (BSA). During the lead in phase of the study, 3 patients will be treated with regular doses of cisplatin. intervention 2: The recommended dose of methotrexate for transarterial chemoperfusion in this study is 100 mg/m\^2 BSA. During the lead in phase of the study, 3 patients will be treated with 50% reduced dose of methotrexate (50 mg/m\^2). intervention 3: The recommended dose of gemcitabine for transarterial chemoperfusion in this study is 1000 mg/m\^2 BSA. During the lead in phase of the study, 3 patients will be treated with regular doses of gemcitabine. intervention 4: Quality of life will be assessed using the modified version of the Lung Cancer Symptom Scale for Mesothelioma questionnaire.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A Phase 2 Study of Transarterial Chemoperfusion Treatment with Cisplatin, 
Methotrexate and Gemcitabine in Patients with Unresectable Pleural 
Mesothelioma 
NCT026611037 
 
Version 7 
March 27, 2018 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
1 
 
 
 
 
 
 
A Phase 2 Study of Transarterial Chemoperfusion Treatment with Cisplatin, 
Methotrexate and Gemcitabine in Patients with Unresectable Pleural 
Mesothelioma 
 
 
 
Sponsor:  
 
 
 
 
 
H. Lee Moffitt Cancer Center and Research Institute 
 
 
 
 
 
 
 
 
 
12902 Magnolia Drive 
 
 
 
 
 
 
 
 
 
Tampa, FL 33612 
 
 
Principal Investigator: 
Bela Kis, MD, PhD 
 
 
 
 
 
 
 
 
 
H. Lee Moffitt Cancer Center and Research Institute 
 
 
 
 
 
 
 
 
 
12902 Magnolia Drive 
Tampa, FL 33612 
Telephone: (813) 745-8425 
Fax: (813) 813-449-8729 
e-mail address: bela.kis@moffitt.org 
 
Agents: 
 
Cisplatin, Methotrexate, Gemcitabine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                          Protocol Version 7: March 27, 2018 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
2 
 
STUDY SYNOPSIS 
 
Title of Study: A Phase 2 Study of Transarterial Chemoperfusion Treatment with Cisplatin, 
Methotrexate and Gemcitabine in Patients with Unresectable Pleural Mesothelioma. 
Sponsor: H. Lee Moffitt Cancer Center and Research Institute 
Primary Investigator: Bela Kis, MD, PhD 
Phase of Development: Phase 2 
Study Duration: 3 years 
Primary Objective: To determine the disease control rate of transarterial chemoperfusion 
treatment with cisplatin, methotrexate and gemcitabine in patients with unresectable malignant 
pleural mesothelioma (MPM). 
Secondary Objectives: To assess overall survival, progression free survival, severity and 
frequency of adverse events and quality of life in patients with MPM treated with transarterial 
chemoperfusion with cisplatin, methotrexate and gemcitabine. 
Rationale: MPM has an extremely poor prognosis with median survival time of less than 12 
months. Surgical resection for stage I and stage II MPM is the only curative option. However, the 
majority of patients present with stage III or IV disease with 85-90% of patients considered 
unresectable at diagnosis. The largely ineffective current treatment approaches to offer long-
term survival and to improve quality of life warrant the search for new therapeutic regimens. 
Study Design: This is an open-label, single arm, phase 2 study with a lead in safety cohort to 
evaluate the safety and efficacy of transarterial chemoperfusion treatment with cisplatin (35 
mg/m2), methotrexate (100 mg/m2) and gemcitabine (1000 mg/m2) in patients with unresectable 
MPM. During the lead in phase of the study 3 patients will be treated with 50% reduced dose of 
methotrexate (50 mg/m2) and regular doses of cisplatin (35 mg/m2 BSA) and gemcitabine (1000 
mg/m2 BSA). Dose escalation will be contingent upon acceptable safety data obtained during 
the first three cycles of treatment (12 weeks). If no dose limiting toxicity observed, dose is 
escalated to methotrexate (100 mg/m2) with cisplatin (35 mg/m2 BSA) and gemcitabine (1000 
mg/m2 BSA). The reduced dose level safety cohort will be expanded from 3 to 6 if one of the 
first 3 patients experiences dose limiting toxicity related to methotrexate. After the 12 weeks of 
dose limiting toxicity observation period for the final patient in the reduced dose safety cohort is 
complete, if less than one third of the patients enrolled in that cohort developed dose limiting 
toxicity, advancement to the regular dose level cohort can begin. If > 2 patients in the safety 
cohort experience dose limiting toxicity the methotrexate dose will be reduced to 25 mg/m2 and 
this will be used further in the study. 
During the chemoperfusion procedure based on the pre-procedural imaging and the 
angiography findings the chemoperfusion catheter will be placed within a tumor supplying 
intercostal artery or within the descending aorta slightly proximal to origin of the most cephalad 
tumor supplying intercostal artery, but below the origin of the left subclavian artery if multiple 
intercostal vessels are supplying the tumor. For tumors located predominantly anteriorly in the 
chest the infusion catheter will be placed into the ipsilateral internal mammary artery. For tumors 
supplied by both intercostal and internal mammary arteries chemoperfusion may be performed 
for the artery predominantly supplying the tumor or for multiple arteries per primary clinician 
discretion. Chemoperfusion treatment will be administered in every 4 weeks until the patient’s 
death unless the treatment is terminated earlier due to treatment toxicity or other reasons. 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
3 
 
Number of Subjects (planned): 32 
Major Inclusion Criteria: 
 
Histologically confirmed unresectable MPM. 
 
Failed first line standard of care chemotherapy or the patient refuses first line 
chemotherapy. 
 
Age >18 years. 
 
Estimated life expectancy > 12 weeks. 
 
ECOG performance status <2. 
 
Adequate organ functions. 
 
Signed informed consent. 
Major Exclusion Criteria: 
 
Allergic reaction to agent used during the study. 
 
Known brain metastases or leptomeningeal metastases. 
 
Uncontrolled severe intercurrent illness. 
 
Women who are pregnant or breastfeeding. 
 
Unable to obtain informed consent. 
Criteria for Evaluation: 
Efficacy Outcome Measures 
Primary: Disease control rate measured by modified RECIST for mesothelioma. 
Secondary: Overall survival defined as the time from the first day of transarterial 
chemoperfusion treatment to death. Progression free survival defined as the time from the first 
day of transarterial chemoperfusion treatment to disease progression based on imaging 
findings using modified RECIST criteria for mesothelioma. 
Safety Outcome Measures 
Safety will be assessed by monitoring adverse events and serious adverse events; the 
association with study treatment will be assessed, and severity will be graded using CTCAE 
v.4.03. 
Quality of Life Measures 
Quality of life will be assessed using the modified version of the Lung Cancer Symptom Scale 
for Mesothelioma questionnaire. 
Statistical Methods: This is an open-label, single arm, phase 2 study to evaluate the safety and 
efficacy of transarterial chemoperfusion treatment in patients with unresectable MPM. The 
statistical power calculations are based on the Simon’s two-stage design. The one-sided and 
two-sided 95% confidence intervals by Atkinson and Brown will be reported, which accounts for 
the nature of two-stage design. The secondary endpoints include overall survival and 
progression free survival which are estimated by the Kaplan-Meier method. For all subjects, 
descriptive statistics (median, range for continuous variables and frequency and proportion for 
categorical variables) will be utilized to summarize patients’ demographic and clinical variables. 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
4 
 
TABLE OF CONTENTS 
 
Page 
 
STUDY SYNOPSIS ........................................................................................................................ 2 
 
1. OBJECTIVES ........................................................................................................................... 6 
1.1 
Primary Objective .......................................................................................................... 6 
1.1 
Secondary Objectives ................................................................................................... 6 
 
2. BACKGROUND ........................................................................................................................ 6 
2.1 
Malignant pleural mesothelioma ................................................................................... 6 
2.2 
Rationale ....................................................................................................................... 7 
 
3. PATIENT SELECTION ............................................................................................................. 8 
3.1 
Eligibility Criteria  ........................................................................................................... 8 
3.2 
Exclusion Criteria ........................................................................................................ 11 
3.3 
Inclusion of Women and Minorities ............................................................................. 12 
3.4 
Patient Registration ..................................................................................................... 12 
 
4. TREATMENT PLAN ............................................................................................................... 12 
4.1  
Method of Assignment to Treatment ........................................................................... 12 
4.2  
Study Design ............................................................................................................... 12 
4.3   
Rationale for Study Design ......................................................................................... 13 
4.4  
Rationale for Cisplatin Dosage ................................................................................... 16 
4.5  
Rationale for Methotrexate Dosage ............................................................................ 16 
4.6  
Rationale for Gemcitabine Dosage ............................................................................. 16 
4.7  
Screening for Study Eligibility and Baseline Evaluation ............................................. 17 
4.8  
Pre-procedure Care and Evaluation ........................................................................... 19 
4.9  
Transarterial Chemoperfusion Procedure .................................................................. 21 
4.10 
Post-procedural Supportive Care................................................................................ 23 
4.11 
Duration of Therapy .................................................................................................... 23 
4.12 
Removal of Patients From Study ................................................................................ 23 
4.13 
Premature Study Termination ..................................................................................... 24 
 
5. DRUG TOXICITIES, DOSE MODIFICATIONS, DOSING DELAYS ...................................... 25 
5.1  
General Considerations .............................................................................................. 25 
5.2  
Definition of Dose-Limiting Toxicity ............................................................................. 25 
5.3  
Hematological Toxicity ................................................................................................ 26 
5.4   
Renal Toxicity .............................................................................................................. 26 
5.5  
Hepatic Toxicity ........................................................................................................... 27 
5.6  
Pericardial Effusion, Pleural Effusion, Ascites ............................................................ 27 
5.7  
Other Toxicities ........................................................................................................... 28 
 
6. PHARMACEUTICAL INFORMATION .................................................................................... 28 
6.1  
Cisplatin  ...................................................................................................................... 28 
6.2  
Methotrexate ............................................................................................................... 28 
6.3  
Gemcitabine ................................................................................................................ 28 
 
7. STUDY CALENDAR ............................................................................................................... 29 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
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8. MEASUREMENT OF EFFECT ............................................................................................... 30 
8.1  
Measurement of Tumor Response Using RECIST 1.1 Criteria .................................. 30 
8.2  
Measurement of Tumor Response Using Modified RECIST for Mesothelioma ......... 36 
8.3  
Overall Survival ........................................................................................................... 37 
8.4  
Progression-Free Survival........................................................................................... 37 
8.5  
Evaluation of Safety .................................................................................................... 38 
8.6  
Evaluation of Quality of Life ........................................................................................ 41 
 
9. ETHICAL AND REGULATORY CONSIDERATIONS ............................................................ 42 
9.1  
Protocol and Regulatory Compliance ......................................................................... 42 
9.2  
Document Audits and Monitoring ................................................................................ 42 
9.3  
Adverse Event Recording and Reporting ................................................................... 43 
9.4  
Protocol Amendments ................................................................................................. 45 
9.5  
Regulatory Binder ........................................................................................................ 45 
9.6  
Informed Consent ........................................................................................................ 45 
9.7  
Institutional Review Board/Independent Ethics Committee ........................................ 46 
9.8  
Patient Confidentiality ................................................................................................. 46 
9.9  
Curriculum Vitae and Medical Licenses ...................................................................... 46 
9.10 
Financial Disclosure .................................................................................................... 47 
 
10. DATA MANAGEMENT AND RECORD KEEPING ................................................................ 47 
 
11. STATISTICAL CONSIDERATIONS ....................................................................................... 47 
11.1 
Study Design and Sample Size Justification .............................................................. 47 
11.2 
Accrual Rate ................................................................................................................ 48 
11.3 
Stratification Factors ................................................................................................... 48 
11.4 
Analysis of Primary and Secondary Endpoints ........................................................... 48 
 
12. REFERENCES........................................................................................................................ 49 
 
APPENDIX A 
Performance Status Criteria .................................................................................................... 52 
 
APPENDIX B 
Cockcroft - Gault Formula ..................................................................................................... 523 
 
APPENDIX C 
Guidance on Contraception .................................................................................................... 54 
 
APPENDIX D 
Quality of Life Questionnaire ................................................................................................... 56 
 
APPENDIX E 
Cisplatin Pharmacologic Information (Package Insert) ......................................................... E-1 
 
APPENDIX F 
Methotrexate Pharmacologic Information (Package Insert) .................................................. F-1 
 
APPENDIX G 
Gemcitabine Pharmacologic Information (Package Insert) .................................................. G-1 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
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1. OBJECTIVES 
 
1.1  
Primary Objective 
 
The primary objective of this study is to determine the disease control rate of 
transarterial chemoperfusion treatment with cisplatin, methotrexate and gemcitabine 
in patients with unresectable malignant pleural mesothelioma using modified RECIST 
criteria for mesothelioma [1]. 
 
 
1.2  
Secondary Objectives 
 
1.2.1 Overall Survival 
To assess overall survival (OS) in patients with malignant pleural 
mesothelioma treated with transarterial chemoperfusion. 
 
1.2.2 Progression Free Survival 
To assess progression free survival (PFS), defined as the time from the first 
day of cisplatin, methotrexate and gemcitabine transarterial chemoperfusion 
treatment to disease progression (either pleural or extrapleural), based on 
imaging findings using modified RECIST criteria for mesothelioma [1] or death 
from any cause. 
 
1.2.3 Safety and Tolerability 
To determine the severity and frequency of adverse events related to 
transarterial chemoperfusion with cisplatin, methotrexate and gemcitabine 
during the chemoperfusion phase and follow-up phase of the study. 
 
1.2.4 Quality of Life 
To assess quality of life in patients with malignant pleural mesothelioma 
treated with transarterial chemoperfusion. 
 
 
2. BACKGROUND 
 
2.1  
Malignant Pleural Mesothelioma 
 
Malignant mesothelioma is a rare form of cancer that develops from cells of the 
mesothelium, the lining of the coelomic cavities of the body: the pleura, the 
peritoneum, the pericardium, and the tunica vaginalis testis. Mesothelioma is 
classified into three broad histological subtypes: epithelioid, sarcomatoid and mixed, 
comprising approximately 50% to 70%, 10% to 20%, and 20% to 40% percent of 
malignant mesothelioma, respectively. Patients with the sarcomatoid and mixed 
subtypes have worse prognosis compared to the epithelioid subtype [2]. 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
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Mesothelioma is associated with asbestos exposure. It was considered a rare 
disease until 50 years ago, but its incidence dramatically increased due to the 
widespread use of asbestos in the early to mid-twentieth century. Since the median 
latency between asbestos exposure and disease onset is 44.6 years, and increases 
over time in a linear fashion, incidence rates are still rising, with peak incidences 
expected around 2020 and beyond [3]. Due to the long latency of the onset of 
disease after exposure to asbestos, mesothelioma typically develops in the sixth or 
seventh decade of life [4]. 
 
Malignant pleural mesothelioma (MPM) is the most common form of mesothelioma 
(67% to 75%) followed by peritoneal mesothelioma (25% to 33%) [4]. In the US there 
are approximately 2400 new MPM cases per year [5]. The clinical presentation of 
MPM at the time of diagnosis is shortness of breath and chest pain in 60% of patients 
[6]. MPM progresses with local invasion of the thoracic wall including the intercostal 
nervous structures causes chest pain and the development of chest wall lumps. 
Loco-regional progression of the tumor results in pneumonia, superior vena cava 
syndrome, Pancoast or Horner’s syndrome, dysphagia, pericardial tamponade, and 
arrhythmias. In most patients, death occurs as a result of loco-regional progression 
within the thoracic cavity. Constitutional symptoms (eg, fatigue and weight loss) and 
lymphatic and hematogenous dissemination occurs late in the disease [7]. 
 
Patients with unresectable MPM carry a poor prognosis. The treatment options for 
unresectable stage III and stage IV MPM are radiation therapy and chemotherapy, 
but survivals are usually less than a year [6]. These very poor survival statistics 
necessitates a search for new, more effective therapies. 
 
 
2.2  
Rationale 
 
MPM has an extremely poor prognosis with median survival time of less than 12 
months [6]. Surgical resection for stage I and stage II MPM is the only curative option. 
However, the majority of patients present with stage III or IV disease with 85-90% of 
patients considered unresectable at diagnosis. The largely ineffective current 
treatment approaches to offer long-term survival and to improve quality of life warrant 
the search for new therapeutic regimens. 
 
Isolated lung perfusion, which permits a selective delivery of high-dose 
chemotherapeutic agents to the tumor, has shown promising results in the treatment 
of lung metastasis in experimental models [8]. These studies have demonstrated the 
superiority of isolated lung perfusion to systemic chemotherapy in terms of 
effectiveness, but despite these results, isolated lung perfusion has not been and 
likely won’t be adopted as a routine clinical treatment because it is a very complex 
procedure requiring thoracotomy for cannulation of the pulmonary arteries and veins, 
which is a high morbidity and mortality surgery with a very high associated cost. 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
8 
 
Transarterial chemoperfusion of the liver in patients with uveal melanoma metastases 
demonstrated prolonged survival [9]. Transarterial chemoperfusion through direct 
injection of drugs into the aorta has been described as a treatment option for 
advanced pelvic tumors [10]. 
 
Vogl et al. recently demonstrated that transarterial chemoperfusion in patients with 
unresectable MPM significantly improve survival [11]. In contrast to isolated lung 
perfusion, transarterial chemoperfusion of the lung and pleural cavity can be easily 
and repeatedly performed percutaneously and it is well tolerated by the patients.  
 
Vogl et al [11] administered mitomycin C with cisplatin, and gemcitabine 
transarterially to patients with unresectable MPM. The reason why this drug 
combination was chosen is not explained in their paper. We are proposing 
transarterial chemoperfusion with cisplatin, metothrexate and gemcitabine in patients 
with unresectable MPM. This drug combination is different than what was used by 
Vogl et al. who used mitomycin C with cisplatin, and gemcitabine. We are proposing 
to use methotrexate instead of mitomycin C because mitomycin C and cisplatin has 
the same mechanism of action, both are DNA crosslinker agent, and we think that 
using chemotherapeutic drugs with different mechanism of action may lead to 
improved clinical response. In addition, folate antimetabolites like methotrexate and 
pemetrexed are regarded as the most active class of cytotoxic drugs against MPM 
[12-14]. In our proposed drug combination each drug acts on different steps of the 
mitotic cycle of cells as cisplatin is a DNA crosslinker, methothrexate is a folate 
antimetabolite and gemcitabine is a nucleoside analogue. 
 
These drugs were proven to be effective in patients with MPM and have established 
safety profiles with intraarterial administration. One could argue to use pemetrexed 
instead of methothrexate since recent reviews [12; 14] showed that the combination 
of pemetrexed with cisplatin achieves the best overall survival and quality of life in 
patients with MPM. However, there is no established safety profile of pemetrexed for 
intraarterial administration. 
 
This proposed transarterial chemoperfusion treatment protocol offers a novel 
approach to treat patients with unresectable MPM. 
 
 
3. PATIENT SELECTION 
 
3.1  
Eligibility Criteria 
 
3.1.1 Patients must have histologically or cytologically confirmed malignant pleural 
mesothelioma (MPM). 
 
3.1.2 Patients have unresectable MPM or the patient refuses surgery for resectable 
MPM. 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
9 
 
3.1.3 Patients who failed to respond first line standard of care chemotherapy or 
chemotherapy suspended due to toxicity or other reasons. 
 
3.1.4 Patients who are refusing first line standard of care chemotherapy. 
 
3.1.5 Patients must have measurable disease, by CT or MRI per modified RECIST 
criteria for mesothelioma . Radiographic tumor assessment must be 
performed within 28 days prior to the first treatment. 
 
3.1.6 The predominant burden of disease lies in an arterial distribution which is 
accessible for transarterial chemoperfusion treatment. 
 
3.1.7 
Men and women >18 years of age. 
 
3.1.8 
ECOG performance status <2 (Karnofsky >60%; see Appendix A). 
 
3.1.9 
All baseline laboratory requirements will be assessed and should be obtained 
within 14 days of first treatment. Screening laboratory values must meet the 
following criteria: 
 
- 
leukocytes  
 
 
 
 
>3,000/L 
 
- 
absolute neutrophil count  
>1,500/L 
 
- 
platelets 
 
 
 
 
 
>100,000/L 
 
- 
prothrombin time  
 
 
< 1.5 x upper limit of normal (ULN); 
 
- 
partial thromboplastin time 
< 1.5 x institutional ULN; 
 
- 
total bilirubin  
 
 
 
< 1.5 x ULN; except subjects with Gilbert 
syndrome who can have total bilirubin < 3.0 
mg/dL) 
 
- 
aspartate amino transferase <2.5 X institutional ULN 
 
- 
alanine amino transferase 
<2.5 X institutional ULN 
 
- 
alkaline phosphatase  
 
<2.5 X institutional ULN 
 
- 
creatinine  
 
 
 
 
within normal institutional limits 
OR 
- 
creatinine clearance  
 
≥50 mL/min based on the standard 
Cockcroft and Gault formula [15]. 
 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
10 
 
3.1.10 Women participate in the study must be surgically sterile, post-menopausal, 
or women of child-bearing potential must agree to use adequate 
contraception (See Appendix C) prior to study entry and for the duration of 
study participation and after for a certain amount of time (as defined below) 
because the therapeutic agents used in this trial and the x-ray used during the 
transarterial treatment and diagnostic imaging are known to be teratogenic. 
 
 
The individual methods of contraception and duration should be determined 
in consultation with the investigator. The duration of mandatory contraception 
is based on clearance of the investigational drug (5 half-lives after treatment 
completion). For women, an additional 30 days is required to complete an 
ovulatory cycle. Calculation of duration of mandatory contraception: The half-
life of cisplatin is 20-30 minutes (Appendix E), half-life of metothrexate is 8-15 
hours (Appendix F) and half-life of gemcitabine is 42-94 minutes (Appendix 
G). Thus, contraception is required for up to 5 weeks after the last treatment 
for women of child-bearing potential. 
 
 
Women must have a negative serum or urine pregnancy test within 24 hours 
prior to the start of transarterial chemoperfusion treatment. 
 
 
Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician 
immediately. 
 
3.1.11 Men participate in the study must be surgically sterile or must agree to use 
adequate contraception (See Appendix C) prior to study entry and for the 
duration of study participation and after for a certain amount of time (as 
defined below) because the therapeutic agents used in this trial and the x-ray 
used during the transarterial treatment and diagnostic imaging are known to 
be teratogenic. The investigator shall review contraception methods and the 
time period that contraception must be followed. The duration of mandatory 
contraception is based on clearance of the investigational drug (5 half-lives 
after treatment completion). For males, an additional 90 days is required to 
complete turnover of drug-exposed sperm. Calculation of duration of 
mandatory contraception: The half-life of cisplatin is 20-30 minutes (Appendix 
E), half-life of metothrexate is 8-15 hours (Appendix F) and half-life of 
gemcitabine is 42-94 minutes (Appendix G). Thus, contraception for men is 
required for up to 14 weeks after the last treatment. 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.13 Patients must have signed and dated an IRB approved written informed 
consent form in accordance with regulatory and institutional guidelines. This 
must be obtained before the performance of any protocol related procedures 
that are not part of normal subject care. 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
11 
 
 
3.1.14 Subjects must be willing and able to comply with scheduled visits, treatment 
schedule, laboratory tests, imaging studies, and other requirements of the 
study. 
 
3.1.15 This study permits the re-enrollment of a patient who has discontinued the 
study for a reason other than treatment failure or adverse event(s) of the 
study treatment. The patient must be re-consented and assigned a new 
subject number. 
 
 
3.2  
Exclusion Criteria 
 
3.2.1 
Patients who have had chemotherapy within 4 weeks prior to entering the 
study or those who have not recovered from adverse events due to agents 
administered more than 4 weeks earlier. Recovery means resolution to at 
least Grade 1 toxicity if there was no baseline toxicity or less than or equal to 
the patient’s baseline value. 
 
3.2.2 
Patients may not be receiving any other investigational agents. 
 
3.2.3 
Patients with known brain metastases or leptomeningeal metastases should 
be excluded from this clinical trial because of their poor prognosis and 
because they often develop progressive neurologic dysfunction that would 
confound the evaluation of neurologic and other adverse events. Patients with 
other extrapleural metastases are included in this study. 
 
3.2.4 
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to cisplatin, metothrexate, gemcitabine or other agents 
used during the study. 
 
 History of allergic reaction to intravenous iodinated contrast media is not 
contraindication to the study. Patients with history of mild allergic reaction to 
iodinated contrast media will be premedicated with 40 mg of prednisone p.o. 
12 and 2 hrs before the transarterial chemoperfusion treatment to prevent 
allergic reaction. Patients with history of moderate and severe allergic reaction 
to iodinated contrast media or patients with history of mild allergic reaction to 
iodinated contrast media despite adequate premedication will undergo 
angiogram using carbon dioxide or a gadolinium based contrast agent. 
 
3.2.5 
Uncontrolled intercurrent illness including, but not limited to, presence of other 
malignancy, ongoing or active infection, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
 
 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
12 
 
3.2.6 
Women who are pregnant or breastfeeding are excluded from the study 
because methotrexate and cisplatin are FDA pregnancy category D agents 
with positive evidence of human fetal risk based on adverse reaction data 
from investigational or marketing experience or studies in humans. 
 
3.2.7 
HIV-positive patients receiving combination anti-retroviral therapy are 
excluded from the study because of possible pharmacokinetic interactions 
with cisplatin, methotrexate and gemcitabine during the study.  
 
3.2.8 
Prisoners or subjects who are involuntarily incarcerated. 
 
3.2.9 
Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness. 
 
 
3.3  
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for 
this trial. 
 
 
3.4  
Patient Registration 
 
Once clinical eligibility is confirmed, patients must sign an informed consent prior to 
registration indicating awareness of the investigation nature of the study and its 
inherent risks in keeping with the policies of the Moffitt Cancer Center and Federal 
regulations (Code of Federal Regulations Part 1X, Subpart B, Sections 50.20-50.27). 
The principal investigator in writing must approve request for an exemption to enroll a 
patient. 
 
 
4. TREATMENT PLAN 
 
4.1  
Method of Assignment to Treatment 
 
 
 
This is an open-label, single arm, phase 2 study. Patients with unresectable MPM 
who meet all criteria for enrollment will be offered to participate in the study. The 
eligible patients can voluntarily enroll in the study after reviewing the consent form 
and after detailed discussion of the procedural protocol and potential risks and 
benefits of this experimental treatment with the principal investigator or one of the co-
investigator. 
 
4.2  
Study Design 
 
This is an open-label, single arm, phase 2 study with a lead in safety cohort to 
evaluate the safety and efficacy of transarterial chemoperfusion treatment with 


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cisplatin, metothrexate and gemcitabine in patients with unresectable MPM. The 
patients receive 15 mg leucovorine po in every 12 hrs for a total of 4 doses starting 
24 hrs after each chemoperfusion procedure. Chemoperfusion treatment will be 
administered in every 4 weeks. The treatment will be continued until the patient’s 
death unless the treatment is terminated earlier due to reasons described in Section 
4.12.1 Removal of Patients From Study and in Section 4.12.2 Premature Study 
Termination. 
 
 
 
The study will be divided into the following phases: 
 
 
 
 
- Screening Phase 
 
 
 
 
- Treatment Phase 
 
 
 
 
- Follow-up Phase 
 
4.2.1 
Screening Phase 
 
 
Screening assessments must occur within 4 weeks of the chemoperfusion 
treatment for determination of a patient’s overall eligibility. These 
assessments will include medical history, ECOG performance status, physical 
exam, full hematology and biochemistry laboratory, radiologic assessments of 
disease status, and an evaluation of vasculature compatibility for 
chemoperfusion. 
 
4.2.2 
Treatment Phase 
 
 
Patients undergo angiogram and transarterial chemoperfusion treatment in 
every 4 weeks (3-6 weeks interval allowed) when cisplatin, methotrexate and 
gemcitabine will be administered into the thoracic aorta and/or the internal 
mammary artery on the side of the disease. 
 
4.2.3 
Follow-up Phase 
 
 
Follow-up assessments will be performed at 4 weeks (3-6 weeks interval 
allowed) after each chemoperfusion treatment. Follow-up assessments must 
occur before the next chemoperfusion is performed. These assessments will 
include medical history, ECOG performance status, full hematology and 
biochemistry laboratory, radiologic assessments of disease status, and 
physical exam with special attention to the arterial access site. Other 
symptoms (severity and duration) such as dyspnea, chest pain, persistent 
cough, etc. will be monitored by using a questionnaire (see Appendix D). The 
questionnaire should be completed and returned to the principal investigator 
before each transarterial chemoperfusion treatment. 
 
 
4.3   
Rationale for Study Design 
 
Transarterial chemoperfusion with mitomycin C, cisplatin and gemcitabine has been 
shown by Vogl et al. to significantly improve survival in patients with unresectable 
MPM [11]. We propose transarterial chemoperfusion with cisplatin, methotrexate and 
gemcitabine as a novel treatment option for patients with unresectable MPM. In our 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
14 
 
protocol we replace mitomycin C with metothrexate because mitomycin C and 
cisplatin are both DNA crosslinker agents and it is potentially more advantageous to 
use a combination of drugs with different intracellular targets to increase the 
effectiveness of the multi agent chemotherapeutic regimen. In addition, folate 
antimetabolites like methotrexate and pemetrexed are regarded as the most active 
class of cytotoxic drugs against MPM [12-14] . Therefore, in our proposed drug 
combination each drug acts on different steps of the mitotic cycle as cisplatin is a 
DNA crosslinker, methotrexate is a folate antimetabolite and gemcitabine is a 
nucleoside analoge. 
 
4.3.1 
Rationale for a Lead in Safety Cohort 
 
 
Although, there are data in the literature regarding the safety of intraarterial 
administration of cisplatin, methotrexate and gemcitabine (for details refer to 
section 4.3.2) there is no safety data regarding the intraarterial administration 
of cisplatin, methotrexate and gemcitabine in combination. Vogl et al. [11] 
used the combination of cisplatin (35 mg/m2 BSA), mitomycin C (8 mg/m2 
BSA) and gemcitabine (1000 mg/m2 BSA) in patients with MPM injected 
intraarterially and demonstrated very favorable safety and tolerability profile. 
We are proposing to replace mitomycin with methotrexate and use the same 
concentrations for cisplatin (35 mg/m2 BSA) and gemcitabine (1000 mg/m2 
BSA) as Vogl et al. did [11]. The new drug in our proposed combination is 
methothrexate. Therefore, in our lead in safety cohort we propose to use a 
50% reduced dose of methotrexate (50 mg/m2) with cisplatin (35 mg/m2 
BSA) and gemcitabine (1000 mg/m2 BSA) in 3 patients. Dose escalation will 
be contingent upon acceptable safety data obtained during the first three 
cycles of treatment (12 weeks). If no dose limiting toxicity observed, dose is 
escalated to methotrexate (100 mg/m2) with cisplatin (35 mg/m2 BSA) and 
gemcitabine (1000 mg/m2 BSA). The reduced dose level safety cohort will be 
expanded from 3 to 6 if one of the first 3 patients experiences dose limiting 
toxicity related to methotrexate. After the 12 weeks of dose limiting toxicity 
observation period for the final patient in the reduced dose safety cohort is 
complete, if less than one third of the patients enrolled in that cohort 
developed dose limiting toxicity, advancement to the regular dose level cohort 
can begin. If > 2 patients in the safety cohort experience dose limiting toxicity 
the methotrexate dose will be reduced to 25 mg/m2 and this will be used in 
the study. 
 
4.3.2 
Rationale for Phase 2 Study 
 
Cisplatin, methotrexate and gemcitabine are commercially available 
chemotherapeutic agents with long history of clinical use and well established 
safety profiles. Although, cisplatin plus methotrexate plus gemcitabine drug 
combination has not been administered during the same treatment cycle in 
MPM, these drugs were used in sequential chemotherapy protocol in MPM 
when patients were treated with cisplatin (75 mg/m2) and gemcitabine (1,200 
mg/m2) for four courses followed by mitoxantrone (10 mg/m2), methotrexate 
(35 mg/m2) and mitomycin (7 mg/m2) for four courses and mild toxicity was 


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Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
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reported [25]. The combination of gemcitabine (usual dose around 1000 
mg/m2) with cisplatin (usual dose around 100 mg/m2) was standard of care in 
the US for treatment of MPM before FDA approval of the use of pemetrexed-
cisplatin combination in 2003 [26]. No unacceptable toxicity was reported in 
studies using cisplatin with gemcitabine in patients with MPM [27]. 
Combination of methotrexate (100 mg/m2) and gemcitabine (800 mg/m2) has 
recently been used to treat MPM and acceptable rate of hematologic toxicity 
was reported and non‑ hematologic toxicity was mild [16]. Combination of 
gemcitabine with cisplatin and methotrexate with cisplatine are also widely 
used in the treatment of muscle invasive bladder cancer with a good safety 
profile [28]. Methotrexate (30 mg/m2) with gemcitabine (800 mg/m2) are used 
in patients with relapsing head and neck cancer with mild to moderate 
reported toxicity [29]. 
 
 
Vogl et al. [11] used the combination of cisplatin with mitomycin and 
gemcitabine for intraarterial chemoperfusion in patients with MPM and 
demonstrated very favorable safety and tolerability profile. We are proposing 
to replace mitomycin with methotrexate and use the same concentrations for 
cisplatin (35 mg/m2 BSA) and gemcitabine (1000 mg/m2 BSA) as Vogl et al. 
did [11]. We propose to use methotrexate in a relatively low concentration 
(100 mg/m2 BSA) compared to treatment protocols when methotrexate was 
used at concentration of 1500 mg/m2 BSA to treat MPM [13].  
 
 
Intraarterial administration of these drugs is proven to be safe. Vogl et al [11] 
used intraarterial administration of cisplatin (35 mg/m2 BSA) with mitomycin (8 
mg/m2 BSA) and gemcitabine (1000 mg/m2 BSA) in patients with MPM and 
demonstrated very favorable safety and tolerability profile. High-dose intra-
arterial cisplatin (150 mg/m2 BSA) therapy was used for advanced squamous 
cell carcinoma of the head and neck with acceptable toxicity profile [30]. 
Intraarterial methotrexate (110 mg/m2 BSA) with cisplatin (35 mg/m2 BSA), 
mitomycin C (4.5 mg/m2 BSA), bleomycin (15 mg/m2 BSA), and 5-fluorouracil 
(1200 mg/m2 BSA) was reported to treat penile cancer and grade 2 anorexia 
was the most frequent chemotherapy-related toxicity [31]. No toxicity was 
reported in the above mentioned studies which developed due to the 
intraarterial administration route.  
 
 
In summary, all the chemotherapeutic agents used in this study have 
established safety profile. 
 
4.3.3 
Rationale for Treatment Interval 
 
The 4-week treatment interval is selected for the chemoperfusion treatment 
protocol because this time frame is normally sufficient for the 
chemotherapeutics to achieve peak effect and also for the side effects of the 
previous chemotherapeutic treatment to have worn off, allowing the patient 
time to recover from the stress of the previous treatment. Efforts will be made 
to treat every patients in 4-week intervals, but the protocol allows treatment 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
16 
 
intervals of 3-6 weeks to accommodate treatments for unforeseen 
circumstances which could prevent the planned 4-week treatment interval. 
 
 
 
4.4  
Rationale for Cisplatin Dosage 
 
The recommended dose of cisplatin for transarterial chemoperfusion in this study is 
35 mg/m2 body surface area (BSA). Vogl et al [11] used this concentration of cisplatin 
in their MPM transarterial chemoperfusion study. This is a relatively low concentration 
of cisplatin compared to standard intravenous administration where the 
recommended dose of cisplatin is 75 mg/m2 BSA to treat MPM. The concentration of 
the administered cisplatin solution will be 1 mg/ml as recommended by the 
manufacturer. Subjects may receive anti-emetics, e.g., ondansetron, 
dexamethasone, prior to cisplatin infusion per standard of care and investigator’s 
practice. Dose reductions may be required for subjects with hepatic or renal 
impairment or history of hematologic or non-hematologic toxicity to cisplatin.  
 
For complete information on cisplatin dosage and administration, contraindications, 
warnings/precautions, adverse reactions, and drug interactions, please see Appendix 
E. 
 
 
4.5  
Rationale for Methotrexate Dosage 
 
The recommended dose of methotrexate for transarterial chemoperfusion in this study is 
100 mg/m2 BSA. The anifolates like methotrexate and pemetrexed are regarded as the 
most effective class of cytotoxic drugs against MPM. Earlier publications reported that 
high-dose methotrexate (1500 mg/m2) to be effective in the treatment of MPM, with a 
response rate of 37% [13]. However, high-dose methotrexate was associated with 
severe toxicity. Recent studies showed that 100 mg/m2 BSA dose of methotrexate in 
combination with gemcitabine was effective in treatment of MPM [16]. 
 
The patients receive 15 mg leucovorin po in every 12 hrs for a total of 4 doses 
starting 24 hrs after the chemoperfusion procedure. Methotrexate level measurement 
will be performed if there is suspicion of methotrexate toxicity. In case of 
methotrexate toxicity the patient will be hospitalized and intravenous leucovorin will 
be administered. 
 
For complete information on methotrexate dosage and administration, 
contraindications, warnings/precautions, adverse reactions, and drug interactions, 
please see Appendix F. 
 
 
4.6  
Rationale for Gemcitabine Dosage 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
17 
 
The recommended dose of gemcitabine for transarterial chemoperfusion in this study 
is 1000 mg/m2 BSA. This is a usual therapeutic dose of gemcitabine to treat MPM 
[17]. Vogl et al [11] also used this concentration of gemcitabine in their MPM 
transarterial chemoperfusion study. 
 
For complete information on gemcitabine dosage and administration, 
contraindications, warnings/precautions, adverse reactions, and drug interactions, 
please see Appendix G. 
 
 
4.7  
Screening for Study Eligibility and Baseline Evaluation 
 
All screening and baseline evaluations including imaging studies must be completed 
within 28 days prior to the first chemoperfusion treatment. The collected information 
will be reviewed against eligibility criteria to determine study eligibility. The 
investigator may use clinical judgment when determining the clinical significance of 
laboratory parameters and imaging findings throughout the study. The participating 
clinicians will be consulted before enrollment about a potential patient with abnormal 
laboratory values that are not considered clinically significant. 
 
The following activities will be completed during the screening period within 28 days 
prior to the first chemoperfusion treatment. 
 
4.7.1 Eligible Patients and Informed Consent 
Any patient who appears to meet the eligibility criteria may be offered the 
opportunity to be evaluated for participation in this clinical trial. All such 
patients must sign and receive a copy of an informed consent form that was 
approved by the Institutional Review Board (IRB) and have the opportunity to 
ask the principal investigator any questions regarding the trial, and their rights 
and obligations as a trial participant before any protocol related evaluations 
can be performed. An original signed consent form will be retained in the 
patient’s source documentation at the site, and a copy will be provided for the 
patient to take home. 
 
4.7.2 Medical History 
Medical history deemed clinically significant by the Investigator will be 
collected per body system with special attention to the diagnosis and 
treatment history of MPM. All on-going medical conditions and adverse events 
arising from treatment of those conditions present for ≥ 30 days are 
considered a part of the patient’s medical history and must be recorded at 
baseline. 
 
4.7.3 Physical Examination 
A physical examination will cover the following: 
• Vital signs: heart rate, respiratory rate, oxygen saturation by pulse oximetry, 
blood pressure taken after sitting for 5 minutes, and temperature (T) 


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• Height and weight 
• Head, eyes, ears, nose, and throat 
• Chest 
• Heart 
• Abdomen 
• Extremities 
• Genitourinary system 
• Endocrine and immune systems 
• Skin and appendages 
• Neurological examination (level of consciousness, orientation, sensation, 
and motor function) 
 
4.7.4 Eastern Cooperative Oncology Group (ECOG) Performance Status 
ECOG Performance Status will be assessed and the following scores will 
assigned: 
Score 0: Asymptomatic (Fully active, able to carry on all pre-disease activities 
without restriction.) 
Score 1: Symptomatic but completely ambulatory (Restricted in physically 
strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature. For example, light housework, office work.) 
Score 2: Symptomatic, spends <50% in bed during the day (Ambulatory and 
capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours.) 
Score 3: Symptomatic, spends >50% in bed, but not bedbound (Capable of 
only limited self-care, confined to bed or chair 50% or more of waking hours.) 
Score 4: Bedbound (Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair). 
 
4.7.5 Allergies and Adverse Reaction 
The patient’s all known allergies and adverse reactions to medications must 
be recorded and added to the patient’s medical record. 
 
4.7.6 Review of Concomitant Medications 
The patient’s  concurrent medications (medications taken within 28 days of 
screening and during the conduct of the study) including prescription and 
over-the-counter medications, herbs, vitamins, minerals, and prophylactic 
vaccines will be reviewed and documented. 
 
4.7.7 Clinical Laboratory 
The following clinical laboratory assessments will be completed: 
• Hematology: white blood cell (WBC) count, platelet count, hematocrit, 
hemoglobin. 
• Chemistry panel: sodium, potassium, chloride, bicarbonate, glucose, blood 
urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase, 


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19 
 
total bilirubin, total protein, albumin, calcium, magnesium• Coagulation panel: 
Prothrombin Time (PT), Partial Thromboplastin Time (PTT), International 
Normalized ratio for prothrombin time (INR) 
• Pregnancy test: serum human choriogonadotropin (hCG) level measurement 
will be performed in females of child-bearing potential. 
 
4.7.8 Electrocardiogram or Echocardiogram 
Resting 12-lead electrocardiogram (ECG) or echocardiogram may be done by 
the discretion of the screening physician based on clinical history, physical 
and laboratory findings. 
 
4.7.9 Imaging Studies 
Contrast-enhanced CT scan of thorax will be performed if one has not been 
done within 28 days before screening. If a patient cannot have a contrast-
enhanced CT scan (e.g., allergy to iodinated intravenous contrast dye) a 
magnetic resonance imaging (MRI) of the chest may be performed. CT with 
FDG-PET scan may be done. 
 
4.7.10 Quality of Life Questionnaire 
Quality of life will be assessed using the modified version of the Lung Cancer 
Symptom Scale for Mesothelioma questionnaire [18] (Appendix D). 
 
 
4.8  
Pre-procedure Care and Evaluation 
 
Pre-procedure evaluation takes place on the day of each chemoperfusion treatment. 
The collected information will be reviewed against eligibility criteria to determine 
eligibility for the treatment. The primary clinician may use clinical judgment when 
determining the clinical significance of laboratory parameters and imaging findings. 
The participating clinicians will be consulted before treatment of a patient with 
abnormal laboratory values that are not considered clinically significant. 
 
The following activities will be completed during the pre-procedure evaluation before 
each chemoperfusion treatment on the day of the treatment. 
 
4.8.1 Medical History 
Patients medical history will be updated with all medical events which has 
happened since the last visit and deemed clinically significant by the 
Investigator. All on-going medical conditions and adverse events arising from 
treatment of those conditions present for ≥ 30 days are considered a part of 
the patient’s medical history and must be recorded. 
 
4.8.2 Focused Physical Examination 
The pre-procedure focused physical examination will cover the following: 
• Vital signs: heart rate, respiratory rate, oxygen saturation by pulse oximetry, 
blood pressure taken after sitting for 5 minutes, and temperature (T) 


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• Height and weight 
• Chest 
• Heart 
• Abdomen 
• Extremities (special attention on peripheral pulses on the extermities which 
has been used for arterial access) 
• Neurological examination (level of consciousness, orientation, sensation, 
and motor function) 
 
4.8.3 Eastern Cooperative Oncology Group (ECOG) Performance Status 
ECOG Performance Status will be assessed and the scores will assigned as 
described in detail in Section 4.7.4. 
 
4.8.4 Allergies and Adverse Reaction 
The patient’s allergies and adverse reactions will be reviewed and updated 
with any new events in the patient’s medical record. 
 
4.8.5 Review of Concomitant Medications  
The patient’s medication list will be reviewed and updated in the patient’s 
medical record. 
 
4.8.6 Clinical Laboratory 
The following clinical laboratory assessments will be completed within 14 days 
of the procedure: 
• Hematology: white blood count (WBC) count, platelet count, hematocrit, 
hemoglobin. 
• Chemistry panel: sodium, potassium, chloride, bicarbonate, glucose, blood 
urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase, 
total bilirubin, total protein, albumin, calcium, magnesium,  
• Coagulation panel: Prothrombin Time (PT), Partial Thromboplastin Time 
(PTT), International Normalized ratio for prothrombin time (INR) 
• Pregnancy test: urine human choriogonadotropin (hCG) level measurement 
will be performed in females of child-bearing potential. 
 
4.8.7 Imaging Studies 
Contrast-enhanced CT scan of thorax will be performed if one has not been 
done within 14 days of the treatment. If a patient cannot have a contrast-
enhanced CT scan (e.g., allergy to iodinated intravenous contrast dye) a 
magnetic resonance imaging (MRI) may be performed. CT with FDG-PET 
scan may be done. 
 
4.8.8 Quality of Life Questionnaire 
Quality of life will be assessed using the modified version of the Lung Cancer 
Symptom Scale for Mesothelioma questionnaire [18] (Appendix D). 


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Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
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4.8.9 Intravenous Access 
Intravenous access will be established either with a new peripheral venous 
stick or accessing the patient’s long term venous access device (e.g. cental 
venous infusion port, PICC line, etc.). The venous access is used for 
administration of medications for moderate procedural sedations, intravenous 
fluids or other necessary medications during the chemoperfusion procedure. 
 
4.8.10 Premedication 
The following medications maybe given before the chemoperfusion treatment 
to alleviate the toxicity of the chemotherapeutic agents: 
5% dextrose in 0.45% NaCl solution with 20 mEq KCl and 8 mEq MgSO4 for 
1 hr before and 1 hr after chemoperfusion at 500 mL/hr rate. 
Ondansetron 8 mg IV 30 min before chemoperfusion. 
Fosaprepitant 150 mg IV 30 min before chemoperfusion. 
Dexamethasone 20 mg IV 30 min before chemoperfusion. 
Procholperazine 10 mg IV 30 min before chemoperfusion. 
Mannitol 12.5 grams in 50 mL 0.9% NaCl solution before chemoperfusion. 
 
 
4.9  
Transarterial Chemoperfusion Procedure 
 
The transarterial chemoperfusion treatment will be administered on an outpatient 
basis. The procedure will be performed in one of the interventional radiology 
procedure suites in the Moffitt Cancer which are equipped with all the necessary 
machines and tools to perform angiograms and other interventional radiology 
procedures. Performance of the procedure requires a procedural team that includes 
an interventional radiologist, an interventional radiology technologist and a procedural 
nurse. 
 
4.9.1 Moderate Procedural Sedation 
The procedure will be performed under moderate procedural sedation. 
Monitored anesthesia care may be provided by Anesthesiology in select 
patients if necessary based on the pre-procedural evaluation. If a patient 
wishes to proceed without sedation the procedure can be done using only 
local anesthesia at the arterial access site. Proceeding without sedation is the 
discretion of the primary clinician. 
 
According to standard institutional protocol moderate procedural sedation will 
be administered by a registered procedural nurse under the direct supervision 
of the interventional radiologist who is performing the procedure. Vital signs, 
oxygen saturation by pulse oximetry, and response to verbal commands will 
be monitored and recorded by the registered nurse throughout the procedure 


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22 
 
and the recovery period. The sedation flow sheet will be placed in the 
patient’s medical record including the medications and dosages used. 
 
 
4.9.2 Angiogram and Chemoperfusion 
The arterial access site will be prepped and draped in standard sterile 
fashion. Local anesthesia (1% lidocaine) will be used at the puncture site to 
access the common femoral artery or the radial artery. The site and side of 
the arterial access will be determined by the interventional radiologist 
performing the procedure based on the patient’s medical history, vascular 
anatomy, pre-procedural physical exam and the planned infusion site. 
Aortogram and selective angiograms will be performed to localize tumor 
feeding intercostal and/or internal mammary arteries.  
 
Based on the pre-procedural imaging and the angiography findings the 
infusion catheter will be placed for the chemoperfusion within a tumor 
supplying intercostal artery or within the descending aorta slightly proximal to 
origin of the most cephalad tumor supplying intercostal artery, but below the 
origin of the left subclavian artery if multiple intercostal vessels are supplying 
the tumor. For tumors located predominantly anteriorly in the chest the 
infusion catheter will be placed into the ipsilateral internal mammary artery. 
For tumors supplied by both intercostal and internal mammary arteries 
chemoperfusion may be performed for the artery predominantly supplying the 
tumor or for multiple arteries per primary clinician discretion. When 
catheterization of the internal mammary artery is performed, intravenous 
administration of heparin is recommended. The level of anticoagulation will be 
determined by the interventional radiologist who is performing the procedure 
based the vascular anatomy and the patient’s medical condition. 
 
Drugs will be prepared individually for patients by the Chemotherapeutic 
Pharmacy of the Moffitt Cancer Center according to the manufacturers’ 
recommendations and the drug doses will be calculated based on individual 
BSA of patients (cisplatin 35 mg/m2 BSA, methotrexate 100 mg/m2 BSA and 
gemcitabine 1000 mg/m2 BSA). The chemotherapeutic drugs will delivered 
freshly prepared from the Chemotherapeutic Pharmacy of the Moffitt Cancer 
Center to Interventional Radiology procedure suite in sterile syringes just 
before the start of the procedure. The intact packages will be stored at room 
temperature and protected from light until administration. The drugs will be 
administered in the following sequence: methotrexate followed by cisplatin, 
then gemcitabine. 
 
After the chemoperfusion the catheters will be removed and will be discarded 
into a selective chemotherapeutic waste container per institutional protocol. 
The arteriotomy sites will be closed by an arterial closure device per primary 
clinician discreation. 
 


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Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
23 
 
After the procedure the patient will be transported into the Interventional 
Radiology post-procedural holding area or to the post-anesthesia care unit of 
the Moffitt Cancer Center for recovery. 
 
 
4.10 
Post-Procedural Supportive Care 
 
Following the transarterial chemoperfusion treatment, the patient will remain under 
observation consistent with standard of care guidelines for aftercare in procedures 
involving femoral or radial arterial catheterization. The patient will be sent home when 
the physician determines that the patient is stable and that there is no risk of bleeding 
from the access site. At the time of discharge, patients will be instructed per 
institutional guidelines regarding after-care and provided with a 24-hour telephone 
number that they may use to contact the principal clinician or the interventional 
radiologist on call if they develop a problem or have questions about their treatment. 
Any concurrent medication or therapy deemed necessary, including post-procedural 
pain management, in the post-treatment period may be administered according to 
institutional standard of clinical care and by the approval of the primary clinician. The 
patients receive 15 mg leucovorin po in every 12 hrs for a total of 4 doses starting 24 
hrs after the chemoperfusion procedure. Methotrexate level measurement will be 
performed if there is suspicion of methotrexate toxicity. In case of methotrexate 
toxicity the patient will be hospitalized and intravenous leucovorin will be 
administered. 
 
 
4.11 
Duration of Therapy 
 
Transarterial chemoperfusion treatment will be administered in every 4 weeks (3-6 
weeks interval allowed). The treatment will be continued until complete response or 
until the patient’s death unless the treatment is terminated earlier due to reasons 
described below. 
 
 
4.12 
Removal of Patients from Study 
 
Patients may be removed from the study at the discretion of the principal investigator 
for any of the following reasons: 
 
 Progression of disease. 
 Patient non-compliance: defined as any deviation from the protocol without prior 
agreement of the principal investigator. 
 Patient’s request to withdraw from the study or refusal of further therapy 
 Unacceptable toxicity. Patients who cannot receive two out of the three individual 
drug component of the chemoperfusion treatment regimen for 49 days from the 
time of last treatment and patients requiring three dose reductions will be 
discontinued from the study (please also see Section 5). 


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Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
24 
 
 A patient may be removed from the study for any complication of treatment that 
the investigator feels is life threatening. 
 If patient does not meet eligibility criteria (e.g. patient becomes pregnant) 
 
All subjects who discontinue investigational product should comply with protocol 
specified follow-up procedures as outlined in the study protocol. The only exception 
to this requirement is when a subject withdraws consent for all study procedures 
including post-treatment study follow-up or loses the ability to consent freely (ie, is 
imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or 
physical illness). If study treatment is discontinued prior to the subject’s completion of 
the study, the reason for the discontinuation must be documented in the subject’s 
medical records and entered on the appropriate case report form. 
 
In this study, disease control rate and overall survival are key endpoints of the study. 
Tumor responses initiated by chemoperfusion with cisplatin, methotrexate and 
gemcitabine may evolve after treatment discontinuation and the treatment may have 
effect on patient’s survival. Therefore, post treatment study follow-up is of critical 
importance and is essential to preserving subject safety and the integrity of the study. 
Subjects who discontinue study treatment must continue to be followed for collection 
of outcome and/or survival follow-up data as required by the study protocol until 
death or the conclusion of the study. 
 
 
4.13 
Premature Study Termination 
 
The Simon’s two-stage design (see Section 11.1) requires 18 patients to be enrolled 
and evaluated in the first stage of the trial. If 4 or less of the patients respond to the 
therapy (CR or PR or SD), the treatment will be stopped. If 5 or more patients 
respond, 14 additional patients (a total of 32 patients per group) will be enrolled. 
 
If conditions arising during the study that indicate that the study should be halted or 
terminated, this action may be taken after appropriate consultation among the clinical 
investigators involved in this study. 
 
Conditions that may warrant termination of the study include, but are not limited to the 
following: 
• The discovery of an unexpected, serious, or unacceptable risk to the subjects 
enrolled in the study. 
• Failure of the investigator to enroll subjects into the study at an acceptable rate. 
• Failure of the investigator to comply with pertinent regulations of appropriate 
regulatory authorities. 
• Submission of knowingly false information from the research facility to the 
appropriate regulatory authority. 
• Insufficient adherence to protocol requirements. 
 
Study termination and follow-up will be performed in compliance with the conditions 


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Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
25 
 
set forth in the International Conference on Harmonisation (ICH) E6,Guideline for 
Good Clinical Practice, Sections 4.12, 4.13, 5.20, and 5.21. 
 
The Principal Investigator, the Protocol Monitoring Committee of Moffitt Cancer 
Center and the IRB have authority to suspend or terminate the study if the study has 
been associated with unexpected problems or serious harm to subjects or the study 
is not conducted in accordance with the IRB or the Moffitt Cancer Center research 
policy and regulatory requirements. 
 
5. Drug Toxicities, Dose Modifications, Dosing Delays 
 
5.1  
General Considerations 
 
 
Any toxicity observed during the course of the study could be managed by 
reduction of dose of the study drugs or delaying the treatment if deemed 
appropriate by the Investigator based on the guidelines below. 
 
 
Where several toxicities with different grades or severity occur at the same time, 
the dose modification applied should be the greatest reduction applicable. 
 
 
Treatment may be delayed for up to 21 days to allow a patient sufficient time for 
recovery from study-related toxicity. A patient who cannot receive two out of the 
three individual drug component of the chemoperfusion treatment regimen for 49 
days from the time of last treatment must be discontinued from the study. 
 
 
A patient requiring three dose reductions will be discontinued from the study. Any 
exceptions to discontinuation for a patient who in the judgment of the investigator 
is receiving clinical benefit and would need a further dose reduction must be 
discussed with the co-investigators and the multidisciplinary Mesothelioma 
Treatment Group of the Moffitt Cancer Center. 
 
 
Doses omitted during a chemoperfusion treatment will not be made up during the 
next treatment cycles. 
 
 
5.2  
Definition of Dose-Limiting Toxicity 
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03 for Adverse Events (AE) and Serious Adverse Event (SAE) 
reporting. A dose-limiting toxicity (DLT) will be defined as Grade 3 and 4 toxicities 
which occur within 30 days after the chemoperfusion and are considered related to 
the treatment. The exceptions are the followings: 
 
Alopecia, vomiting, or diarrhea (unless not controlled by optimal anti-emetics 
or anti-diarrheals) 
 
Grade 1 or 2 neurotoxicity. The investigator and patient may decide to 
continue the treatment at a reduced dose of cisplatin (25 mg/m2 BSA) and full 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
26 
 
dose of methotrexate (100 mg/m2 BSA) and gemcitabine (1000 mg/m2 BSA), 
with no delay required, as neurotoxicity may not resolve to baseline values. 
 
Grade 3 laboratory AEs that are asymptomatic and return to baseline or 
Grade 1 within 3 days, unless identified specifically as DLT by the 
investigator. 
 
Grade 3 fatigue 
 
Grade 3 systemic reactions (such as fever, headache, influenza like 
symptoms, myalgia, malaise, or nausea) that have returned to baseline or 
Grade 1 within 3 days of study inoculation  
 
Hospitalizations primarily intended to expedite diagnostic evaluations or for 
elective surgery will not be considered as SAEs for the purpose of 
ascertaining DLT. 
 
Treatment should be delayed until resolution of DLT to at least Grade 1 toxicity if 
there was no baseline toxicity or less than or equal to the patient’s baseline value 
before resuming treatment. 
 
 
5.3  
Hematological Toxicity 
 
Dose adjustments at the start of a subsequent transarterial chemoperfusion therapy 
will be based on platelet and absolute neutrophil counts (ANC) measured within 2 
days of the actual treatment. The ANC must be >1.5 x 109/L and platelet count must 
be >100 x 109/L before any chemoperfusion treatment. Dose delays will occur for up 
to 21 days if the ANC or platelet count has not sufficiently recovered by the time of 
the next cycle. Upon recovery, if treatment is resumed, it must be according to the 
dose modification guideline provided in the table below. Hematological toxicities not 
listed in the table, including non-hemolytic anemia do not require dose adjustments. 
 
ANC 
x 109/L 
 
Platelet 
count 
x 109/L 
Cisplatin 
dose 
(mg/m2 BSA) 
Methotrexate 
dose 
(mg/m2 BSA) 
Gemcitabine 
dose 
(mg/m2 BSA) 
> 1.0 
and 
> 100 
35 
100 
1000 
0.5 – 1.0 
or 
50 - 100 
35 
75 
750 
< 0.5 
or 
< 50 
delay dose 
delay dose 
delay dose 
 
 
5.4  
Renal Toxicity 
 
Dose adjustments at the start of a subsequent transarterial chemoperfusion therapy 
will be based on creatinine clearance calculated from serum creatinine level which is 
measured within 2 days of the actual treatment. Creatinine clearance will be 
calculated using the Cockcroft and Gault formula [15] (Appendix B). The creatinine 
clearance must be >30 ml/min before any chemoperfusion treatment. Dose delays 
will occur for up to 21 days if creatinine clearance has not sufficiently recovered by 
the time of the next cycle. Upon recovery, if treatment is resumed, it must be 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
27 
 
according to the dose modification guideline provided in the table below. 
 
Creatinine 
clearance 
(ml/min) 
Cisplatin 
dose 
(mg/m2 BSA) 
Methotrexate 
dose 
(mg/m2 BSA) 
Gemcitabine 
dose 
(mg/m2 BSA) 
> 50 
35 
100 
1000 
30 - 50 
25 
50 
750 
< 30 
delay dose 
delay dose 
delay dose 
 
 
5.5  
Hepatic Toxicity 
 
Dose adjustments at the start of a subsequent transarterial chemoperfusion therapy 
will be based on bilirubin, aspartate amino transferase (AST), alanine amino 
transferase (ALT) and alkaline phosphatase (ALP) levels measured within 2 days of 
the actual treatment. Bilirubin level must be < 3 x institutional institutional upper limit 
of normal (ULN), AST, ALT and ALP levels must be < 5 x ULN before any 
chemoperfusion treatment. Dose delays will occur for up to 21 days if the liver 
function test has not sufficiently recovered by the time of the next cycle. Upon 
recovery, if treatment is resumed, it must be according to the dose modification 
guideline provided in the table below. 
 
Bilirubin 
( x ULN) 
 
AST, ALT 
and ALP 
( x ULN) 
Cisplatin 
dose 
(mg/m2 BSA) 
Methotrexate 
dose 
(mg/m2 BSA) 
Gemcitabine 
dose 
(mg/m2 BSA) 
< 2 
and 
< 3 
35 
100 
1000 
2 – 3 
or 
3 - 5 
25 
75 
750 
> 3 
or 
> 5 
delay dose 
delay dose 
delay dose 
 
 
5.6  
Pericardial Effusion, Pleural Effusion, Ascites 
 
Methotrexate exits slowly from third space compartments (e.g. pericardial effusion, 
pleural effusion or ascites). This results in a prolonged plasma half-life and could 
result in unexpected toxicity. Patients with third space fluid collections require 
especially careful monitoring for toxicity.  
 
Patients with pleural effusion or ascites should undergo drainage of the fluid 
collection immediately before the transarterial chemoperfusion treatment. If the 
thoracentesis and/or paracentesis is not possible due to anatomic or other reason or 
the patient refuses the procedure, those patients will be treated with cisplatin and 
gemcitabine and methotrexate will not be administered during the chemoperfusion 
treatment. Patients with moderate to severe pericardial effusion will be treated with 
cisplatine and gemcitabine and methotrexate will not be administered during the 
chemoperfusion treatment. 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
28 
 
 
 
5.7  
Other Toxicities 
 
More detailed information regarding drug specific toxicities please refer to the 
package inserts of cisplatin, methotrexate and gemcitabine in Appendix E, F and G. 
 
 
6. PHARMACEUTICAL INFORMATION 
 
 
All agents used in this study are commercially available. 
 
6.1  
Cisplatin 
For complete product information on dosage and administration, contraindications, 
warnings/precautions, adverse reactions, and drug interactions, see the package 
insert for cisplatin (Appendix E). 
 
 
6.2  
Methotrexate 
For complete product information on dosage and administration, contraindications, 
warnings/precautions, adverse reactions, and drug interactions, see the package 
insert for cisplatin (Appendix F). 
 
 
6.3  
Gemcitabine 
For complete product information on dosage and administration, contraindications, 
warnings/precautions, adverse reactions, and drug interactions, see the package 
insert for cisplatin (Appendix G). 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
29 
 
7. STUDY CALENDAR 
 
Baseline screening evaluations are to be conducted within 4 weeks prior to start of the 
transarterial chemoperfusion therapy. In the event that the patient's condition is deteriorating, 
evaluations should be repeated within 48 hours prior to initiation of the next transarterial 
chemoperfusion. 
 
Transarterial chemoperfusion is performed in every 4 weeks until the patient’s death unless 
the treatment is terminated earlier due to reasons described in Section 4.12. Post-treatment 
follow-up will be performed 4 weeks (3-6 weeks interval allowed) after the chemoperfusion 
treatment. Preferentially, the post-treatment follow-up and the upcoming chemoperfusion 
treatment performed on the same day. 
 
 
a Transarterial chemoperfusion performed in every 4 weeks (3-6 weeks interval allowed) with cisplatin (35 
mg/m2 BSA), methotrexate (100 mg/m2 BSA), and gemcitabine (1000 mg/m2 BSA), as described in 
Section 4.9 unless there is necessary treatment delay and/or dose reduction as described in Section 5. 
Transarterial chemoperfusion treatments will be administered until the patient’s death unless the treatment 
 
Screening Evaluation 
(0-4 weeks before first 
treatment) 
Chemoperfusion 
Treatment 
(every 4 weeks)a 
Post-treatment follow-up 
(4 weeks after last 
treatment)b 
Long term follow-up 
(every 2 months) 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Review of Concomitant 
Medications 
X 
X 
X 
 
Vital signs 
X 
X 
X 
 
Height 
X 
X 
X 
 
Weight 
X 
X 
X 
 
Physical exam 
X 
X 
X 
 
Performance status (ECOG) 
X 
X 
X 
 
Clinical laboratory testsc 
X 
X 
X 
 
Serum pregnancy test 
X 
 
 
 
Urine pregnancy test 
 
X 
 
 
Allergic event evaluation 
X 
X 
X 
 
Adverse event evaluation 
X 
X 
X 
 
Quality of life questionaire 
X 
X 
X 
 
Radiologic evaluationd 
X 
X 
X 
 
Transarterial chemoperfusiona 
 
X 
 
 
Survivale 
 
 
 
X 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
30 
 
is terminated earlier due to reasons described Section 4.11. 
 
b If transarterial chemoperfusion treatment is terminated earlier due to reasons described Section 4.12. the 
patient will have a clinic follow-up in 4 weeks (3-6 weeks interval allowed).  
 
c Clinical laboratory tests include white blood cell count, platelet count, hematocrit, hemoglobin, sodium, 
potassium, chloride, bicarbonate, glucose, blood urea nitrogen (BUN), creatinine, lactate dehydrogenase 
(LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total 
bilirubin, total protein, albumin, calcium, magnesium, Prothrombin Time (PT), Partial Thromboplastin Time 
(PTT), International Normalized ratio for prothrombin time (INR).  
 
dRadiologic evaluation using modified RECIST criteria performed at baseline during the screening 
evaluation and before each transarterial chemoperfusion treatment as described in Section 8.2. 
 
eOverall survival will be followed every 2 months via in person or phone contact after subjects discontinue 
the study drug. 
 
 
8. MEASUREMENT OF EFFECT 
 
For the purposes of this study, patients are evaluated for response in every 4 weeks (3-6 
weeks interval allowed) before they undergo the next transarterial chemoperfusion 
treatment. The evaluation includes focused medical history, quality of life questionnaire, 
physical exam, imaging study, laboratory tests amongst others. The complete list of studies 
included in the evaluation is detailed in Section 4.8 Pre-procedure Care and Evaluation. 
 
8.1  
Measurement of Tumor Response Using RECIST 1.1 Criteria 
 
The primary objective of this study is to determine the disease control rate of 
transarterial chemoperfusion treatment with cisplatin, metothrexate and gemcitabine 
in patients with unresectable MPM. Tumor response and progression will be 
evaluated in this study using the new international criteria proposed by the revised 
Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [19]. 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions 
and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST 1.1 criteria. 
 
8.1.1 Definitions 
Evaluable for Objective Response: Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for 
response.  These patients will have their response classified according to the 
definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response: Patients who have lesions present 
at baseline that are evaluable but do not meet the definitions of measurable 
disease, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for non-target disease.  
The response assessment is based on the presence, absence, or 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
31 
 
unequivocal progression of the lesions. 
 
 
 
8.1.2 Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm 
with calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). Tumor lesions that are 
situated in a previously irradiated area are considered measurable in this 
protocol. 
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by 
CT scan (CT scan slice thickness recommended to be no greater than 5 mm). 
At baseline and in follow-up, only the short axis will be measured and 
followed. 
 
Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm or pathological lymph nodes with ≥ 
10 to <15 mm short axis), are considered non-measurable disease.  Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal 
masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, these 
are preferred for selection as target lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. A sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
32 
 
If lymph nodes are to be included in the sum, then only the short axis is added 
into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of 
the disease. 
Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions and should also be recorded at baseline. Measurements 
of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
8.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a 
ruler or calipers. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before 
the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-
up. Imaging-based evaluation is preferred to evaluation by clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and >10 mm 
diameter as assessed using calipers (e.g., skin nodules). In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
 
Chest x-ray: Not acceptable for tumor evaluation in this study.  
 
Conventional CT and MRI: This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. 
If CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable 
in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement.  Furthermore, the availability of MRI is variable globally. As 
with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of 
the RECIST guidelines to prescribe specific MRI pulse sequence parameters 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
33 
 
for all scanners, body parts, and diseases. Ideally, the same type of scanner 
should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans. Body scans should be performed with 
breath-hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a diagnostic 
CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, 
however, that the PET portion of the CT introduces additional data which may 
bias an investigator if it is not routinely or serially performed.   
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should 
not be used as a method of measurement. Ultrasound examinations cannot 
be reproduced in their entirety for independent review at a later date and, 
because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next. 
If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective 
tumor evaluation is not advised. However, such techniques may be useful to 
confirm complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete response 
(CR) or surgical resection is an endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess response. If 
markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Cytology, Histology: These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases. 
 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
 
FDG-PET: While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
34 
 
'new' disease).  New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional follow-up CT  scans are 
needed to determine if there is truly progression occurring at that site (if so, 
the date of PD will be the date of the initial abnormal FDG-PET scan).  If the 
positive FDG-PET at follow-up corresponds to a pre-existing site of disease 
on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner 
similar to a biopsy in cases where a residual radiographic abnormality is 
thought to represent fibrosis or scarring.  The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported 
by disease-specific medical literature for the indication.  However, it must be 
acknowledged that both approaches may lead to false positive CR due to 
limitations of FDG-PET and biopsy resolution/sensitivity. 
  
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
 
8.1.4 Response Criteria for Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have reduction 
in short axis to <10 mm. 
 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline sum diameters 
 
 
Progressive Disease (PD): At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note:  the appearance of one or more new lesions 
is also considered progressions). 
 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
8.1.5 Response Criteria for Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
35 
 
normalization of tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis) 
 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal 
progression should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel or 
principal investigator. 
 
8.1.6 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
36 
 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
 
 
 
For Patients with Non-Measurable Disease 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
8.1.7 Duration of Response 
Duration of overall response is measured from the time measurement criteria 
are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since 
the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria 
are first met for CR until the first date that progressive disease is objectively 
documented. 
 
Duration of stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements. 
 
 
8.2  
Measurement of Tumor Response Using Modified RECIST Criteria for 
Mesothelioma 
 
The above mentioned RECIST 1.1 criteria a well-established tool of tumor response 
assessment. However, MPM most commonly grows as a rind around the pleural 
surface and the selection of measurement sites in MPM is difficult, and without 
further definition of the method of measurement, the RECIST 1.1 criteria could be 
applied differently by different investigators. 
 
Byrne and Nowak developed a Modified RECIST criteria for mesothelioma [1] which 
is specifically designed to address the unique growth pattern of MPM and it is better 
suited for response assessment in this disease.  


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
37 
 
 
The modified RECIST criteria for mesothelioma [1] is using contrast enhanced CT 
scans of the chest. Where CT is contraindicated MRI may be used. At the level of the 
pleura, tumor thickness perpendicular to the chest wall, spine or mediastinum is 
measured in 2 positions at 3 separate levels on transverse cuts of CT scans. The 
sum of six measurements defines a pleural unidimensional measure. Transverse 
cuts, at least 1 cm apart and related to anatomical landmarks in the thorax, are 
chosen to allow reproducible assessment at later time points. If measureable tumor is 
present, transverse cuts in the upper thorax, above the level of division of the main 
bronchi are preferred. Nodal, subcutaneous, and other bidimensionally measurable 
lesions are measured unidimensionally as per the RECIST 1.1 criteria. 
Unidimensional measurements are added to obtain the total tumor measurement. 
 
Modified RECIST criteria for pleural mesothelioma are as follows: 
 
• Complete Response: Complete response (CR) is defined as the disappearance of 
all target 
lesions with no evidence of tumor elsewhere. 
 
• Partial Response: Partial response is defined as at least a 30% reduction in the 
total tumor 
measurement. 
 
• Stable Disease: Stable disease is defined as subjects who fulfilled the criteria for 
neither PR 
nor PD. 
 
• Progressive Disease: Progressive disease is defined as an increase of at least 20% 
in the total tumor measurement over the nadir measurement, or the appearance of 
one or more new 
lesions. 
 
 
8.3  
Overall Survival 
 
Overall survival is defined as the time between the date of treatment and the date of 
death due to any cause. A subject who has not died will be censored at the last 
known alive date. Overall survival will be followed continuously while subjects are on 
the study drug and every 2 months via inperson or phone contact after subjects 
discontinue the study drug. 
 
 
8.4  
Progression Free Survival 
 
Progression free survival is defined as the time from the date of treatment to the date 
of the first documented tumor progression, as determined by the investigator (per 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
38 
 
modified RECIST criteria as detailed in Section 8.2), or death due to any cause, 
whichever occurs first. Subjects who die without a reported prior progression will be 
considered to have progressed on the date of their death. Subjects who did not 
progress or die will be censored on the date of their last evaluable tumor 
assessment. 
 
 
8.5  
Evaluation of Safety 
 
8.5.1 Adverse Events 
This study will utilize the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03 for Adverse Events and Serious Adverse Event 
reporting. A copy of the CTCAE Version 4.03 can be downloaded from the 
NCI Cancer Therapy Evaluation Program home page (http://ctep.cancer.gov). 
All appropriate treatment areas should have access to a copy of the CTCAE 
Version 4.03. 
 
An Adverse Event (AE) is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medical treatment or procedure that may or may not be 
considered related to the medical treatment or procedure. An AE is a term 
that is a unique representation of a specific event used for medical 
documentation and scientific analyses. CTCAE is a descriptive terminology 
for AE reporting. A grading (severity) scale is provided for each AE term. 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 
5 with unique clinical descriptions of severity for each AE based on this 
general guideline: 
 
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 activities of daily living (preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, 
etc.). 
 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self care activities of daily living (bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden). 
 
Grade 4 Life-threatening consequences; urgent intervention indicated.  
 
Grade 5 Death related to AE. 
 
 


Bela Kis, MD, PhD 
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39 
 
 
8.5.2 Serious Adverse Events 
Serious Adverse Event (SAE) is any adverse drug event (experience) 
occurring at any dose that results in ANY of the following outcomes:  
1) Death.  
2) A life-threatening adverse drug experience.  
3) Inpatient hospitalization or prolongation of existing hospitalization (for >24 
hours).  
4) A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events that may not result in death, be life threatening, 
or require hospitalization may be considered a serious adverse drug 
experience when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition (FDA, 21 CFR 312.32; ICH E2A 
and ICH E6). 
 
It is important to distinguish between serious criteria and severity grade of an 
AE. Severity is a measure of intensity (see Section 8.5.1) whereas 
seriousness is defined by the criteria as listed above in this Section. A Grade 
3 severity AE is not necessarily considered an SAE whereas a Grade 2 AE 
resulting in a hospital admission would be considered an SAE. 
 
8.5.3 Safety Data Collection 
AEs will be collected throughout the treatment period from the time of the first 
transarterial chemoperfusion treatment until 30 days after the last 
chemoperfusion treatment.  
 
At baseline evaluation, a medical history will be obtained to capture relevant 
underlying conditions. The baseline examination also includes physical 
examination, vital signs, ECOG performance status, medications, ECG, 
laboratory and imaging assessments as detailed in Section 4.7 and 
summarized in the Study Calendar in Section 7. The baseline evaluation 
should be performed within 28 days of the first chemoperfusion treatment. 
Similar to the baseline evaluation, patients will be evaluated before each 
chemoperfusion treatment in every 4 weeks as detailed in Section 4.8 and 
summarized in the Study Calendar in Section 7. Pre-procedure evaluation 
takes place on the day of each chemoperfusion treatment. Toxicity 
assessments will also be performed during the chemoperfusion treatment. 
Subjects who discontinue study treatment for reasons detailed in Section 4.12 
must continue to be followed for collection of toxicity data for 30 days.  
 
Incidences of AEs will be summarized by system organ class, preferred term, 
and severity (grading per CTCAE v. 4.03). Each patient will be counted only 
once within a system organ class or a preferred term by using the AEs with 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
40 
 
the highest severity grade within each category. AEs will also be summarized 
by system organ class, preferred term, and relationship to treatment (drugs, 
procedure, device, or unrelated). AEs may be considered related to more than 
one of the causalities listed. AE onset will be shown relative (in number of 
days) to the day of the first study treatment 
 
8.5.4 Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the patient or reported in response to the 
open question from the study personnel: ‘What health problems have you 
hadsince the previous visit/you were last asked?’, or revealed by observation 
will be collected and recorded. When collecting AEs, the recording of 
diagnoses is preferred (when possible) to recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each 
sign or symptom will be recorded separately. 
 
8.5.5 Adverse Events Based on Examinations and Tests 
The results from protocol mandated vital signs, laboratory tests and imaging 
results will be summarized in the clinical study report. Any laboratory value, 
vital sign that is clinically significant or meets the definition of an AE should be 
reported. Abnormal laboratory values, vital signs or test results that do not 
induce clinical signs/symptoms or require therapy, will not be considered 
clinically significant and will not be reported as AE. Deterioration of a 
laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE.  
 
 
8.5.6 Causality Collection 
The principal investigator will assess causal relationship between 
investigational transarterial chemoperfusion treatment and each AE, and 
answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the 
investigational product?’ The principal investigator may discuss this question 
with co-investigators involved in this study. 
 
8.5.7 Interpretation of Causality 
The following factors should be considered when deciding if there is a 
“reasonable possibility” that an AE may have been caused by the drug: 
• Time course of exposure to suspect drug. 
Has the subject actually received the suspect drug? Did the AE occur in a 
reasonable temporal relationship to the administration of the suspect drug? 
• Consistency with known drug profile. 
Was the AE consistent with the previous knowledge of the suspect drug 
(pharmacology and toxicology) or drugs of the same pharmacological class? 
OR could the AE be anticipated from its pharmacological properties? 
• Dechallenge experience. 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
41 
 
Did the AE resolve or improve on stopping or reducing the dose of the 
suspect drug? 
• No alternative cause. The AE cannot be reasonably explained by another 
aetiology such as the underlying disease, other drugs, other host or 
environmental factors. 
• Rechallenge experience. Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? Rechallenge is generally not 
recommended. It may be utilized only in questionable cases and only if patient 
safety is not jeopardized. 
• Laboratory tests.  
A specific laboratory investigation (if performed) has confirmed the 
relationship? 
 
A “reasonable possibility” could be considered to exist for an AE where one or 
more of the above mentioned factors exist. In contrast, there would not be a 
“reasonable possibility” of causality if none of the above criteria apply or 
where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more 
likely cause of the AE. 
 
Ambiguous cases should be considered as being a “reasonable possibility” of 
a causal relationship unless further evidence becomes available to refute this. 
Causal relationship in cases where the disease under study has deteriorated 
due to lack of effect should be classified as no reasonable possibility. 
 
 
8.6  
Evaluation of Quality of Life 
 
Patient-reported symptoms will be assessed using the modified version of the Lung 
Cancer Symptom Scale for Mesothelioma questionnaire [18](Appendix D). 
 
This is a 7-question questionnaire, which covers the most common issues that can 
arise in patients with MPM, such as cough, chest pain, shortness of breath, etc. The 
questionnaire is available in English and Spanish. 
 
The questionnaire will be completed prior to the first chemoperfusion treatment and in 
every 4 weeks before each additional chemoperfusion treatment. Subjects who 
discontinue study treatment for reasons detailed in Section 4.12 will be assessed 
using the questionnaire 4 weeks after the last chemoperfusion treatment. A patient is 
expected to complete the above questionnaires only when a translation is available in 
a language in which the patient is fluent. 
 
 
 
 
 


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42 
 
 
9. ETHICAL AND REGULATORY CONSIDERATIONS 
 
9.1  
Protocol and Regulatory Compliance 
 
The Principal Investigator has primary responsibility for the study The Principal 
Investigator must conduct the study according to this protocol. 
 
The study must be conducted by all Investigators in compliance with Good Clinical 
Practices (GCP) as defined as described in the U.S. FDA Code of Federal 
Regulations 21 CFR 312 (Investigational New Drug Application), 21 CFR 50 
(Protection of Human Subjects), 21 CFR 54 (Financial Disclosure by Clinical 
Investigators), 21 CFR 56 (Institutional Review Boards) and  International 
Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) guidelines (Guideline to Good Clinical 
Practice). 
 
The Principal Investigator of this study is ultimately responsible for every aspect of 
the design, conduct and actions of all members of the research team. This includes 
the final analysis of the protocol. 
 
All protocols include a Data Safety Monitoring Plan (DSMP) and procedures for its 
implementation commensurate with the risk and complexity of the study. The DSMP 
must include a structured adverse event determination, monitoring and reporting 
system, including standardized forms and procedures for referring and/or treating 
subjects experiencing adverse events. 
 
The Principal Investigator of this study will have primary responsibility for ensuring 
that the protocol is conducted as approved by the Scientific Review Committee of 
Moffitt Cancer Center and IRB. The Principal Investigator will ensure that the 
monitoring plan is followed, that all data required for oversight of monitoring are 
accurately reported to a DSMP and/or to the Protocol Monitoring Committee (PMC) 
and IRB as required, that all adverse events are reported according to protocol 
guidelines, and that any adverse actions reflecting patient safety concerns are 
appropriately reported. 
 
 
9.2  
Document Audits and Monitoring 
 
Data will be captured in Oncore, Moffitt Cancer Center’s Clinical Trials Database. 
Regulatory documents and case report forms will be monitored internally according to 
Moffitt Cancer Center Monitoring Policies. Monitoring will be performed regularly to 
verify data is accurate, complete, and verifiable from source documents; and the 
conduct of the trial is in compliance with the currently approved 
protocol/amendments, Good Clinical Practice (GCP), and applicable regulatory 
requirements. 


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43 
 
 
The Protocol Monitoring Committee (PMC) monitors its assigned ongoing research 
protocols monthly for: adverse event reporting, data and safety monitoring, and 
internal audit findings. The PMC upon review of any agenda item may approve the 
study for continuation, require revisions, suspend or close a protocol. 
 
Investigators of studies which are designed to be reviewed by the PMC for data and 
safety monitoring, shall provide a statistical report of the study’s progress and 
summary of adverse events and deviations based on the phase of the study and the 
associated risk of the study. 
 
 
9.3  
Adverse Event Recording and Reporting 
 
Adverse Event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medical treatment or procedure that may or may not be considered related to the 
medical treatment or procedure. A more detailed definition of AEs can be found in 
Section 8.5.1. 
 
Adverse events should only be recorded by an investigator or by a health-care 
provider qualified by training and experience. Patients should be asked in an open-
ended manner about the occurrence of AEs. 
 
AEs will be collected throughout the treatment period from the time of the first 
transarterial chemoperfusion treatment and up to and including the 30-day follow-up 
period after the last chemoperfusion treatment. All ongoing and any new AE identified 
during the 30 calendar days follow up period after last chemoperfusion treatment 
must be followed to resolution. 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for adverse event 
reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.03. A list of adverse events that have occurred or might occur can 
be found in Section 5 and Appendix E, F and G (Pharmaceutical Information). A copy 
of the CTCAE Version 4.03 can be downloaded from the NCI Cancer Therapy 
Evaluation Program home page (http://ctep.cancer.gov). 
 
AEs will be listed by patient ID number. Deaths and other SAEs will be listed and 
summarized by patient ID number and treatment duration. Additionally, AEs leading 
to discontinuations will be listed separately. Incidence of AEs will be summarized by 
preferred term, maximum grade reported, and relationship to study treatment. 
 
It is the Investigator’s responsibility to report serious adverse events or pregnancy 
occurring during the treatment period or within 30 days following cessation of 
treatment, to the regulatory agencies and Institutional Review Board/ Independent 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
44 
 
Ethics Committee as defined by policies and requirements (Table 1). 
 
Table 1. Expedited Reporting Requirements for Adverse Events that Occur within 30 
Days of the Last Transarterial Chemoperfusion Treatment 
 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death  
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
IRB within the timeframes per IRB  policies and requirements.  


Bela Kis, MD, PhD 
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45 
 
 
9.4  
Protocol Amendments 
 
Any changes to this protocol will be initiated by the investigators or by the Regulatory 
Sponsor (Moffitt cancer Center) as a protocol amendment. The Investigator must 
submit the amendment to the IRB, with a revised Informed Consent Document if 
applicable. The Investigator must receive written approval from the IRB before the 
amendment may take effect. 
 
 
9.5  
Regulatory Binder 
 
To be in compliance with Good Clinical Practice, the Investigator must maintain 
accurate, complete, and organized documentation supporting the conduct of the 
study. This documentation includes, but is not limited to, the following: study 
personnel’s qualifications and training, IRB approvals and communications, 
communications with the Regulatory Sponsor, Site Signature & Responsibility Log, 
laboratory accreditations and reference ranges, and Informed Consent Documents 
(copies of IRB approved versions, signed/dated originals, or copies for all enrolled 
patients). 
 
 
9.6  
Informed Consent 
 
Prior to the performance of any protocol-specific procedures, informed consent must 
be obtained and documented by the use of a written Informed Consent Document 
approved by the IRB. The Informed Consent Document must be signed and dated by 
the patient or by the patient’s legally authorized representative and by the person 
conducting the informed consent discussion. The Informed Consent Document must 
fulfill the requirements as contained in the U.S. Code of Federal Regulations (21 CFR 
50.25), the ICH guidelines, and the Declaration of Helsinki. The Informed Consent 
Document must be written in a language understandable to the patient or to the 
representative. 
 
A signed and dated copy of the Informed Consent Document must be given to the 
person signing the document. The original must be retained by the Investigator with 
the study documentation and be available for inspection by persons conducting an 
audit of the study. 
 
Modifications to this template may be made by study site personnel to be in 
compliance with national, regional (e.g., state) or local laws and/or institutional 
requirements. 
 
 
 
 


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Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
46 
 
 
9.7  
Institutional Review Board/Independent Ethics Committee 
 
The protocol, Informed Consent Document, patient recruitment procedures (e.g., 
advertisements), information about payments and compensation available to 
patients, and any amendments must be approved by a properly constituted 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) in compliance 
with current regulations of the U.S. FDA, ICH guidelines, and any country-specific 
regulations. Before study initiation, the investigator must have written and dated 
approval/favorable opinion from the IRB/IEC for the protocol, consent form, subject 
recruitment materials/process (eg, advertisements), and any other written information 
to be provided to subjects. The investigator or sponsor should also provide the 
IRB/IEC with a copy of the Investigator Brochure or product labeling, information to 
be provided to subjects and any updates. The investigator or sponsor should provide 
the IRB/IEC with reports, updates and other information (eg, expedited safety reports, 
amendments and administrative letters) according to regulatory requirements or 
institution procedures. 
 
9.8  
Patient Confidentiality 
 
The Investigators must ensure that the patient’s confidentiality is maintained. Patient 
medical information obtained for the purposes of this study is confidential, and 
disclosure to third parties, other than those noted below, is prohibited. Patients 
should be identified only by their initials and protocol-assigned patient ID number. For 
those patients whose surgical specimen is processed and read by the central 
pathology laboratory, the patient’s billing information will be requested by this 
laboratory and will not be shared with the sponsor or any of its affiliates or 
representatives. 
 
Study personnel should follow the requirements of the Health Insurance Portability 
and Accountability Act (HIPAA). 
 
All clinical information is confidential, but data generated for this study must be 
available for inspection on request to representatives of the U.S. FDA, other national 
or local regulatory or health authorities and the associated IRB. 
 
All records must be kept in a secured area. 
 
 
9.9  
Curriculum Vitae and Medical Licenses 
 
The Principal Investigator is responsible for ensuring that the study is being 
conducted by qualified personnel. Documentation of these qualifications must be 
maintained within the Regulatory Binder, and includes the following: 
 
 


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 
Curriculum Vitae (CV): CVs for the Principal Investigator and all Sub-
investigators listed in this study protocol must be signed and dated. These CVs 
must show affiliation with the institution conducting the study and be current 
within two years of the personnel initiating their participation in the study. 
 
 
Medical Licenses: Medical licenses (physicians, physician assistants, nurses) 
listed in this study must be valid according to the regulations of the Florida Board 
of Medicine and the regulations of the Moffitt Cancer Center, and copies are 
maintained in the Human Resources Office of the Moffitt Cancer Center during 
the entire period of the person’s participation in the study. 
 
 
9.10 
Financial Disclosure 
 
The Financial Disclosure process for Investigator Initiated studies outlined in Moffitt 
Policy MRI-S.CRO.73 will be followed. Financial Disclosure forms will not be utilized 
for this Investigator Initiated trial. The assigned regulatory specialist will work with 
corporate compliance to ensure proper documentation in Oncore of any significant 
financial interests that may exist. 
 
 
 
 
10. DATA MANAGEMENT AND RECORD KEEPING 
 
Data will be maintained by the Moffitt Cancer Center. 
 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design and Sample Size Justification 
 
From historical data [20] we will consider a rate of 23% for response rate (either 
complete response or partial response evaluated by modified RECIST for 
mesothelioma) as not warranting further study. We will use 45% for disease control 
rate as a promising result to pursue further study. Using Simon’s two-stage minimax 
[21] design with 10% type I error rate and 10% type II error rate, 18 patients 
(including patient from the lead in safety cohort) will be enrolled and will be evaluated 
in the first stage of the trial. If 4 or less of the patients respond to the therapy (CR or 
PR or SD), the treatment will be stopped. If 5 or more patients respond, 14 additional 
patients (a total of 32 patients per group) will be enrolled. If a total number of 
responders (CR or PR or SD) are greater than or equal to 11, the null hypothesis will 
be rejected and the treatment is considered “promising” for further study. The actual 
type I error rate and power are 8.8% and 90.1%, respectively. The expected sample 
size under the null hypothesis (i.e., a disease control rate of 23%) is 23.62. 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
48 
 
11.2 
Accrual Rate 
 
We expect that a total of 10 ~ 15 patients will accrued per year. Thus, it will take no 
more than 3 years to complete patient accrual. 
 
 
11.3 
Stratification Factors 
 
No stratification factor is considered in this study. 
 
 
11.4 
Analysis of Primary and Secondary Endpoints 
 
The primary endpoint of this study is to estimate the response rate (either partial or 
complete response). The one-sided and two-sided 95% confidence intervals by 
Atkinson and Brown [22] will be reported, which accounts for the nature of two-stage 
design. The secondary endpoints include OS and PFS, which are estimated by the 
Kaplan-Meier method [23]. Point-wise 95% confidence intervals for survival curves 
and cumulative incidence curves were computed using log-log transformation. The 
association of these time-to-events data with other covariates will be examined by the 
Cox proportional hazards regression model [24]. For all subjects, descriptive 
statistics (median, range for continuous variables and frequency and proportion for 
categorical variables) is utilized to summarize patients’ demographic and clinical 
variables. 
 
All statistical analyses and summaries will be performed by a statistician using SAS 
statistical software (version 9.3). 


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49 
 
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31. Chiang PH, Chen CH, Shen YC. Intraarterial chemotherapy as the first-line therapy in 
penile cancer. Br J Cancer. 2014;111(6):1089-94. 
 
 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
52 
 
APPENDIX A 
 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 


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Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
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APPENDIX B 
 
Cockcroft - Gault Formula 
 
 
 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
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APPENDIX C 
 
 
Guidance on Contraception 
 
Investigators are expected to communicate the importance of pregnancy prevention because of 
the increased potential for an adverse reproductive outcome. The investigator shall describe the 
length of time that strict precautions against pregnancy must be observed and provide guidance 
on the use of appropriate methods for sexually active subjects and their partners. Women and 
men who are not capable of reproduction or choose to be abstinent shall be exempt from 
following the pregnancy prevention requirements specified below. All subjects shall be 
counseled on pregnancy prevention and follow pregnancy testing requirements as specified in 
the protocol. 
 
 
1. Duration of Mandatory Contraception 
 
The duration of mandatory contraception is based on clearance of the investigational drug (5 
half-lives after treatment completion). For males, an additional 90 days is required to 
complete turnover of drug-exposed sperm. For women, an additional 30 days is required to 
complete an ovulatory cycle. 
 
 
2. Calculation of Duration of Mandatory Contraception 
 
Males: (Duration of treatment) + (5 half-lives of the investigational drug) + (90 days) 
 
Females: (Duration of treatment) + (5 half-lives of the investigational drug) + (30 days) 
 
 
3. Contraceptive Methods 
 
3.1 Highly Effective Methods of Contraception 
 
Highly effective methods of contraception have a failure rate of < 1% when used 
consistently and correctly. Women of child bearing potential (WOCBP) and female 
partners of male subjects who are WOCBP (unless the male is azoospermic), are 
expected to use one of the highly effective methods of contraception listed below: 
 
1) Male condoms with spermicide 
2) Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena 
3) IUDs, such as ParaGard 
4) Tubal ligation 
5) Vasectomy 
 


Bela Kis, MD, PhD 
Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
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Studies that administer drugs known to be teratogenic or drugs that have not undergone 
requisite preclinical testing for teratogenicity require two forms of contraception for both 
WOCBP and female partners of male subjects who are WOCBP (unless the male is 
azoospermic). One method must be highly effective and the second method may also be 
highly effective or selected from the list of other contraceptive methods in Section B. 
WOCBP are exempt from this requirement if a commitment to abstinence is made. 
 
 
3.2 Other Contraceptive Methods 
 
1) Diaphragm with spermicide 
2) Cervical cap with spermicide 
3) Vaginal sponge 
4) Male condom without spermicide 
5) Progestin only pills 
6) Female condom (A male and a female condom must not be used together.) 
 
3.3 Hormone Based Methods of Contraception 
 
The treating physician, who must consider a recommendation from the relevant clinical 
pharmacologist, must agree that the use of a hormone-based contraceptive is safe and 
efficacious for WOCBP. A drug-drug interaction study should have been completed, if 
appropriate. Or there must be compelling evidence to substantiate that the investigational 
product(s) or concomitant medications will not adversely affect hormone exposures such 
that efficacy might be compromised or present additional risk. 
Female partners of male subjects participating in the study may use hormone based 
contraceptives as one of the acceptable methods of contraception since they will not be 
receiving drug. 
 
3.4 Abstinence 
 
Abstinence is an acceptable form of contraception for all study drugs. It is not necessary 
to use a second method of contraception when abstinence is elected. Subjects who 
choose abstinence must continue to have pregnancy tests, as specified. Acceptable 
alternate methods of highly effective contraception must be discussed in the event that 
the subject chooses to forego abstinence. 
 
3.5 Methods of Contraception with Insufficent Data to Support Effectiveness 
 
No method 
Withdrawal 
Rhythm 
Spermicide alone 


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Transarterial Chemoperfusion Treatment of Pleural Mesothelioma 
 
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APPENDIX D 
 
Mesothelioma Symptom Scale Questionnaire