Cancer Chemother Pharmacol (2014) 74: 1227-1234
DOI 10.1007/300280-014-2600-2
ORIGINAL ARTICLE

Phase I clinical trial of temsirolimus and vinorelbine in advanced

solid tumors

Caroline I. Piatek – Grace L. Raja – Lingyun J i ° Barbara Jennifer Gitlitz

Tanya B. Dorff – David 1. Quinn – James Hu – Anthony B. El-Khoueiry

Huyen Q. Pham – Lynda Roman ° Agustin A. Garcia

Received: 31 March 2014 / Accepted: 1 October 2014 / Published online: 6 November 2014

Springer-Verlag Berlin Heidelberg 2014

Abstract hyperglycemia (1), hypertriglyceridemia ( 1), and hypoka-

Purpose To determine the maximal tolerated dose (MTD) lemia (1). Best response included two patients (prostate and

of the combination of weekly temsirolimus and every other non-small cell lung cancer) with partial response and eight

week vinorelbine in patients with advanced or refractory patients with stable disease with median duration of best

solid tumors. response of 3.2 months.

Methods Patients were treated with intravenous temsiroli- Conclusions Temsirolimus 25 mg given days 1, 8, 15, and

mus on days 1, 8, 15, and 22 and intravenous vinorelbine 22 in combination with vinorelbine 20 mg/m2 given days 1

on days 1 and 15. Cycles were repeated every 28 days. and 15 every 4 weeks was found to be the MTD. This dose

Results Nineteen patients were enrolled in the study. combination is considered feasible in phase II trials.

Tumor types included lung (5), prostate (2), neuroendo-

crine of pancreas (1), bladder (2), uterus (3), cervix (4), and Keywords Temsirolimus – Vinorelbine

vagina (2). All patients had received prior chemotherapy. Metastatic carcinoma – Phase I trial

Four patients were enrolled to dose level 1, nine to dose

level II, and six to dose level III. Six patients were inevalu-

able and replaced. Fifty-seven total cycles were adminis- Introduction

tered. There was 1 dose-limiting toxicity at level 11 (grade

3 anorexia/dehydration) and 2 at level III (grade 3 hypoka- The signaling pathway phosphatidylinositol 3-kinase

lemia; grade 4 neutropenia). Two patients died at dose (PI3K)/AKT/mammalian target of rapamycin (mTOR)

level III; one was study-related with grade 4 neutropenia. plays a central role in cell survival, proliferation, and

Grade 3/4 toxicities observed during the first cycle included angiogenesis. Aberrance in the PI3K/AKT/mTOR path-

neutropenia (2), anemia (1), anorexia (1), dehydration (1), way is commonly implicated in cancer development and is
strongly associated with metastasis and poor survival across

tumor types [1, 2]. Activation of the PI3K/AKT/mTOR

C. I. Piatek – G. L. Raja – B. J. Gitlitz ‘ T. B. Dorff – D. 1. Quinn – pathway also plays an important role in the resistance to

J’.H.u.’ A’ 3′ El’Khoueiry ‘A’ A’ Gama (E) . . anticancer therapy including cytotoxic, biologic, hormo-

D1V1Slon of Medical Oncology, Department of Med1c1ne, Keck

School of Medicine of the University of Southern California, nal, and radlatlon therapy [3] Through SPCCIfiC mhlbl’

Los Angeles, CA, USA tion of mTOR, temsirolimus and everolimus affect tumor

e-maili agustin-garCia@med-USOCdu cell growth, proliferation, and survival. The use of mTOR

L. Ji inhibitors as single agents or in combination with other

Department of Preventive Medicine, Keck School of Medicine anticancer therapy has become an important Strategy in

of the University of Southern California, Los Angeles, CA, USA overcoming acquired resistance to standard therapy [3].

H Ph L R Intravenous mTOR inhibitor temsirolimus is currently

Div?sion:?Gyneccorlro:ilc Oncology, Department of Obstetrics approved for_the treatment Of advanced renél cell .CarCI-

and Gynecology, Keck School of Medicine of the University noma (RCC) 1n the USA and the European Unlon’ It IS also

of Southern California, Los Angeles, CA, USA approved for the treatment of relapsed or refractory mantle

Springer

PHASE II RESEARCH PROJECT PROTOCOL
GUIDE

PROTOCOL TITLE: Title of your clinical trial

PROTOCOL N0.:   Student #
For de-identified forms – Leave this blank

PRINCIPAL INVESTIGATOR: Your name

TABLE OF CONTENTS

GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS

For example:
AE
Adverse Event

1    STUDY SYNOPSIS (MAX 1 PAGE)
THIS MUST BE COMPLETED ON ONE PAGE – IT SERVES AS A QUICK OVERVIEW FOR YOUR PROPOSAL AND SHOULD CONTAIN TOO DETAILED INFORMATION. THERE ARE OTHER AREAS IN THE APPLICATION TO EXPAND ON YOUR INFORMATION.

Indication:     What is your target? (be specific – just the cancer type isn’t enough information)

Study Therapy:
What are you examining? (eg drug A vs drug B or varying doses or a drug etc)

Study Population:

Who do you need to recruit to conduct this study (no need to specify criteria at this point)

No. Centres:
Number of centres involved

Study Design:
What type of trial is in eg single blinded etc.  Consider feasibility.

Study Duration:

How long will the trial run?  Consider feasibility.

Objectives of the
Study:

What is the question/s you are trying to answer.  The original Phase I paper may act as a guide.

Study Endpoints:
(Primary and Secondary)

Briefly describe the endpoints and when/how they will be assessed.  You will be asked to provide more detail at a later date.

2    INTRODUCTION AND BACKGROUND

2.1    Background (Max 800 wds)
This should inform anyone unfamiliar with the cancer field and this particular cancer as to why this proposal is worthwhile.  You will use your Phase I as a guide but will need to conduct more research into that cancer you are looking at – and potentially other previous treatments. This section should also provide some background into the therapy that is being provided.

2.2    Study Rationale
Why are you conducting this study?  (and no stating its part of CSB483 assessment is not sufficient).
2.3    Risks and Known Side Effects
Again use the phase 1 to inform you of this.  Address who you will assess for these, monitor and deal with such events.

3    OBJECTIVES
This will expand on endpoints from the synopsis section.
4    STUDY DESIGN
This will expand on the study design from the synopsis section.  Consider screening, number of visits, follow ups etc.  Again feasibility should be considered.
5    STUDY POPULATION
Here you need to specify all aspects of the study population (eg numbers, Inclusion/Exclusion criteria.  You will also need to rationalise these characteristics.  Consider feasibility –(eg if the cancer is rare esp at stage IV can you get 200 participants etc???).
6    STUDY RESTRICTIONS
What limitations (if any) do you need to impose on the participants (eg dietary restrictions).  You will need to rationalise these restrictions.
7    SAFETY ASSESSMENTS – ADVERSE EFFECTS AND MONITORING
The Phase I paper will help inform you (as a guide) but you may want to consider other factors.  List how you will identify and monitor (inc how often) any adverse effects.
8    IDENTIFICATION AND DESCRIPTION OF DRUG
Discuss the drug to be tested (form, administration, dose etc).  Use the Phase I paper as a guide. Also discuss your process of administering the drug (eg if randomising – how will this be done etc).  Note the characteristics that you have defined in the study design section of the synopsis needs to be described here.
9    STUDY PARTICIPANT WITHDRAWAL AND DISCONTINUATION
9.1    Study participant Withdrawal
How/when can your participant’s withdrawal?  What will be the process and how will this affect the outcome of your study.  Yes this needs to be consider in advanced.
9.2    Early Termination of the Study
When would you consider early termination of this study – what parameters would need to take place in order to do this.  Use your knowledge of clinical trials to inform you of these paramenters.
10    DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
10.1    Hypotheses
What exactly are you testing?  This needs to be written as a scientific hypothesis (1 sentence).
10.2    Sample Size
This is the total of your study population (n=?).  Consider males/females, stage of cancer, other characteristics. Should be brief.
10.3    Statistical Methodology (brief description required only)
This is a very brief section.  How are you going to analyse (I don’t want calculations)?  How will you consider withdrawn participants, outliers, missing data etc??  How will you endpoints be measured??
11    DATA MANAGEMENT
Again a brief description of how you manage data (storage, location, accessibility, duration etc).  Will it be identifiable?  De-identifiable etc Consider ethical implications.
12    ETHICAL CONSIDERATIONS
The ethical considerations considered above needs to be highlighted.  Briefly discuss consent, release of identifying information (too whom and when), publication of material etc. You will need to research ethical considerations (if unfamiliar) but they are detailed in clinical trial network and human ethic websites.  MAKE sure it is feasible.
13    REFERENCES

APPENDIX 1 – Procedures Flow Chart

Appendix should cover an overview of your study design.  You may also wish to provide a figure on proposed mechanism of action of your drug or any other aspects that may help describe the sections detailed in your proposal (eg table of outcome measurements etc).

Cancer Chemother Pharmacol (2014) 74: 1227-1234
DOI 10.1007/300280-014-2600-2
ORIGINAL ARTICLE

Phase I clinical trial of temsirolimus and vinorelbine in advanced

solid tumors

Caroline I. Piatek – Grace L. Raja – Lingyun J i ° Barbara Jennifer Gitlitz

Tanya B. Dorff – David 1. Quinn – James Hu – Anthony B. El-Khoueiry

Huyen Q. Pham – Lynda Roman ° Agustin A. Garcia

Received: 31 March 2014 / Accepted: 1 October 2014 / Published online: 6 November 2014

Springer-Verlag Berlin Heidelberg 2014

Abstract hyperglycemia (1), hypertriglyceridemia ( 1), and hypoka-

Purpose To determine the maximal tolerated dose (MTD) lemia (1). Best response included two patients (prostate and

of the combination of weekly temsirolimus and every other non-small cell lung cancer) with partial response and eight

week vinorelbine in patients with advanced or refractory patients with stable disease with median duration of best

solid tumors. response of 3.2 months.

Methods Patients were treated with intravenous temsiroli- Conclusions Temsirolimus 25 mg given days 1, 8, 15, and

mus on days 1, 8, 15, and 22 and intravenous vinorelbine 22 in combination with vinorelbine 20 mg/m2 given days 1

on days 1 and 15. Cycles were repeated every 28 days. and 15 every 4 weeks was found to be the MTD. This dose

Results Nineteen patients were enrolled in the study. combination is considered feasible in phase II trials.

Tumor types included lung (5), prostate (2), neuroendo-

crine of pancreas (1), bladder (2), uterus (3), cervix (4), and Keywords Temsirolimus – Vinorelbine

vagina (2). All patients had received prior chemotherapy. Metastatic carcinoma – Phase I trial

Four patients were enrolled to dose level 1, nine to dose

level II, and six to dose level III. Six patients were inevalu-

able and replaced. Fifty-seven total cycles were adminis- Introduction

tered. There was 1 dose-limiting toxicity at level 11 (grade

3 anorexia/dehydration) and 2 at level III (grade 3 hypoka- The signaling pathway phosphatidylinositol 3-kinase

lemia; grade 4 neutropenia). Two patients died at dose (PI3K)/AKT/mammalian target of rapamycin (mTOR)

level III; one was study-related with grade 4 neutropenia. plays a central role in cell survival, proliferation, and

Grade 3/4 toxicities observed during the first cycle included angiogenesis. Aberrance in the PI3K/AKT/mTOR path-

neutropenia (2), anemia (1), anorexia (1), dehydration (1), way is commonly implicated in cancer development and is
strongly associated with metastasis and poor survival across

tumor types [1, 2]. Activation of the PI3K/AKT/mTOR

C. I. Piatek – G. L. Raja – B. J. Gitlitz ‘ T. B. Dorff – D. 1. Quinn – pathway also plays an important role in the resistance to

J’.H.u.’ A’ 3′ El’Khoueiry ‘A’ A’ Gama (E) . . anticancer therapy including cytotoxic, biologic, hormo-

D1V1Slon of Medical Oncology, Department of Med1c1ne, Keck

School of Medicine of the University of Southern California, nal, and radlatlon therapy [3] Through SPCCIfiC mhlbl’

Los Angeles, CA, USA tion of mTOR, temsirolimus and everolimus affect tumor

e-maili agustin-garCia@med-USOCdu cell growth, proliferation, and survival. The use of mTOR

L. Ji inhibitors as single agents or in combination with other

Department of Preventive Medicine, Keck School of Medicine anticancer therapy has become an important Strategy in

of the University of Southern California, Los Angeles, CA, USA overcoming acquired resistance to standard therapy [3].

H Ph L R Intravenous mTOR inhibitor temsirolimus is currently

Div?sion:?Gyneccorlro:ilc Oncology, Department of Obstetrics approved for_the treatment Of advanced renél cell .CarCI-

and Gynecology, Keck School of Medicine of the University noma (RCC) 1n the USA and the European Unlon’ It IS also

of Southern California, Los Angeles, CA, USA approved for the treatment of relapsed or refractory mantle

Springer

PHASE II RESEARCH PROJECT PROTOCOL
GUIDE

PROTOCOL TITLE: Title of your clinical trial

PROTOCOL N0.:   Student #
For de-identified forms – Leave this blank

PRINCIPAL INVESTIGATOR: Your name

TABLE OF CONTENTS

GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS

For example:
AE
Adverse Event

1    STUDY SYNOPSIS (MAX 1 PAGE)
THIS MUST BE COMPLETED ON ONE PAGE – IT SERVES AS A QUICK OVERVIEW FOR YOUR PROPOSAL AND SHOULD CONTAIN TOO DETAILED INFORMATION. THERE ARE OTHER AREAS IN THE APPLICATION TO EXPAND ON YOUR INFORMATION.

Indication:     What is your target? (be specific – just the cancer type isn’t enough information)

Study Therapy:
What are you examining? (eg drug A vs drug B or varying doses or a drug etc)

Study Population:

Who do you need to recruit to conduct this study (no need to specify criteria at this point)

No. Centres:
Number of centres involved

Study Design:
What type of trial is in eg single blinded etc.  Consider feasibility.

Study Duration:

How long will the trial run?  Consider feasibility.

Objectives of the
Study:

What is the question/s you are trying to answer.  The original Phase I paper may act as a guide.

Study Endpoints:
(Primary and Secondary)

Briefly describe the endpoints and when/how they will be assessed.  You will be asked to provide more detail at a later date.

2    INTRODUCTION AND BACKGROUND

2.1    Background (Max 800 wds)
This should inform anyone unfamiliar with the cancer field and this particular cancer as to why this proposal is worthwhile.  You will use your Phase I as a guide but will need to conduct more research into that cancer you are looking at – and potentially other previous treatments. This section should also provide some background into the therapy that is being provided.

2.2    Study Rationale
Why are you conducting this study?  (and no stating its part of CSB483 assessment is not sufficient).
2.3    Risks and Known Side Effects
Again use the phase 1 to inform you of this.  Address who you will assess for these, monitor and deal with such events.

3    OBJECTIVES
This will expand on endpoints from the synopsis section.
4    STUDY DESIGN
This will expand on the study design from the synopsis section.  Consider screening, number of visits, follow ups etc.  Again feasibility should be considered.
5    STUDY POPULATION
Here you need to specify all aspects of the study population (eg numbers, Inclusion/Exclusion criteria.  You will also need to rationalise these characteristics.  Consider feasibility –(eg if the cancer is rare esp at stage IV can you get 200 participants etc???).
6    STUDY RESTRICTIONS
What limitations (if any) do you need to impose on the participants (eg dietary restrictions).  You will need to rationalise these restrictions.
7    SAFETY ASSESSMENTS – ADVERSE EFFECTS AND MONITORING
The Phase I paper will help inform you (as a guide) but you may want to consider other factors.  List how you will identify and monitor (inc how often) any adverse effects.
8    IDENTIFICATION AND DESCRIPTION OF DRUG
Discuss the drug to be tested (form, administration, dose etc).  Use the Phase I paper as a guide. Also discuss your process of administering the drug (eg if randomising – how will this be done etc).  Note the characteristics that you have defined in the study design section of the synopsis needs to be described here.
9    STUDY PARTICIPANT WITHDRAWAL AND DISCONTINUATION
9.1    Study participant Withdrawal
How/when can your participant’s withdrawal?  What will be the process and how will this affect the outcome of your study.  Yes this needs to be consider in advanced.
9.2    Early Termination of the Study
When would you consider early termination of this study – what parameters would need to take place in order to do this.  Use your knowledge of clinical trials to inform you of these paramenters.
10    DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
10.1    Hypotheses
What exactly are you testing?  This needs to be written as a scientific hypothesis (1 sentence).
10.2    Sample Size
This is the total of your study population (n=?).  Consider males/females, stage of cancer, other characteristics. Should be brief.
10.3    Statistical Methodology (brief description required only)
This is a very brief section.  How are you going to analyse (I don’t want calculations)?  How will you consider withdrawn participants, outliers, missing data etc??  How will you endpoints be measured??
11    DATA MANAGEMENT
Again a brief description of how you manage data (storage, location, accessibility, duration etc).  Will it be identifiable?  De-identifiable etc Consider ethical implications.
12    ETHICAL CONSIDERATIONS
The ethical considerations considered above needs to be highlighted.  Briefly discuss consent, release of identifying information (too whom and when), publication of material etc. You will need to research ethical considerations (if unfamiliar) but they are detailed in clinical trial network and human ethic websites.  MAKE sure it is feasible.
13    REFERENCES

APPENDIX 1 – Procedures Flow Chart

Appendix should cover an overview of your study design.  You may also wish to provide a figure on proposed mechanism of action of your drug or any other aspects that may help describe the sections detailed in your proposal (eg table of outcome measurements etc).