MODULE 6 ASSIGNMENT

TITLE/ TOPIC: PROPOSED STRATEGY FOR CLINICAL EVALUATION OF

PTK/ZK, A VEGF INHIBITOR IN PATIENTS WITH LIVER
METASTASES FROM SOLID TUMOURS

SUBMITTED BY : ADERSH.S.U.

BATCH : 2009 - 2011

REGISTRATION NO. : s044603

MENTOR NAME : Dr. Lincy Jaison

LEARNING GROUP NO. : 03

LOCATION : BANGALORE

On BB Hard Copy
DATE OF SUBMISSION : 07/02/2011 07/02/2011
BACKGROUND INFORMATION

Cancer is on of the deadliest of all diseases and has now become more common. It is
the uncontrollable and unorganized rapid growth of cells in the body, most time originated
from a single cell genetic mutation. The rapidly growing mass of tissue is referred as tumour.
The prevalence of cancer has been increasing each year and it is the leading cause of death of
people in many developed countries. Cancer can progress into any part, any organ of the
body. Even though complete cure of cancer is not possible, there are many treatments
available today which are helpful in alleviating the intensity of the disease to the maximum
and to prevent the progression of the disease. However there are some misbelieves among
most people that cancer is an incurable disease and the patient has to bear the immense pain
throughout his life. There are many researches going on worldwide in the purpose of finding
out a better treatment and sometimes for the complete eradication of the disease.

Pertaining to the mechanism and progression of the cancer, the process of

angiogenesis is very important. Angiogenesis is the process of development of new blood
vessels from the pre existing ones (National Cancer Institute 2005). These new vessels supply
nutrients and oxygen to the tumour cells, allowing the rapid growth. Inhibition of
angiogenesis in and around the rapidly growing cells could effectively prevent the
progression of cancer to the other sites. Today cancer researches concentrate more on
angiogenesis inhibition and there are many angiogenesis inhibiting drugs under clinical
evaluation in recent years (NCI 2005).

Growth factors are the important promoters of angiogenesis and among them vascular
endothelial growth factors (VEGF) are the key players. VEGF have vital role in vascular
permeability and neovascularisation (Scappaticci FA eta l 2002, Ferrara N. Et al 1992).
VEGF acts mainly by binding to the VEGF receptor families. Activation of VEGF receptors
activate tyrosine kinase receptors that results in endothelial cell proliferation and migration
(Mross et al 2005). VEGF inhibitors inhibit or blocks VEGF legands from VEGF receptors.
PTK/ZK is an effective VEGF receptor inhibitor that inhibits all known VEGF receptors and
blocks the activity of tyrosine kinase. This could possibly be a long term therapy of vascular
permeability and neovascularisation (Wood JM., Bold G. eta l 2000).

PHASE I EVALUATION OF PTK/ZK – THE PUBLISHED STUDY

The clinical and pharmacokinetic properties of PTK/ZK had been tested in a phase I
study in patients with liver metastases from solid tumours. It was a phase I/II (oncology trial)
clinical evaluation of PTK/ZK aimed to find out safety, efficacy and pharmacokinetic profile.
The study had a total of 27 patients. Liver metastases and breast or colorectal cancer patients
with no standard therapy was the main eligibility criteria for the respected study.
Other Inclusion Criteria:

 Estimated life expectancy: ≥3 months

 Absolute Neutrophil Count (ANC): 1500µL
 Haemoglobin: ≥9g/dL
 WHO performance rate: ≤2
 Platelet count: ≥100,000 µL
 Alanine aminotransferase (ALT) ) and Aspartate aminotransferase (AST): ≤25

Exclusion Criteria:

 Pregnant and Lactating women

 Uncontrollable or concurrent medical diseases
 Patients diagnosed with brain metastases
 History of high dose chemotherapy

All the patients were administered with an oral dose of PTK/ZK ranging from 300 to
1200 mg/day. Once daily dose was given to all patients for 28 days (1 cycle). Any adverse
events during the first cycle (first 28 days) following the initial dose of PTK/ZK were
considered to be dose-limiting toxicity (DLT). Proteinuria (≥grade 2), neutropenia (Grade 4),
thrombocytopenia (grade 4), serum creatinine (grade 2) etc were considered to be DLT.
Nausea, vomiting etc were considered to be general symptoms but not DLT. Southwest
Oncology Group (SWOG) criteria were used at the end of each cycle to assess tumour
response. Plasma concentration of drug were determined based on parameters such as
apparent plasma clearance, volume of distribution, terminal elimination half life, area under
the curve, maximum concentration and time of maximum concentration. The study was
reviewed by the Freiburg University ethical committee.
The results of the study were indeed promising. Common adverse drug reactions
observed were fatigue, nausea, vomiting and dizziness. Serious adverse events reported in 3
patients and it is suspected to be due to the study drug. The severe adverse reactions observed
were, ataxia (grade 3), dyspnea (grade 3) and hypertensive crisis (grade 4). The area under
the concentration-time curve was found to be increased with a dose ranging between 300 to
1000 mg/day, but there is no further increase in the area with a dose range of 1000 to 1200
mg/day. The area under the curve (AUC) decreased to 50% between day 1 to 15 of the first
cycle. There is no decrease in AUC between day 15 and day 28.
A significant reduction in tumour blood flow (measured as ki) was detected at day 2
at doses ≥750mg/day by DCE – MRI. Stable disease was observed in 13 patients for at least 2
cycles (56 days). The results of the study suggested that long term treatment of patients with
liver metastases from solid tumours with PTK/ZK was safe and feasible demonstrated with
predictable pharmacokinetics.
MOVING TO THE NEXT PHASE – THE PROPOSED STRATEGY

The positive outcome of phase I study opened a way for PTK/ZK, the respected drug
in the published study to move to the next phase of development. The proposed strategy is to
conduct a phase III clinical evaluation to assess the safety and efficacy of PTK/ZK compared
with a standard chemotherapy (5 – fluorouracil/oxaciplatin/leukovorin [FOLFOX 4]). This
strategy is based on the new trend in oncology that uses various antiangiogenic substances,
especially the VEGF inhibitors for the treatment of various types of cancers. The phase I
evaluation of PTK/ZK in patients with liver metastases recommended a dose of 1200 mg/day
to be used for phase III and it may shall quite helpful for the biological activity.

The trial has to be a randomized, open labeled, parallel, and active-control one. The
study will be multicentric and there would be at least 50 study locations across the globe.
Patient enrolment will be felicitated through advertisements, hospitals, cancer institutes etc.
Written consent will be taken from patients after having explained about all the aspects of the
study during the informed consent process. Patients will be randomly assigned to either of the
treatment groups – active or control, post to enrolment. Investigators, study professionals and
other personals will be selected based on the prior experience in the current research stream.
Applications will be submitted to the concerned regulatory authorities of respected countries
prior to the study to get the necessary approval for the study. The estimated study duration is
5 years. The quality of the research (in accordance with regulations) will be ensured through
proper auditing and reviewing by IEC’s or IRB’s. Patients in the active group will receive a
daily dose of 1200mg of PTK/ZK and a respected FOLFOX 4 dose to those in the control
group. All the patients will be examined with colonoscopy soon after enrolment and
randomization.

New Drug Application (NDA) will be submitted to the concerned regulatory

authorities to get approval for marketing the drug in respected countries. All safety, efficacy,
pharmacokinetic and pharmacodynamic profile of drug with early clinical evaluation data
will be submitted along with NDA. All the sites will be ready for regulatory inspections at
any point of time. Once the approval has been given, drugs will be distributed to the market
and will be made available to the public as soon as possible. Phase IV studies will be started
with the availability of all resources for many purposes. The study will concentrate more on
addition effects of PTK/ZK in large as well as diverse population. The adverse reactions that
had never been reported at any course during the evaluation will be monitored in phase IV
study. The risk-benefit ratio as well as cost effectiveness of PTK/ZK will be assessed in large
population through the post marketing surveillance study. The study will also concentrate on
collecting additional information on safety and efficacy data.
RATIONALE OF THE PROPOSED STUDY
The positive outcome of the phase I study urged need of conducting a phase III study
which evaluates safety and efficacy of PTK/ZK in large population. Angiogenesis is common
in carcinoma and angiogenic drugs will be much effective in most types of cancers and so
phase II can be skipped. Antiangiogenic substances are widely been used in many oncology
trials in recent years and it is found to be effective in many cases. The proposed strategy is
based on this information and data. Phase III clinical studies usually compare the
experimental drug to a standard drug. In the proposed study PTK/ZK will be compared with
FOLFOX 4, a standard chemotherapic substance. Chemotherapy is the standard treatment
option for many cancers, including colorectal cancer with liver metastases. The process of
randomization will help to avoid many selection or allocation bias and help to randomly
assign the patients to each treatment groups.

The study will be multicentric and will have sites in developed as well as developing
countries. There would be more sites in the developed countries since the prevalence of
cancer has been increasing in many developed countries in recent years. The dose of PTK/ZK
will be 1200mg/day and it was recommended by phase I study. In phase I evaluation,
biological effect was obtained at a dose range of 300 – 1000mg/day. Progression free survival
and overall survival would be the primary as well as secondary outcome measures for this
study respectively, and these are the important means of quality of life of people (patients) in
any cancer types.

OUTLINE OF THE PROPOSED STUDY

Title of the Study:

A Phase III, Randomized, Open labelled, Multinational, Multicentric, Parallel, Active-
Control study to evaluate the Safety and Efficacy of PTK/ZK in patients with Liver
Metastases, compared to standard chemotherapy (FOLFOX 4).

Purpose of the Study:

The purpose of the study is to increase the quality of life of patients with liver metastases
with other forms of cancer by increasing overall as well as progression free survival with
long term therapy with PTK/ZK compared with FOLFOX 4, a standard chemotherapic
regimen.

Study Design:
The study will be a randomized, open labelled, parallel, active-control design, having
PTK/ZK as active drug and FOLFOX 4 as standard drug.
Primary Outcome Assessment:
Progression free survival, with a minimum of 150 – 180 weeks.

Secondary Outcome Assessment:

Overall survival with a minimum of 150 – 180 weeks.

Description of the Study:

Randomized active-control study, with two arms.

 Left Arm: Active drug (PTK/ZK)

 Right Arm: Standard drug (FOLFOX 4)

Patients in the active group will be provided with a daily dose of about 1200mg PTK/ZK

Selection Procedure:
Liver metastases patients with colorectal or breast cancer will be primarily eligible for the
study.

Age group: 18 years and above

Gender: Both male and female

Nature of subjects: Only patients, not healthy volunteers

Inclusion Criteria:
 Patients with liver metastases and colorectal, brain or pancreatic cancer
 Patients must have an at least 16 weeks life expectancy.
 Liver metastases and colorectal cancer must be proved in biopsy
 Not less than 18 years of age
 ECOG performance: 0.2
 Able to understand and sign written informed consent.

Exclusion Criteria:
 Patients who are receiving any other antiangiogenic medications.
 Patients who had the history of surgical resection
 Patients having tumour greater than 7.5cm in any organ
 Pregnant and breast feeding women
 Patients who are participating in any other concurrent evaluation studies.
 Patients with uncontrollable diabetes or hypertension
Measurement of Efficacy:
All the patients will be imaged with Dynamic Contrast Enhanced Magnetic Resonance
Imaging (DCE-MRI) to detect the tumour blood supply. Vascularity and permeability of
tumour cells will be assessed by calculating the bidirectional transfer constant (Ki).

Safety Assessments:
Adverse drug reactions and serious adverse events would be the parameters of safety
measures. All such events will be reported to sponsors, then to ethics committee, followed by
regulatory authorities within the time schedules given by the regulatory bodies.

Statistical Analysis:
Chi square test will be the major test used for the statistical analysis purpose with a
probability (p) of <0.05. The survival rate (overall and progression free) of patients will be
measured using Kaplan-Meier test in both arms. Sample size will be calculated with a 50%
significance level and 90% power with respect to the prevalence rate.

Ethical Considerations:
Prior to the commencement of the study, necessary approval for all documents – protocols,
SOPs, informed consent documents will be collected from the ethics committee. They will
also be informed with all serious adverse events occurring during the study on time. Entire
study will be reviewed by IEC or IRB. All the aspects of the study will be explained well in
detail to each patient during the informed consent process and signed dated written consent
will be taken from them. All the details of the subjects will be kept confidentially throughout
the study. The entire study will be conducted in accordance with all the concerned regulations
and guidelines to ensure quality research.
 REFERENCES

1. Ferrara N, Houck K, Jakeman L, et al., 1992. Molecular and biological properties of

the vascular endothelial growth factor family of proteins. Endocrine Reviews, pp.13:
18–32
2. Mross K, Drevs J, et al, 2005. Phase I clinical and pharmacokinetic study of PTK/ZK,
a multiple VEGF receptor inhibitor, in patients with liver metastases from solid
tumours, European Journal of Cancer, pp.41: 1291–1299
3. National Cancer Institute (NIC), 2005. Understanding Cancer Series:
Angiogenesis [Online] (Updated 09/01/2006)
Available at: http://www.cancer.gov
4. Scappaticci FA, 2002. Mechanisms and future directions for angiogenesis- based
cancer therapies, Journal of Clinical Oncology,pp.20:3906–3927
5. Wood JM, Bold G, Buchdunger E, et al., 2000. PTK787/ZK 222584, a novel and
potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases,
impairs vascular endothelial growth factor-induced responses and tumour growth after
oral administration. Cancer Res, pp.60:2178–2189