Clinical trial design and patients with brain metastases

Clinical trial design and patients with brain metastases

The most common spread of metastatic solid tumours in central nerve system (CNS) is as parenchymal brain metastases or as leptomeningeal disease (metastases in brain membrane or spinal cord). Because the brain is protected by blood-brain barrier many drugs in standard dose will not achieve the required concentrations to be effective in CNS. Some anti-cancer drugs, however, do not cross blood-brain barrier at all but activate lymphocytes that can penetrate to CNS; while other drugs do not have effect on CNS.

For many experimental anti-cancer therapeutics there may be not sufficient information regarding their activity on CNS. As a result if the studied drugs do not have effect on CNS patients with brain metastases will progress quickly and this may affect the overall outcome of the clinical trials. On the other hand if the anti-cancer drugs have CNS activity and patients with brain metastases are excluded from the clinical trials there will be no information on drug activity on CNS and patients will miss new treatment option.

What types of clinical trial designs are possible for patients with CNS disease?

Design 1 – if the drug is considered unlikely to have CNS activity or efficacy

There are 2 possible designs to overcome the challenges above:

  • Exclude patients with CNS disease
  • Exclude patients with untreated or unstable CNS disease – CNS disease has to be either asymptomatic on stable dose of corticosteroids or off corticosteroids.

Design 2 – if the drug is considered likely to have CNS activity or efficacy

  • Permit untreated CNS metastases
  • If untreated CNS disease is measurable, mandate that these lesions be captured as target lesions
  • Define whether a growing CNS lesion previously treated with radiotherapy is permissible as a target lesion
  • Standardise CNS imaging frequency
  • Define if symptomatic, or if steroids or anticonvulsants permitted initially, or later
  • Specify bicompartmental endpoints and action if progression is observed in one but not both compartments
  • For randomised studies, stratify according to:
  • Whether CNS disease is present or absent
  • Whether CNS disease is treated or untreated
  • If treated, whether CNS progression has occurred

Design 3 – if there is minimum information on drug activity on CNS

Appropriate for phase 1 studies

This model includes dose escalation until the optimum dose is achieved. Then it is followed by molecularly or histologically defined efficacy expansion cohorts; food effect and drug-drug  interaction sub-studies and CNS metastases sub-study.

Appropriate for phase 2 and 3 studies

  • Initially permit only absent or treated and non-progressing CNS metastases in general trial population
  • Permit separate single-arm early CNS cohort with defined number of patients with measurable untreated or progressing CNS disease with separate early efficacy analysis such as CNS objective response
  • Minimise risk in this early CNS cohort by only allowing in asymptomatic cases
  • Modify protocol (as either amendments or following pre-written decision pathways) as data emerge to be like either scenario A or scenario B

CNS progression is a big challenge in treating patients with metastatic solid tumours. New approaches are required to assess when patients with CNS disease could be appropriately included or excluded from clinical trials.


Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group

Published on 1 Oct 2018

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

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FDA legislation changes and clinical trials: July 2018

FDA legislation changes and clinical trials: July 2018

FDA extends access to experimental drugs

FDA extended access program started back in 2009 and it allowed patients with life-threatening diseases who have exhausted all other options to try experimental drugs, which are not on the market yet. After the implementation the program for the period between 2009 and 2014 FDA has approved almost 6000 requests for experimental treatment, however some view the current process as ineffective.

The new legislation ‘Federal Right to Try Act’ will further increase the access to experimental drugs and change the pathway to obtain approvals. However, the agency remains committed to protect patients’ safety and provide more treatment options to patients with life-threatening diseases.


FDA prepares guidance on including adolescent in adult oncology clinical trials

It is known that cancer in young paediatric patients may differ from adults and therefor needs new approaches and treatments; there is an acute demand for treatment options for paediatric cancer patients. It was established that in some type of cancers there is similarity in paediatric and adult cancer histology and biological behaviour – for example, some soft tissue and bone sarcomas, central nervous system tumours, leukaemia, lymphomas and melanomas.

Often paediatric clinical trials are conducted long after adult trials and this could lead to delay in access to potentially effective therapies.

In June 2018 FDA released guidance on inclusion of adolescents (age between 12 and 17 years) in clinical trials. The guideline outlines appropriate criteria for inclusion of adults and adolescents at different stages of drug development; recommendations regarding dosing, pharmacokinetics, safety, monitoring and ethical considerations.

According to the guide doses have to be selected based on whether the adult dose is fixed or based on body size; dosing should be supported by pharmacokinetic characteristics of the drug, the therapeutic index of the drug and dose- and exposure-response relationships. Pharmacokinetic samples for adolescents should be collected according to the drug development programme to verify exposure in adolescents and adults. In case of body size-adjusted dosing adolescents should receive the same body size-adjusted dose as adults; however if it is fixed dose then a minimum body weight threshold should be defined to prevent adolescents with a lower than average body weight from exceeding adult exposure. While in early drug development long term safety follow up may not be possible the guide recommends sponsors to develop plan for long term safety evaluation where feasible. Under the federal regulations, IRBs reviewing adult oncology clinical trials that allow for the enrolment of adolescents must ensure that the provisions of 21 CFR Part 50, Subpart D (‘Additional Safeguards for Children in Clinical Investigations’) and 21 CFR 50.52 (‘Clinical Investigations involving Greater than Minimal Risk but Presenting the Prospect of Direct Benefit to Individual Subjects’) are satisfied before approving the trials.


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Circulating tumor cells and their future in oncology diagnostic

Circulating tumor cells and their future in oncology diagnostic

Circulating tumour cells (CTCs) are rare tumor cells that have been investigated for diagnostic, prognosis and predictive biomarkers for different types of cancer. CTCs have been described back in 1869. They are not used in clinical practice at the moment, however CTCs were explored in breast, lung, prostate and colorectal cancers.

How rare are CTCs?

There is approximately 1 circulating tumor cell per ml of blood released by primary tumors or metastases that can be detected in peripheral blood.

What types of circulating tumor cells exist in clinical practice?

  1. Treatment based on CTCs used as liquid biopsy: Biopsies are invasive, expensive, time-consuming and potential harmful so using CTCs is one way of avoiding this procedure.
  2. Treatment based on CTC count or CTC variations: This depends on technique used and volume of blood screened.
  3. Treatment based on CTC biomarker expression: Isolating single cell of CTCs could be challenging.

What are the challenges of using circulating tumor cells in cancer screening?

Usage of Cellsearch technique in early non-metastatic cancer have shown low CTC detection rates (5-30% depending on the cancer type). This method is limited to some circulating epithelial cells so it cannot be used wildly. Unfortunately other techniques have not shown better detection rates.

How could CTCs be used as prognostic value?

Analysis of 1944 patients with breast cancer using CellSearch has shown that patients with increased CTCs have poor prognosis and decreased progression-free survival. Also evaluating CTCs count at baseline allows better prognosis of survival. Similar results are observed in patients with metastatic colon cancer, castration-resistant prostate cancer and small cell and non-small cell lung cancer.

CTCs value as prognostic factor was also observed in non-metastatic cancers with similar correlation – the higher amount of CTCs means poor prognosis.

How could CTCs be used in monitoring treatment response?

Studies with patients with metastatic breast cancer have shown that women with high baseline CTC counts, which is reduced after one cycle of chemotherapy have better prognosis than patients where their CTC count is elevated.

While CTCs have great potential as prognostic factor and in monitoring therapy, there are still lots of challenges before their implementation in clinical practise with biggest among them – discovering new methods and techniques for detection of CTCs.


Circulating tumor cells: clinical validity and utility

Published on 2 July 2018

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

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Paediatrics Clinical Trials: Children Are Not Simply Small Adults

Paediatrics Clinical Trials: Children Are Not Simply Small Adults

Children often have the same diseases as adults, however many of the approved drugs on the market are not tasted in children. Many rare and serious diseases affecting children have no treatment options and as a result clinicians are forced to use “off label” drugs (drugs not approved to be used in children population).

Undoubtedly clinical research involving kids have plenty of challenges. There are many initiatives from regulatory agencies, which are trying to encourage pharmaceutical companies to include children in clinical trials or to obtain information for the application of marketed drugs in children.

Why is important to have drugs tested for children?

  • Paediatricians could be denied access to potential beneficial treatment for children just because there is no data from that population.
  • Children are treated with medications based on adults’ data or empirical experience in children. This could increase the safety risk for the young patients.

Controlled clinical trials are the best way to provide children with access to new treatments and at the same time obtain relevant safety data.

What are the most common challenges in clinical research, which lead to exclusion of children?

  • The research topic is not relevant for children;
  • Laws or regulations that do not allow children to participate;
  • There is already some knowledge on the topic;
  • The condition is rare in children;
  • Limited number of children which does not allow enough data to be generated;
  • Not enough data about adults to judge the potential risks for children;
  • Children are not homogenous group and absorption, distribution, metabolism and excretion of the drugs depend of age and their current organs development;

Since 2000 in USA and Europe regulatory agencies require pharmaceutical companies to include paediatric data in all new drug application and licence extensions when there is an expectation that the drugs will be used in children.

Another initiative in USA and Europe is the “orphan” drug status which encourages development of drugs for rare diseases; however it is not expected to benefit paediatrics research significantly.

FDA Modernization Act which has similar regulations in Europe gives 6 month extension to drug licences or patents for drugs, which have paediatric data.

There are a number of ethical considerations which have to be observed when conducting research with children:

  • Children can be included in clinical trials after it was established that the drug could be beneficial.
  • Protocols involving paediatric population should be reviewed by Ethics Committee which includes members knowledgeable in ethical, clinical and psychosocial issues.
  • Informed consent is obtained from parent / guardian unless children are in intellectual maturity which allows them to make decision for themselves.
  • If the information can be obtained in less vulnerable population, it should be preferred to vulnerable population – for example, if the studies in adolescents that can be consented could be used for younger children, the study should include adolescents and not younger children who cannot consent.
  • Studies in handicapped or institutionalised paediatric populations should be limited to diseases found in this specific population or when it is expected the disease and the treatment to be affected in such population – for example, studies cannot include children with disabilities if they can use children without disabilities and will provide adequate data.
  • Paediatrics studies have to be conducted by experienced and trained clinician.
  • The design of clinical trials should try to minimise the amount of children involved and required procedures without affecting data integrity.
  • All measure to be taken to minimise the discomfort and distress that could be caused to the children.

While paediatric clinical trials have their challenges obtaining safety data for children is vital for providing adequate treatment.


Clinical Trials in Paediatrics


Published on 1 June 2018

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

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Review: Clinical trials and restricted medications

Review: Clinical trials and restricted medications

During my recent work I came across 2 cases of usage of restricted medications in patients participating in clinical trials. In both cases restricted medications were prescribed by GP or physician at local hospital without realising that patients should not take these medications. Just to put your mind at rest both patients are well, but what happened is something that everyone in clinical research should be concerned about.
But let’s start with what is restricted medication and why such medications exist?
All medications are metabolised in specific parts in the human body (in most cases liver is involved) and sometimes some medications can influence (increase or decrease) the plasma concentration of other medications. This could be potential safety issue for the patient as they could be exposed to overdose or lower than the required therapeutic dose. So it is understandable that such medications would be considered “restricted”. This is, of course, the simplest explanation.
Why restricted medications are very important in clinical trials?
As we know clinical trials drugs are newly developed compounds and there are lots of unknown about them. While they are in clinical trials it is important that patients do not take “restricted medications”, which could affect the plasma concentration of the study medication because this could be significant safety issue.
Then how these 2 cases happened and patients were prescribed restricted medications?
The discussion below is relevant to UK and I have to admit I am not familiar how health care systems around the world operate. In a perfect world all health care providers will have access to patients’ electronic medical records and they will be able to obtain the most up to date information. Unfortunately the world is not so perfect and each health care provider in UK has their own EMR or paper records that other providers do not have access to. This means that, more or less, we rely on patients to provide adequate information to different health care providers. However this is not a solution to the problem because patients cannot be expected to be able to explain what medications they should not take.
How to avoid “restricted medications” to be prescribed to patients on clinical trials from third parties?
The only possible option that the research team has is to ask their patients to contact them if they have medications prescribed by GP or local hospital so that they can advise them if they can take them. Although this again puts the focus on patients communicating to different providers this is still less complicated solution to the problem.
What is the big safety issue?
While patients participating in clinical trials are monitored closely and although such cases are not unusual research teams are able to react adequately to guarantee patients’ safety. The question is who is monitoring all these licensed medications on the market that have restricted medications too?
Published on 
2 May 2017
Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe.
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