Overview
- Patients with advanced rare cancers are eligible to participate in the RATIONALE study.
- Patients can participate if treatment aimed at a cure is no longer possible.
- RATIONALE investigates whether a molecularly targeted treatment is more effective than the current standard of care.
Study status: The study is enrolling patients (recruitment open).
Cancer develops when the genetic material within our cells changes. Cancer cells therefore differ from healthy body cells, and cancer cells are not all the same even among themselves — cancer cells exhibit different genetic and biological characteristics.
These differences also influence how well a particular therapy works. That is why a certain type of treatment may work very well for one person, but not at all, or only to a lesser extent, for another.
Researchers observe such differences very closely. Sometimes this allows them to identify whether tumor characteristics have influenced the effectiveness of a treatment, and if so, which ones.
The RATIONALE study builds on the findings and experience of another study — the MASTER program. As in the MASTER program, researchers in the RATIONALE study are examining the characteristics of tumor cells from all participants using various modern methods. The goal is to find the best possible treatment tailored to the unique biological characteristics of the tumor cells.
You can read more about the goals the scientists are pursuing with RATIONALE in the section “What is the aim of the RATIONALE study?”.
Patients with rare types of carcinomas or sarcomas are eligible to participate in the RATIONALE study. However, they must meet various requirements. The most important ones are:
- The disease has already spread extensively within the affected area of the body and/or has formed metastases and is expected to continue progressing.
- The patient has already received at least one treatment that is typically used for this disease — if such a treatment exists.
- There is no available standard therapy that can cure the disease.
To find out what other eligibility criteria apply for patients to participate in the study, please read the section “Who is the study suitable for?”.
RATIONALE stands for the study title “Randomized Comparison of a Therapy Guided by Comprehensive Genomic and Transcriptomic Analysis with Standard Treatment in Patients with Advanced Rare Cancers”.
This means that researchers are investigating whether a treatment tailored to the characteristics of the tumor is more effective than the current standard of care.
To do this, they are using modern testing methods that allow researchers to examine the genetic information and activity of tumor cells.
Objectives of the RATIONALE Study
The scientists involved in the study aim to determine:
- Whether patients receiving treatment tailored to their individual tumor survive longer without the disease progressing than those receiving the current standard of care.
- Whether the disease worsens less rapidly in patients receiving treatment tailored to their individual tumor than in those receiving the current standard of care.
Who is the study suitable for?
Patients can participate in the study if all the following criteria are met:
- The participant is 18 years of age or older.
- The participant has a rare carcinoma or sarcoma.
- The participant’s cancer has already spread extensively into surrounding tissue and/or formed metastases. Treatment aimed at a cure is no longer possible.
- The disease is progressing or is expected to progress. This is assessed using appropriate biological markers (biomarkers), laboratory test results, and further examinations.
- The participant has already received at least one standard therapy for advanced disease. Exception: No such treatment is available.
- There is at least one detectable tumor that has already been reliably measured using computed tomography, CT or magnetic resonance imaging, MRI. In addition, the tumor should be oriented spatially so that future images can be easily compared.
- It is possible to perform a biopsy of the tumor as part of the study following a specified procedure. Alternatively, existing samples may be used. These samples must have been collected no more than 3 months prior to enrollment in the study.
- Complete information is available regarding all previous treatments. This includes, among other things, how well the tumor has responded to previous therapies, when the tumor progressed during these treatments, and the dosages and scheduling of the medications administered.
- The patient is willing and able to participate in the treatment proposed in the study.
- The participants’ health is not significantly impaired: Experts rate their performance status according to the ECOG (Eastern Cooperative Oncology Group) as 2 or less.
- The participant understands what the study is about and the risks that may arise from it.
Patients cannot participate in the study if at least one of the following applies:
- The patient has dementia or has difficulty thinking, remembering, or understanding.
- The patient has epilepsy and must take medication for it.
- The patient has already received a bone marrow transplant using donor cells or an organ transplant.
- The patient has blood cancer or a brain tumor.
- Comprehensive molecular genetic testing has already been performed.
- The patient has metastases in the brain or spinal cord that are causing symptoms or are not responding to treatment. Patients with successfully treated metastases in the brain or spinal cord may participate under certain conditions.
- The patient had another type of cancer within 5 years prior to the start of the study (except for: successfully treated non-melanoma skin cancer, successfully treated in situ tumors of the cervix or breast, or similar tumors considered very likely to be cured).
- There is or has been bleeding in the brain or spinal cord. Patients can find out at the study center in which medical situations they may still be eligible to participate.
- The patient has a severe cardiovascular disease.
- The patient has liver cirrhosis.
- The patient has a neurological or psychiatric disorder and is therefore unable to decide for themselves whether to participate in the study.
- There is (suspected) abuse of alcohol, drugs, or medications.
- Patients for whom standard treatment options remain available or who cannot immediately start off-label use.
- The participant is unable to swallow medication.
The RATIONALE study is a:
- Diagnostic study: Researchers are investigating the value of a new diagnostic procedure. For example, to determine whether the method provides better, less invasive, or more accurate results.
- Multicenter study: Patients can participate at all NCT study centers in Germany.
- Two-arm study: The study compares two groups of participants with each other.
- Randomized study: In a randomized study, participants are assigned to groups at random. This allows the results to be evaluated as objectively as possible.
(1) Consultation and Informed Consent
Once a patient has registered, an initial consultation takes place at the study center.
During this session, the study physician will provide the participant with detailed information about the study and any potential risks. If the person wishes to participate, they must submit a signed informed consent form. Signing this form does not mean that the patient will be able to participate in the study. First, the physicians must determine whether the patient is eligible for the study.
(2) Preliminary Screening for Eligibility
To determine whether participants are suitable for the study, they will undergo a thorough physical examination. Imaging tests, such as CT or MRI scans, may also be necessary.
The doctors will also need the following additional information:
- personal details (age, gender, ethnicity, etc.),
- current medical history, including all relevant findings and information about previous treatments,
- information about past illnesses and comorbidities,
- information on any functional limitations the so-called ECOG status
- information on current and past medications and treatments and the patient’s responses to them,
- information on health-related quality of life.
The study physicians can decide whether the patient is suitable for the study by evaluating the provided information.
(3) Sample Collection
For the examinations, the researchers need tumor cells, and, for comparison, healthy cells from the patient. They obtain this material through a blood draw and a biopsy.
Sometimes, appropriate tissue samples are already available, in which case a biopsy is unnecessary.
(4) Molecular Diagnostics
In the laboratory, the researchers perform various tests on the samples. These include:
- A genetic analysis of the entire genome (Whole Genome Sequencing, WGS).
- An analysis of total RNA, which ensures that the DNA’s blueprints are translated into proteins (RNA sequencing).
Using samples from the first 200 eligible participants, the researchers are conducting further analyses:
- Analysis of the proteins in the cell and how they are activated (phospho-)proteomic analysis).
- Analysis of which cells and signaling molecules are present in the immediate vicinity of the tumor (tumor microenvironment).
- Testing drugs on tumor cells.
Through this, the researchers hope to gain new insights. For example, into:
- regulatory processes that influence gene activity (DNA methylation).
- new biomarkers to predict who will respond to a specific therapy.
Using bioinformatics methods, the researchers interpret the data they have collected. This provides them with information about:
- the individual changes in the tumor of the affected study participant.
- potential targets within the tumor cells and suitable drugs to target them. This allows for a better assessment of a therapy’s chances of success.
It takes about 4 weeks to analyze the samples.
(5) Treatment
First, participants are randomly assigned to two groups of equal size:
- Test group: Patients in the test group receive a treatment recommendation based on molecular analysis.
- Control group: Patients in the control group initially receive the current standard of care. If the disease progresses despite receiving the standard therapy, the patients in the control group will also receive a treatment recommendation based on molecular analysis.
(6) Follow-up Appointments
Follow-up examinations are conducted every 3 months for all participants. During these visits, the doctors assess whether the treatment is effective or whether the disease is progressing.
As part of these examinations, the researchers will also decide whether participants in the control arm should receive a targeted treatment recommendation.
The total duration of the study is up to 4 years.
These are the potential benefits of participating in the RATIONALE study:
- The patient`s individual disease situation will be discussed and analyzed by experts.
- The results of the molecular tests may lead to new treatment approaches for the patient’s cancer.
- The proposed treatment could be more effective than previous treatments or the treatments that would have been offered to participants without these analyses. It could also have fewer side effects.
- Further laboratory tests may reveal genetic changes. These can indicate a higher risk for certain types of cancer—including within the family. If participants wish to be informed of this, they can indicate so in the informed consent form. If an increased risk is indeed present, they and their family members can seek genetic counseling and potentially take preventive measures.
However, participating in the RATIONALE study may also have some drawbacks:
- The necessary examinations may involve some discomfort or potential risks, for example, from blood draws, tissue biopsies, MRI or CT scans, or other medical tests.
- Further laboratory tests may reveal genetic mutations. These could indicate a higher risk for certain types of cancer. Participants will then be informed of future health risks, which may also apply to family members. However, participants may choose not to be informed of such test results. Participation in the study is still possible in this case.
- Despite comprehensive data protection and high data security, there is a small residual risk that the genetic data could be traced back to the participant if this data falls into the wrong hands.
Where is the study being conducted?
Cancer patients can participate in the RATIONALE study at all Comprehensive Cancer Centers or clinics affiliated with the NCT.
What costs will participants incur?
Participation in the trial is free of charge for patients. However, you will not receive any compensation for your time or expenses. Travel expenses are not reimbursed as part of the trial. All examinations conducted as part of the trial are free of charge.
Patients can ask the study team questions about the study’s funding, for example, during the informational meeting.
How many participants will the study accept? Are there still places available?
A total of up to 946 patients can participate in the study.
Recruitment is currently open. This means the study is still accepting participants and is expected to until at least 2028.
In principle, any oncologist can enroll patients in RATIONALE.
Cancer patients interested in participating should first discuss with their treating physician whether they are generally eligible for the study. If applicable, the physician will contact the study center at the nearest NCT site. There, the patient’s medical records will be reviewed. If participation is possible, the patient will be given an appointment at the appropriate study center for an informational consultation.
Scientific Publications (Selection)
Horak P, Heining C, Kreutzfeldt S, Hutter B, Mock A, Hüllein J, Fröhlich M, Uhrig S, Jahn A, Rump A, et al. Comprehensive genomic and transcriptomic analysis to guide therapeutic decisions in patients with rare cancers. Cancer Discov. November 2021;11(11):2780-2795. doi: 10.1158/2159-8290.CD-21-0126.
van der Graaf WTA, Tesselaar MET, McVeigh TP, Oyen WJG, Fröhling S. Biology-guided precision medicine in rare cancers: Lessons from sarcomas and neuroendocrine tumors. Semin Cancer Biol. 2022 Sep;84:228-241. doi: 10.1016/j.semcancer.2022.05.011.
Jahn A, Rump A, Widmann TJ, Heining C, Horak P, Hutter B, Paramasivam N, Uhrig S, Gieldon L, Drukewitz S, et al. Comprehensive cancer predisposition testing within the -prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers. Ann Oncol. 2022;33(11):1186-1199. doi: 10.1016/j.annonc.2022.07.008.
This study description was prepared by authors from the Cancer Information Service, under the direction of Dr. S. Weg-Remers, based on the study documentation.