Using genome and RNA analysis to guide treatment for advanced rare cancers

Randomized Comparison of Treatment Guided by Comprehensive Genome and Transcriptome Analysis Versus Standard of Care in Patients With Advanced Rare Cancers (RATIONALE)

This project will test whether using detailed tumor DNA, RNA and methylation analyses to guide treatment helps adults with advanced rare cancers respond better than standard care.

Quick facts

• Study type: Observational
• Enrollment: 946 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: German Cancer Research Center (other)
• Locations: 16 sites (Augsburg and 15 other locations)
• Trial ID: NCT06855134 on ClinicalTrials.gov

What this trial studies

This program uses comprehensive tumor profiling — whole-genome/exome sequencing, RNA sequencing and genome-wide DNA methylation — to generate molecularly informed treatment recommendations reviewed by a molecular tumor board. Eligible adults with locally advanced or metastatic rare epithelial or mesenchymal cancers provide a fresh biopsy or recent frozen tumor sample and clinical data. The molecular recommendations are used to guide treatment choices and patient outcomes such as response and disease control are tracked and compared to standard care outcomes. The approach builds on the DKFZ/NCT/DKTK MASTER workflow and aims to expand personalized options for patients who have progressed after at least one standard therapy.

Who should consider this trial

Good fit: Adults (≥18) with locally advanced or metastatic rare epithelial or mesenchymal cancers, ECOG performance status ≤2, progressive disease after at least one standard therapy (or no standard options), and able to provide a fresh biopsy or a recent frozen tumor sample are ideal candidates.

Not a fit: Patients who cannot provide sufficient tumor tissue, have poor performance status (ECOG >2), or whose tumors lack actionable alterations are less likely to benefit from this approach.

Why it matters

Potential benefit: If successful, this approach could offer more personalized treatment options and improve response and disease control for patients with advanced rare cancers.

How similar studies have performed: Related programs such as the DKFZ/NCT/DKTK MASTER initiative have reported improved outcomes (about 24% overall response rate and 55% disease control rate) with molecularly guided therapies, though randomized comparisons remain limited.

Eligibility criteria

Inclusion Criteria:

* Age ≥ 18years, no upper age limit
* Patients with locally advanced and/or metastatic rare epithelial or mesenchymal cancer (equal numbers of patients) without curative treatment option
* Progressive disease or expected progression of the disease estimated by clinical parameters, suitable biomarkers, and other (e.g. radiographic) methods \* At least one measurable lesion that has been accurately assessed by computed tomography (CT) or magnetic resonance imaging (MRI) at baseline and is amenable to repeat evaluation in MRI/CT images
* Patients must have received at least one standard therapy for advanced disease according to current guidelines or consensus recommendations or have no standard therapy available
* Possibility to perform fresh tumor biopsy according to local SOPs or Availability of fresh frozen tumor samples with sufficient tumor cell content collected within 3 months prior to enrolment
* ECOG PS ≤ 2.
* Ability of patient to understand character and consequences of the clinical trial
* Patient must be willing and able to undergo subsequent treatment (e.g. in a clinical trial) with molecularly guided therapy according to the MTB recommendation
* Availability of complete information about all medical treatment given before study participation, i.e. remission status before start of treatment, dosage and timing of drugs applied, remission status and date of progression after treatment

Exclusion Criteria:

* Dementia or significant cognitive impairment
* Epilepsy requiring pharmacologic treatment
* Prior allogeneic bone marrow or solid organ transplantation
* Hematological malignancies and primary brain tumors.
* Prior comprehensive molecular profiling by WGS, WES, RNA-Seq, or large targeted panels.
* Patients with symptomatic or uncontrolled brain metastases and patients with symptomatic or uncontrolled spinal cord compression. Patients with previously treated brain metastases are eligible, provided that the patient has neither experienced a seizure nor had a clinically significant change in neurological status within the three months prior to enrollment. All patients with previously treated brain metastases must be clinically stable for at least 1 month after completion of treatment and off steroid treatment for one month, both prior to study enrollment.
* Malignancy other than study indication within the last 5 years except: curatively treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma, low-risk prostate cancer, or other malignancies curatively treated with no evidence of disease for ≥5 years.
* History of intracranial hemorrhage or spinal cord haemorrhage; no ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted
* Known uncontrolled or significant cardiovascular disease, including any of the following:
* History of heart failure NYHA class 3 or 4
* History of uncontrolled angina pectoris, arrhythmias, or myocardial infarction within 12 months prior to screening.
* History of liver cirrhosis
* Neurologic or psychiatric disorder interfering with ability of giving informed consent.
* Known or suspected active alcohol or drug abuse.
* Patients with inability to receive oral medications.
* Failure to provide consent for the registration, storage, and processing of individual disease characteristics and clinical course, as well as for informing the primary care physician about the participant's involvement in the study.

Where this trial is running

Augsburg and 15 other locations

• Universitätsklinikum Augsburg — Augsburg, Germany (RECRUITING)
• Charité Berlin — Berlin, Germany (RECRUITING)
• Universitäts-Klinikum Köln — Cologne, Germany (RECRUITING)
• Medizinische Fakultät der TU Dresden — Dresden, Germany (RECRUITING)
• Uniklinikum Erlangen — Erlangen, Germany (RECRUITING)
• Universitätsmedizin Essen — Essen, Germany (NOT_YET_RECRUITING)
• Universitätsklinikum Freiburg, Tumorzentrum Freiburg - CCCF — Freiburg im Breisgau, Germany (NOT_YET_RECRUITING)
• Universitätsklinikum Hamburg-Eppendorf (UKE) — Hamburg, Germany (NOT_YET_RECRUITING)
• Universitätsklinikum Heidelberg — Heidelberg, Germany (RECRUITING)
• Universitätsmedizin der Johannes Gutenberg- Universität Mainz — Mainz, Germany (NOT_YET_RECRUITING)
• Comprehensive Cancer Center , LMU München — München, Germany (NOT_YET_RECRUITING)
• Comprehensive Cancer Center Ostbayern (CCCO) Universitätsklinikum Regensburg, — Regensburg, Germany (RECRUITING)
• Robert Bosch Krankenhaus Stuttgart — Stuttgart, Germany (RECRUITING)
• Universitätsklinikum Tübingen — Tübingen, Germany (RECRUITING)
• Universitätsklinikum Ulm — Ulm, Germany (RECRUITING)
• Universitätsklinium Würzburg — Würzburg, Germany (RECRUITING)

Study contacts

• Principal investigator: Stefan Fröhling, MD — German Cancer Research Center
• Study coordinator: CTC-NCT Heidelberg Trial Management and Services

Conditions: Rare Cancer, Molecular tumor board, molecularly informed treatment recommendation