Clinical trials

Rare cancers, defined by an incidence of fewer than 6 cases per 100,000 persons per year, constitute nearly 25% of adult malignancies. They are associated with poor patient outcomes due to incomplete biological understanding and inadequate representation in clinical trials. To address this gap, the DKFZ/NCT/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program, developed by NCT and DKFZ, integrates whole-genome/exome sequencing (WGS/WES), RNA sequencing (RNA-seq), and genome-wide DNA methylation profiling to inform clinical decision-making in patients with advanced rare cancers. This approach has demonstrated significant improvements in overall response rates (ORR) in 24% and disease control rates (DCR) in 55% of cases, with a progression-free survival (PFS) ratio greater than 1.3 in 36% of patients. The randomized, multi-basket, phase II, Italian multicenter ROME study conducted among pretreated patients with metastatic cancer, demonstrated that targeted therapy guided by comprehensive genomic profiling and molecular tumor board (MTB) recommendations significantly improved overall response rate and progression-free survival. Additionally, the study revealed a substantial long-term PFS benefit extending to 12 months and beyond. Although the toxicity profiles differed between the targeted therapy and standard-of-care groups, the incidence of adverse events was comparable. These findings, reported at the ESMO Congress 2024, emphasize the pivotal role of MTBs in advancing precision oncology through a tumor agnostic, molecularly guided therapeutic approach. The objective of the randomized, multicentric, diagnostic RATIONALE trial is to evaluate the efficacy of molecularly guided treatment versus standard treatment in patients with rare cancers by comparing progression-free survival (PFS) between the two arms: an immediate molecular profile-informed treatment arm (MPI arm) and a standard treatment arm with molecular profile-informed treatment upon progression or intolerable toxicity after standard therapy (MPP arm). Patients with rare epithelial and mesenchymal neoplasms are evenly randomized in a 1:1 ratio to either the MPl arm or MPP arm. Comprehensive molecular profiling includes WGS and RNA-seq for both arms. A multidisciplinary MTB evaluates these molecular profiles and provides clinically relevant management recommendations, including diagnostic reevaluation, genetic counseling, and molecularly informed treatment options. Recommendations may include matching patients to molecularly stratified clinical trials or - if no suitable clinical trials can be identified - coordinated applications will be provided for off-label use in routine clinical care. The primary efficacy endpoint is progression-free survival (PFS), whereas secondary endpoints are overall survival (OS), overall response rate (ORR), disease control rate (DCR) after three and six months, and patient-reported outcomes (PROs). Based on data from the MASTER cohort, it is anticipated a median PFS of three months with treatment selected by the physician's discretion. Drawing on findings from the CRAFT trial (ClinicalTrials.gov: NCT04551521), MTB-guided treatment is expected to positively impact the primary endpoint with a hazard ratio (HR) ranging from 0.4 to 0.6. Assuming 30% implementation rate of MTB recommendations, a sample size of 756 eligible patients will be required to demonstrate a significant improvement in PFS with immediate MTB guided treatment, yielding an HR of 0.5 for the MPI arm and overall study HR of 0.7862. The calculation is based on a type 1 error of 5% and a statistical power of 90%. Considering a conservative estimate that that 20% of patients will not be evaluable, the total rounded required sample size is 946 patients.

CATCH is an indication-specific diagnostic platform, which drives the implementation of integrative, genomic profiling for metastatic breast cancer into the clinics. The main objective of this approach is to identify biomarkers and drug targets to guide targeted therapeutic interventions. Eligible are all metastatic breast cancer patients (independent of gender), irrespective of molecular subtype. At initial diagnosis of distant metastasis or progress at disease progression, biopsy samples from a prognostic-relevant metastasis are retrieved during standard-of-care procedures for central analyses, together with blood samples. In parallel to all standard-diagnostic measures, genomic and transcriptomic profiling is conducted to infer the underlying biology of the disease and identify patients who might profit from biomarker-guided interventions in clinical trials. Samples not required for standard-of-care clinical procedures or genomic profiling are systematically collected in a dedicated bio-repository to fuel translational scientific companion programs. The continuously growing comprehensive database serves as an integrative resource for systematic, prospective multidimensional data collection (clinical records, biomaterial, genomic data). In summary, the overarching goal is to generate a precision oncology platform to i) identify clinically-actionable biomarkers and drug targets that drive genomics-guided therapies and ii) couple the observational, diagnostic registry platform to an increasing number of independent, biomarker-stratified clinical therapy trials (CATCH-GUIDE).

First-in-human, phase I, single-center, open-label, dose-escalation trial in healthy volunteers. Investigation of safety and tolerability of ascending doses of PANHPVAX, a vaccine against human papilloma L2 antigens formulated with cdA (adjuvant) as compared to the formulation without cdA.

This trial is a first in human (FIH) clinical trial in patients with Colorectal cancer (CRC) after failure of at least three lines of previous therapy aiming to evaluate safety and efficacy of CC-3, a bispecific antibody (bsAb) with CD276xCD3 specificity developed within DKTK. CC-3 binds to CD276 on cancer cells as well as to tumor vessels of CRC, thereby allowing for a dual mode of anti-cancer action. CC-3 was developed in a novel format which not only prolongs serum half-life, but most importantly reduces off-target T cell activation with expected fewer side effects. A similar construct in this format with PSMAxCD3 specificity is presently undergoing clinical evaluation in patients with prostate cancer (NCT04104607), with very favorable safety and preliminary efficacy. The optimized format that CC-3 shares with its PSMAxCD3 "sister molecule" allows for application of effective bsAb doses with expected high anticancer activity. The clinical trial comprises two phases: The first phase is a dose-escalation part to evaluate the maximally tolerated dose (MTD) of CC-3. This is followed by a dose-expansion part to defined the recommended phase II dose. A translational research program comprising, among others, analysis of CC-3 half-life and the induced immune response will serve to better define the mode of action of CC-3.

In early breast cancer (eBC), pathological complete response (pCR) after neoadjuvant therapy acts as surrogate marker for metastasis and overall survival. Therapy intensification by adding an adjuvant therapy line (post-neoadjuvant treatment) substantially lowers the risk of relapse in high-risk breast cancer patients with residual disease after neoadjuvant treatment (non-pCR). While this approach was exemplified in two phase III trials without biomarker-stratification (CREATE-X, KATHERINE), even higher efficiency might be achieved by individualized genomic-guided post-neoadjuvant therapies. Within the seven-arm umbrella phase-II clinical trial COGNITION-GUIDE, we aim to deliver molecularly-tailored cancer care by implementing an additional response- and genomics-guided post-neoadjuvant therapy after finishing the guideline-compliant post-neoadjuvant treatment in high-risk breast cancer patients with residual cancer burden after neoadjuvant therapy to reduce the substantial risk of local and distant relapse. The trial evaluates not a single drug but rather a general strategy of precision oncology in the curative setting and provides the basis for future confirmatory biomarker-driven trials. Allocation to the therapy-arms is conducted by in depth molecular characterization of tumors within the COGNITION registry program. The study aims to show an overall benefit of the precision medicine approach in high-risk eBC patients and to allow for secondary exploratory evaluation of each study-arm. The primary endpoint of the study is invasive Disease-Free Survival (IDFS) after 4 years measured from surgery to local or distant relapse or death. The sample size of the entire trial is 240 eligible patients.

The COGNITION diagnostic platform elucidates the biomarker profile of neoadjuvant chemotherapy-resistant residual bulk tumors in high risk early breast cancer patients. The major goal is to provide a framework for genomic profiling, which serves as infrastructure for systematic biomarker-screening and -stratification for concise therapy-arm allocation in the interventional clinical phase II trial COGNITION-GUIDE (NCT05332561). In patients, who display a poor response to standard-of-care neoadjuvant chemotherapy, tissue samples before and after neoadjuvant therapy are subjected together with blood samples to comprehensive genomic profiling to identify patients potentially benefiting from biomarker-guided interventions in COGNITION-GUIDE. Samples not required for standard-of-care clinical procedures or genomic profiling are systematically collected in a dedicated bio-repository to fuel translational scientific companion programs. The continuously growing comprehensive database serves as an integrative resource for systematic, prospective multidimensional data collection (clinical records, biomaterial, genomic data). In summary, the overarching goal is to generate a precision oncology platform i) to identify clinically-actionable biomarkers and drug targets that drive genomics-guided therapies and ii) to couple the observational, diagnostic registry platform to the independent, biomarker-stratified clinical therapy trial COGNITION-GUIDE.

The study "GALAXY33" is an open-label, prospective, nonrandomized, one arm phase I clinical trial in which patients with relapsed AML after allogeneic hematopoietic stem cell transplantation will be transplanted with CD33-deleted CD34+ HSC derived from the initially matched family donor.

NCT/DKFZ/DKTK MASTER is a prospective, continuously recruiting, multicenter observational study for biology-guided stratification of adults with rare cancers, including rare subtypes of common entities, using comprehensive molecular profiling, and clinical decision-making in a multidisciplinary molecular tumor board.

The goal of this study is to develop supportive diagnostic artificial intelligence algorithms to distinguish melanoma from nevi or other benign pigmented skin lesions, especially in younger patients (below the age of 30). The main goals it aims to achieve are: * development of an algorithm based on dermatoscopic images, targeting skin cancer screening in vulnerable populations * development of another algorithm based on histological images, intended to be used by pathologists on lesions that are still suspicious of melanoma after dermatologic assessment * implementation of explainability methods to enable the user to better comprehend the systems' decisions, avoid biases and increase trust in these applications There is no additional time commitment for the study participants for this study, as the data used in this project will be collected in routine clinical practice anyway.

Therapy resistance remains the major obstacle to cure in many types of cancer. In particular in leukemia, therapy resistance depends on leukemic stem cells (LSC) that exhibit inherent therapy resistance to multiple drugs and contribute to overt leukemic relapse. Cellular therapies alone or in combination with other targeted or chemotherapeutic approaches can overcome drug mediated therapy resistance and induce long lasting remissions. Several trials have shown that adoptive transfer of allogeneic NK cells can induce clinical remission in patients with myeloid malignancies. In addition, the antileukemic efficacy of alloreactive NK cells has been shown to facilitate cure after T cell depleted haploidentical stem cell transplantation. Recently, it was demonstrated that absence of NKGD2 ligand expression on leukemic stem cells determines therapy resistance and immune escape towards NK cells in AML. PARP1 inhibitors can induce re-expression of NKG2D ligands. This phase I/II clinical trial will evaluate the combination of NK cell therapy and PARP inhibition by Talazoparib in patients with poor prognosis AML as characterized by Minimal Residual Disease (MRD) or overt relapse with less than 20% bone marrow blasts. The hypothesis that allogeneic NK cell therapy combined with PARP inhibition will increase the response rate (CR/CRi for relapsed/ refractory patients and MRD-response for MRD positive patients) from 35% to 60% will be tested. The co-primary endpoints are i) response to treatment defined as complete remission (CR) for patients with overt leukemia at time of inclusion and MRD decrease \>1log10 for patients with rising MRD at time of inclusion as well as ii) safety and feasibility of the protocol. Key secondary endpoints are event free survival and overall survival. Two cohorts will be assessed independently: patients with i) overt leukemia and ii) patients with rising MRD at time of inclusion. Safety and feasibility will be analyzed continuously during the entire trial. The NAKIP-AML trial will analyze efficacy and feasibility of NK cell transplantation together with PARP1 inhibition.

This randomized, controlled clinical trial compares the perioperative treatment with acetylsalicylic acid (aspirin) in patients with cancer of the pancreatic head. The main question it aims to answer is: Do patients treated perioperatively with aspirin develop less metastasis after curative resection of pancreatic head tumors? Participants will be asked to : * take a daily aspirin tablet starting 1-4 weeks before surgery until 6 months after surgery * participate in regular follow-up visits.