Whole-genome and transcriptome sequencing of patients with advanced solid tumors enrolled in the NCT/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program revealed genetic alterations in a substantial proportion of patients including (i) alterations that lead to aberrant activation of BRAF, ERBB2, ALK, and the PI3K-AKT and MAPK pathways and (ii) changes that predict sensitivity to immune checkpoint inhibition, such as high tumor mutational burden and specific alterations of the PD-L1 locus. Within this seven-arm basket phase II clinical trial, we aim to investigate the efficacy of targeted-therapy plus immune checkpoint inhibition in patients with advanced tumors exhibiting one of the following genetic alterations detected within the NCT/DKTK MASTER study: (i) BRAF V600E/K, (ii)ERBB2 amplification and/or overexpression or activating ERBB2 mutation, (iii) ALK rearrangement or activating ALK mutation, (iv) activating PIK3CA or AKT mutations or other aberration predicting increased PI3K-AKT pathway activity, (v) abberations predicting increased RAF-MEK-ERK pathway activity; (vi) patients with high tumor mutational burden and/or specific alteration predicting sensitivity to PD-1/PD-L1 inhibition are eligible within this study for immune checkpoint inhibition. Recruitment of adequate patient numbers into these well-defined molecular subgroup is achieved in a multicenter approach including NCT Heidelberg and NCT Dresden as well as DKTK partner sites. Eligible patients will be identified by in-depth molecular characterization of tumors within the NCT/DKTK MASTER program. All study arms are based on similar biometrical assumptions, and sample size as well as power calculations are based on Simon's optimal two-stage design for each study arm separately. The overall aim is to reduce the cumulative hazard of progression-free survival observed within the study (PFS2) compared to the cumulative hazard of the progression-free time before inclusion into the study (PFS1) using a paired log-rank test. The sample size of the entire trial varies according to the performance of the individual study arms, ranging between 98 and 175 patients.
Name: Vemurafenib
Name: Cobimetinib
Name: Atezolizumab
Name: Trastuzumab
Name: Pertuzumab
Name: Alectinib
Name: Ipatasertib
Name: Cobimetinib
Name: Atezolizumab
Name: Atezolizumab
Name: Atezolizumab
Name: Ipatasertib
Name: Atezolizumab
Name: Atezolizumab
Description: Primary endpoint of the study is to DCR according to RECIST v1.1 including complete response (CR), partial response (PR) and stable disease (SD).
Measure: Disease Control Rate Time: Day 110 (+/- 5 days)Description: Paired Progression-free Survival 2 (PFS2) and Progression-free Survival 1 (PFS1)
Measure: Progression-free survival Time: 24 months (median)Allocation: Non-Randomized
Parallel Assignment
There is one SNP
Within this seven-arm basket phase II clinical trial, we aim to investigate the efficacy of targeted-therapy plus immune checkpoint inhibition in patients with advanced tumors exhibiting one of the following genetic alterations detected within the NCT/DKTK MASTER study: (i) BRAF V600E/K, (ii)ERBB2 amplification and/or overexpression or activating ERBB2 mutation, (iii) ALK rearrangement or activating ALK mutation, (iv) activating PIK3CA or AKT mutations or other aberration predicting increased PI3K-AKT pathway activity, (v) abberations predicting increased RAF-MEK-ERK pathway activity; (vi) patients with high tumor mutational burden and/or specific alteration predicting sensitivity to PD-1/PD-L1 inhibition are eligible within this study for immune checkpoint inhibition. --- V600E ---
- Arm 1 (BRAF V600E/K): BRAF V600E/K mutation - Arm 2 (ERBB2): ERBB2 amplification/overexpression, activating ERBB2 mutation - Arm 3 (ALK): ALK rearrangement or activating ALK mutations including alternative transcription initiation (ALK-ATI) or RET-fusions - Arm 4 (PI3K-AKT): Activating PIK3CA or AKT mutations; other aberrations predicting increased PI3K-AKT pathway activity, e.g. --- V600E ---
- Arm 1 (BRAF V600E/K): BRAF V600E/K mutation - Arm 2 (ERBB2): ERBB2 amplification/overexpression, activating ERBB2 mutation - Arm 3 (ALK): ALK rearrangement or activating ALK mutations including alternative transcription initiation (ALK-ATI) or RET-fusions - Arm 4 (PI3K-AKT): Activating PIK3CA or AKT mutations; other aberrations predicting increased PI3K-AKT pathway activity, e.g. --- V600E --- --- V600E ---
PTEN lossa - Arm 6 (MAPK): Aberrations other than BRAF V600E/K predicting increased RAF-MEK- ERK pathway activity - Arm 7 (Immune evasion): High tumor mutational burden and/or specific alterations predicting sensitivity to PD1/PDL1 inhibition (e.g. --- V600E ---