CRAFT: The NCT-PMO-1602 Phase II Trial

Summary

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 mutations or amplification of AKT, loss of PTEN, (v) activating PIK3CA mutations, (vi) abberations predicting increased RAF-MEK-ERK pathway activity; (vii) 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 subgroups 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.

Conditions

• Metastatic or Locally Advanced Malignancies

Interventions

DRUG

Vemurafenib

960 mg twice daily during run-in Phase, followed by 720 mg twice daily

DRUG

Cobimetinib

60 mg once daily

DRUG

Atezolizumab

840 mg every 2 weeks

DRUG

Trastuzumab

8 mg per kilogram of body weight as a loading dose, followed by 6 mg per kilogram every 3 weeks

DRUG

Pertuzumab

840 mg as a loading dose, followed by 420 mg intravenously every 3 weeks

DRUG

Alectinib

600 mg twice daily

DRUG

Ipatasertib

400 mg once daily

DRUG

Atezolizumab

1200 mg every 3 weeks

DRUG

Atezolizumab

1200 mg in the first cycle, followed by 840 mg every 3 weeks

DRUG

Atezolizumab

1,200 mg every 3 weeks

DRUG

Inavolisib

9 mg once daily

Sponsors & Collaborators

• German Cancer Research Center

  lead OTHER

Principal Investigators

• Richard Schlenk, Prof. Dr. · NCT Studienzentrale

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2021-10-13

Primary Completion

2024-12-30

Completion

2024-12-30

Countries

• Germany

Study Locations