CRAFT: The NCT-PMO-1602 Phase II Trial

NCT04551521 | Completed Phase 2 DMC

• 1 other identifier: NCT-PMO-1602
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 9

Brief 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

Outcome Measures

Primary Outcomes (1)

• Disease Control Rate

  Primary endpoint of the study is to DCR according to RECIST v1.1 including complete response (CR), partial response (PR) and stable disease (SD).

  Day 110 (+/- 5 days)

Secondary Outcomes (1)

• Progression-free survival

  24 months (median)

Study Arms (7)

BRAF V600E/K

EXPERIMENTAL

Drug: Vemurafenib; Drug: Cobimetinib; Drug: Atezolizumab

ERBB2

EXPERIMENTAL

Drug: Trastuzumab; Drug: Pertuzumab; Drug: Atezolizumab

ALK

EXPERIMENTAL

Drug: Alectinib

AKT/PTEN

EXPERIMENTAL

Recruitment stopped

Drug: Ipatasertib; Drug: Atezolizumab

PI3K

EXPERIMENTAL

Recruitment stopped

Drug: Inavolisib

MAPK

EXPERIMENTAL

Drug: Cobimetinib; Drug: Atezolizumab

Immune evasion

EXPERIMENTAL

Drug: Atezolizumab

Interventions

Vemurafenib DRUG

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

BRAF V600E/K

Cobimetinib DRUG

60 mg once daily

BRAF V600E/K; MAPK

Atezolizumab DRUG

840 mg every 2 weeks

BRAF V600E/K; MAPK

Trastuzumab DRUG

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

ERBB2

Pertuzumab DRUG

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

ERBB2

Alectinib DRUG

600 mg twice daily

ALK

Ipatasertib DRUG

400 mg once daily

AKT/PTEN

Inavolisib DRUG

9 mg once daily

PI3K

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of written informed consent
• Ability of patient to understand and comply with the protocol for the duration of the study, including treatment and scheduled visits and examinations
• Diagnosis of a metastatic or locally advanced malignancy
• Progressive disease
• At least one measurable lesion that can be accurately assessed at baseline by computed tomography or magnetic resonance imaging and is suitable for repeated assessment
• Prior administration of at least one standard chemotherapy for primary and/or relapsed malignancy according to current guidelines. Patients must have received standard therapy or have no standard therapy available. Or, in the opinion of investigator have been considered ineligible for a particular form of standard therapy on medical reasons.
• ECOG Performance Status ≤2
• Age ≥18 years, no upper age limit
• Postmenopausal or evidence of non-childbearing status.
• Female patients of childbearing potential and male patients with partners of childbearing potential who are sexually active must agree to the use of two highly effective forms of contraception. These should be started immediately after signing the informed consent form and continued throughout the period of study treatment plus at least seven months for both sexes after taking the last dose of study drug.
• Availability of complete information about the last medical treatment given before study participation, i.e. remission status before start of treatment, dosage and timing of drugs applicated, remission status and date of progression after treatment (in order to calculate PFS 1)
• 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 (AKT/PTEN): Activating AKT1/2/3 mutations or amplifications; PTEN loss

You may not qualify if:

• Other malignancy except for study indication within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma, or other malignancies curatively treated with no evidence of disease for ≥5 years
• Concurrent or previous treatment within 30 days prior to C1D1 in another interventional clinical trial with an investigational anticancer therapy
• Persistent toxicity (≥Grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0) caused by previous cancer therapy, excluding alopecia
• Clinical signs of active infection (\>Grade 2 according to CTCAE version 5.0)
• History of human immunodeficiency virus (HIV) infection and immunocompromised patients
• Active Hepatitis A virus infection
• Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface antigen (HBsAg) test at baseline patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at baseline , are eligible for the study if active HBV infection is ruled out on the basis of HBV DNA viral load per local guidelines
• Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at baseline confirmed by a polymerase chain reaction (PCR) positive for HCV RNA
• Dementia or significant impairment of cognitive state
• Epilepsy requiring pharmacologic treatment
• Pregnancy or breastfeeding
• Inability to take oral medication orgastrointestinal disorders likely to interfere with absorption of the study medication (except Arm 2 and Arm 7)
• Major surgery within four weeks of starting study treatment
• Systemic chemotherapy or radiotherapy within two weeks prior to start of study treatment or a longer period depending on the characteristics of the agents used (at least five-half lives)
• Heart failure New York Heart Association (NYHA) II/III/IV

Sponsors & Collaborators

• German Cancer Research Center: lead

Study Sites (9)

Charité - Universitätsmedizin Berlin

Berlin, 12203, Germany

Location

Nationales Centrum für Tumorerkrankungen (NCT)

Dresden, 01307, Germany

Location

Universitätsklinikum Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Nationales Centrum für Tumorerkrankungen (NCT)

Heidelberg, 69120, Germany

Location

Universitätsklinikum Schleswig-Holstein

Lübeck, 23538, Germany

Location

Universitätsmedizin der Johannes Gutenberg- Universität Mainz

Mainz, 55131, Germany

Location

Klinikum Rechts der Isar der TU München

München, 81675, Germany

Location

Universitätsklinikum Tübingen, Medizinische Klinik I

Tübingen, 72076, Germany

Location

Universitätsklinikum Würzburg, Interdisziplinäres Studienzentrum mit ECTU

Würzburg, 97080, Germany

Location

Related Publications (1)

• Heilig CE, Horak P, Kreutzfeldt S, Teleanu V, Mock A, Renner M, Bhatti IA, Hutter B, Hullein J, Frohlich M, Uhrig S, Susse H, Heiligenthal L, Ochsenreither S, Illert AL, Vogel A, Desuki A, Heinemann V, Heidegger S, Bitzer M, Scheytt M, Brors B, Hubschmann D, Baretton G, Stenzinger A, Steindorf K, Benner A, Jager D, Heining C, Glimm H, Frohling S, Schlenk RF. Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter phase II trial. ESMO Open. 2021 Dec;6(6):100310. doi: 10.1016/j.esmoop.2021.100310. Epub 2021 Nov 20.

  PMID: 34808524 DERIVED

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

Vemurafenib; cobimetinib; atezolizumab; Trastuzumab; pertuzumab; alectinib; ipatasertib; inavolisib

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Richard Schlenk, Prof. Dr.

  NCT Studienzentrale

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 24, 2020
• First Posted: September 16, 2020
• Study Start: October 13, 2021
• Primary Completion: December 30, 2024
• Study Completion: December 30, 2024
• Last Updated: January 8, 2025

Record last verified: 2024-05

Locations

DE (9)