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JOURNAL ONKOLOGIE – STUDIE

ARROW Phase 1/2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors

Rekrutierend

NCT-Nummer:
NCT03037385

Studienbeginn:
März 2017

Letztes Update:
24.08.2020

Wirkstoff:
pralsetinib (BLU-667)

Indikation (Clinical Trials):
Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Thyroid Diseases, Thyroid Neoplasms, Carcinoma, Neuroendocrine, Thyroid Cancer, Papillary, Carcinoma, Neoplasms, Adenocarcinoma, Lung Diseases, Neuroendocrine Tumors, Colorectal Neoplasms, Neuroectodermal Tumors, Neuroectodermal Tumors, Primitive, Head and Neck Neoplasms, Gastrointestinal Diseases, Digestive System Diseases, Respiratory Tract Diseases, Colonic Neoplasms, Gastrointestinal Neoplasms, Digestive System Neoplasms, Endocrine System Diseases, Colonic Diseases, Neoplasms by Site, Intestinal Diseases, Neoplasms by Histologic Type, Thoracic Neoplasms, Intestinal Neoplasms, Neoplasms, Glandular and Epithelial, Respiratory Tract Neoplasms, Bronchial Neoplasms, Carcinoma, Bronchogenic, Endocrine Gland Neoplasms, Neoplasms, Germ Cell and Embryonal, Neoplasms, Nerve Tissue, Adenocarcinoma, Papillary

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
Blueprint Medicines Corporation

Collaborator:
-

Kontakt

Studienlocations (3 von 79)

HELIOS Klinikum Emil von Behring
14165 Berlin
(Berlin)
GermanyRekrutierend» Google-Maps
Kinderonkologisches Zentrum Universitätsklinikum Essen
Hufelandstraße 55
45147 Essen
DeutschlandRekrutierend» Google-Maps
Lungenkrebszentrum des NCT Heidelberg; Thoraxklinik Heidelberg
Im Neuenheimer Feld 672
69126 Heidelberg
DeutschlandRekrutierend» Google-Maps
Klinikum der Universitat Munchen
81377 Munich
(Bayern)
GermanyRekrutierend» Google-Maps
Pius-Hospital Oldenberg
26121 Oldenburg
(Niedersachsen)
GermanyRekrutierend» Google-Maps
UC Irvine Medical Center
92868 Orange
United StatesRekrutierend» Google-Maps
University of Colorado Cancer Center
80045 Aurora
United StatesRekrutierend» Google-Maps
Georgetown University Medical Center
20007 Washington
United StatesRekrutierend» Google-Maps
University of Miami Hospitals and Clinics, Sylvester Comprehensive Cancer Center
33136 Miami
United StatesRekrutierend» Google-Maps
Maryland Oncology Hematology, PA - Columbia
21044-3257 Columbia
United StatesRekrutierend» Google-Maps
Massachusetts General Hospital
02114 Boston
United StatesRekrutierend» Google-Maps
University of Michigan
48109 Ann Arbor
United StatesRekrutierend» Google-Maps
Washington University School of Medicine, Siteman Cancer Center
63110 Saint Louis
United StatesRekrutierend» Google-Maps
Albany Medical Center
12208-3412 Albany
United StatesRekrutierend» Google-Maps
Jack D. Weiler Hospital
10461-2301 Bronx
United StatesRekrutierend» Google-Maps
Oregon Health and Science University
97239 Portland
United StatesRekrutierend» Google-Maps
University of Pennsylvania Hospital
19104 Philadelphia
United StatesRekrutierend» Google-Maps
UPMC CancerCenter
15213-1862 Pittsburgh
United StatesRekrutierend» Google-Maps
Texas Oncology - Austin
78705-1165 Austin
United StatesRekrutierend» Google-Maps
Texas Oncology - Baylor Charles A. Sammons Cancer Center
75246 Dallas
United StatesRekrutierend» Google-Maps
University of Texas MD Anderson Cancer Center
77030 Houston
United StatesRekrutierend» Google-Maps
University of Washington, Seattle Cancer Care Alliance
98109 Seattle
United StatesRekrutierend» Google-Maps
West China Hospital, Sichuan University
610041 Chengdu
ChinaRekrutierend» Google-Maps
Sichuan Cancer Hospital & Institute
400030 Chongqing
ChinaRekrutierend» Google-Maps
Fujian Provincial Cancer Hospital
350014 Fuzhou
ChinaRekrutierend» Google-Maps
First Affiliated Hospital of Gannan Medical University
341000 Ganzhou
ChinaRekrutierend» Google-Maps
Sun Yat-sen University Cancer Center
510060 Guangzhou
ChinaRekrutierend» Google-Maps
Guangdong Provincial People's Hospital
510080 Guangzhou
ChinaRekrutierend» Google-Maps
Nanfang Hospital of Southern Medical University
510515 Guangzhou
ChinaRekrutierend» Google-Maps
Zhejiang Provincial People's Hospital
310000 Hangzhou
ChinaRekrutierend» Google-Maps
Anhui Provincial Cancer Hospital
230031 Hefei
ChinaRekrutierend» Google-Maps
Gansu Provincial Cancer Hospital
730050 Lanzhou
ChinaRekrutierend» Google-Maps
Fudan University Shanghai Cancer Center
200032 Shanghai
ChinaRekrutierend» Google-Maps
Liaoning Cancer Hospital & Institute
110042 Shenyang
ChinaRekrutierend» Google-Maps
Tianjin Medical University Cancer Institute and Hospital
300041 Tianjin
ChinaRekrutierend» Google-Maps
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
430022 Wuhan
ChinaRekrutierend» Google-Maps
CHRU de Lille - Hôpital Claude Hurier Servide d'Endocrinologie et Diabétologie
59037 Lille
FranceRekrutierend» Google-Maps
CHU de Rennes - Hôpital Pontchaillou
35033 Rennes
FranceRekrutierend» Google-Maps
The Chinese University of Hong Kong
Hong Kong
Hong KongRekrutierend» Google-Maps
Istituto Europeo di Oncologia Sviluppo Nuovi Farmaci per Terapie Innovative
20141 Milano
ItalyRekrutierend» Google-Maps
Grande Ospedale Metropolitano Niguarda
20162 Milan
ItalyRekrutierend» Google-Maps
Ospedale Santa Maria delle Croci
48124 Ravenna
ItalyRekrutierend» Google-Maps
Istituto Nazionale Tumori Regina Elena
144 Rome
ItalyRekrutierend» Google-Maps
Seoul National University Hospital
03080 Seoul
Korea, Republic ofRekrutierend» Google-Maps
Asan Medical Center
05505 Seoul
Korea, Republic ofRekrutierend» Google-Maps
Samsung Medical Center
6351 Seoul
Korea, Republic ofRekrutierend» Google-Maps
Nederlands Kanker Instituut - Antoni van Leeuwenhoek Ziekenhuis
1066 CX Amsterdam
NetherlandsRekrutierend» Google-Maps
University Medical Center Groningen
9713 Groningen
NetherlandsRekrutierend» Google-Maps
National Cancer Centre Singapore
169160 Singapore
SingaporeRekrutierend» Google-Maps
Hospital Universitari Vall d'Hebron
08035 Barcelona
SpainRekrutierend» Google-Maps
Hospital Universitario Ramon y Cajal
28034 Madrid
SpainRekrutierend» Google-Maps
Hospital Universitario 12 de Octubre Servicio de Oncologia Medica
28041 Madrid
SpainRekrutierend» Google-Maps
National Taiwan University Hospital
10002 Taipei City
TaiwanRekrutierend» Google-Maps
Taipei Veterans General Hospital
11217 Taipei
TaiwanRekrutierend» Google-Maps
NHS Grampian - Aberdeen Royal Infirmary
AB25 2ZN Aberdeen
United KingdomRekrutierend» Google-Maps
Sarah Cannon Research Institute
W1G 6AD London
United KingdomRekrutierend» Google-Maps
Guy's Hospital St. Thomas NHS Foundation Trust
London
United KingdomRekrutierend» Google-Maps
NIHR UCLH Clinical Research Facility, University College of London NHS Foundation Trust
London
United KingdomRekrutierend» Google-Maps
The Christie NHS Foundation Trust
Manchester
United KingdomRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

The study consists of 2 parts, a dose-escalation part (Phase 1) and an expansion part (Phase 2). Both parts will enroll patients with advanced non-resectable NSCLC, advanced non-resectable thyroid cancer and other advanced solid tumors that have progressed following standard systemic therapy, have not adequately responded to standard systemic therapy, or the patients must be intolerant to or the Investigator has determined that treatment with standard therapy is not appropriate, or there must be no accepted standard therapy for their disease.

Ein-/Ausschlusskriterien

Key Inclusion Criteria:

- Diagnosis during dose escalation (Phase 1) - Pathologically documented, definitively diagnosed non-resectable advanced solid tumor.

- All patients treated at doses > 120 mg per day must have medullary thyroid cancer (MTC), or a RET-altered solid tumor per local assessment of tumor tissue and/or blood.

- Diagnosis during dose expansion (Phase 2) - All patients (with the exception of patients with MTC enrolled in Groups 3, 4, and 9) must have an oncogenic RET-rearrangement/fusion or mutation (excluding synonymous, frameshift, and nonsense mutations) solid tumor, as determined by local or central testing of tumor or circulating tumor nucleic acid in blood; as detailed below.

- Group 1 - patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion previously treated with a platinum-based chemotherapy.

- Group 2 - patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion not previously treated with a platinum-based chemotherapy, including those who have not had any systemic therapy. Prior platinum chemotherapy in the neoadjuvant and adjuvant setting is permitted if the last dose of platinum was 4 months or more before the first dose of study drug.

- Group 3 - patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was previously treated with cabozantinib and/or vandetanib.

- Group 4 - patient must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was not previously treat with cabozantinib and/or vandetanib.

- Group 5 -patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion, have previously received SOC appropriate for their tumor type (unless there is no accepted standard therapy for the tumor type or the Investigator has determined that treatment with standard therapy is not appropriate), and must not be eligible for any of the other groups.

- Group 6 - patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation that was previously treated with a selective TKI that inhibits RET

- Group 7 - patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET mutation previously treated with SOC appropriate for the tumor type and not eligible for any of the other groups

- Group 8 - patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion that was previously treated with a platinum based chemotherapy (China only).

- Group 9 - patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit, and was not previously treated with systemic therapy (except prior cytotoxic chemotherapy is allowed) for advanced or metastatic disease (China only).

- Patients must have non-resectable disease.

- Patient agrees to provide tumor tissue (archived, if available or a fresh biopsy) for RET status confirmation and is willing to consider an on-treatment tumor biopsy, if considered safe and medically feasible by the treating Investigator. For Phase 2, Group 6, patients are required to undergo a pretreatment biopsy to define baseline RET status in tumor tissue.

- Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.

Key Exclusion Criteria:

- Patient's cancer has a known primary driver alteration other than RET. For example, NSCLC with a targetable mutation in EGFR, ALK, ROS1 or BRAF; colorectal with an oncogenic KRAS, NRAS, or BRAF mutation.

- Patient has any of the following within 14 days prior to the first dose of study drug:

1. Platelet count < 75 × 10^9/L.

2. Absolute neutrophil count <1.0 × 10^9/L.

3. Hemoglobin < 9.0 g/dL (red blood cell transfusion and erythropoietin may be used to reach at least 9.0 g/dL, but must have been administered at least 2 weeks prior to the first dose of study drug.

4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × the upper limit of normal (ULN) if no hepatic metastases are present; >5 × ULN if hepatic metastases are present.

5. Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin > 1.5 × ULN in presence of Gilbert's disease.

6. Estimated (Cockcroft-Gault formula) or measured creatinine clearance <40 mL/min.

7. Total serum phosphorus >5.5 mg/dL

- QT interval corrected using Fridericia's formula (QTcF) >470 msec or history of prolonged QT syndrome or Torsades de pointes, or familial history of prolonged QT syndrome.

- Clinically significant, uncontrolled, cardiovascular disease.

- Central nervous system (CNS) metastases or a primary CNS tumor that is associated with progressive neurological symptoms.

- Clinically symptomatic interstitial lung disease or interstitial pneumonitis including radiation pneumonitis

- Patients in Groups 1-5 and 7 (Phase 2) previously treated with a selective RET inhibitor

Studien-Rationale

Primary outcome:

1. (Phase 1) Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of pralsetinib (Time Frame - Cycle 1 (28 days) of treatment for MTD and at the end of every cycle (28 days) for RP2D for approximately 12 months or earlier if patient terminates from the study)

2. (Phase 1) Number of patients with adverse events and serious adverse events (Time Frame - Every cycle (28 days) for approximately 24 months or earlier if patient terminates from the study, and 30 days after the last dose)

3. (Phase 2) Overall response rate (Time Frame - Approximately every 8 weeks or 16 weeks based on the treatment cycle):
As assessed by RECIST v1.1 or RANO, as appropriate per tumor type

4. (Phase 2) Number of patients with adverse events and serious adverse events (Time Frame - Every cycle (28 days) for approximately 24 months or earlier if patient terminates from the study, and 30 days after the last dose)

Secondary outcome:

1. (Phase 1) Overall response rate (Time Frame - Approximately every 8 weeks during treatment, 14 days after the last dose, and every 3 months after the last dose (up to 2 years) in patients without progressive disease):
As assessed by RECIST v1.1 or RANO, as appropriate per tumor type

2. (Phase 1) RET gene status and correlation between RET gene status and ORR, CBR, DOR, DCR, PFS and other antineoplastic measures (Time Frame - Approximately every 8 weeks or 16 weeks based on the treatment cycle)

3. (Phase 2 ) Clinical Benefit Rate (CBR) (Time Frame - Approximately every 8 weeks or 16 weeks based on the treatment cycle)

4. (Phase 2 ) Duration of Response (DOR) (Time Frame - Approximately every 8 weeks or 16 weeks based on the treatment cycle)

5. (Phase 2 ) Disease Control Rate (DCR) (Time Frame - Approximately every 8 weeks or 16 weeks based on the treatment cycle)

6. (Phase 2 ) Progression Free Survival (PFS) (Time Frame - Approximately every 8 weeks or 16 weeks based on the treatment cycle)

7. (Phase 2 ) Overall Survival (OS) (Time Frame - Approximately every 8 weeks or 16 weeks based on the treatment cycle)

8. (Phase 2) RET gene status and correlation between RET gene status and ORR, CBR, DOR, DCR and other antineoplastic measures (Time Frame - Approximately every 8 weeks or 16 weeks based on the treatment cycle):
RET gene status (i.e. gene fusion partner or primary mutation and, for MTC, whether hereditary or sporadic)

9. (Phases 1 and 2) Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) (Time Frame - Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4)

10. (Phases 1 and 2) Pharmacokinetic parameters including area under the plasma concentration versus time curve from time 0 to 24 hours postdose (AUC0-24) (Time Frame - Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4)

11. (Phases 1 and 2) Pharmacokinetic parameters including terminal elimination half-life (t1/2) (Time Frame - Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4)

12. (Phase 2) Electrocardiogram (ECG) Assessment using QT analysis (Time Frame - Effects of BLU-667 on ECG parameters on Cycle 1 Day 1 and Cycle 1 Day 15):
Will be measured from lead II and will be corrected for heart rate (QTc)n using Fridericia's correction factors

13. (Phases 1 and 2) Pharmacodynamic parameters including changes in blood calcitonin (Time Frame - Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 13):
MTC patients only

14. (Phases 1 and 2) Pharmacodynamic parameters including tumor marker, carcinoembryonic antigen (CEA) (Time Frame - Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 13):
MTC patients only

15. (Phase 2) Assess intracranial response rate and time to intracranial progression in patients with NSCLC (Time Frame - Approximately every 8 weeks or 16 weeks based on the treatment cycle):
Target by RECIST v1.1 or RANO

Studien-Arme

  • Experimental: Phase 1 Dose Escalation
    Multiple doses of pralsetinib (BLU-667) for oral administration.
  • Experimental: Phase 2 Dose Expansion
    Oral dose of pralsetinib (BLU-667) as determined during Dose Escalation.

Geprüfte Regime

  • pralsetinib (BLU-667) (BLU-667):
    pralsetinib (BLU-667) is a potent and selective inhibitor of the RET mutations, fusions, and predicted resistant mutants

Quelle: ClinicalTrials.gov


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