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

Neoplasms Clinical Trial

— ARROW  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03037385
• Other study ID #: BO42863
• Secondary ID: 2016-004390-41BL
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 17, 2017
• Est. completion date: March 21, 2024

Study information

• Verified date: April 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antineoplastic activity of pralsetinib (BLU-667) administered orally in participants with medullary thyroid cancer (MTC), RET-altered NSCLC and other RET-altered solid tumors.

Description:

The study consists of 2 parts, a dose-escalation part (Phase 1) and an expansion part (Phase 2). Both parts will enroll participants 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 participants 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 589
• Est. completion date: March 21, 2024
• Est. primary completion date: March 21, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

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

• All participants treated at doses > 120 mg per day must have MTC, or a RET-altered solid tumor per local assessment of tumor tissue and/or blood.

• Diagnosis during dose expansion (Phase 2) - All participants (with the exception of participants 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 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion previously treated with a platinum-based chemotherapy.

• Group 2 - participants 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 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit and was previously treated with cabozantinib and/or vandetanib.

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

• Group 5 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion, have previously received standard of care (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 have been eligible for any of the other groups.

• Group 6 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation that was previously treated with a selective tyrosine kinase inhibitor (TKI) that inhibits RET

• Group 7 - participants 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 - participants 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 - participants must have pathologically documented, definitively diagnosed advanced MTC that had 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).

• Participants must have non-resectable disease.

• Dose expansion (Phase 2): Participants in all groups (except Group 7) must have measurable disease per RECIST v1.1 (or RANO, criteria if appropriate for tumor type).

• Participants 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, participants are required to undergo a pretreatment biopsy to define baseline RET status in tumor tissue.

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

Key Exclusion Criteria:

• Participant'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.

• Participants had 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

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

• Participant had a major surgical procedure within 14 days of the first dose of study drug

• Participant had a history of another primary malignancy that had been diagnosed or required therapy within the a year prior to the study

• Pregnant or breastfeeding female participants

Related Conditions & MeSH terms

• Adenocarcinoma
• Adenocarcinoma, Papillary
• Bronchial Neoplasms
• Carcinoma
• Carcinoma, Bronchogenic
• Carcinoma, Neuroendocrine
• Carcinoma, Non-Small-Cell Lung
• Colonic Diseases
• Colonic Neoplasms
• Colorectal Neoplasms
• Digestive System Disease
• Digestive System Diseases
• Digestive System Neoplasm
• Digestive System Neoplasms
• Endocrine Gland Neoplasm
• Endocrine Gland Neoplasms
• Endocrine System Diseases
• Gastrointestinal Disease
• Gastrointestinal Diseases
• Gastrointestinal Neoplasms
• Head and Neck Neoplasms
• Intestinal Disease
• Intestinal Diseases
• Intestinal Neoplasms
• Lung Diseases
• Lung Neoplasm
• Lung Neoplasms
• Medullary Thyroid Cancer
• Neoplasms
• Neoplasms by Histologic Type
• Neoplasms by Site
• Neoplasms, Germ Cell and Embryonal
• Neoplasms, Glandular and Epithelial
• Neoplasms, Nerve Tissue
• Neuroectodermal Tumors
• Neuroectodermal Tumors, Primitive
• Neuroendocrine Tumors
• Respiratory Tract Disease
• Respiratory Tract Diseases
• Respiratory Tract Neoplasms
• RET-altered Colon Cancer
• RET-altered Non Small Cell Lung Cancer
• RET-altered Papillary Thyroid Cancer
• RET-altered Solid Tumors
• Thoracic Neoplasms
• Thyroid Cancer, Papillary
• Thyroid Diseases
• Thyroid Neoplasm
• Thyroid Neoplasms

Intervention

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

Locations

Country	Name	City	State
Belgium	Antwerp University Hospital	Edegem
China	Beijing Cancer Hospital	Beijing
China	The affiliated Cancer Hospital, School of Medicine, UESTC	Chengdu
China	West China Hospital, Sichuan University	Chengdu
China	Chongqing Cancer Hospital	Chongqing
China	Fujian Provincial Cancer Hospital	Fuzhou City
China	First Affiliated Hospital of Gannan Medical University	Ganzhou
China	Guangdong General Hospital	Guangzhou
China	Sun Yet-sen University Cancer Center	Guangzhou City
China	Zhejiang Provincial People?s Hospital	Hangzhou
China	Jinan Central Hospital	Jinan City
China	Gansu Cancer Hospital	Lanzhou
China	Fudan University Shanghai Cancer Center	Shanghai City
China	Tianjin Medical University Cancer Institute & Hospital	Tianjin
China	Union Hospital Tongji Medical College Huazhong University of Science and Technology	Wuhan City
China	Zhejiang Cancer Hospital	Zhejiang
China	Henan Cancer Hospital	Zhengzhou
France	Institut Bergonie	Bordeaux
France	Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez	Lille
France	Centre Léon Bérard	Lyon
France	Centre Antoine Lacassagne	Nice
France	Institut Curie	Paris
France	CHU de Rennes - Hopital de Pontchaillo	Rennes
France	Hôpital Larrey;Université Paul Sabatier	Toulouse
France	Gustave Roussy	Villejuif
Germany	Helios Klinikum Emil von Behring GmbH	Berlin
Germany	Universitätsklinikum Essen; Innere Klinik und Poliklinik für Tumorforschung	Essen
Germany	Thoraxklinik Heidelberg gGmbH	Heidelberg
Germany	Klinikum der Universität München	Muenchen
Germany	Pius-Hospital; Klinik fuer Haematologie und Onkologie	Oldenburg
Hong Kong	The Chinese University of Hong Kong	Shatin
Italy	Asst Grande Ospedale Metropolitano Niguarda	Milano	Lombardia
Italy	IEO; Divisione di Sviluppo di Nuovi Farmaci per Terapie Innovative	Milano	Lombardia
Italy	Ospedale Santa Maria Delle Croci	Ravenna	Emilia-Romagna
Italy	Istituto Nazionale Tumori Regina Elena	Roma	Lazio
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System; Oncology	Seoul
Netherlands	Antoni van Leeuwenhoek Ziekenhuis	Amsterdam
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Singapore	National Cancer Centre	Singapore
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Vall d?Hebron Institute of Oncology (VHIO), Barcelona	Barcelona
Spain	Institut Catala d Oncologia Hospitalet	Hospitalet de Llobregat	Barcelona
Spain	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid
Spain	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei City
United Kingdom	Guys and St Thomas NHS Foundation Trust, Guys Hospital	London
United Kingdom	Sarah Cannon Research Institute	London
United Kingdom	University College London Hospitals NHS Foundation Trust; NIHR UCLH Clinical Research Facility	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United States	Albany Medical Center	Albany	New York
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Colorado Anschutz Medical Campus	Aurora	Colorado
United States	Texas Oncology-Austin Midtown	Austin	Texas
United States	Massachusetts General Hospital.	Boston	Massachusetts
United States	Maryland Oncology Hematology, P.A.	Columbia	Maryland
United States	Texas Oncology - Baylor Charles A. Sammons Cancer Center	Dallas	Texas
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic-Jacksonville	Jacksonville	Florida
United States	Sylvester Comprehensive Cancer Center; University of Miami School of Medicine	Miami	Florida
United States	Weill Cornell Medical College-New York Presbyterian Hospital	New York	New York
United States	UC Irvine Medical Center	Orange	California
United States	Stellar - Chance Laboratories	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	Oregon Health & Science University	Portland	Oregon
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	Washington University School of Medicine in St. Louis	Saint Louis	Missouri
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	Georgetown University Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Belgium,  China,  France,  Germany,  Hong Kong,  Italy,  Korea, Republic of,  Netherlands,  Singapore,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	(Phase 1) Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib		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 participant terminates from the study
Primary	(Phase 1) Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)		Every cycle (28 days) for approximately 12 months or earlier if participant terminates from the study, and 30 days after the last dose
Primary	(Phase 2) Overall Response Rate (ORR)	As assessed by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) or Response Assessment in Neuro-Oncology (RANO), as appropriate per tumor type	Approximately every 8 weeks or 16 weeks based on the treatment cycle
Primary	(Phase 2) Number of Participants with AEs and SAEs		Every cycle (28 days) for approximately 24 months or earlier if participant terminates from the study, and 30 days after the last dose
Secondary	(Phase 1) ORR	As assessed by RECIST v1.1 or RANO, as appropriate per tumor type	Approximately every 8 weeks during treatment, 14 days after the last dose, and every 3 months after the last dose (Up to 12 months) in participants without progressive disease
Secondary	(Phase 1) RET Gene Status and Correlation Between RET Gene Status and ORR, CBR, DOR, DCR, PFS and Other Antineoplastic Measures	Clinical Benefit Rate (CBR), Duration of Response (DOR), Disease Control Rate (DCR), Progression Free Survival (PFS)	Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 12 months)
Secondary	(Phase 2) CBR		Approximately every 8 weeks or 16 weeks based on the treatment cycle
Secondary	(Phase 2) DOR		Approximately every 8 weeks or 16 weeks based on the treatment cycle
Secondary	(Phase 2) DCR		Approximately every 8 weeks or 16 weeks based on the treatment cycle
Secondary	(Phase 2) PFS		Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 84 months)
Secondary	(Phase 2) Overall Survival (OS)		Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 84 months)
Secondary	(Phase 2) RET Gene Status and Correlation Between RET Gene Status and ORR, CBR, DOR, DCR and Other Antineoplastic Measures	RET gene status (i.e. gene fusion partner or primary mutation and, for MTC, whether hereditary or sporadic)	On Day 1 of Cycle 1 (each cycle is of 28 days), 2 and 3 and every other cycle thereafter up to Cycle 13
Secondary	(Phases 1 and 2) Pharmacokinetic Parameters Including Maximum Plasma Drug Concentration (Cmax)		Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4
Secondary	(Phases 1 and 2) Pharmacokinetic Parameters Including Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24)		Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4
Secondary	(Phases 1 and 2) Pharmacokinetic Parameters Including Terminal Elimination Half-life (t1/2)		Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4
Secondary	(Phase 2) Electrocardiogram (ECG) Assessment Using QT Analysis	Will be measured from lead II and will be corrected for heart rate (QTc)n using Fridericia's correction factors	Effects of BLU-667 on ECG parameters on Cycle 1 Day 1 and Cycle 1 Day 15
Secondary	(Phases 1 and 2) Pharmacodynamic Parameters Including Changes in Blood Calcitonin	MTC participants only	Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 13
Secondary	(Phases 1 and 2) Pharmacodynamic Parameters Including Tumor Marker, Carcinoembryonic Antigen (CEA)	MTC participants only	Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 13
Secondary	(Phase 2) Assess Intracranial Response Rate and Time to Intracranial Progression in Participants With NSCLC	Target by RECIST v1.1 or RANO	Approximately every 8 weeks or 16 weeks based on the treatment cycle

External Links

•   More information about the study