ARROW: 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

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03037385

Collaborator

(none)

589

Enrollment

Locations

Arms

83.4

Anticipated Duration (Months)

9.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
RET-altered Non Small Cell Lung Cancer Medullary Thyroid Cancer RET-altered Papillary Thyroid Cancer RET-altered Colon Cancer RET-altered Solid Tumors Lung Neoplasm Carcinoma, Non-Small-Cell Lung Thyroid Diseases Thyroid Neoplasm Thyroid Cancer, Papillary Carcinoma, Neuroendocrine Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site Neoplasms Lung Diseases Respiratory Tract Disease Carcinoma, Bronchogenic Bronchial Neoplasms Endocrine System Diseases Endocrine Gland Neoplasm Head and Neck Neoplasms Adenocarcinoma, Papillary Adenocarcinoma Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neuroendocrine Tumors Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Colonic Neoplasms Colorectal Neoplasms Intestinal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasm Digestive System Disease Gastrointestinal Disease Colonic Diseases Intestinal Disease	Drug: pralsetinib (BLU-667)	Phase 1/Phase 2

Detailed 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

589 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Phase 1 (Complete): Advanced MTC, NSCLC or other solid tumor 30-600mg (PO QD or BID) Phase 2 (400mg QD): Group 1: RET fusion NSCLC previously treated with a platinum chemotherapy Group 2: RET fusion NSCLC not previously treated for metastatic disease Group 3: MTC previously treated with cabozantinib and/or vandetanib Group 4: MTC not previously treated with cabozantinib or vandetanib Group 5: Other solid tumors with a RET fusion not eligible for any of the other groups and previously treated with SOC or have no acceptable SOC for their tumor type as determined by the investigator Group 6: Any solid tumor with a RET alteration (fusion or mutation) previously treated with a selective RET Inhibitor Group 7: Other solid tumors with a RET mutation previously treated with SOC Group 8: RET fusion NSCLC previously treated with a platinum chemotherapy (China only) Group 9: MTC not previously treated with systemic therapy for advanced or metastatic disease (China only)Phase 1 (Complete):Advanced MTC, NSCLC or other solid tumor 30-600mg (PO QD or BID)Phase 2 (400mg QD):Group 1: RET fusion NSCLC previously treated with a platinum chemotherapy Group 2: RET fusion NSCLC not previously treated for metastatic disease Group 3: MTC previously treated with cabozantinib and/or vandetanib Group 4: MTC not previously treated with cabozantinib or vandetanib Group 5: Other solid tumors with a RET fusion not eligible for any of the other groups and previously treated with SOC or have no acceptable SOC for their tumor type as determined by the investigator Group 6: Any solid tumor with a RET alteration (fusion or mutation) previously treated with a selective RET Inhibitor Group 7: Other solid tumors with a RET mutation previously treated with SOC Group 8: RET fusion NSCLC previously treated with a platinum chemotherapy (China only) Group 9: MTC not previously treated with systemic therapy for advanced or metastatic disease (China only)

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 17, 2017

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Feb 29, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1 Dose Escalation Multiple doses of pralsetinib (BLU-667) for oral administration.	Drug: pralsetinib (BLU-667) pralsetinib (BLU-667) is a potent and selective inhibitor of the RET mutations, fusions, and predicted resistant mutants Other Names: BLU-667
Experimental: Phase 2 Dose Expansion Oral dose of pralsetinib (BLU-667) as determined during Dose Escalation.	Drug: pralsetinib (BLU-667) pralsetinib (BLU-667) is a potent and selective inhibitor of the RET mutations, fusions, and predicted resistant mutants Other Names: BLU-667

Arm

Intervention/Treatment

Experimental: Phase 1 Dose Escalation

Multiple doses of pralsetinib (BLU-667) for oral administration.

Drug: pralsetinib (BLU-667)

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

Other Names:

BLU-667

Experimental: Phase 2 Dose Expansion

Oral dose of pralsetinib (BLU-667) as determined during Dose Escalation.

Drug: pralsetinib (BLU-667)

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

Other Names:

BLU-667

Outcome Measures

Primary Outcome Measures

(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]
(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]
(Phase 2) Overall Response Rate (ORR) [Approximately every 8 weeks or 16 weeks based on the treatment cycle]
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
(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 Outcome Measures

(Phase 1) ORR [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]
As assessed by RECIST v1.1 or RANO, as appropriate per tumor type
(Phase 1) RET Gene Status and Correlation Between RET Gene Status and ORR, CBR, DOR, DCR, PFS and Other Antineoplastic Measures [Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 12 months)]
Clinical Benefit Rate (CBR), Duration of Response (DOR), Disease Control Rate (DCR), Progression Free Survival (PFS)
(Phase 2) CBR [Approximately every 8 weeks or 16 weeks based on the treatment cycle]
(Phase 2) DOR [Approximately every 8 weeks or 16 weeks based on the treatment cycle]
(Phase 2) DCR [Approximately every 8 weeks or 16 weeks based on the treatment cycle]
(Phase 2) PFS [Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 84 months)]
(Phase 2) Overall Survival (OS) [Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 84 months)]
(Phase 2) RET Gene Status and Correlation Between RET Gene Status and ORR, CBR, DOR, DCR and Other Antineoplastic Measures [On Day 1 of Cycle 1 (each cycle is of 28 days), 2 and 3 and every other cycle thereafter up to Cycle 13]
RET gene status (i.e. gene fusion partner or primary mutation and, for MTC, whether hereditary or sporadic)
(Phases 1 and 2) Pharmacokinetic Parameters Including Maximum Plasma Drug Concentration (Cmax) [Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4]
(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]
(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]
(Phase 2) Electrocardiogram (ECG) Assessment Using QT Analysis [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
(Phases 1 and 2) Pharmacodynamic Parameters Including Changes in Blood Calcitonin [Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 13]
MTC participants only
(Phases 1 and 2) Pharmacodynamic Parameters Including Tumor Marker, Carcinoembryonic Antigen (CEA) [Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 13]
MTC participants only
(Phase 2) Assess Intracranial Response Rate and Time to Intracranial Progression in Participants With NSCLC [Approximately every 8 weeks or 16 weeks based on the treatment cycle]
Target by RECIST v1.1 or RANO

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

Platelet count < 75 × 10^9/L.
Absolute neutrophil count < 1.0 × 10^9/L.
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.
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.
Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin > 1.5 × ULN in presence of Gilbert's disease.
Estimated (Cockcroft-Gault formula) or measured creatinine clearance < 40 mL/min.
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Hospital	Phoenix	Arizona	United States	85054
2	UC Irvine Medical Center	Orange	California	United States	92868
3	University of Colorado Anschutz Medical Campus	Aurora	Colorado	United States	80045
4	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
5	Mayo Clinic-Jacksonville	Jacksonville	Florida	United States	32224
6	Sylvester Comprehensive Cancer Center; University of Miami School of Medicine	Miami	Florida	United States	33136
7	Maryland Oncology Hematology, P.A.	Columbia	Maryland	United States	21044
8	Massachusetts General Hospital.	Boston	Massachusetts	United States	02114
9	University of Michigan	Ann Arbor	Michigan	United States	48109-0934
10	Mayo Clinic Rochester	Rochester	Minnesota	United States	55902
11	Washington University School of Medicine in St. Louis	Saint Louis	Missouri	United States	63110
12	Albany Medical Center	Albany	New York	United States	12208
13	Weill Cornell Medical College-New York Presbyterian Hospital	New York	New York	United States	10021
14	Oregon Health & Science University	Portland	Oregon	United States	97239
15	Stellar - Chance Laboratories	Philadelphia	Pennsylvania	United States	19104
16	Texas Oncology-Austin Midtown	Austin	Texas	United States	78705
17	Texas Oncology - Baylor Charles A. Sammons Cancer Center	Dallas	Texas	United States	75246
18	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030-4009
19	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
20	Beijing Cancer Hospital	Beijing		China	100142
21	The affiliated Cancer Hospital, School of Medicine, UESTC	Chengdu		China	610041
22	West China Hospital, Sichuan University	Chengdu		China	610041
23	Chongqing Cancer Hospital	Chongqing		China	400030
24	Fujian Provincial Cancer Hospital	Fuzhou City		China	350014
25	First Affiliated Hospital of Gannan Medical University	Ganzhou		China	341000
26	Sun Yet-sen University Cancer Center	Guangzhou		China	510060
27	Guangdong General Hospital	Guangzhou		China	510080
28	Zhejiang Provincial People's Hospital	Hangzhou		China	310014
29	Jinan Central Hospital	Jinan City		China	250013
30	Gansu Cancer Hospital	Lanzhou		China	730050
31	Fudan University Shanghai Cancer Center	Shanghai City		China	200120
32	Tianjin Medical University Cancer Institute & Hospital	Tianjing		China	300060
33	Tianjin Cancer Hospital	Tianjin		China	300060
34	Union Hospital Tongji Medical College Huazhong University of Science and Technology	Wuhan City		China	430023
35	Zhejiang Cancer Hospital	Zhejiang		China	310022
36	Henan Cancer Hospital	Zhengzhou		China	450008
37	Helios Klinikum Emil von Behring GmbH	Berlin		Germany	14165
38	Universitätsklinikum Essen; Innere Klinik und Poliklinik für Tumorforschung	Essen		Germany	45122
39	Thoraxklinik Heidelberg gGmbH	Heidelberg		Germany	69126
40	Klinikum der Universität München	Muenchen		Germany	80336
41	Pius-Hospital; Klinik fuer Haematologie und Onkologie	Oldenburg		Germany	26121
42	The Chinese University of Hong Kong	Shatin		Hong Kong	123456
43	Ospedale Santa Maria Delle Croci	Ravenna	Emilia-Romagna	Italy	48100
44	Istituto Nazionale Tumori Regina Elena	Roma	Lazio	Italy	00144
45	IEO; Divisione di Sviluppo di Nuovi Farmaci per Terapie Innovative	Milano	Lombardia	Italy	20141
46	Asst Grande Ospedale Metropolitano Niguarda	Milano	Lombardia	Italy	20162
47	Seoul National University Hospital	Seoul		Korea, Republic of	03080
48	Asan Medical Center	Seoul		Korea, Republic of	05505
49	Samsung Medical Center	Seoul		Korea, Republic of	06351
50	Severance Hospital, Yonsei University Health System; Oncology	Seoul		Korea, Republic of	120-752
51	Antoni van Leeuwenhoek Ziekenhuis	Amsterdam		Netherlands	1066 CX
52	Universitair Medisch Centrum Groningen	Groningen		Netherlands	9713 GZ
53	National Cancer Centre	Singapore		Singapore	169610
54	Institut Catala d Oncologia Hospitalet	Hospitalet de Llobregat	Barcelona	Spain	08908
55	Vall d´Hebron Institute of Oncology (VHIO), Barcelona	Barcelona		Spain	08035
56	Hospital Clinic de Barcelona	Barcelona		Spain	08036
57	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid		Spain	28034
58	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid		Spain	28041
59	Taipei Veterans General Hospital	Taipei City		Taiwan	11217
60	National Taiwan University Hospital	Taipei		Taiwan	10002
61	Aberdeen Royal Infirmary	Aberdeen		United Kingdom	AB25 2ZN
62	Guys and St Thomas NHS Foundation Trust, Guys Hospital	London		United Kingdom	SE1 9RT
63	Sarah Cannon Research Institute	London		United Kingdom	W1G 6AD
64	University College London Hospitals NHS Foundation Trust; NIHR UCLH Clinical Research Facility	London		United Kingdom	W1T 7HA
65	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX