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 (ARROW)

• ClinicalTrials.gov Identifier: NCT03037385
• Recruitment Status: Active, not recruiting
• First Posted: January 31, 2017
• Last Update Posted: February 10, 2023
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: January 20, 2017
• First Posted Date: January 31, 2017
• Last Update Posted Date: February 10, 2023
• Actual Study Start Date: March 17, 2017
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 10, 2022)

• (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 participant terminates from the study ]
• (Phase 1) Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: Every cycle (28 days) for approximately 24 months or earlier if participant terminates from the study, and 30 days after the last dose ]

Original Primary Outcome Measures (submitted: January 27, 2017)

• Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of BLU-667 [ 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 ]
• 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 ]
• Changes in clinical laboratory results [ Time Frame: Every cycle (28 days) for approximately 24 months or earlier if patient terminates from the study, and 14 days after the last dose ]
• Changes in ECG findings [ Time Frame: Every cycle (28 days) up to Cycle 4 ]

Current Secondary Outcome Measures (submitted: May 10, 2022)

• (Phase 1) ORR [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
• (Phase 2) DOR [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
• (Phase 2) DCR [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
• (Phase 2) PFS [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 84 months) ]
• (Phase 2) Overall Survival (OS) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4 ]
• (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
• (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 participants only
• (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 participants only
• (Phase 2) Assess Intracranial Response Rate and Time to Intracranial Progression in Participants With NSCLC [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
  Target by RECIST v1.1 or RANO

Original Secondary Outcome Measures (submitted: January 27, 2017)

• Maximum plasma concentration (Cmax) of BLU-667 [ Time Frame: Every cycle (28 days) up to Cycle 4 ]
• Time to maximum plasma concentration (Tmax) of BLU-667 [ Time Frame: Every cycle (28 days) up to Cycle 4 ]
• Area under the plasma concentration time curve from 0 to 24 hours (AUC0-24) and from 0 to infinity (AUCinf) of BLU-667 [ Time Frame: Every cycle (28 days) up to Cycle 4 ]
• Terminal half-life (t1/2) of BLU-667 [ Time Frame: Every cycle (28 days) up to Cycle 4 ]
• RET gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue [ Time Frame: 28-day treatment Cycles 1, 2, and 3, every other cycle thereafter through the first 12 months of treatment, and 14 days after the last dose ]
• Change in blood calcitonin (medullary thyroid cancer patients) [ Time Frame: 28-day treatment Cycles 1, 2, and 3, every other cycle thereafter through the first 12 months of treatment, and 14 days after the last dose ]
• Change in tumor biomarker levels (phosphorylated SHC adaptor protein [p-SHC] and dual specificity phosphatase 6 [DUSP6] [ Time Frame: 28-day treatment Cycles 1, 2, and 3, every other cycle thereafter through the first 12 months of treatment, and 14 days after the last dose ]
• Overall response rate (ORR) [ 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 ]
  ORR is defined as the rate of complete response (CR) and partial response (PR).
• Duration of response (DOR) [ 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 ]
• Clinical benefit rate (CBR) [ 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 ]
  CBR is defined as the rate of CR, PR, and stable disease (SD).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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
• 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.
• 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 Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

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)

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• 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

Intervention

Drug: pralsetinib (BLU-667)

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

Other Name: BLU-667

Study Arms

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

Publications *

• Subbiah V, Cassier PA, Siena S, Garralda E, Paz-Ares L, Garrido P, Nadal E, Vuky J, Lopes G, Kalemkerian GP, Bowles DW, Seetharam M, Chang J, Zhang H, Green J, Zalutskaya A, Schuler M, Fan Y, Curigliano G. Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat Med. 2022 Aug;28(8):1640-1645. doi: 10.1038/s41591-022-01931-y. Epub 2022 Aug 12.
• Popat S, Liu SV, Scheuer N, Hsu GG, Lockhart A, Ramagopalan SV, Griesinger F, Subbiah V. Addressing challenges with real-world synthetic control arms to demonstrate the comparative effectiveness of Pralsetinib in non-small cell lung cancer. Nat Commun. 2022 Jun 17;13(1):3500. doi: 10.1038/s41467-022-30908-1.
• Subbiah V, Hu MI, Wirth LJ, Schuler M, Mansfield AS, Curigliano G, Brose MS, Zhu VW, Leboulleux S, Bowles DW, Baik CS, Adkins D, Keam B, Matos I, Garralda E, Gainor JF, Lopes G, Lin CC, Godbert Y, Sarker D, Miller SG, Clifford C, Zhang H, Turner CD, Taylor MH. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol. 2021 Aug;9(8):491-501. doi: 10.1016/S2213-8587(21)00120-0. Epub 2021 Jun 9. Erratum In: Lancet Diabetes Endocrinol. 2021 Oct;9(10):e4.
• Gainor JF, Curigliano G, Kim DW, Lee DH, Besse B, Baik CS, Doebele RC, Cassier PA, Lopes G, Tan DSW, Garralda E, Paz-Ares LG, Cho BC, Gadgeel SM, Thomas M, Liu SV, Taylor MH, Mansfield AS, Zhu VW, Clifford C, Zhang H, Palmer M, Green J, Turner CD, Subbiah V. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021 Jul;22(7):959-969. doi: 10.1016/S1470-2045(21)00247-3. Epub 2021 Jun 9. Erratum In: Lancet Oncol. 2021 Aug;22(8):e347.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 4, 2022): 589
• Original Estimated Enrollment (submitted: January 27, 2017): 115
• Estimated Study Completion Date: December 31, 2023
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China, France, Germany, Hong Kong, Italy, Korea, Republic of, Netherlands, Singapore, Spain, Taiwan, United Kingdom, United States
• Removed Location Countries: Belgium

Administrative Information

• NCT Number: NCT03037385
• Other Study ID Numbers: BO42863; 2016-004390-41 ( EudraCT Number ); BLU-667-1101 ( Registry Identifier: CT.Gov )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Blueprint Medicines Corporation
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Blueprint Medicines Corporation
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: February 2023