(VELA) Study of BLU-222 in Advanced Solid Tumors

A Phase 1/2 Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of BLU-222 as a Single Agent and in Combination Therapy for Patients With Advanced Solid Tumors

This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anticancer activity of BLU-222, a selective inhibitor of CDK2.

Study Overview

• Status: Recruiting
• Conditions: Gastric Cancer; Ovarian Cancer; Carcinosarcoma; Advanced Solid Tumors; Endometrial Cancer; Esophageal Adenocarcinoma; HER2-negative Breast Cancer; CCNE1 Amplification; HR+ Breast Cancer
• Intervention / Treatment: Drug: BLU-222; Drug: Fulvestrant; Drug: Carboplatin; Drug: Ribociclib

Detailed Description

This study will include a dose-escalation phase in patients with advanced/relapsed tumors (Part 1A); platinum-resistant or platinum-refractory ovarian cancer, endometrial cancer (with prior platinum therapy) that has progressed following 2 or more lines of therapies and gastric cancer (with prior platinum therapy) that has progressed following 2 or more lines of therapies (Part 1C); and ER+ HER2- BC that has progressed despite CDK4/6i (Part 1D). This will be followed by expansion groups consisting of patients with tumors harboring specific mutation profiles: Platinum-resistant or platinum-refractory CCNE1 amplified ovarian cancer (Group 1); CCNE1 amplified endometrial cancer that has failed 2 or more lines of therapies (Group 2); CCNE1 amplified advanced/relapsed tumors that do not belong to the other groups (Group 3); ER+ HER2- BC that has progressed despite CDK4/6i (Group 4); platinum-resistant or platinum-refractory CCNE1 amplified ovarian cancer (Group 5); and ER+ HER2- BC that has progressed despite CDK4/6i (Group 6).

• Study Type: Interventional
• Enrollment (Estimated): 366
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Blueprint Medicines; Phone Number: 617-714-6707; Email: medinfo@blueprintmedicines.com

Study Locations

• Italy
  • Milano, Italy, 20141
    • Recruiting
    • Instituto Europeo di Oncologia
  • Milano, Italy, 20133
    • Recruiting
    • Fondazione IRCCS Istituto Nazionale dei Tumori
  • Rome, Italy, 00168
    • Recruiting
    • Fondazione Policlinico Universitario A Gemelli-Rome
• United Kingdom
  • Middlesex
    • London, Middlesex, United Kingdom, EC1A 7BE
      • Recruiting
      • St Bartholomew's Hospital
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Recruiting
      • University of Arkansas for Medical Sciences
  • California
    • San Francisco, California, United States, 94158
      • Recruiting
      • UCSF Helen Diller Family Comprehensive Cancer Center
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford Women's Cancer Center
  • Florida
    • Sarasota, Florida, United States, 34232
      • Recruiting
      • Florida Cancer Specialists
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • University of Chicago Medical Center
      • Principal Investigator: Gini Fleming, MD
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (SKCCC)
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana-Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Recruiting
      • Henry Ford Health System
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Herbert Irving Comprehensive Cancer Center
    • New York, New York, United States, 10461
      • Recruiting
      • Montefiore Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Recruiting
      • UNC Hospitals at Chapel Hill - The University of North Carolina at Chapel Hill
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • OU Health Stephenson Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Recruiting
      • Hospital of the Fox Chase Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37204
      • Recruiting
      • Vanderbilt Breast Center at One Hundred Oaks
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • University of Utah - Huntsman Cancer Institute - PPDS
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Recruiting
      • University of Virginia Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Advanced solid tumors that has progressed beyond standard of care OR
2. HR+ HER2- BC that has progressed following treatment with a CDK4/6 inhibitor OR
3. Endometrial and gastric cancer that has progressed after at least 2 prior therapies (including one prior platinum therapy) OR
4. Platinum refractory or platinum resistant ovarian cancer CCNE1 amplified tumors that have progressed beyond standard of care

Exclusion Criteria:

1. Have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis.

2. Have received the following anticancer therapy:

   a. Previous therapy with CDK2i, PKMYT1i, or WEE1i, except in Part 1A where up to 10 patients who previously received PKMYT1i, or WEE1 inhibitor will be permitted.

3. Have central nervous system (CNS) metastases or spinal cord compression that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease.
4. Have known intracranial hemorrhage and/or bleeding diatheses.
5. Have clinically active ongoing ILD of any etiology, including drug-induced ILD, and radiation pneumonitis within 28 days prior to initiation of study treatment.
6. Have any unresolved toxicities from prior therapy greater than CTCAE Grade 1 or that have not resolved to baseline at the time of starting the study.
7. Have mean resting QTcF > 450 msec in men or QTcF > 470 msec in women, a history of prolonged QT syndrome or Torsades de pointes, or a familial history of prolonged QT syndrome.
8. Have clinically significant, uncontrolled, cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension, or clinically significant, uncontrolled arrhythmias, including bradyarrhythmia that may cause QT prolongation (eg, Type II second degree heart block or third-degree heart block).
9. Have a history of another primary malignancy other than completely resected carcinomas in situ) that has been diagnosed or required therapy within 2 years prior to initiation of study treatment.
10. Have known active, uncontrolled infection (viral, bacterial, or fungal), including tuberculosis, hepatitis B virus (HBV), hepatitis C virus, AIDS-related illness, or COVID-19 infection (symptoms and a positive test result).
11. Requires treatment with a prohibited medication or herbal remedy that cannot be discontinued at least 2 weeks before the start of study drug administration.
12. Have planned major surgical procedure within 14 days of the first dose of study drug (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures).
13. Unwilling or unable to comply with scheduled visits, study drug administration plan, laboratory tests, or other study procedures and study restrictions.
14. Patient is a woman who is not postmenopausal or surgically sterile, and is unwilling to abstain from sexual intercourse or employ highly effective contraception OR is a man who is not surgically sterile, and is unwilling to abstain from sexual intercourse or employ highly effective contraception
15. Patient is a pregnant female

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BLU-222 Monotherapy; Dose Escalation: Multiple doses for BLU-222 for oral administration Dose Expansion: Oral dose of BLU-222 as determined during Dose Escalation	Drug: BLU-222; Oral administration
Experimental: BLU-222 + Ribociclib + Fulvestrant; Dose Escalation: Multiple doses for BLU-222 for oral administration at doses deemed appropriate based on BLU-222 Monotherapy arm along with Ribociclib and Fulvestrant at the approved doses. Dose Expansion: Oral dose of BLU-222 as determined during dose escalation and approved doses of Ribociclib and Fulvestrant	Drug: BLU-222; Oral administration; Drug: Fulvestrant; Intra muscular administration; Drug: Ribociclib; Oral administration
Experimental: BLU-222 + Carboplatin; Dose Escalation: Multiple doses for BLU-222 for oral administration at doses deemed appropriate based on BLU-222 Monotherapy arm and multiple doses of Carboplatin at the approved dose. Dose Expansion: Oral dose of BLU-222 as determined during Dose Escalation and Carboplatin IV infusion at approved dose	Drug: BLU-222; Oral administration; Drug: Carboplatin; IV Infusion
Experimental: BLU-222 + Fulvestrant; Dose Expansion: Oral dose of BLU-222 as determined during Dose Escalation + fulvestrant at the approved dose	Drug: BLU-222; Oral administration; Drug: Fulvestrant; Intra muscular administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
[Phase 1] Determine the maximum tolerated dose (MTD) of BLU-222	Approximately 21 months
[Phase 1] Determine the recommended Phase 2 dose (RP2D) of BLU-222	Approximately 21 months
[Phase 1] Rate and severity of adverse events	Approximately 21 months
[Phase 2] Overall response rate (ORR)	Approximately 43 months
[Phase 2] Rate and severity of adverse events	Approximately 43 months

Secondary Outcome Measures

Outcome Measure	Time Frame
[Phase 1] Overall response rate (ORR)	Approximately 21 months
[Phase 1] Time of last quantifiable plasma drug concentration (Tlast)	Approximately 21 months
[Phase 1] Trough concentration (Ctrough)	Approximately 21 months
[Phase 1] Apparent volume of distribution (Vz/F)	Approximately 21 months
[Phase 1] Terminal elimination half-life (t½)	Approximately 21 months
[Phase 1] Apparent oral clearance(CL/F)	Approximately 21 months
[Phase 1] Accumulation ratio (R)	Approximately 21 months
[Phase 1 and Phase 2] Duration of Response (DOR)	Approximately 43 months
[Phase 1 and Phase 2] Change in CA-125 levels	Approximately 43 months
[Phase 1 and Phase 2] Disease control rate (DCR)	Approximately 43 months
[Phase 1 and Phase 2] Clinical benefit rate (CBR)	Approximately 43 months
[Phase 2] Overall survival (OS)	Approximately 43 months
[Phase 1] Area under the plasma concentration time curve from time 0 to 12 hours (AUC0-12)	Approximately 21 months
[Phase 1] Area under the plasma concentration time curve from time 0 to 24 hours (AUC0-24)	Approximately 21 months
[Phase 1] To assess treatment-induced modulation of biomarkers	Approximately 21 months
[Phase 1 and Phase 2] Progression free survival (PFS)	Approximately 43 months
[Phase 1 and Phase 2] Maximum plasma drug concentration (Cmax)	Approximately 43 months
[Phase 1 and Phase 2] Time to maximum plasma drug concentration (Tmax)	Approximately 43 months
[Phase 1 and Phase 2] Last measurable concentration (Clast)	Approximately 43 months
[Phase 1 and Phase 2] Area under the concentration-time curve from time 0 to the time of the last measured concentration AUC(0-last)	Approximately 43 months

Collaborators and Investigators

• Sponsor: Blueprint Medicines Corporation

Study record dates

Study Major Dates

• Study Start (Actual): April 7, 2022
• Primary Completion (Estimated): November 30, 2025
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: January 25, 2022
• First Submitted That Met QC Criteria: February 11, 2022
• First Posted (Actual): February 23, 2022

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 22, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Carboplatin; Ribociclib; Fulvestrant; Platinum-refractory; CDK2; CCNE1; Platinum-resistance; CDK4/6i; ER+ Breast Cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Breast Diseases; Neoplasms, Complex and Mixed; Sarcoma; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Breast Neoplasms; Endometrial Neoplasms; Carcinosarcoma; Mixed Tumor, Mullerian; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Carboplatin; Fulvestrant
• Other Study ID Numbers: BLU-222-1101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No