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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Endometrial Cancer, Advanced Solid Tumors, HR+ Breast Cancer, CCNE1 Amplification, HER2-negative Breast Cancer, Ovarian Cancer, Gastric Cancer, Esophageal Adenocarcinoma, Carcinosarcoma

Intervention / Treatment
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* Drug: BLU-222
* Drug: Carboplatin
* Drug: Ribociclib
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced solid tumors that has progressed beyond standard of care OR HR+ HER2- BC that has progressed following treatment with a CDK4/6 inhibitor OR Endometrial and gastric cancer that has progressed after at least 2 prior therapies (including one prior platinum therapy) OR Platinum refractory or platinum resistant ovarian cancer CCNE1 amplified tumors that have progressed beyond standard of care Exclusion Criteria: Have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis. 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. 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. Have known intracranial hemorrhage and/or bleeding diatheses. Have clinically active ongoing ILD of any etiology, including drug-induced ILD, and radiation pneumonitis within 28 days prior to initiation of study treatment. 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. 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. 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). 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. 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). Requires treatment with a prohibited medication or herbal remedy that cannot be discontinued at least 2 weeks before the start of study drug administration. 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). Unwilling or unable to comply with scheduled visits, study drug administration plan, laboratory tests, or other study procedures and study restrictions. 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 Patient is a pregnant female

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BLU-222 Monotherapy<br>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<br>* Oral administration<br>|
| Experimental: BLU-222 + Carboplatin<br>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<br>* Oral administration<br>Drug: Carboplatin<br>* IV Infusion<br>|
| Experimental: BLU-222 + Ribociclib + Fulvestrant<br>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<br>* Oral administration<br>Drug: Ribociclib<br>* Oral administration<br>Drug: Fulvestrant<br>* Intra muscular administration<br>|
| Experimental: BLU-222 + Fulvestrant<br>Dose Expansion: Oral dose of BLU-222 as determined during Dose Escalation + fulvestrant at the approved dose | Drug: BLU-222<br>* Oral administration<br>Drug: Fulvestrant<br>* Intra muscular administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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] 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] 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] To assess treatment-induced modulation of biomarkers |  | Approximately 21 months | 
| [Phase 1 and Phase 2] Duration of Response (DOR) |  | 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 1 and Phase 2] Progression free survival (PFS) |  | Approximately 43 months | 
| [Phase 1 and Phase 2] Change in CA-125 levels |  | 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 | 
| [Phase 2] Overall survival (OS) |  | Approximately 43 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CDK2, CCNE1, Platinum-resistance, Platinum-refractory, CDK4/6i, Ribociclib, Carboplatin, Fulvestrant, ER+ Breast Cancer