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
Overview
- Phase
- Phase 1
- Intervention
- BLU-222
- Conditions
- Advanced Solid Tumors
- Sponsor
- Blueprint Medicines Corporation
- Enrollment
- 50
- Locations
- 23
- Primary Endpoint
- [Phase 1] Determine the recommended Phase 2 dose (RP2D) of BLU-222
- Status
- Terminated
- Last Updated
- 5 months ago
Overview
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 anticancer activity of BLU-222, a selective inhibitor of CDK2.
Investigators
Eligibility Criteria
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.
Arms & Interventions
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
Intervention: BLU-222
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
Intervention: BLU-222
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
Intervention: Carboplatin
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
Intervention: BLU-222
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
Intervention: Ribociclib
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
Intervention: Fulvestrant
BLU-222 + Fulvestrant
Dose Expansion: Oral dose of BLU-222 as determined during Dose Escalation + fulvestrant at the approved dose
Intervention: BLU-222
BLU-222 + Fulvestrant
Dose Expansion: Oral dose of BLU-222 as determined during Dose Escalation + fulvestrant at the approved dose
Intervention: Fulvestrant
Outcomes
Primary Outcomes
[Phase 1] Determine the recommended Phase 2 dose (RP2D) of BLU-222
Time Frame: Approximately 21 months
[Phase 1] Determine the maximum tolerated dose (MTD) of BLU-222
Time Frame: Approximately 21 months
[Phase 1] Rate and severity of adverse events
Time Frame: Approximately 21 months
[Phase 2] Overall response rate (ORR)
Time Frame: Approximately 43 months
[Phase 2] Rate and severity of adverse events
Time Frame: Approximately 43 months
Secondary Outcomes
- [Phase 1] Apparent volume of distribution (Vz/F)(Approximately 21 months)
- [Phase 1] Accumulation ratio (R)(Approximately 21 months)
- [Phase 1 and Phase 2] Time to maximum plasma drug concentration (Tmax)(Approximately 43 months)
- [Phase 1] Terminal elimination half-life (t½)(Approximately 21 months)
- [Phase 1] Overall response rate (ORR)(Approximately 21 months)
- [Phase 1 and Phase 2] Duration of Response (DOR)(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] 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] To assess treatment-induced modulation of biomarkers(Approximately 21 months)
- [Phase 1 and Phase 2] Disease control rate (DCR)(Approximately 43 months)
- [Phase 1 and Phase 2] Last measurable concentration (Clast)(Approximately 43 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 oral clearance(CL/F)(Approximately 21 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] Area under the concentration-time curve from time 0 to the time of the last measured concentration AUC(0-last)(Approximately 43 months)