Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations

• Status: Not yet recruiting
• Trial end date: 2024-12-23
• Target enrollment: 0
• Participant gender: All

Summary

This is a Phase 1/2, open-label study of the safety, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity of single-agent BLU-451. All subjects will receive BLU-451 as a single agent administered once daily (QD) or twice daily (BID) on a 21-day treatment cycle.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Blueprint Medicines Corporation

Criteria

INCLUSION CRITERIA:

1. Males & females age ≥ 18 years at time of signing the informed consent document.

2. Histologically or cytologically confirmed recurrent/metastatic NSCLC (Phase 1 and Phase 2) or other cancer except for primary CNS tumors (Phase 1 only).

3. Documented EGFR Ex20ins based on NGS or PCR testing of tumor or liquid biopsy. ° For Phase 1 only, cancers with EGFR Exon 18 G719X or Exon 21 L861Q mutation are eligible with Sponsor approval. Other EGFR mutations (e.g., L858R or Exon 19 deletion) may be eligible if T790M mutation is not present and if approved by the Sponsor Medical Monitor.

4. Prior treatment in the recurrent/metastatic disease setting

(4a) Phase 1 NSCLC subjects:

° Platinum-based chemotherapy or other chemotherapy regimen if platinum-based chemotherapy is contraindicated.

° Prior treatment with up to 1 prior line of EGFR Ex20ins-targeted therapy is allowed but not required. EGFR Ex20ins targeted therapy includes amivantamab or mobocertinib. Other agents including investigational EGFR Ex20ins-targeted therapy or other approved EGFR-targeted TKIs are allowed with Sponsor Medical Monitor approval.

• Prior ICI (e.g., programmed cell death protein 1 [PD-1] or PD-L1 inhibitors) are allowed but not required. If a subject with NSCLC has not received a prior ICI, documentation must be provided in the medical record or informed consent that this has been discussed as a therapeutic option.

(4b) Phase 1 other cancers:

• Any approved standard therapy that is available to the subject that is known to confer clinical benefit, unless this therapy is contraindicated, intolerable to the patient, or is declined by the subject.

(4c) Phase 2: All Cohorts:

• Platinum-based chemotherapy or other chemotherapy regimen if platinum-based chemotherapy is contraindicated.

• Prior ICI (e.g., PD-1 or PD-L1 inhibitors) are allowed but not required. If a subject with NSCLC has not received a prior ICI, documentation must be provided in the medical record or informed consent that this has been discussed as a therapeutic option.

Phase 2: Cohort 2A:

° Prior treatment with one EGFR Ex20ins targeted therapy including amivantamab or mobocertinib. Other agents including investigational EGFR Ex20ins-targeted therapy or other approved EGFR-targeted TKIs are allowed with Sponsor Medical Monitor approval.

Phase 2: Cohort 2B:

° No prior treatment with an EGFR Ex20ins-targeted agent including amivantamab, mobocertinib, or other EGFR Ex20ins-targeted therapy.

Phase 2: Cohort 2C:

• Prior treatment with up to one line of EGFR EX20ins-targeted therapy is allowed but not required

(5) Progression on or after or intolerance to most recent systemic therapy.

(6) Evaluable disease (Phase 1 only) or measurable disease (Phase 1 and Phase 2) per RECIST v1.1.

(7) Brain Metastases:

(7a) Phase 1 and 2 (all cohorts):

• Stable, treated brain metastases (defined as prior local treatment > 28 days prior to first dose of study drug and no evidence of progression at baseline brain MRI) are allowed but not required. Corticosteroid use at a dose of ≤ 2 mg/day dexamethasone or equivalent with no change in steroid dose for > 2 weeks prior to first dose of study drug is allowed with Sponsor Medical Monitor approval.

(7b) Phase 1: Dose Expansion Cohort in Subjects with Active Brain Metastases

• Asymptomatic active brain metastases ≤ 2 cm in size not requiring corticosteroids for symptom management at a dose > 2 mg/day dexamethasone or equivalent.

(i) Asymptomatic active brain metastases are defined as lesions not associated with clinical symptoms, or equivalent, no change in corticosteroid dose < 14 days prior to start of study drug, and no immediate need for treatment for based on anatomic location.

Phase 1: All other Phase 1 Cohorts:

° Subjects with asymptomatic active brain metastases ≤ 2 cm in size and no systemic corticosteroids > 2mg/day dexamethasone or equivalent for symptom management or change in corticosteroid dose < 14 days prior to start of study drug, may be eligible for enrollment into cohorts at dose levels where clinical activity has been demonstrated (e.g., target lesion shrinkage > 30%) with approval from the Sponsor Medical Monitor.

(7c) Phase 2: Cohort 2C (NSCLC subjects with active brain metastases):

• Measurable (per RANO-BM) asymptomatic active brain metastases ≤ 2 cm in size not requiring corticosteroids for symptom management at a dose > 2 mg/day dexamethasone or equivalent.

(8) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

(9) All toxicity resulting from prior cancer therapies must have resolved to NCI CTCAE v5.0 Grade ≤ 1 or pre-therapy baseline with the exception of alopecia or ≤ Grade 2 neuropathy (except for laboratory parameters outlined below).

(10) Adequate hematological, renal, and hepatic function (assessment performed within 14 days prior to first dose of BLU-451).

• ANC ≥ 1.0 × 109/L

• Platelet count ≥ 75 × 109/L (transfusion > 14 days prior to first dose of study drug allowed)

• Hemoglobin ≥ 9.0 g/dL (transfusion > 14 days prior to first dose of study drug allowed)

• ALT ≤ 3 × ULN (if liver metastases are present, ≤ 5.0 × ULN)

• AST ≤ 3 × ULN (if liver metastases are present, ≤ 5.0 × ULN)

• Total bilirubin ≤ 1.5 × ULN (subjects with known Gilbert's Syndrome may enroll with 2.5 × ULN provided the direct bilirubin is ≤ 1.5 mg/dL)

• Calculated glomerular filtration rate ≥ 60 mL/min to be calculated per by Cockcroft-Gault formula (Appendix D)

• Prothrombin time (PT) and/or International Normalized Ratio (INR) and partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 × ULN

EXCLUSION CRITERIA:

1. Known ROS, RAF, ALK or EGFR C797S mutation.

2. Treatment with any of the following:

(2a) An EGFR TKI ≤ 5 days or 5X the terminal phase elimination half-lives, whichever is longer, prior to the first dose of study drug BLU-451.

(2b) Systemic anticancer treatment other than ICI (excluding EGFR-TKIs as described above) ≤ 14 days prior to the first dose of study drug BLU-451.

(2c) Immunotherapy with ICI ≤ 28 days prior to the first dose of study drug BLU-451.

(2d) Definitive radiotherapy < 28 days and palliative radiation ≤ 14 days prior to the first dose of study drug BLU-451. If previously irradiated, lesions must have demonstrated clear-cut progression prior to being eligible for evaluation as target lesions.

(3) Brain metastases:

(3a) Symptomatic brain metastases, any lesion in an anatomic location thought to require immediate treatment, any lesion > 2 cm in size unless specifically approved by the Sponsor Medical Monitor, radiation treatment for brain metastases < 28 days prior to first dose of study drug, or corticosteroids > 2 mg/day dexamethasone or equivalent for treatment of brain metastases < 14 days prior to first dose of study drug.

(4) Known leptomeningeal disease (LMD). If LMD has been reported radiographically on baseline MRI, but is not suspected clinically by the Investigator, the subject must be free of neurological symptoms of LMD.

(5) New intracranial hemorrhage within 28 days prior to the start of study treatment. If punctate intracranial hemorrhages < 3 mm are present, the subject may be eligible with Sponsor approval.

(6) QT interval calculated using the Fridericia's formula (QTcF) > 470 msec, or history or family history of congenital long QT syndrome.

(7) History of myocardial infarction or unstable angina within 6 months prior to enrollment, or clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension, or any history of symptomatic congestive heart failure.

(8) Past medical history of interstitial lung disease (ILD), drug induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD.

(9) Known chronic liver disease, including the following:

(9a) Acute or chronic hepatitis B.

(9b) Chronic infection with hepatitis C except for subjects who have completed curative viral therapy ≥ 12 weeks prior to enrollment, and viral load is negative.

(10) Active ocular disorders requiring treatment, such as corneal ulcer, herpetic keratitis, uncontrolled glaucoma (stable topical medication is allowed), uncontrolled diabetic retinopathy, iritis or vitritis, or papilledema.

(11) Acute or chronic uncontrolled renal disease, pancreatitis, or liver disease (with exception of subjects with Gilbert's Syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per Investigator assessment).

(12) Major surgery (excluding placement of vascular access) ≤ 28 days of the first dose of study drug BLU-451.

(13) Other prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.

(14) Pregnant or breastfeeding. Subjects with elevated human chorionic gonadotropin (HCG) due to underlying malignancy may be eligible as long as confirmed not to be pregnant.

(15) Any other significant medical condition or social situation that, in the opinion of the Investigator or Medical Monitor, could impact safety or compliance with study procedures, including inability to swallow pills.

(16) Have received or will receive a live vaccine ≤ 28 days or coronavirus disease 2019 (COVID-19) vaccine ≤ 14 days prior to the first dose of BLU-451. Seasonal flu vaccines that do not contain live vaccine are permitted.