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

This is an interventional treatment trial for Lung Neoplasm Malignant focused on measuring protein kinase inhibitors, thoracic neoplasms Read More

INCLUSION CRITERIA:

1. Males & females age ≥ 18 years at time of signing the informed consent document.
2. Histologically or cytologically confirmed metastatic NSCLC stage IVA & IVB per AJCC 8th Edition (Phase 1 and Phase 2) or other metastatic cancers except for primary CNS tumors (Phase 1 only).

3. Documented EGFR Ex20ins based on NGS testing of tumor or liquid biopsy.

   • For Phase 1 only, cancers with EGFR Exon 18 G719X or Exon 21 L861Q mutation that have failed standard of care therapy, 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 at least 1 EGFR TKI was tried and failed and if approved by the Sponsor Medical Monitor.

4. Prior treatment in the recurrent/metastatic disease setting:

   Phase 1 NSCLC patients:

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

   ° Prior treatment with at least 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 patient 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 1 other cancers:

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

   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 patient 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 at least 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. Phase 1 and 2 Cohorts A and B: Brain metastases are permitted but not required. Brain metastases that are not associated with symptoms and do not require increasing doses of corticosteroids to control the CNS disease are allowed.

   ° Phase 2 Cohort C (NSCLC patients with measurable brain metastases): Patients are required to have at least 1 measurable brain lesion (per RECIST 1.1)

8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
9. Patients enrolled in Phase 1 at doses expected to result in efficacious exposure levels must be willing to undergo on-treatment biopsy.
10. 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).

11. 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 (patients 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 Cockcroft-Gault formula (Appendix D)
    • PT and/or International Normalized Ratio (INR) and PTT or activated PTT (aPTT) ≤ 1.5 × ULN

EXCLUSION CRITERIA:

1. Have disease that is suitable for local therapy administered with curative intent.
2. Have tumor that harbors known driver alterations (including, but not limited to ROS, BRAF V600E, ALK, RET, HER2, MET, KRAS, NTRK1/2/3, or EGFR C797X mutation).
3. Have NSCLC with mixed cell histology or a tumor with known histologic transformation (NSCLC to SCLC, SCLC to NSCLC, or epithelial to mesenchymal transition).
4. Treatment with any of the following:

4a. 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.

4b. Systemic anticancer treatment other than ICI (excluding EGFR-TKIs as described above) ≤ 14 days prior to the first dose of study drug BLU-451.

4c. Immunotherapy with an ICI or antibody therapy (including bi-specific antibodies) ≤ 28 days prior to the first dose of study drug BLU-451.

4d. 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.

5. Brain metastases: 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 brain metastases that require increasing doses of corticosteroids.

6. Leptomeningeal disease.

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

8. QT interval calculated using the Fridericia's formula (QTcF) > 450 msec, or history or family history of congenital long QT syndrome.

9. 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.

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

11. Known chronic liver disease, including the following: 11a. Acute or chronic hepatitis B. 11b. Chronic infection with hepatitis C except for patients who have completed curative viral therapy ≥ 12 weeks prior to enrollment, and viral load is negative.

12. 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.

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

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

15. 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.

16. 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.

17. 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.

18. Patient is a pregnant female, as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test consistent with pregnancy, obtained within 7 days prior to the first dose of study drug.

19. Is a female who is breastfeeding.