A Study of Sonodynamic Therapy Using SONALA-001 and Exablate 4000 Type 2.0 in Subjects With Recurrent GBM

A Phase 1/2 Dose Escalation and Expansion Study of Sonodynamic Therapy With SONALA-001 in Combination With Exablate 4000 Type 2.0 MR-Guided Focused Ultrasound in Subjects With Progressive or Recurrent Glioblastoma Multiforme (rGBM)

The primary objectives of this trial are to evaluate the safety, dose-limiting toxicities, maximum tolerated dose (MTD), maximum administered dose (MAD) and recommended Phase 2 dose (RP2D) for future study after a single treatment of SONALA-001 in combination with MRgFUS and to evaluate preliminary efficacy of sonodynamic therapy (SDT) using SONALA-001 and Exablate Type 2.0 device in subjects with progressive or recurrent GBM.

Inclusion Criteria

1. Must be 18 years or older at the screening visit.

2. Histologically proven GBM (as defined in 2021 WHO Classification of Tumors of the Central Nervous System; Louis, Perry, et al. 2021) that has recurred or progressed, and for which resection is not indicated.

3. Tumor must be located in the supratentorial or cerebellar region. Tumors with infratentorial locations require consultation with the Sponsor/Medical Monitor to confirm suitability for treatment.

4. Previous treatment with standard of care radiotherapy (RT) and temozolomide (temozolomide required only if tumor has at least partial methylation of the O6-methylguanine-DNA methyltransferase promoter). Temozolomide should be administered concurrent with RT and adjuvantly for newly diagnosed disease unless intolerant or ineligible for treatment.

5. No recurrence within 4 weeks of completion of RT, defined from the imaging assessment immediately after completion of RT.

6. Up to two prior systemic treatments for recurrent or progressing disease.

7. If receiving corticosteroids, must be maintained on a stable or decreasing dosage of steroids for at least 7 days prior to C1D1.

8. Karnofsky Performance Score (KPS) ≥ 70 assessed within 14 days of C1D1.

9. Must have adequate organ and marrow function as defined below:

   • Absolute neutrophil count ≥ 1.5 ×10⁹/L (1,500/μL), without the use of myeloid growth factors (e.g., granulocyte-colony stimulating factor) within 7 days prior to C1D1 for short acting growth factors and 14 days for long-acting growth factors to meet eligibility.
   • Platelets ≥ 75 × 10⁹/L (100,000/μL), unsupported, defined as no platelet transfusion within 7 days prior to C1D1.
   • Hemoglobin ≥ 9 g/dL maintained without the need for erythropoietin stimulating agents; subjects that require transfusion or growth factors need to demonstrate stable hemoglobin of ≥ 9 g/dL over at least a 7-day period immediately prior to C1D1.
   • Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN), in subjects with Gilbert syndrome, total bilirubin >1.5 ULN as long as direct bilirubin is normal.
   • ALT (SGPT) < 3 x institutional ULN.
   • AST (SGOT) < 3 x institutional ULN.
   • Albumin ≥ 3 g/dl.
   • Potassium ≥ lower limit of normal (LLN).
   • Serum total calcium (correct for serum albumin) or ionized calcium ≥ LLN.
   • Estimated creatinine clearance (CrCl) by the Cockcroft-Gault (C-G) equation or measured ≥ 60 mL/min. Actual body weight will be used for calculation of the C-G equation. If estimated CrCl is abnormal, accurate measurement should be obtained by 24-hour urine collection to measure CrCl.

10. All colony-forming growth factor(s) (i.e., filgrastim, sargramostim or erythropoietin) must have been discontinued for at least 7 days prior to C1D1 or 14 days if pegylated (PEG) formulations were received.

11. Have a life expectancy of at least 12 weeks.

12. An understanding, ability, and willingness to fully comply with study procedures and restrictions.

13. Ability to provide written, signed, and dated (personally or via a legally authorized representative) informed consent at screening as applicable to participate in the study.

14. Females of childbearing potential (FOCP) must have a negative serum pregnancy test at screening. Subjects of childbearing or child-fathering potential must be willing to use highly effective birth control during the entire study. Acceptable forms of birth control include hormonal contraceptives (oral, depot, injectable, transdermal, or intravaginal) or intrauterine device (IUD) for at least one week prior to study treatment, condom and spermicidal or diaphragm and spermicidal. Other acceptable forms of birth control include a) abstinence for subjects who are not sexually active or b) if the subject is in a monogamous relationship with a partner who is sterile (e.g., vasectomy performed at least 6 months prior to subject's first study treatment). Subjects who become sexually active or begin to have relations with a partner who is not sterile during the trial must agree to use an effective form of birth control for the duration of the study. FOCP taking hormonal therapy must be on treatment for at least 12 weeks prior to C1D1 and must not change their dosing regimen during the study.

Exclusion Criteria

Target disease

1. Tumor in the brainstem (not including fluid-attenuated inversion recover [FLAIR] changes), or a diagnosis of gliomatosis cerebri (highly infiltrative T2 hyperintense tumor with ill-defined margins encompassing at least three lobes of the brain). Tumors with infratentorial locations require consultation with the Sponsor/Medical Monitor to confirm suitability for treatment.

   Concurrent or prior therapy

2. Subjects who have not recovered to Grade 1 or baseline from AEs (CTCAE v 5.0, or most current) related to prior anticancer therapy (excluding alopecia, lymphopenia, peripheral neuropathy, and ototoxicity, which are excluded only if ≥ Grade 3).

3. Prior systemic anticancer treatment:

   1. Chemotherapy, biologic therapy (i.e., small molecular inhibitors), monoclonal antibodies, investigational agents) within 21 days or 5 half-lives (whichever is shorter), prior to C1D1 or per below:
   2. Nitrosoureas or bevacizumab within 2 weeks prior to C1D1
   3. If a subject is receiving an anti-PD-1 or anti-PD-L1 antibody on a shorter frequency (i.e., every two weeks), then the subject is eligible if last dose was within 2 weeks prior to C1D1.

4. Prior therapy such as interstitial brachytherapy, Gliadel® Wafers (carmustine implants), laser interstitial thermal therapy (LITT), or Optune therapy, within 4 weeks prior to C1D1 or as long as there are any ongoing treatment-related CTCAE Grade ≥2 AEs or intolerable side effects.

5. Radiation therapy within 4 weeks prior to C1D1.

6. Use of potentially phototoxic substances (e.g., St. John's wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, tetracyclines, sulfonamides, quinolones, hypericin extracts, topical preparations containing ALA) within 24 hours before and after SONALA-001 infusion.

7. Use of fish oil supplements within 24 hours of C1D1 is allowed if the subject's clotting parameters fall within normal limits.

8. Use of blood thinning agents within 7 days prior to C1D1. Subjects whose medical condition does not permit discontinuation of this therapy are excluded.

9. Prior major surgery within 3 weeks prior to C1D1. Major surgery is defined as any significantly invasive procedure into a major body cavity (abdomen, cranium etc.) and/or surgery requiring extensive recuperation (joint replacement). Please discuss with the Sponsor/Medical Monitor if there are any questions.

   Medical history and concurrent disease

10. Diagnosis of porphyria.

11. Hypersensitivity to porphyrins.

12. Known history of allergy to gadolinium contrast agents.

13. Inability to undergo MRI (e.g., verify the model of the pacemaker for ability to be used with MRI).

14. Malignant disease, other than that being treated in this study. Note: Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Other exceptions include malignancies that were treated curatively and have not recurred within 2 years prior to C1D1 and any malignancy considered indolent or that do not require therapy.

15. Significant acute deterioration in neurologic status within 7 days prior to C1D1, in the opinion of the investigator, including but not limited to new onset seizures and/or increasing doses of corticosteroids.

16. Uncontrolled concurrent illness including, but not limited to:

    • ongoing or active infection.
    • transfusion dependent thrombocytopenia or anemia that prevent meeting hematological inclusion criteria.
    • psychiatric illness/social situations that would limit compliance with study requirements.

17. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.

18. Pregnancy or breastfeeding.

19. A known or underlying medical condition that, in the opinion of the investigator or Sponsor, could make the administration of investigational drug/ study treatment hazardous to the subject, or could adversely affect the ability of the subject to comply with or tolerate the study.

20. Inability to participate in the opinion of the investigator, by being unwilling or unable to return for required follow-up visits or to obtain follow-up studies to assess toxicity to therapy or to adhere to study plan, procedures, and restrictions.