A Phase 1/2 Study of Sonodynamic Therapy Using SONALA-001 and Exablate 4000 Type 2 in Patients With DIPG

Inclusion Criteria:

1. Newly diagnosed, radiographically typical DIPG, defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons and without evidence of dissemination, are eligible with or without histologic confirmation.

   • Subjects with pontine lesions that do not meet radiographic criteria will be eligible if there is histologic confirmation of DIPG.
   • Subjects may be asked to agree to provide access to previously obtained biopsy results.
   • If tumor status is unknown or archival tumor tissue is not available, subjects may be asked to agree to submit a post-mortem biopsy specimen to enable molecular profiling of tumor.
2. Prior treatment consisting of a minimum of 54 Gy standard focal radiotherapy administered over 42-49 days.
3. Must be ≥ 4 weeks and ≤ 24 weeks post radiotherapy and must have recovered from acute effects to CTCAE Grade 1 or baseline prior to Day 1.
4. Must have stable to improved imaging by RAPNO criteria and be on a stable to decreasing dose of steroids (maximum dexamethasone of 1 mg/m^2/day) prior to Day 1, as obtained during the Screening period.
5. A minimum head circumference of 52 cm. Subjects with a minimum head circumference of 52 cm, younger than 5 years old, may be eligible after discussion with the medical monitor.
6. An Overall Skull Density Ratio greater than 0.45 (±0.05) as calculated from the screening CT.
7. Females of childbearing potential (FOCP) must have a negative serum or urine 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, injectable, transdermal or intravaginal) or intrauterine device (IUD) for at least one week prior to ALA SDT, 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 ALA SDT 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 study entry and must not change their dosing regimen during the study.
8. Ability to provide written, signed, and dated (personally or via a legally authorized representative) informed consent/and assent at screening as applicable to participate in the study.
9. Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within 14 days of Visit 1 must be ≥ 50%. Subjects who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

10. Subjects must have adequate organ and marrow function as defined below:

    • Absolute neutrophil count ≥ 1,000/mm^3, without the use of GCSF within 7 days prior to Day 1.
    • Platelets ≥ 100,000/ mm^3 (unsupported, defined as no platelet transfusion within 7 days prior to Day 1)
    • Hemoglobin ≥ 8 g/dl (may have received last transfusion within 7 days prior to Day 1.)
    • Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN)
    • 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
    • Renal Function as defined below:
    • Age 5-17 years: GFR ≥ 70 mL/min/1.73m2as estimated by Schwartz formula (Schwartz, 2009). If eGFR is abnormal for age based on Schwartz formula, accurate measurement should be obtained by 24 hour creatinine clearance.
    • Age ≥ 18 years: Creatinine clearance (CLcr) ≥ 60 mL/min/1.73m2as estimated by the Cockcroft-Gault (C-G) equation. If estimated CLCr is abnormal, accurate measurement should be obtained by 24 hour creatinine clearance.

11. Cardiac Function as defined below:

    • Left ventricular ejection fraction ≥ 50 by gated radionuclide study OR shortening fraction of ≥ 27% by echocardiogram
    • Presence of no ventricular arrhythmias except for benign premature ventricular contractions.
    • QTc (Frideriica) interval < 450 ms.
12. All colony-forming growth factor(s) (i.e., filgrastim, sargramostim or erythropoietin) must have been discontinued for at least 7 days prior to Day 1 or 14 days if PEG formulations were received.
13. An understanding, ability, and willingness to fully comply with study procedures and restrictions.

Exclusion Criteria:

1. Evidence of progressive disease by radiologic criteria (RAPNO)
2. Increasing steroid dose prior to Day 1
3. Diagnosis of porphyria
4. Hypersensitivity against porphyrins
5. Current or relevant history of other malignancy, physical or psychiatric illness, any medical disorder that may require treatment or make the subject unlikely to fully complete the study, or any condition that presents undue risk from the investigational product or procedures
6. Known history of human immunodeficiency virus (HIV), hepatitis B or C infection, or any active systemic infection
7. 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
8. Prior or concurrent therapy with any other anticancer (including radiotherapy) or investigational drug or other investigational intervention.
9. Use of herbal and fish oil supplements: use of herbal supplements within 7 days prior to Visit 1 are excluded. Use of fish oil supplements within 24 hours of Visit 1 are allowed and if the subject's clotting parameters fall within normal limits, the subject is eligible for entry into the study.
10. Use of blood thinning agents within 7 days prior to Visit 1
11. Significant acute deterioration in neurologic status within 7 days prior to Day 1, in the opinion of the investigator
12. Inability to undergo MRI (e.g., presence of a pacemaker)
13. Pregnancy or breastfeeding
14. An Overall Skull Density Ratio of 0.45 (±0.05) or less as calculated from the screening CT
15. 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.