Study of Sonodynamic Therapy Using SONALA-001 and Exablate 4000 Type 2 in Subjects With Progressive or Recurrent GBM

• ClinicalTrials.gov Identifier: NCT05370508
• Recruitment Status: Recruiting
• First Posted: May 11, 2022
• Last Update Posted: June 1, 2023
• Sponsor: SonALAsense, Inc.
• Information provided by (Responsible Party): SonALAsense, Inc.

Study Description

Brief Summary:

The primary objectives of this trial are to evaluate the safety, dose-limiting toxicities, recommended Phase 2 schedule, and preliminary efficacy of sonodynamic therapy (SDT) using SONALA-001 and Exablate Type-2 device in subjects with progressive or recurrent GBM.

Condition or disease	Intervention/treatment	Phase
Recurrent GBM	Combination Product: SONALA-001 (ALA) and MR-Guided Focused Ultrasound device (MRgFUS)	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 44 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: February 6, 2023
• Estimated Primary Completion Date: April 14, 2026
• Estimated Study Completion Date: November 30, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; 10 mg/kg IV SONALA-001 (ALA) and MR-guided Focused Ultrasound (MRgFUS) Energy Level 1	Combination Product: SONALA-001 (ALA) and MR-Guided Focused Ultrasound device (MRgFUS); SONALA-001(ALA) given 6-9 hours prior to receiving the MRgFUS; Other Name: Exablate Type-2
Experimental: Cohort 2; 10 mg/kg IV SONALA-001 (ALA) and MR-guided Focused Ultrasound (MRgFUS) Energy Level 2	Combination Product: SONALA-001 (ALA) and MR-Guided Focused Ultrasound device (MRgFUS); SONALA-001(ALA) given 6-9 hours prior to receiving the MRgFUS; Other Name: Exablate Type-2
Experimental: Cohort 3; 10 mg/kg IV SONALA-001 (ALA) and MR-guided Focused Ultrasound (MRgFUS) Energy Level 3	Combination Product: SONALA-001 (ALA) and MR-Guided Focused Ultrasound device (MRgFUS); SONALA-001(ALA) given 6-9 hours prior to receiving the MRgFUS; Other Name: Exablate Type-2
Experimental: Cohort 4; 10 mg/kg IV SONALA-001 (ALA) and MR-guided Focused Ultrasound (MRgFUS) Energy Level 4	Combination Product: SONALA-001 (ALA) and MR-Guided Focused Ultrasound device (MRgFUS); SONALA-001(ALA) given 6-9 hours prior to receiving the MRgFUS; Other Name: Exablate Type-2
Experimental: Cohort 5; 20 mg/kg IV SONALA-001 (ALA) and MR-guided Focused Ultrasound (MRgFUS) Energy Level 3	Combination Product: SONALA-001 (ALA) and MR-Guided Focused Ultrasound device (MRgFUS); SONALA-001(ALA) given 6-9 hours prior to receiving the MRgFUS; Other Name: Exablate Type-2
Experimental: Cohort 6; 20 mg/kg IV SONALA-001 (ALA) and MR-guided Focused Ultrasound (MRgFUS) Energy Level 4	Combination Product: SONALA-001 (ALA) and MR-Guided Focused Ultrasound device (MRgFUS); SONALA-001(ALA) given 6-9 hours prior to receiving the MRgFUS; Other Name: Exablate Type-2

Outcome Measures

Primary Outcome Measures :

1. Safety and Tolerability of SONALA-001 SDT as assessed by the frequency and severity of dose-limiting toxicities (DLTs) [ Time Frame: Day 1 to 12 months ]

   Safety and tolerability of SONALA-001 SDT

   Definitions of Dose Limiting Toxicities (DLTs):

   The DLT window is the 21-day period following the first study treatment per patient.

   DLTs are defined as the following events during the DLT window, not clearly related to underlying disease, disease progression or intercurrent illness, as determined by safety review committee:

   Any death

   Non-hematologic toxicity:

   Any CTCAE Grade 3 or higher Hy's law cases Moderate heating/burning at the scalp Grade 3 or greater neurological toxicities Evidence of clinically significant tissue damage outside the region targeted by MRgFUS Grade 3 or greater photosensitivity in subjects strictly following restrictions to light exposure to sunlight or room lights for 48 hours after SONALA-001 administration

   Hematologic toxicity:

   Grade 4 neutropenia for more than 7 days Grade 3 or higher thrombocytopenia with clinically significant bleeding Neutropenic fever

2. Safety and Tolerability of SONALA-001 SDT as assessed by the number of subjects with Adverse Events (AEs) [ Time Frame: Day 1 to 12 months ]

   Safety and tolerability of SONALA-001 SDT

   Definition of Adverse Event (AE) An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after the first dose of investigational drug. Abnormal laboratory values or test results occurring after the first dose of investigational drug constitute AEs only if they induce clinical signs or symptoms, are considered clinically significant, require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem cell support) except electrolytes which require replacement therapy and correct to CTCAE grade ≤ 1 within 48 hours unless considered life-threatening, or require changes in study medication(s).

3. Safety and Tolerability of SONALA-001 SDT as assessed by the number of subjects with abnormal hematology, chemistry, coagulation and urinalysis laboratory tests. [ Time Frame: Day 1 to 12 months ]
   Lab tests covered by CTCAE version 5.0 or most current will be graded accordingly. For lab tests covered by CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be used. For lab tests where grades are not defined by CTCAE, results will be categorized by low/normal/high classifications based on lab normal ranges or categorized by normal/abnormal for character (descriptive) lab values.
4. To determine the Maximum Administered Dose, Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of MR-Guided Focused Ultrasound (MRgFUS) energy in combination with SONALA-001 SDT in subjects with recurrent GBM [ Time Frame: Up to 3 weeks post treatment ]
5. Progression-free survival rate at 6 Months (Phase 2) [ Time Frame: 6 Months ]
   To evaluate preliminary efficacy (PFS rate at 6 months) of the RP2D of ALA SDT treatments by mRANO in subjects with recurrent GBM
6. Safety of the RP2D of ALA SDT as assessed by the number of subjects with AEs, SAEs, abnormal laboratory tests, and abnormal physical examinations [ Time Frame: Day 1 to 12 months ]
   Safety of the RP2D of ALA SDT

Secondary Outcome Measures :

1. To evaluate the pharmacokinetics (PK) of ALA and Protoporphyrin IX (PpIX) following intravenous (IV) dosing with SONALA-001 by calculating Area Under the plasma Concentration (AUC) vs. time from time 0 to the last measurable time point (AUC-t) [ Time Frame: Day 1 to 24 hours post SONALA-001 dosing ]
   Samples will be collected at 12 time points during 24 hours pre/post SONALA-001 administration.
2. To evaluate the pharmacokinetics (PK) of ALA and Protoporphyrin IX (PpIX) following intravenous (IV) dosing with SONALA-001 by calculating AUC for plasma concentration vs. time from time 0 to infinity (AUC0-∞) [ Time Frame: Day 1 to 24 hours post SONALA-001 dosing ]
   Samples will be collected at 12 time points during 24 hours pre/post SONALA-001 administration.
3. To evaluate the pharmacokinetics (PK) of ALA and Protoporphyrin IX (PpIX) following intravenous (IV) dosing with SONALA-001 by calculating AUC for plasma concentration vs. time from time 0 to time to maximum drug concentration (Tmax) [ Time Frame: Day 1 to 24 hours post SONALA-001 dosing ]
   Samples will be collected at 12 time points during 24 hours pre/post SONALA-001 administration.
4. To evaluate the pharmacokinetics (PK) of ALA and Protoporphyrin IX (PpIX) following intravenous (IV) dosing with SONALA-001 by calculating AUC for plasma concentration vs. time from time 0 to time to terminal elimination half-life (t½) [ Time Frame: Day 1 to 24 hours post SONALA-001 dosing ]
   Samples will be collected at 12 time points during 24 hours pre/post SONALA-001 administration.
5. To evaluate the pharmacokinetics (PK) of ALA and Protoporphyrin IX (PpIX) following intravenous (IV) dosing with SONALA-001 by calculating AUC for plasma concentration vs. time from time 0 to time to clearance. [ Time Frame: Day 1 to 24 hours post SONALA-001 dosing ]
   Samples will be collected at 12 time points during 24 hours pre/post SONALA-001 administration.
6. To evaluate the pharmacokinetics (PK) of ALA and Protoporphyrin IX (PpIX) following intravenous (IV) dosing with SONALA-001 by calculating AUC for plasma concentration vs. time from time 0 to time to elimination rate constant. [ Time Frame: Day 1 to 24 hours post SONALA-001 dosing ]
   Samples will be collected at 12 time points during 24 hours pre/post SONALA-001 administration.
7. To evaluate the preliminary antitumor activity Objective Response Rate (ORR): Complete Response (CR) and Partial Response (PR) by mRANO [ Time Frame: Day 1 to 12 months ]
   ORR defined as the proportion of subjects with a best overall response (BOR) of CR or PR as assessed per mRANO by investigator assessment
8. To evaluate preliminary efficacy and Duration of Response (DOR) (Phase 1) [ Time Frame: Up to 12 months ]

   DOR, defined as time from date of first documented objective response (CR or PR) to the first documented progression or death due to any cause.

   .

9. To evaluate preliminary efficacy and Overall Survival (OS) (Phase 1) [ Time Frame: Up to 12 months ]
   OS, defined as time from first dose of study treatment to death due to any cause.
10. To evaluate preliminary efficacy and Overall Response Rate (ORR) [ Time Frame: Up to 12 months ]
11. To evaluate preliminary efficacy and clinical benefit rate Clinical Benefit Rate (CBR) (Complete Response (CR), Partial Response (PR), and Stable Disease (SD) [ Time Frame: Up to 12 months ]
    CBR defined as the proportion of subjects with a BOR of CR or PR or SD.
12. To evaluate preliminary efficacy and Duration of Clinical Benefit (DOCB) (Phase 2) [ Time Frame: Up to 12 months ]
    DOCB defined as time from date of first documented objective response (CR or PR) and SD to first documented progression or death due to any cause.
13. To evaluate preliminary efficacy and Time To Response (TTR) [ Time Frame: Up to 12 months ]
    TTR, calculated as time from first dose of study treatment to first documented objective response (CR or PR).
14. To evaluate preliminary efficacy and Progression Free Survival (PFS) [ Time Frame: Up to 12 months ]
    PFS defined as time from first dose of study treatment to progression or death due to any cause.
15. To evaluate preliminary efficacy and PFS rate at 12 months [ Time Frame: Up to 12 months ]
    PFS rate at 6 months (Phase 1) and 12 months defined as the percentage of subjects without progression or death at 6 months and 12 months.
16. To evaluate preliminary efficacy and and OS (Phase 2) [ Time Frame: Up to 12 months ]
    OS, defined as time from first dose of study treatment to death due to any cause.
17. Radiographic evidence of tumor physiological changes associated with ALA SDT. [ Time Frame: Up to 12 months post SDT treatment ]
    Diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI) will be obtained to evaluate for changes in cell density and extracellular water that may reflect tumor response.
18. Radiographic evidence of tumor physiological changes associated with ALA SDT. [ Time Frame: Up to 12 months post SDT treatment ]
    Magnetic resonance (MR) perfusion with performed dynamic contract enhanced (DEC) magnetic resonance imaging (MRI) and dynamic susceptibility contrast (DSC) MRI to evaluate changes in vessel density and vascularity that may reflect treatment response.
19. Radiographic evidence of tumor physiological changes associated with ALA SDT. [ Time Frame: Up to 12 months post SDT treatment ]
    T1 maps and susceptibility weighted imaging (SWI) will be acquired immediately before and after MRgFUS application to detect regional changes in oxidative stress and free radical formation.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

1. Must be 18 years or older at screening visit.
2. Histologically proven, primary (de novo) GBM, 2021 WHO Classification of Tumors of the Central Nervous System, (Louis, Perry et al. 2021) that has recurred or progressed (first or second recurrence, including this recurrence) and resection not indicated.
3. A single recurrent or progressing tumor that must be supratentorial or cerebellar, contrast-enhancing, and bi-dimensionally measurable that is 5 mL to 30 mL in volume, based on MRI within 14 days prior to Cycle 1 Day 1.
4. Previous first-line treatment with at least 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 12 weeks of completion of RT, defined from the imaging assessment immediately after completion or RT.
6. Up to one prior systemic treatment for recurrent or progressing disease.
7. If receiving corticosteroids, must be maintained on a stable or decreasing dosage of steroids for 7 days prior to the Screening MRI scan.
8. If receiving corticosteroids, must be maintained on a stable or decreasing dosage of steroids for at least 7 days prior to Cycle 1 Day 1.
9. Karnofsky Performance Score (KPS) ≥ 70.

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

    • Absolute neutrophil count ≥ 1.5 × 10⁹/L (1,500/µL), without the use of granulocyte-colony stimulating factor within 7 days prior to Cycle 1 Day 1 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 Cycle 1 Day 1.
    • Hemoglobin ≥ 9 g/dL, subjects that require transfusion or growth factors need to demonstrate stable hemoglobin of ≥ 9 g/dL over at least a 7-day periodimmediately prior to Cycle 1 Day 1.
    • 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.
11. All colony-forming growth factor(s) (i.e., filgrastim, sargramostim or erythropoietin) must have been discontinued for at least 7 days prior to Cycle 1 Day 1 or 14 days if pegylated (PEG) formulations were received.
12. Have a life expectancy of at least 12 weeks.
13. An understanding, ability, and willingness to fully comply with study procedures and restrictions.
14. 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.
15. 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 weeksprior to Cycle 1 Day 1 and must not change their dosing regimen during the study.

Exclusion Criteria

Target disease

1. Secondary glioblastoma with IDH1 mutations (i.e., glioblastoma that progressed from low- grade diffuse astrocytoma or anaplastic astrocytoma).

2. Tumor in the brainstem (not including fluid-attenuated inversion recover [FLAIR] changes), an infratentorial tumor (except for cerebellum location), diagnosis of gliomatosis cerebri (highly infiltrative T2 hyperintense tumor with ill-defined margins encompassing at least three lobes of the brain.

   Concurrent or prior therapy

3. Prior surgical resection for progressive or rGBM.
4. 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.

5. Prior systemic anticancer treatment (i.e., chemotherapy, biologic therapy [i.e., small molecular inhibitors], monoclonal antibodies, investigational agents]) within 21 days or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1 or per below:

   • Temozolomide (low-dose, continuous administration) within 28 days prior to Cycle 1 Day 1
   • Nitrosoureas within 6 weeks prior to Cycle 1 Day 1
   • 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 within 2 weeks prior to Cycle 1 Day 1
   • Bevacizumab within 2 weeks prior to Cycle 1 Day 1
6. Prior therapy that included interstitial brachytherapy or Gliadel® Wafers (carmustine implants) for newly diagnosed GBM within 12 weeks prior to Cycle 1 Day 1. Subjects treated with interstitial brachytherapy or Gliadel Wafers at first recurrence are excluded.
7. Laser interstitial thermal therapy (LITT) within 12 weeks prior to Cycle 1 Day 1. Subjects receiving LITT at first recurrence are excluded.
8. Optune therapy for newly diagnosed GBM within 3 weeks prior to Cycle 1 Day 1. Subjects treated with Optune therapy at first recurrence are excluded.
9. Radiation therapy within 12 weeks prior to Cycle 1 Day 1.
10. Use of potentially phototoxic substances (e.g., St. John's wort, griseofulvin, thiazidediuretics, sulfonylureas, phenothiazines, tetracyclines, sulfonamides, quinolones, hypericin extracts, topical preparations containing ALA) within 24 hours before and after SONALA-001 infusion.

11. Use of herbal and fish oil supplements:

    1. Use of herbal supplements within 7 days prior to Cycle 1 Day 1 are excluded.
    2. Use of fish oil supplement within 24 hours of Cycle 1 Day 1 are allowed and if the subject's clotting parameters fall within normal limits, the subject is eligible for entry into the study.
12. Use of blood thinning agents within 7 days prior to Cycle 1 Day 1.

13. Prior major surgery within 3 weeks prior to Cycle 1 Day 1. 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 Medical Monitor if there are any questions.

    Medical history and concurrent disease

14. Diagnosis of porphyria.
15. Hypersensitivity against porphyrins.
16. Known history of allergy to gadolinium contrast agents.
17. Inability to undergo MRI (e.g., presence of a pacemaker).
18. 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 Cycle 1 Day 1 and any malignancy considered indolent and has never required therapy.
19. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by local health authority.
20. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required.
21. Significant acute deterioration in neurologic status within 7 days prior to Cycle 1 Day 1, in the opinion of the investigator including but not limited to new onset seizures and/or increasing doses of corticosteroids.

22. 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.

23. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:

    • Symptomatic congestive heart failure
    • Unstable angina pectoris or cardiac arrhythmia
    • Baseline QTcF (Fridericia) ≥ 470 milliseconds
    • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome
24. Pregnancy or breastfeeding.
25. 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.
26. 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 totherapy or to adhere to study plan, procedures, and restrictions.

Contacts and Locations

Contacts

Contact: Patient Advocacy; 510-831-2220; info@sonalasense.com

Contact: Patient Advocacy

Locations

United States, Arizona

Ivy Brain Tumor Center; Recruiting

Phoenix, Arizona, United States, 85013

Contact: Phase 0 Navigator 602-406-8605 Research@ivybraintumorcenter.org

Principal Investigator: Nader Sanai, MD

United States, Minnesota

Mayo Clinic; Recruiting

Rochester, Minnesota, United States, 55905

Contact: Clinical Trials Referral Office 855-776-0015 mayocliniccancerstudies@mayo.edu

Principal Investigator: Terence C Burns, M.D., Ph.D

United States, New York

NYU Langone Health; Recruiting

New York, New York, United States, 10016

Contact: David Hargrove 646-501-0368 David.Hargrove@nyulangone.org

Principal Investigator: Dimitris Placantonakis, MD, PhD

United States, Ohio

Cleveland Clinic; Recruiting

Cleveland, Ohio, United States, 44195

Contact: Rachel Hufsey hufseyr@ccf.org

Principal Investigator: Matthew Grabowski, MD

United States, Texas

MD Anderson Cancer Center; Not yet recruiting

Houston, Texas, United States, 77030

Contact: Summer Stovall 713-745-4243 SStovall@mdanderson.org

Principal Investigator: Jeffrey Weinberg, MD

Sponsors and Collaborators

SonALAsense, Inc.

Investigators

• Study Director: Corina Andresen, MD; SonALAsense, Inc.

More Information

• Responsible Party: SonALAsense, Inc.
• ClinicalTrials.gov Identifier: NCT05370508
• Other Study ID Numbers: SDT-202; R44CA275508 ( U.S. NIH Grant/Contract )
• First Posted: May 11, 2022
• Last Update Posted: June 1, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

Keywords provided by SonALAsense, Inc.:

Sonodynamic Therapy; SONALA-001; Exablate 4000 Type 2.0; MR-guided Focused Ultrasound; SDT; rGBM

Additional relevant MeSH terms:

Recurrence; Disease Attributes; Pathologic Processes