Combining N-803 and PD-L1 t-haNK with Bevacizumab for treating recurrent glioblastoma

Open-Label, Single-Arm Phase 2 Study of Nogapendekin Alfa Inbakicept, PD-L1 t-haNK, Bevacizumab and Randomized Phase 2B Study of Nogapendekin Alfa Inbakicept, Bevacizumab, and Tumor Treatment Fields With or Without PD-L1 t-haNK in Participants With Recurrent or Progressive Glioblastoma

This study is testing a new combination of treatments for people with recurrent glioblastoma to see if it can help them live longer and feel better.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 34 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: ImmunityBio, Inc. (Industry-sponsored)
• Drugs / interventions: bevacizumab, chemotherapy, immunotherapy, radiation
• Locations: 4 sites (El Segundo, California and 3 other locations)
• Trial ID: NCT06061809 on ClinicalTrials.gov

What this trial studies

This phase 2 open-label study aims to evaluate the safety and efficacy of a combination therapy involving N-803, PD-L1 t-haNK, and Bevacizumab in patients with recurrent or progressive glioblastoma. Participants will receive these treatments over repeated 28-day cycles for up to 76 weeks, with administration occurring on specific days of each cycle. The study will monitor participants for any unacceptable toxicity and assess their survival status every 12 weeks during the treatment period.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with histologically-confirmed recurrent or progressive glioblastoma who have previously undergone standard treatments.

Not a fit: Patients with glioblastoma variants such as gliosarcoma or those who have not received prior treatment may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with recurrent or progressive glioblastoma, potentially improving survival outcomes.

How similar studies have performed: Other studies have shown promise with similar combination therapies in glioblastoma, indicating potential for success in this approach.

Eligibility criteria

Phase 2 Inclusion Criteria:

1. Age ≥ 18 years.
2. Able to understand and provide a signed informed consent that fulfills the relevant IRB or IEC guidelines.
3. Histologically-confirmed glioblastoma in accordance with the 2021 WHO Classification of Tumors of the CNS (WHO CNS5) that has progressed after initial therapy or therapies. The digital image to be provided for confirmation of histology by the Sponsor. Gliosarcoma, small cell GBM or other GBM variants, and molecular GBM are allowed.
4. Progressive or recurrent disease will be confirmed (i.e. contrast enhanced magnetic resonance imaging (MRI) performed within 3 weeks prior to study treatment per RANO criteria or diagnostic biopsy).
5. Previous first line treatment with at least radiotherapy and temozolomide. Subjects must have been off prior treatment at least 28 days prior to initiation of study therapy. Subjects must be at least 90 days from completion of radiation to reduce the risk of pseudoprogression being misdiagnosed as progression, unless the recurrence is a new enhancement on MRI outside the radiation treatment field or progression is confirmed by biopsy.
6. Subjects must have recovered from prior treatment-related toxicities to Grade 2 or less.
7. Life expectancy \> 12 weeks.
8. Karnofsky Performance Status ≥ 70.
9. Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
10. Agreement to practice effective contraception for female subjects of child-bearing potential and non-sterile males. Female subjects of child-bearing potential must agree to use effective contraception for up to 6 months after completion of therapy, and non-sterile male subjects must agree to use a condom for up to 6 months after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), two forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), and abstinence.
11. Craniotomy must be adequately healed (at least 28 days between study treatment initiation and surgery).

Exclusion Criteria:

1. Serious uncontrolled concomitant disease that would contraindicate the use of the investigational drugs used in this study or that would put the subject at high risk for treatment related complications.
2. Prior anticancer treatment of glioblastoma with bevacizumab or other anti-angiogenic treatment.
3. Current chronic daily treatment (continuous for \> 3 months) with systemic corticosteroids (dose equivalent to or greater than 8 mg/day dexamethasone), excluding inhaled steroids. Short-term steroid use to prevent intravenous (IV) contrast allergic reaction or anaphylaxis in subjects who have known contrast allergies is allowed.
4. History of surgery in the past 28 days or with surgical wound not healed.
5. History of serious hemorrhage as defined by NCI CTCAE 5.0 grading.
6. Evidence of \> Grade 1 CNS hemorrhage on the baseline MRI scan.
7. History of recent hemoptysis.
8. Subjects receiving therapeutic anticoagulation.
9. Subjects with a history or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding.
10. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease) requiring any treatment within the last 5 years.
11. History of organ transplant requiring immunosuppression.
12. History of active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis).
13. Dyspnea at rest due to complications of advanced malignancy or other disease requiring continuous oxygen therapy.
14. Body weight ≤ 40 kg at screening.
15. Inadequate organ function, evidenced by the following laboratory results:

    1. Absolute neutrophil count (ANC) \< 1,000 cells/mm3.
    2. Hemoglobin \< 9 g/dL.
    3. Platelet count \< 100,000 cells/mm3.
    4. Total bilirubin \> 2 × upper limit of normal (ULN; unless the subject has documented Gilbert's syndrome).
    5. Aspartate aminotransferase (AST \[SGOT\]) or alanine aminotransferase (ALT \[SGPT\]) \> 2.5 × ULN (\> 5 × ULN in subjects with liver metastases).
    6. Alkaline phosphatase (ALP) levels \> 2.5 × ULN (\> 5 × ULN in subjects with liver metastases, or \> 10 × ULN in subjects with bone metastases).
    7. Serum creatinine \> 2.0 mg/dL or 177 µmol/L.
    8. Albumin \< 3.0 g/dL.

    Note: Each study site should use its institutional Upper Limit of Normal (ULN) to determine eligibility.
16. Clinically significant (ie, active) cardiovascular disease or myocardial infarction within 6 months prior to first study medication; unstable angina; congestive heart failure of New York Heart Association grade 2 or higher; or serious cardiac arrhythmia. Subjects with uncontrolled hypertension should be medically managed on a stable regimen to control hypertension prior to study entry.
17. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute arrhythmia or ventricular arrhythmias classified as Lown III, IV or V.
18. Known hypersensitivity to any component of the study medication(s).
19. Participation in an investigational drug study or receiving any investigational treatment within 28 days prior to study treatment. No wash out is necessary for subjects previously receiving Tumor treating field (TTF); TTF will be allowed to continue at the discretion of the Investigator. FDA-authorized drugs for the prevention and treatment of COVID-19 are permitted.
20. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.
21. Concurrent participation in any interventional clinical trial.
22. Pregnant and nursing women.

Phase 2B Inclusion Criteria

1. Age ≥ 22 years.
2. Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines.
3. Histologically-confirmed GBM in accordance with the 2021 WHO CNS5 (grade 4 Glioma, IDH-wildtype) that has progressed after initial therapy or therapies (prior surgical resection if feasible, plus radiotherapy with concurrent and/or adjuvant temozolomide), limited to first-line progression. A second surgical resection is allowed but not required. Gliosarcoma, small cell GBM or other GBM variants, and molecular GBM are allowed.
4. Progressive or recurrent disease will be confirmed (ie, contrast enhanced magnetic resonance imaging \[MRI\] performed within 4 weeks prior to study treatment per RANO v02 criteria or diagnostic biopsy), or progression that does not meet RANO v02 criteria if the disease progression is otherwise obvious in the opinion of the Investigator and is discussed with the Medical Monitor. Participants must be a minimum of 3 months from the completion of radiotherapy to distinguish true progression from pseudoprogression.
5. Previous first-line treatment with at least radiotherapy and temozolomide.
6. Have received and recovered from standard treatments. At least 4 weeks since any cytotoxic chemotherapy (eg, temozolomide/nitrosoureas), 28 days since any investigational agent, and 6 to 12 weeks since radiation before starting study drug(s).
7. Willingness to use TTFields device. Both experimental arms require wearing the TTFields device ≥ 18 hours a day. Participants must be willing to shave their head twice a week and use the TTFields device as instructed. They should have no scalp condition or implanted device that contraindicates TTFields use (eg, no non-MRI-safe metal in the skull, ventricular peritoneal shunt is generally okay, but no active scalp infections or wounds).
8. Life expectancy ≥ 12 weeks.
9. ECOG performance status of 0 to 2.
10. Have recovered from prior treatment-related toxicities to grade 2 or less.
11. Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
12. Agreement to practice highly effective contraception for female participants of childbearing potential and nonsterile males. Female participants of childbearing potential are defined as any female who has experienced menarche and who is NOT permanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause. Female participants of childbearing potential must have a negative pregnancy test and adhere to using a highly effective method of contraception (eg, tubal ligation, approved hormonal contraceptive, or an intrauterine device \[IUD\]) prior to screening and agree to continue its use during the study or be surgically sterilized (eg, hysterectomy) while on study and for 7 months post last dose of study drug. Male participants must agree to use barrier methods of birth control while on study and for 7 months post last dose of study drug.
13. Craniotomy must be adequately healed (at least 28 days between study treatment initiation and surgery).

Exclusion Criteria:

1. Received any further therapy beyond initial first-line therapy other than surgical resection.
2. Prior therapy with bevacizumab for GBM.
3. Serious uncontrolled concomitant disease that would contraindicate the use of the investigational drugs used in this study or that would put the participant at high risk for treatment-related complications.
4. History of surgery in the past 28 days or with surgical wound not healed.
5. History of serious hemorrhage as defined by NCI CTCAE v5.0 grading.
6. Evidence of \> grade 1 CNS hemorrhage on the baseline MRI scan.
7. History of recent hemoptysis.
8. Participants receiving therapeutic anticoagulation or antiplatelet therapy.
9. Participants with a history or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding.
10. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease) requiring any treatment within the last 5 years.
11. History of organ transplant requiring immunosuppression.
12. History of active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis).
13. Prior use of anti-PD1 or PD-L1 immunotherapy or cellular therapy targeting PD-1/PD-L1 (or any NK cell therapy) for GBM.
14. Prior treatment with TTFields.
15. Uncontrolled seizures or neurological instability.
16. Should not require high-dose corticosteroids (eg, dexamethasone dose of ≤ 4 mg/day, or lowest dose to manage symptoms).
17. Other active malignancy requiring treatment.
18. Body weight ≤ 40 kg at screening.
19. Inadequate organ function, evidenced by the following laboratory results:

    1. ANC \< 1,000 cells/mm3.
    2. Hemoglobin \< 8 g/dL.
    3. Platelet count \< 100,000 cells/mm3.
    4. Total bilirubin \> 2 × ULN. For participants with documented Gilbert's syndrome, total bilirubin must be \< 3 × ULN.
    5. AST (SGOT) or ALT (SGPT) \> 2.5 × ULN (\> 5 × ULN in participants with liver metastases).
    6. ALP levels \> 2.5 × ULN (\> 5 × ULN in participants with liver metastases, or \> 10 × ULN in participants with bone metastases).
    7. Serum creatinine \> 2.0 mg/dL or 177 µmol/L. Note: Each study site should use its institutional ULN to determine eligibility.
20. Clinically significant (ie, active) cardiovascular disease or myocardial infarction within 6 months prior to first study medication; unstable angina; congestive heart failure of New York Heart Association grade 2 or higher; or serious cardiac arrhythmia. Participants with uncontrolled hypertension should be medically managed on a stable regimen to control hypertension prior to study entry.
21. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute arrhythmia or ventricular arrhythmias classified as Lown III, IV or V.
22. Known hypersensitivity to any component of the study medication(s).
23. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol, including the use of the TTFields device as required or any psychiatric/social situation that would limit adherence to protocol.
24. Participation in an investigational drug study or receiving any investigational treatment within 28 days prior to study treatment or concurrent participation in any interventional clinical trial.
25. Pregnant and nursing women.
26. Active implanted medical device, a skull defect (such as, missing bone with no replacement) or bullet fragments. Examples of active electronic devices include deep brain stimulators, spinal cord stimulators, vagus nerve stimulators, pacemakers, defibrillators, and programmable shunts.
27. Known sensitivity to conductive hydrogels like the gel used on transcutaneous electrical nerve stimulation (TENS) electrodes.
28. A tumor located in the lower parts of the brain close to the spinal cord.

Where this trial is running

El Segundo, California and 3 other locations

• Chan Soon-Shiong Institute for Medicine (CSSIFM) — El Segundo, California, United States (Not_yet_recruiting)
• Providence Medical Foundation — Fullerton, California, United States (Recruiting)
• Hoag Memorial Hospital Presbyterian — Newport Beach, California, United States (Recruiting)
• Vanderbilt-Ingram Cancer Center — Nashville, Tennessee, United States (Recruiting)

Study contacts

• Study coordinator: Raymond Atiata

Conditions Glioblastoma; Progressive Glioblastoma; Recurrent Glioblastoma; N-803; ALT-803; PD-L1 t-haNK; Immunotherapy; Bevacizumab