N-803 and PD-L1 t-haNK Combined With Bevacizumab for Recurrent or Progressive Glioblastoma

Study Overview
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Brief Summary
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This is a phase 2 open-label study to evaluate the safety and efficacy of N-803 and PD-L1 t-haNK when combined with Bevacizumab in subjects with recurrent or progressive GBM. Participants will receive N-803 subcutaneously (SC), PD-L1 t-haNK intravenously (IV), and Bevacizumab IV combination therapy. Treatment for all enrolled participants will consist of repeated cycles of 28 days for a maximum treatment period of 76 weeks (19 cycles). Treatment will be administered on days 1 and day 15 of each cycle. Treatment will be discontinued if the participant reports unacceptable toxicity (not corrected with dose reduction), withdraws consent, if the Investigator feels it is no longer in the participant's best interest to continue treatment, or the participant has confirmed progressive disease by iRANO, unless the participant is potentially deriving benefit per Investigator's assessment. Participants will be followed for collection of survival status every 12 weeks (± 2 weeks) for the first 2 years, then yearly thereafter.

Official Title
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Open-label Phase 2 Study of N-803 and PD-L1 t-haNK Combined With Bevacizumab in Subjects With Recurrent or Progressive Glioblastoma

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: PD-L1 t-haNK
* Drug: N-803


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Able to understand and provide a signed informed consent that fulfills the relevant IRB or IEC guidelines. 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. 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). 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. Subjects must have recovered from prior treatment-related toxicities to Grade 2 or less. Life expectancy > 12 weeks. Karnofsky Performance Status ≥ 70. Ability to attend required study visits and return for adequate follow-up, as required by this protocol. 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. Craniotomy must be adequately healed (at least 28 days between study treatment initiation and surgery). Exclusion Criteria: 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. Prior anticancer treatment of glioblastoma with bevacizumab or other anti-angiogenic treatment. 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. History of surgery in the past 28 days or with surgical wound not healed. History of serious hemorrhage as defined by NCI CTCAE 5.0 grading. Evidence of > Grade 1 CNS hemorrhage on the baseline MRI scan. History of recent hemoptysis. Subjects receiving therapeutic anticoagulation. Subjects with a history or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease) requiring any treatment within the last 5 years. History of organ transplant requiring immunosuppression. History of active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis). Dyspnea at rest due to complications of advanced malignancy or other disease requiring continuous oxygen therapy. Body weight ≤ 40 kg at screening. Inadequate organ function, evidenced by the following laboratory results: Absolute neutrophil count (ANC) < 1,000 cells/mm3. Hemoglobin < 9 g/dL. Platelet count < 100,000 cells/mm3. Total bilirubin > 2 × upper limit of normal (ULN; unless the subject has documented Gilbert's syndrome). Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT]) > 2.5 × ULN (> 5 × ULN in subjects with liver metastases). Alkaline phosphatase (ALP) levels > 2.5 × ULN (> 5 × ULN in subjects with liver metastases, or > 10 × ULN in subjects with bone metastases). Serum creatinine > 2.0 mg/dL or 177 µmol/L. Albumin < 3.0 g/dL. Note: Each study site should use its institutional Upper Limit of Normal (ULN) to determine eligibility. 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. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute arrhythmia or ventricular arrhythmias classified as Lown III, IV or V. Known hypersensitivity to any component of the study medication(s). 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. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol. Concurrent participation in any interventional clinical trial. Pregnant and nursing women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pilot Combination Therapy<br>Participants will receive N-803 1 mg subcutaneously (SC), PD-L1 t-haNK ( 2 × 10^9 cells/infusion) intravenously (IV), and Bevacizumab (10 mg/kg IV) combination therapy during 28-day cycles on days 1 and 15 of each cycle. Maximum treatment period is 76 weeks, 19 cycles. | Drug: Bevacizumab<br>* Participants will receive 10mg/kg of Bevacizumab intravenously (IV) on Day 1 and Day 15 of each repeated cycle of treatment.<br>* Other names: Avastin;Drug: PD-L1 t-haNK<br>* Participants will receive PD-L1 t-haNK ( 2 × 109 cells/infusion) intravenously (IV) on Day 1 and Day 15 of each repeated cycle of treatment.<br>Drug: N-803<br>* Participants will receive 1mg subcutaneously (SC) on Day 1 and Day 15 of each repeated cycle of treatment.<br>* Other names: Anktiva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of clinically significant changes in Hematology blood panel. | Blood test checking the levels for White Blood Cell, Red Blood Cell, Platelets, Hemoglobin, Hematocrit, Basophils, Eosinophils, Lymphocytes, Monocytes and Neutrophils per unit volume. Each clinical site will use their local laboratory upper limit of normal (ULN) range. The treating investigator will assess each component of the Hematology panel and determine if each result is within expected normal range or outside of the expected normal range. | From baseline, pre-intervention, Cycle 1 (each cycle is 28 days) and each subsequent treatment Cycle on Days 1 and Day 15 and at the end of treatment study visit. | 
| Incidence of clinically significant changes in Urinalysis. | Checking the appearance, concentration and content of urine for any abnormalities. Each clinical site will use their local laboratory upper normal limit (UNL) range. The treating investigator will assess each component of the urinalysis and determine if each result is within expected normal range or outside of the expected normal range. | From baseline, pre-intervention, Cycle 1 (each cycle is 28 days) and each subsequent treatment Cycle on Days 1 and Day 15 and at the end of treatment study visit. | 
| 12-lead Electrocardiogram (ECG) | Perform 12-lead ECG as safety monitoring measurement. The parameters to be assessed for each one are the following: QT Interval, QTc Interval, QTcB Interval, QTcF Interval, PR Interval, QRS Duration and RR Interval with the unit in msec. | From baseline, pre-intervention, Cycle 1 (each cycle is 28 days) and each subsequent Cycle Day1 through to the end of treatment study visit. | 
| Incidence of clinically significant changes in Temperature | Temperature measured in either Fahrenheit or Celsius and for any abnormalities. Each site will assess to determine if temperature is within expected normal range or outside of the expected normal range. | From baseline, pre-intervention, Cycle 1 (each cycle is 28 days) and Cycle 2 on days 1, 2 and 15, followed by each subsequent treatment Cycle on Days 1 and 15 and on the end of treatment study visit. | 
| Incidence of clinically significant changes in Heart Rate | Heart rate measured in beats/minute. Each site will assess to determine if heart rate is within expected normal range or outside of the expected normal range. | From baseline, pre-intervention, Cycle 1 (each cycle is 28 days) and Cycle 2 on days 1, 2 and 15, followed by each subsequent treatment Cycle on Days 1 and 15 and on the end of treatment study visit. | 
| Incidence of clinically significant changes in Respiratory Rate | Respiratory rate measured in breaths/minute. Each site will assess to determine if respiratory rate is within expected normal range or outside of the expected normal range. | From baseline, pre-intervention, Cycle 1 (each cycle is 28 days) and Cycle 2 on days 1, 2 and 15, followed by each subsequent treatment Cycle on Days 1 and 15 and on the end of treatment study visit. | 
| Incidence of clinically significant changes in Blood Pressure | Blood pressure measured in Systolic and Diastolic mmHg. Each site will assess to determine if blood pressure is within expected normal range or outside of the expected normal range. | From baseline, pre-intervention, Cycle 1 (each cycle is 28 days) and Cycle 2 on days 1, 2 and 15, followed by each subsequent treatment Cycle on Days 1 and 15 and on the end of treatment study visit. | 
| Incidence of clinically significant changes in Oxygen Saturation | A pulse oximeter measures oxygen saturation as a percentage. Determines the ratio of the current levels of oxygenated hemoglobin to deoxygenated hemoglobin. Each site will assess to determine if oxygen saturation is within expected normal range or outside of the expected normal range. | From baseline, pre-intervention, Cycle 1 (each cycle is 28 days) and Cycle 2 on days 1, 2 and 15, followed by each subsequent treatment Cycle on Days 1 and 15 and on the end of treatment study visit. | 
| Neurological assessment to grade Immune effector cell-associated neurotoxicity syndrome (ICANS) | Using a 10-point immune effector cell encephalopathy [ICE] score for the grading of ICANS. A score of 10 represents no impairment, 7-9 score is grade 1 ICANS, 3-6 score is grade 2 ICANS, 0-2 score is grade 3 ICANS and finally grade 4 ICANs is where cannot perform assessment of tasks. | On Cycle 1 (each cycle is 28 days) Day1, Day2, Day 15 and Day16, followed by each subsequent treatment Cycle on Days 1 and 15. Collection stops at the end of treatment study visit. | 
| Safety assessed by Cytokine Levels | The safety cytokine levels are TNF-α and IL-6 | From Cycle 1 (each cycle is 28 days) Day1, Day2, Day 15 and Day16, followed by each subsequent treatment Cycle on Day 1. Collection stops at the end of treatment study visit. | 
| Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) | TEAEs and SAEs graded using the NCI CTCAE v5.0 | From beginning of Cycle 1 (each cycle is 28 days) to 30 days after end of treatment study visit. | 
| Incidence of clinically significant changes in comprehensive metabolic panel (CMP) | Standard blood chemistry panel made up of 14 separate chemistry measurements so can detect a range of abnormalities in blood sugar, nutrient balance, and liver and kidney health. Each clinical site will use their local laboratory upper limit of normal (ULN) range. The treating investigator will assess each result composing the CMP and determine if each result is within expected normal range or outside of the expected normal range. | From baseline, pre-intervention, Cycle 1 (each cycle is 28 days) and each subsequent treatment Cycle on Days 1 and Day 15 and at the end of treatment study visit. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of N-803 Pharmacokinetic (PK) | Profile of each participant PK profile of N-803 from their serum sample | On Cycle 1 (each cycle is 28 days) and Cycle 3 on treatment days 1, 2, 3, 4, 5 and 8. | 
| Concentration of PD-L1 t-haNK Pharmacokinetic (PK) | Profile of each participant PK profile of PD-L1 t-haNK from their serum sample | On Cycle 1 (each cycle is 28 days) and Cycle 3 on treatment days 1, 2, 3, 4, 5 and 8. | 
| Detection of Immunogenicity of N-803 | Detection of N-803 in each participant ADA serum blood samples | On Cycle 1 (each cycle is 28 days) Cycle 2 on treatment days 1 and 15, followed by Cycle 7 Day 1 and at the End of Treatment study visit. | 
| Detection of Immunogenicity of PD-L1 t-haNK | Detection of PD-L1 t-haNK in each participant ADA serum blood samples | On Cycle 1 (each cycle is 28 days) Cycle 2 on treatment days 1 and 15, followed by Cycle 7 Day 1 and at the End of Treatment study visit. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Progressive Glioblastoma, Recurrent Glioblastoma, N-803, ALT-803, PD-L1 t-haNK, Immunotherapy, Bevacizumab, Glioblastoma