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 consists of 2 portions. The phase 2 portion is an open-label, single-arm study to evaluate the safety and efficacy of NAI, PD-L1 t-haNK, and bevacizumab combination therapy in participants with recurrent or progressive GBM. The phase 2B portion is an open-label, randomized study to evaluate the efficacy and safety for the following 2 experimental arms in participants with recurrent or progressive GBM: NAI, bevacizumab, and TTFields combination therapy (Arm A) or NAI, PD-L1 t-haNK, bevacizumab, and TTFields combination therapy (Arm B). Phase 2 Treatment for all enrolled participants will consist of repeated cycles of 28 days for a maximum treatment period of 76 weeks (19 cycles) as follows: Every 2 weeks (Days 1 and 15 of a 28-day cycle) Fourteen (14) participants were enrolled in the phase 2 portion of this study as of the date of this v02 protocol. No additional participants will be administered therapy in phase 2. Phase 2B Participants will be randomized 1:1 to 1 of 2 experimental arms (Arm A or Arm B). Treatment for all enrolled participants will consist of repeated 8-week cycles for a maximum treatment period of up to 80 weeks (10 cycles). Experimental Arm (A): Every 2 weeks (Days 1, 15, 29, and 43 of an 8-week cycle) Up to twenty (20) participants will be randomized in phase 2B (up to 10 participants/arm. Duration of Treatment: Participants will receive study treatment for up to 76 weeks during phase 2 (up to 19 repeated 28-day cycles) and for up to 80 weeks (up to 10 repeated 8-week cycles) during phase 2B or until they report unacceptable toxicity (not corrected with dose reduction), withdraw consent, or if the Investigator feels it is no longer in the participant's best interest to continue treatment. Treatment may also be discontinued if the participant has confirmed PD per iRANO, unless the participant is clinically stable and is considered potentially deriving benefit per Investigator's assessment. Duration of Follow-up: Participants who discontinue study treatment should remain in the study for follow-up. Participants should be followed for collection of survival status, posttreatment therapies (phase 2 and phase 2B), and medical history (phase 2B only) every 12 weeks (± 2 weeks) for the first 2 years then yearly thereafter for an additional 3 years. The maximum duration of follow-up is 5 years (260 weeks).
• 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).
• Age ≥ 22 years.
• Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines.
• 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.
• 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.
• Previous first-line treatment with at least radiotherapy and temozolomide.
• 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).
• 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).
• Life expectancy ≥ 12 weeks.
• ECOG performance status of 0 to 2.
⁃ Have recovered from prior treatment-related toxicities to grade 2 or less.
⁃ Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
⁃ 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.
⁃ Craniotomy must be adequately healed (at least 28 days between study treatment initiation and surgery).