CUE-102 in Recurrent Glioblastoma

Inclusion Criteria:

• Have HLA-A*0201 genotype as determined by genomic testing performed locally;

• Have histologically confirmed World Health Organization (WHO) Grade 4 glioblastoma,other WHO grade 4 malignant glioma or molecular GBM (based on the 2021 WHOClassification) at first recurrence. Patients with gliosarcoma are NOT eligible;

• Be willing and able to provide written informed consent/assent for the trial;

• Be ≥ 18 years of age on day of signing informed consent;

• Have a Karnofsky performance status (KPS) ≥ 70 (Appendix A);

• Participants must be at least 4 weeks from start of last chemotherapy cycle (atleast 6 weeks for nitrosoureas and at least 1 week for metronomic dosing) and atleast 4 weeks or 5 half-lives (whichever is shorter) for any prior investigationalagent. There is no minimal time from cessation of Optune TTF nor for prior cancervaccine therapy.

• MRI within 14 days prior to registration. MRIs should include vascular imaging whenpossible. Corticosteroid dose must be stable or decreasing for at least 5 days priorto the scan. If steroids are added or the steroid dose is increased between the dateof the screening MRI scan and the start of treatment, a new baseline MRI or CT isrequired;

• Patients must have fully completed initial radiation therapy with or without dailytemozolomide including 60 Gy in 30 fractions, 59.4 Gy in 1.8 Gy per fraction orequivalent;

• At least 12 weeks from completion of radiotherapy +/- temozolomide. Patients < 12weeks from the completion of radiation therapy may be eligible if they have eitherof the following: 1) histopathologic confirmation of recurrent tumor; or 2) newcontrast enhancing disease outside the primary radiation field. Participants whohave received investigational therapies as a component of treatment for newlydiagnosed GBM as long as remaining eligibility criteria are satisfied;

• Participants must have recovered to grade 0 or 1 or pre-treatment baseline fromclinically significant toxic effects of prior therapy (exceptions include alopecia,laboratory values listed per inclusion criteria, and lymphopenia, which is commonafter therapy with temozolomide);

• Participants must meet the following organ and marrow function as defined below, allscreening labs should be performed within 14 days of registration:

• Absolute neutrophil count (ANC) ≥1,500 /mcL

• Platelets ≥100,000 / mcL

• Hemoglobin ≥9 g/dL or ≥5.6 mmol/L (Criteria must be met without erythropoietindependency and without packed red blood cell (pRBC) transfusion within last 2weeks)

• Serum creatinine ≤ 1.5 X institutional ULN OR

• Measured or calculated creatinine clearance (CrCl) ≥45 mL/min for participantwith creatinine levels > 1.5 X institutional ULN (CrCl should be calculated perinstitutional standard, GFR can also be used in place of creatinine or CrCl)

• Serum total bilirubin ≤ 1.5 X institutional ULN OR

• Direct bilirubin ≤ institutional ULN for participants with total bilirubinlevels > 1.5 X institutional ULN

• AST (SGOT) and ALT (SGPT) ≤ 3.0 X institutional ULN OR ≤ 5 X institutional ULNfor participants with Gilberts syndrome

• International Normalized Ratio (INR) OR Prothrombin Time (PT) and ActivatedPartial Thromboplastin Time (aPTT) ≤1.5 X institutional ULN unless participantis receiving anticoagulant therapy as long as PT or aPTT is within therapeuticrange of intended use of anticoagulants

• Resting baseline oxygen saturation by pulse oximetry ≥92% at rest

• Women of child-bearing potential (WOCBP), defined as all women physiologicallycapable of becoming pregnant, must have a negative urine or serum pregnancy within 72 hours prior to enrollment. If the urine test is positive or cannot be confirmedas negative, a serum pregnancy test will be required;

--Women in the following categories are not considered WOCBP:

• Premenarchal

• Premenopausal female with 1 of the following:

• Documented hysterectomy

• Documented bilateral salpingectomy

• Documented bilateral oophorectomy

• Note: Documentation can come from the site personnel's review of theparticipant's medical records, medical examination, or medical historyinterview.

• Postmenopausal female

• A postmenopausal state is defined as no menses for 12 months without analternative medical cause. -----A high follicle stimulating hormone (FSH) level in the postmenopausalrange may be used to confirm a postmenopausal state in women not usinghormonal contraception or hormonal replacement therapy (HRT). However, inthe absence of 12 months of amenorrhea, confirmation with two FSHmeasurements in the postmenopausal range is required.

• Females on HRT and whose menopausal status is in doubt will be required touse one of the non-hormonal highly effective contraception methods if theywish to continue their HRT during the study. Otherwise, they mustdiscontinue HRT to allow confirmation of postmenopausal status beforestudy enrollment.

• Women of child-bearing potential (WOCBP; see definition above), must agree to use ahighly effective method of contraception consistently and correctly as describedbelow during study treatment and for 120 days after study treatment discontinuationor the initiation of other cancer therapy (whichever is shorter);

• Highly Effective Contraceptive Methods That Are User Dependent a (Failure rateof < 1% per year when used consistently and correctly.)

• Combined (estrogen- and progestogen- containing) hormonal contraception

• i. Oral

• ii. Intravaginal

• iii. Transdermal

• iv. Injectable

• Progestogen-only hormonal contraception

• v. Oral

• vi. Injectable

• Highly Effective Methods That Have Low User Dependency (Failure rate of <1% peryear when used consistently and correctly)

• Progestogen- only contraceptive implant

• Intrauterine hormone-releasing system (IUS) Intrauterine device (IUD)

• Bilateral tubal occlusion

• Vasectomized partner (A vasectomized partner is a highly effectivecontraception method provided that the partner is the sole male sexualpartner of the WOCBP and the absence of sperm has been confirmed. If not,an additional highly effective method of contraception should be used).

• Sexual abstinence (Sexual abstinence is considered a highly effectivemethod only if defined as refraining from heterosexual intercourse duringthe entire period of risk associated with the study treatment. Thereliability of sexual abstinence needs to be evaluated in relation to theduration of the study and the preferred and usual lifestyle of theparticipant).

• NOTES: Use should be consistent with local regulations regarding the useof contraceptive methods for participants of clinical studies.

• a. Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and correctly).

• b. If hormonal contraception efficacy is potentially decreased due tointeraction with study treatment, condoms must be used in addition tothe hormonal contraception during the treatment period and for atleast during study treatment and for 120 days after study treatmentdiscontinuation after the last dose of study treatment or theinitiation of other cancer therapy (whichever is shorter).

• c. If locally required, in accordance with Clinical TrialFacilitation Group (CTFG) guidelines, acceptable contraceptiveimplants are limited to those which inhibit ovulation.

• Male participants must agree to use at least one of the following methods ofcontraception starting with the first dose of study therapy through 120 days afterthe last dose of therapy or the initiation of other cancer therapy (whichever isshorter):

• Be abstinent from penile-vaginal intercourse as their usual and preferredlifestyle (abstinent on a long term and persistent basis) and agree to remainabstinent

• Use a male condom plus partner use of a contraceptive method with a failurerate of <1% per year when having penile-vaginal intercourse with a woman ofchildbearing potential who is not currently pregnant.

• a. Note: Men with a pregnant or breastfeeding partner must agree to remainabstinent from penile-vaginal intercourse or use a male condom during eachepisode of penile penetration.

Exclusion Criteria:

• Received any therapy for tumor recurrence other than surgery;

• More than one episode of recurrent or progressive tumor;

• Is currently participating or plans to participate in another study of aninvestigational agent or using an investigational device.

• Tumor primarily localized to the brainstem or spinal cord;

• Presence of multifocal tumor, bi-hemispheric tumor (radiographic evidence of tumorextending from one hemisphere into the other through the corpus callosum), diffuseleptomeningeal or extracranial disease;

• Has a diagnosis of immunodeficiency;

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with theparticipant's participation for the full duration of the trial, or is not in thebest interest of the participant to participate, in the opinion of the treatinginvestigator. Examples include - but are not limited to - unstable angina pectoris,cardiac arrhythmia or psychiatric illness/social situations that would limitcompliance with study requirements;

• Has history of known coagulopathy that increases risk of bleeding or a history ofclinically significant hemorrhage within 12 months of enrollment;

• Has evidence of intratumoral or peritumoral hemorrhage on baseline MRI scan otherthan those that are grade ≤ 1 and either post-operative or stable on at least 2consecutive MRI scans;

• Has gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3within 6 months of enrollment;

• Has a known additional malignancy that is progressing or requires active treatmentwithin 1 year of start of study drug, except for those treated with surgical therapyonly (e.g. basal cell carcinoma of the skin, squamous cell carcinoma of the skin, orin situ cervical cancer that has undergone potentially curative therapy);

• Has active autoimmune disease requiring systemic treatment in the past 2 years (i.e.with use of disease modifying agents, corticosteroids or immunosuppressive drugs).Replacement therapy (eg thyroxine, insulin, or physiologic corticosteroidreplacement for adrenal insufficiency or pituitary/hypothalamic dysfunction, etc.)is not considered a form of systemic treatment;

• Has history of (non-infectious) pneumonitis that required steroids or has currentpneumonitis;

• Has an active infection requiring systemic therapy within 7 days before enrollment;

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial;

• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) andis receiving antiretroviral therapy.

• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected);

• Has a history of non-healing wounds or ulcers, or bone refractures within 3 monthsof fracture;

• Has a history of arterial thromboembolism within 12 months of enrollment;

• Has had clinically significant cardiovascular disease within 12 months of start ofstudy drug, including myocardial infarction, unstable angina, grade 2 or greaterperipheral vascular disease, cerebrovascular accident, transient ischemic attack,congestive heart failure, or arrhythmias not controlled by outpatient medication,percutaneous transluminal coronary angioplasty/stent;

• Has a known history of active TB (Bacillus Tuberculosis);

• Has a known hypersensitivity to any of the study therapy products and/or any oftheir excipients;

• Is pregnant or breastfeeding or expecting to conceive within the projected durationof the trial, starting with the screening visit through 120 days after the last doseof trial treatment or the initiation of other cancer therapy (whichever is shorter).Pregnant women are excluded because there is an unknown but potential risk foradverse events affecting a developing fetus and/or the mother secondary to treatmentwith CUE-102. There is also an unknown but potential risk for adverse eventsaffecting nursing infants secondary to treatment of the mother with CUE-102, thus,breastfeeding must be discontinued if the mother is treated with CUE-102;

• Is receiving any form of immunosuppressive therapy (e.g. chronic systemic steroidtherapy exceeding dosage of 10 mg daily of prednisone equivalent) within 7 daysprior to enrollment;

• Has received systemic immunosuppressive treatments, aside from systemiccorticosteroids (such as methotrexate, chloroquine, azathioprine, etc), within sixmonths of enrollment;

• Requires treatment with high dose systemic corticosteroids defined as dexamethasone > 2 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks ofenrollment;

• Inhaled or topical steroids and adrenal replacement doses ≤ 10 mg dailyprednisone equivalents are permitted in the absence of active autoimmunedisease.

• Participants are permitted to use topical, ocular, intra-articular, intranasal,and inhalational corticosteroids (with minimal systemic absorption).

• Physiologic replacement doses of systemic corticosteroids are permitted, ≤10mg/day prednisone equivalents.

• A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) orfor treatment of non-autoimmune conditions (eg, delayed-type hypersensitivityreaction caused by contact allergen) is permitted.

• Requires therapeutic anticoagulation with warfarin at baseline; patients must be offwarfarin or warfarin-derivative anti-coagulants for at least 7 days prior toenrollment; however, therapeutic or prophylactic therapy with low-molecular weightheparin is allowed;

• Has received a live vaccine within 30 days prior to enrollment;

• Examples of live vaccines include - but are not limited to - the following:measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies,Bacillus Calmette- Guérin (BCG), and typhoid vaccine. Seasonal influenzavaccines for injection are generally killed virus vaccines and are allowed;however, intranasal influenza vaccines (eg, FluMist®) are live attenuatedvaccines and are not allowed.

• History of acute pancreatitis within 3 months before enrollment;

• Diverticulitis that is clinically significant in the opinion of the Investigatorbased on the extent or severity of known disease and/or the occurrence of clinicallysignificant flares within 4 weeks before enrollment.