ASP8374 + Cemiplimab in Recurrent Glioma

Inclusion Criteria:

• Have histologically confirmed WHO grade IV GBM or its variants. Participants will beeligible if the original histology was low-grade glioma and a subsequenthistological diagnosis of GBM is made. Participants with WHO grade III recurrentmalignant glioma will be allowed to enroll to Cohort 1 only.

• 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).

• Previous first line therapy with at least radiotherapy.

• Be at first or second relapse. Note: Relapse is defined as progression followinginitial therapy (i.e., radiation ± chemotherapy). For participants who had priortherapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma willbe considered the first relapse.

• Participants must have shown unequivocal evidence for tumor progression by MRI or CTscan.

• Demonstrate adequate organ function as defined in Table 1, all screening labs shouldbe performed within 14 days of registration.

• Table 1: Adequate Organ Function Laboratory Values

• System Laboratory Value

• Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusionor EPO dependency (within 7 days of assessment)

• Renal Serum creatinine OR measured or calculated a creatinineclearance (GFR can also be used in place of creatinine or CrCl) ≤1.5X institutional upper limit of normal (ULN) OR ≥60 mL/min for participant with creatinine levels > 1.5 Xinstitutional ULN a Creatinine clearance should be calculated perinstitutional standard.

• Hepatic Serum total bilirubin ≤ 1.5 X institutional ULN OR Directbilirubin ≤ institutional ULN for participants with total bilirubinlevels > 1.5 institutional ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 Xinstitutional ULN OR ≤ 5 X institutional ULN for participants with Gilberts syndromeAlbumin >2.5 mg/dL

• Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤1.5 Xinstitutional ULN unless participant is receiving anticoagulanttherapy as long as PT or PTT is within therapeutic range of intendeduse of anticoagulants ≤1.5 X institutional ULN unless participant isreceiving anticoagulant therapy as long as PT or PTT is withintherapeutic range of intended use of anticoagulants

• Contrast enhanced CT or MRI within 14 days prior to registration. NOTE: For Cohort 2participants only: due to the fact that the screening MRI will not be used forresponse purposes, participants may be registered if the screening scan is >14 daysfrom registration with prospective approval from Overall PI, Dr. David Reardon (forprospectively approved circumstances, an eligibility exception will not need to befiled).

• An interval of at least 3 weeks (to registration) between prior surgical resectionor one week for stereotactic biopsy.

• An interval of at least 12 weeks from the completion of radiation therapy toregistration unless there is unequivocal histologic confirmation of tumorprogression or radiographic progression outside of the prior radiation field.

• Participants must have recovered to grade 0 or 1 or pre-treatment baseline fromclinically significant toxic effects of prior therapy (exceptions include but notlimited to alopecia, laboratory values not listed per inclusion criteria, andlymphopenia which is common after therapy with temozolomide).

• From start of study therapy, the following time periods must have elapsed:

• 5 half-lives from any small molecule investigational agent

• 4 weeks from cytotoxic therapy (except 23 days for temozolomide, 6 weeks fromnitrosoureas, and 7 days from daily administered agents)

• 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter)from other anti-tumor therapies

• No wash-out period required for prior TTF or vaccine therapies

• Participants must be planned to undergo surgery that is clinically indicated asdetermined by their care providers (Cohort 2 only).

• Female participant of childbearing potential should have a negative urine or serumpregnancy within 72 hours prior to registration. If the urine test is positive orcannot be confirmed as negative, a serum pregnancy test will be required. Women areconsidered post-menopausal and not of child bearing potential if they have had 12months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneousamenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have hadsurgical bilateral oophorectomy (with or without hysterectomy) at least six weeksago. In the case of oophorectomy alone, only when the reproductive status of thewoman has been confirmed by follow up hormone level assessment she considered not ofchild bearing potential.

• Women of child-bearing potential (WOCBP), defined as all women physiologicallycapable of becoming pregnant, must use highly effective contraception during studytreatment and for 120 days after study discontinuation. Highly effectivecontraception is defined as either:

• i. True Abstinence: When this is in line with the preferred and usual lifestyleof the participant. Periodic abstinence (e.g., calendar, ovulation,symptothermal, post-ovulation methods) and withdrawal are not acceptablemethods of contraception.

• ii. Sterilization: Surgical bilateral oophorectomy (with or withouthysterectomy) or tubal ligation at least six weeks ago. In case of oophorectomyalone, only when the reproductive status of the woman has been confirmed byfollow up hormone level assessment (as described in item 12 above).

• iii. Male Partner Sterilization (with the appropriate post-vasectomydocumentation of the absence of sperm in the ejaculate). For femaleparticipants on the study, the vasectomized male partner should be the solepartner for that participant.

• Use of a combination of any two of the following:

1. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm orcervical/vault caps) with spermicidal foam/gel/film/cream/vaginalsuppository
3. Appropriate hormonal contraceptives (including any registered and marketedcontraceptive agent that contains an estrogen and/or a progestationalagent - including oral, subcutaneous, intrauterine, or intramuscularagents)

• Male participants should agree to use adequate method of contraception starting withthe first dose of study therapy through 120 days after the last dose of therapy.

Exclusion Criteria:

• Current or planned participation in a study of an investigational agent or using aninvestigational device.

• Has a diagnosis of immunodeficiency.

• Has tumor primarily localized to the brainstem or spinal cord.

• Has presence of diffuse leptomeningeal disease or extracranial disease.

• Has received systemic immunosuppressive treatments, aside from systemiccorticosteroids as described in Section 3.2.7, (such as methotrexate, chloroquine,azathioprine, etc.) within six months of registration.

• Has received anti-VEGF or anti-VEGFR targeted agents (e.g. bevacizumab, cediranib,aflibercept, vandetanib, XL-184, sunitinib, etc.).

• Requires treatment with moderate or high dose systemic corticosteroids defined asdexamethasone > 2 mg/day or bioequivalent for at least 3 consecutive days within 7days of registration.

• Has received prior interstitial brachytherapy or stereotactic radiosurgery (Cohort 2only).

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

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

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

• Has a known additional malignancy that is progressing or requires active treatmentwithin 2 years of registration. Exceptions include malignancies treated with surgeryalone including but not limited to basal cell carcinoma of the skin, squamous cellcarcinoma of the skin, or in situ cervical cancer that has undergone potentiallycurative therapy.

• Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids, orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment. See Section 5.4.3 for additional information on allowed corticosteroid dosing.

• Has confirmed history or any evidence of active non-infectious pneumonitis.

• Has an active infection requiring systemic therapy.

• 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 symptomatic congestive heartfailure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/socialsituations that would limit compliance with study requirements.

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

• 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. It is unknown whether ASP8374 and/or cemiplimab is excreted inhuman milk or may have adverse effects on a fetus in utero. Since many drugs areexcreted in human milk, and because of the potential for serious adverse reactionsin the nursing infant or fetus, these participants are not eligible for enrollment.

• Has received prior therapy with an anti-TIGIT, anti-PD-1, anti-PD-L1, anti-cytotoxicT-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab), or anyother antibody or drug specifically targeting T-cell co-stimulation or checkpointpathways.

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

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

• Has received a live vaccine within 30 days prior to registration.

• Has a known hypersensitivity to any of the study therapy products.

• Has been previously treated with the PI3K inhibitor idelalisib.