Phase Ib Trial of ASP8374 and Cemiplimab in Recurrent Malignant Glioma Patients

This study is looking at the safety and efficacy of the drug combination of ASP8374 with
cemiplimab in people with recurrent malignant glioma.

The study will be conducted in two parts, the first portion of the study will be to establish
the highest dose of ASP8374 that can be given safely with cemiplimab and will be used as the
recommended dose of ASP8374 in combination with cemiplimab for the second portion of the
study. The second portion of the study will be to compare the effect of having ASP8374 in
combination with cemiplimab prior to surgery.

The names of the study drugs involved in this study are:

- ASP8374

- Cemiplimab

Inclusion Criteria:

- Have histologically confirmed WHO grade IV GBM or its variants. Participants will be
eligible if the original histology was low-grade glioma and a subsequent histological
diagnosis of GBM is made. Participants with WHO grade III recurrent malignant 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 following
initial therapy (i.e., radiation ± chemotherapy). For participants who had prior
therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be
considered the first relapse.

- Participants must have shown unequivocal evidence for tumor progression by MRI or CT
scan.

- Demonstrate adequate organ function as defined in Table 1, all screening labs should
be 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 transfusion or
EPO dependency (within 7 days of assessment)

- Renal Serum creatinine OR measured or calculated a creatinine clearance
(GFR can also be used in place of creatinine or CrCl) ≤1.5 X
institutional upper limit of normal (ULN) OR

≥60 mL/min for participant with creatinine levels > 1.5 X institutional
ULN a Creatinine clearance should be calculated per institutional
standard.

- Hepatic Serum total bilirubin ≤ 1.5 X institutional ULN OR Direct
bilirubin ≤ institutional ULN for participants with total bilirubin
levels > 1.5 institutional ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X
institutional ULN OR

≤ 5 X institutional ULN for participants with Gilberts syndrome Albumin
>2.5 mg/dL

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

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

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

- An interval of at least 12 weeks from the completion of radiation therapy to
registration unless there is unequivocal histologic confirmation of tumor progression
or radiographic progression outside of the prior radiation field.

- Participants must have recovered to grade 0 or 1 or pre-treatment baseline from
clinically significant toxic effects of prior therapy (exceptions include but not
limited to alopecia, laboratory values not listed per inclusion criteria, and
lymphopenia 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 from
nitrosoureas, 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 as
determined by their care providers (Cohort 2 only).

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

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

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

- ii. Sterilization: Surgical bilateral oophorectomy (with or without hysterectomy)
or tubal ligation at least six weeks ago. In case of oophorectomy alone, only
when the reproductive status of the woman has been confirmed by follow up hormone
level assessment (as described in item 12 above).

- iii. Male Partner Sterilization (with the appropriate post-vasectomy
documentation of the absence of sperm in the ejaculate). For female participants
on the study, the vasectomized male partner should be the sole partner 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 or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository

3. Appropriate hormonal contraceptives (including any registered and marketed
contraceptive agent that contains an estrogen and/or a progestational agent
- including oral, subcutaneous, intrauterine, or intramuscular agents)

- Male participants should agree to use adequate method of contraception starting with
the 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 an
investigational 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 systemic
corticosteroids 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 as
dexamethasone > 2 mg/day or bioequivalent for at least 3 consecutive days within 7
days of registration.

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

- Has history of known coagulopathy that increases risk of bleeding or a history of
clinically 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 > 3
within 6 months of registration.

- Has a known additional malignancy that is progressing or requires active treatment
within 2 years of registration. Exceptions include malignancies treated with surgery
alone including but not limited to basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or in situ cervical cancer that has undergone potentially
curative therapy.

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, 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 laboratory abnormality
that might confound the results of the trial, interfere with the participant's
participation for the full duration of the trial, or is not in the best interest of
the participant to participate, in the opinion of the treating investigator. Examples
include but are not limited to symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit
compliance with study requirements.

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

- Is pregnant or breastfeeding or expecting to conceive within the projected duration of
the trial, starting with the screening visit through 120 days after the last dose of
trial treatment. It is unknown whether ASP8374 and/or cemiplimab is excreted in human
milk or may have adverse effects on a fetus in utero. Since many drugs are excreted in
human milk, and because of the potential for serious adverse reactions in 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-cytotoxic
T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab), or any
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint
pathways.

- 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.