A Phase I/II Study of M3814 and Avelumab in Combination with Hypofractionated Radiation in Patients with Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies.

Inclusion Criteria

- PHASE 1: Patients must have a histologically confirmed metastatic or locally advanced

unresectable solid tumor that has progressed on or after available standard of care

therapy or for which no acceptable standard of care therapy exists, or in which the

patient declines standard of care therapy (each patient that declines standard of care

therapy will be documented in the case report form)

- PHASE 2: Patients must have a histologically confirmed metastatic or locally advanced

unresectable cholangiocarcinoma/gallbladder carcinoma that has progressed on at least

1 prior standard of care therapy or for which no acceptable standard of care therapy

exists, or in which the patient declines standard of care therapy (each patient that

declines standard of care therapy will be documented in the case report form)

- Age >= 18 years

- Because no dosing or adverse event data are currently available on the use of

M3814 in combination with avelumab in patients < 18 years of age

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Patients with at least 1 index lesion to irradiate for whom palliative radiation

treatment is indicated (including but not limited to pain and/or symptom control,

prevention of disease -related complications, and preservation of organ function).

Lung and liver lesions are preferred, though alternate lesions may be considered after

discussion with trial principal investigator (PI). Up to 2 lesions may be considered

for irradiation provided at least 1 lesion will receive the study treatment of total

of 60 Gy and all prescribed irradiation will be completed within the radiation window

- Patients with at least 1 Response Evaluation Criteria in Solid Tumors (RECIST)

measurable lesion (to be unirradiated) (defined as those accurately measured in at

least one dimension, with the longest diameter to be recorded for non-nodal lesions

and the shortest diameter for nodal lesions). Measurable is defined as at least 10 mm

in longest diameter for solid tumors, at least 15 mm in shortest diameter for lymph

nodes

- Patients must be willing to undergo fresh biopsies at baseline (as opposed to using

archival tissue), in the event their baseline tissue was obtained > 12 months prior to

study consent and/or they are randomized to the gamma H2AX pNBS1 multiplex IFA assay

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelet count >= 100,000/mcL

- Hemoglobin >= 9.0 g/dL

- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR calculated serum creatinine

clearance (glomerular filtration rate [GFR] can be used in place of creatinine or

creatinine clearance) >= 60 mL/min for participants with creatinine levels > 1.5 x

institutional ULN

- Calculate serum creatinine clearance using the standard Cockcroft-Gault formula

- Serum total bilirubin =< 1.5 x ULN or direct bilirubin =< ULN for participants with

total bilirubin > 1.5 x ULN

- Patients with known Gilbert disease with serum bilirubin level =< 3 x ULN are

eligible

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and

alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x

ULN or =< 5.0 x ULN for patients with hepatobiliary tumors/liver metastases

- Albumin >= 2.8 g/L

- International normalized ratio (INR) or prothrombin time (PT) or activated partial

thromboplastin time (aPTT) =< 1.5 x ULN

- This applies only to patients not receiving therapeutic anticoagulation; patients

receiving therapeutic anticoagulation should be on a stable dose

- Participants must have the ability to swallow and retain oral medication and not have

any clinically significant gastrointestinal abnormalities that might alter absorption

- Female patients of childbearing potential must have a negative urine or serum

pregnancy test within 72 hours prior to receiving the first dose of study medication.

If the urine test is positive or cannot be confirmed as negative, a serum pregnancy

test will be required. The effects of M3814 and avelumab on the developing human fetus

are unknown and there is the potential for teratogenic or abortifacient effects. For

this reason, women and men of child-bearing potential must agree to use adequate

contraception (hormonal or barrier method of birth control; abstinence) prior to study

entry, for the duration of study treatment, and for 6 months after completion of M3814

and avelumab administration. Should a woman become pregnant or suspect she is pregnant

while she or her partner is participating in this study, she should inform her

treating physician immediately. Because there is an unknown but potential risk for

adverse events in nursing infants secondary to treatment of the mother with M3814 and

avelumab, breastfeeding should be discontinued if the mother is treated with M3814 and

avelumab

- Ability to understand and the willingness to sign a written informed consent document.

Participants with impaired decision-making capacity (IDMC) who have a close caregiver

or legally authorized representative (LAR) and/or family member available will also be

eligible

Exclusion Criteria

- PHASE I: Patients who have received prior anti-CTLA-4, anti-PD-1, anti-PD-L1 or other

immune checkpoint inhibitor therapeutic antibodies or pathway-targeting agents

- PHASE II: Patients who have received prior anti-CTLA-4, anti-PD-1, anti-PD-L1 or other

immune checkpoint inhibitor therapeutic antibodies or pathway-targeting agents with

the following exceptions:

- Patients who have only received previous durvalumab (anti-PD-L1) in combination

with gemcitabine +/- cisplatin as part of first line therapy (TOPAZ-1 regimen)

are eligible

- Patients who have only received previous pembrolizumab (anti-PD-1) in combination

with gemcitabine +/- cisplatin as part of first line therapy (KEYNOTE-966

regimen) are eligible

- Patients who have had chemotherapy, definitive radiation, biological cancer therapy,

or investigational agent/device within 21 days of first planned dose of study therapy

(within 14 days for palliative radiation). Previously irradiated lesions may be

re-irradiated provided there is disease progression in the irradiated lesion and the

prescribed radiation dosage can safely be re- administered

- Patients who have not recovered from adverse events due to prior anti-cancer therapy

(i.e., have residual toxicities > Common Terminology Criteria for Adverse Events

[CTCAE] grade 1) with the exception of alopecia

- Patients with untreated/uncontrolled central nervous system (CNS)/leptomeningeal

disease. Patients with asymptomatic, treated CNS disease are eligible if the treating

physician determines that immediate CNS specific treatment is not required and is

unlikely to be required during the first cycle of therapy and the following criteria

are met:

- Radiographic demonstration of clinical stability upon the completion of

CNS-directed therapy and no evidence of interim progression between the

completion of CNS-directed therapy and the screening radiographic study done >= 4

weeks from completion of radiotherapy and >= 2 weeks from discontinuation of

corticosteroids

- No stereotactic radiation or whole-brain radiation within 28 days prior to

randomization

- Patients with active autoimmune disease requiring systemic corticosteroids greater

than the equivalent of prednisone 10 mg daily including but not limited to: systemic

lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, colitis,

vascular thrombosis associated with antiphospholipid syndrome, Wegener's

granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple

sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis, with the

following exceptions:

- Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid

replacement hormone are eligible

- Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are

eligible

- Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with

dermatologic manifestations only who require only low potency topical steroids

(e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%,

desonide 0.05%, alclometasone dipropionate 0.05%) are eligible

- Patients receiving treatment with systemic immunosuppressive medications (including,

but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate,

thalidomide, and anti-tumor necrosis factor [TNF] agents) within 6 weeks must

discontinue these medications prior to starting M3814 and avelumab on day 7, with the

exception of:

- Patients with active autoimmune disease managed with systemic corticosteroids

less than the equivalent of prednisone 10 mg daily

- Patients who have received acute, low dose, systemic immunosuppressant

medications (e.g., a one-time dose of dexamethasone for nausea)

- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)

for patients with orthostatic hypotension and adrenocortical insufficiency

- Patients who have undergone prior solid organ or bone marrow transplant with the

exception of patients with prior renal transplant for whom dialysis may be employed in

the event of graft rejection

- Patients with uncontrolled intercurrent illness (e.g., including but not limited to

uncontrolled hypertension [HTN] [systolic blood pressure (BP) > 150, diastolic BP >

100], symptomatic congestive heart failure [CHF], unstable angina pectoris, ischemic

myocardial infarction [MI] within 6 months, cardiac arrhythmia, recent transient

ischemic attack [TIA or cerebrovascular accident (CVA)]) within 6 months

- Patients with serious active infection (e.g. requiring hospitalization and/or

intravenous [IV] antibiotics) within 4 weeks prior to starting M3814 and avelumab, or

signs/symptoms of infection or receiving oral or IV antibiotics for the treatment of

active systemic infection within 2 weeks prior to starting M3814 and avelumab.

Patients receiving prophylactic antibiotics are eligible

- Patients with known chronic hepatitis B virus (HBV) infection must have an

undetectable viral load on suppressive therapy if indicated. Patients with known

chronic hepatitis C (HCV) infection must have been treated and cured. Patients who are

currently on curative treatment are eligible if they have an undetectable HCV viral

load

- Patients with known human immunodeficiency virus (HIV) are allowed on study provided

they have:

- A stable regimen of highly active anti-retroviral therapy (HAART)

- No requirement for concurrent antibiotics or antifungal agents for the prevention

of opportunistic infection

- A CD4 count above 250 cells/mcL

- An undetectable HIV viral load on standard polymerase chain reaction (PCR)-based

testing

- Patients with history of idiopathic pulmonary fibrosis, pneumonitis (including drug

induced), organizing pneumonia (e.g., bronchiolitis obliterans, cryptogenic organizing

pneumonia), or evidence of active pneumonitis on screening chest computed tomography

(CT) scan

- Patients with known concurrent malignancy that is expected to require active treatment

within two years, or may interfere with the interpretation of the efficacy and safety

outcomes of this study in the opinion of the treating investigator. Superficial

bladder cancer, nonmelanoma skin cancers, and low-grade prostate cancer not requiring

cytotoxic therapy should not exclude participation in this trial. Patients with

chronic lymphocytic leukemia (CLL) may be enrolled if they do not require active

chemotherapy and their hematologic, renal and hepatic function meets criteria

previously mentioned

- Patients with psychiatric illness/social situations that would limit compliance with

study requirements

- History of allergic reactions attributed to compounds of similar chemical or biologic

composition to M3814 or avelumab

- Patients unable to discontinue medications or substances that are potent inhibitors,

inducers or sensitive substrates of CYP3A4/5 or CYP2C19 prior to starting M3814 and

avelumab are ineligible. Medications or substances that are strong inhibitors of

CYP3A4/5 or CYP2C19 must be discontinued at least 1 week prior to first M3814 dose.

Strong inducers of CYP3A4/5 or CYP2C19 must be stopped at least 3 weeks prior to the

first dose. Drugs mainly metabolized by CYP3A with a narrow therapeutic index as

judged by the investigator must stop at least 1 day prior to first M3814 dose. Because

the lists of these agents are constantly changing, it is important to regularly

consult a frequently-updated medical reference. As part of the enrollment/informed

consent procedures, the patient will be counseled on the risk of interactions with

other agents, and what to do if new medications need to be prescribed or if the

patient is considering a new over-the-counter medicine or herbal product. The primary

elimination mechanism of avelumab is proteolytic degradation, thus there are no

contraindicated medications with respect to avelumab

- Patients who cannot discontinue concomitant proton-pump inhibitors (PPIs) prior to

starting M3814 and avelumab. These must be discontinued >= 5 days prior to starting

M3814 and avelumab. Patients do not need to discontinue calcium carbonate. H2 blockers

are allowed provided they are taken at least 2 hours after M3814 dose

- Patients receiving sorivudine or any chemically related analogues (such as brivudine)

and not able to discontinue prior to starting M3814 and avelumab are excluded

- Pregnant and lactating women are excluded from this study because M3814 and avelumab

are agents with the potential for teratogenic or abortifacient effects. Because there

is an unknown but potential risk for adverse events in nursing infants secondary to

treatment of the mother with M3814 and avelumab, breastfeeding should be discontinued

if the mother is treated with M3814 and avelumab

- Patients who have received live vaccination within 30 days before starting M3814 and

avelumab