PRIMARY OBJECTIVES:
I. To determine the safety and tolerability and recommended phase 2 dose (RP2D) of peposertib
(M3814) in combination with hypofractionated radiation and avelumab in patients with
advanced/metastatic solid tumors. (Phase I) II. To determine the efficacy of the combination
of hypofractionated radiation, M3814, and avelumab as compared to the combination of
hypofractionated radiation and avelumab in patients with advanced/metastatic hepatobiliary
tumors by objective response rate (ORR) in non-irradiated lesions. (Phase II)
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. (Phase I) II. To characterize the
pharmacokinetic (PK) profile of M3814 in combination with avelumab. (Phase I) III. To
determine the efficacy and safety of the combination of hypofractionated radiation, M3814,
and avelumab as compared to hypofractionated radiation and avelumab by measurement of disease
control rate (DCR), duration of response (DOR), progression free survival (PFS), PFS outside
the irradiated field, and overall survival (OS) in patients with advanced/metastatic
hepatobiliary tumors. (Phase II) IV. To determine if baseline deoxyribonucleic acid (DNA)
repair defects inherent to some cholangiocarcinomas correlate with a more dramatic response
to radiation compared to those without as measured by gamma H2AX phosphorylated (p)NBS1
multiplex immunofluorescence (IFA) assay. (Phase II) V. To characterize the pharmacokinetic
(PK) profiles of M3814 and avelumab. (Phase II)
EXPLORATORY OBJECTIVES:
I. To perform molecular profiling assays on malignant and normal tissues, including, but not
limited to, whole exome sequencing (WES), ribonucleic acid (RNA) sequencing (RNAseq), mass
cytometry (CyTOF), multiplexed ion beam imaging (MIBI), and T cell receptor sequencing in
order to:
Ia. To determine if baseline tumor mutation burden and pattern, and neoantigen burden
correlate with response.
Ib. To determine if combination therapy results in changes in the immune landscape in both
the tumor and the host that correlate with response.
Ic. To determine if baseline defects in deoxyribonucleic acid (DNA) damage repair in some
cholangiocarcinomas correlate with an increased response.
OUTLINE: This is a phase I, dose-escalation study of peposertib followed by a phase II study.
PHASE I:
Patients with advanced/metastatic malignant solid tumors undergo 5 fractions of
hypofractionated radiation therapy (RT) every other day (QOD) on days -17 to -7. Patients
also receive peposertib orally (PO) twice daily (BID) on days 1-28, and avelumab
intravenously (IV) over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the
absence of disease progression or unacceptable toxicity.
PHASE II: Patients advanced/metastatic cholangiocarcinoma/gallbladder cancer are randomized
to 1 of 2 arms.
ARM A: Patients undergo 5 fractions of hypofractionated RT QOD on days -17 to -7. Patients
also receive avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the
absence of disease progression or unacceptable toxicity.
ARM B: Patients undergo 5 fractions of hypofractionated RT QOD on days -17 to -7. Patients
also receive peposertib PO BID on days 1-28, and avelumab IV over 60 minutes on days 1 and
15. Cycles repeat every 28 days in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up at 30 days, every 6 months for
2 years, then annually thereafter.
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)
- 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 50 Gy
- 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 enrollment 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:
- 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 who received prior immunotherapy
- 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 within 4 weeks prior to enrollment (e.g.
requiring hospitalization and/or intravenous [IV] antibiotics), signs/symptoms of
infection within 2 weeks prior to enrollment, or currently receiving oral or IV
antibiotics for the treatment of infection. 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 on day 7 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 study
treatment. 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 the study
