PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of M3814 (peposertib) in combination with
hypofractionated radiotherapy in patients receiving treatment for locally advanced pancreatic
adenocarcinoma (LAPC). (Phase I) II. To determine the difference in progression free survival
(PFS) between patients with LAPC treated with hypofractionated radiotherapy in combination
with M3814 (peposertib) as compared to patients treated with hypofractionated radiotherapy
alone. (Phase II)
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. (Phase I) II. To evaluate plasma
pharmacokinetic (PK) profiles of M3814 (peposertib) in patients receiving hypofractionated
radiotherapy. (Phase I) III. To compare the 2-year overall survival (OS) rate of patients
treated with hypofractionated radiotherapy plus M3814 (peposertib) to that of those treated
with hypofractionated radiotherapy alone. (Phase II) IV. To compare the objective response
rate (ORR) by imaging of patients treated with hypofractionated radiotherapy plus M3814
(peposertib) to that of those treated with hypofractionated radiotherapy alone. (Phase II) V.
To compare the disease control rate in patients treated with hypofractionated radiotherapy
plus M3814 (peposertib) as compared to those patients treated with hypofractionated
radiotherapy alone. (Phase II) VI. To explore gene signature patterns in baseline patient
tumor tissues that may suggest response to the combination of M3814 (peposertib) and
radiotherapy, as identified on whole exome sequencing and ribonucleic acid (RNA) sequencing
(seq). (Phase II)
EXPLORATORY OBJECTIVE:
I. To explore changes in gene signature induced by M3814 (peposertib) and hypofractionated
radiotherapy treatment as identified in analysis of cell-free deoxyribonucleic acid (DNA)
from the peripheral blood. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of M3814 followed by a phase II study.
PHASE I: Patients undergo hypofractionated radiation therapy for 5 fractions every other day
(QOD) over 2 weeks and receive M3814 orally (PO) once daily (QD) for 14 days in the absence
of disease progression or unacceptable toxicity.
PHASE II: Patients are randomized to 1 of 2 groups.
GROUP I: Patients undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks
and receive M3814 PO QD for 14 days in the absence of disease progression or unacceptable
toxicity.
GROUP II: Patients undergo hypofractionated radiation therapy for 5 fractions QOD over 2
weeks and receive placebo PO QD for 14 days in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up at 30, 60, and 90 days, and
then every 3 months for up to 2 years.
Inclusion Criteria:
- Patients must have pathologically confirmed pancreatic adenocarcinoma
- Received 4-6 months of induction chemotherapy with either fluorouracil, irinotecan,
leucovorin and oxaliplatin (FOLFIRINOX) or gemcitabine/Abraxane, as per standard of
care
- Patients must have locally advanced pancreatic cancer according to National
Comprehensive Cancer Network (NCCN) Guidelines (Version 1.2020) on CT scan performed
within 21 days of registration. Locally advanced disease is defined as any of the
following:
- For head or uncinate process tumors:
- Solid tumor contact with superior mesenteric artery > 180 degrees
- Solid tumor contact with the celiac axis > 180 degrees
- Solid tumor contact with the common or proper hepatic arteries > 180 degrees
or
- For pancreatic body or tail tumors:
- Solid tumor contact of > 180 degrees with the superior mesenteric artery or
celiac axis
- Solid tumor contact with the celiac axis and aortic involvement or
- Unreconstructible superior mesenteric vein or portal vein due to tumor
involvement or occlusion (can be due to tumor or bland thrombus)
- Age >= 18 years. Because no dosing or adverse event data are currently available on
the use of M3814 (peposertib) in combination with hypofractionated radiation in
patients < 18 years of age, children are excluded from this study, but will be
eligible for future pediatric trials
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Leukocytes >= 4,000/mcL
- Absolute neutrophil count >= lower limits of normal (LLN)
- Hemoglobin >= 9 g/dL
- Platelets >= LLN
- Total bilirubin =< 2.0 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
3 x institutional ULN
- Creatinine =< 1.5 x institutional ULN
- Glomerular filtration rate (GFR) >= 51 mL/min/1.73 m^2
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- 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. Female patients of childbearing potential and male patients
must be willing to use an adequate method of contraception for the course of the study
through 12 weeks after the last dose of study medication.
- Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the patient.
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a legally
authorized representative (LAR) and/or family member available will also be eligible
Exclusion Criteria:
- Patients who have completed induction chemotherapy less than 2 weeks or more than 8
weeks prior to study enrollment
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia and
neuropathy grade =< 2
- Patients who are receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to M3814 (peposertib)
- Evidence of distant metastatic disease
- More than 1 line of chemotherapy for the treatment of localized pancreatic cancer
- Prior abdominal radiation
- Active inflammatory bowel disease or connective tissue disease
- Inability to swallow oral medications or gastrointestinal disease limiting absorption
of oral agents
- History of anaphylactic reaction to iodinated IV contrast required for radiation
simulation. Patients with mild reactions may be enrolled, but must receive
premedications for contrast allergy prior to imaging
- Patients who cannot discontinue concomitant medications or herbal supplements that are
strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5,
CYP2CP, and CYP2C19. Concomitant use of CYP1A2, CYP2B6, and CYP3A4/5 substrates with a
narrow therapeutic index are also excluded. Patients may confer with the study doctor
to determine if alternative medications can be used. The following categories of
medications and herbal supplements must be discontinued for at least the specified
period of time before the patient can be treated:
- Strong inducers of CYP3A4/5, CYP2C9 and CYP2C19: >= 3 weeks prior to study
treatment
- Strong inhibitors of CYP3A4/5, CYP2C9 and CYP2C19: >= 1 week prior to study
treatment
- Substrates of CYP1A2, CYP2B6, and CYP3A4/5 with a narrow therapeutic index: >= 1
day prior to study treatment
- 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
- Patients who cannot discontinue concomitant proton-pump inhibitors (PPIs). Patients
may confer with the study doctor to determine if such medications can be discontinued.
These must be discontinued >= 5 days prior to study treatment. Patients do not need to
discontinue calcium carbonate. H2 blockers and antacids are allowed.
- Patients who have received a live attenuated vaccine within 30 days of dosing with
M3814 (peposertib)
- Patients with uncontrolled intercurrent illness
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study because M3814 (peposertib) is a
DNA-protein kinase (PK) inhibitor 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 (peposertib), breastfeeding
should be discontinued if the mother is treated with M3814 (peposertib)
- Patients with a history of malignancy within 3 years of the screening visit. Patients
with cutaneous carcinomas or in-situ carcinoma will be considered for study entry on a
case-by-case basis
