Clinical trial NCT04172532: Testing the Addition of a New Anti-cancer Drug, M3814 (Peposertib), to the Usual Radiotherapy in Patients With Locally Advanced Pancreatic Cancer
Official title: A Phase 1/2 Study of M3814 (Peposertib) in Combination With Hypofractionated Radiotherapy for the Treatment of Locally Advanced Pancreatic Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Locally Advanced Pancreatic Adenocarcinoma
Stage III Pancreatic Cancer AJCC v8
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2019-11-21
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase I/II trial studies the safety, side effects and best dose of M3814 and to see how well it works when given together with radiation therapy in treating patients with pancreatic cancer that has spread to nearby tissue or lymph nodes (locally advanced). M3814 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Giving M3814 and hypofractionated radiation therapy together may be safe, tolerable and/or more effective than radiation therapy alone in treating patients with locally advanced pancreatic cancer.

Detailed description: 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.

Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo computed tomography (CT) and magnetic resonance imaging (MRI) during screening and on study.

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.

Eligibility criteria: Inclusion Criteria:

* Patients must have pathologically confirmed pancreatic adenocarcinoma
* Received 4-6 months of induction chemotherapy with fluorouracil, irinotecan, leucovorin and oxaliplatin (FOLFIRINOX), fluorouracil, liposomal irinotecan, luecovorin, oxaliplatin (NALIRIFOX), 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 pancreas protocol 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)
* The determination of locally advanced pancreatic cancer and plan for non-operative treatment on this clinical trial must be confirmed through local multi-disciplinary review
* Measurable disease per response evaluation criteria in solid tumors (RECIST) version (v)1.1
* 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 \>= 1.5 x 10\^9/L.
* Hemoglobin \>= 9 g/dL
* Platelets \>= 100 x 10\^9/L
* 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. To be eligible for this trial, patients should be American Heart Association Stage B (people without current or previous symptoms of heart failure but with either structural heart disease, increased filling pressures in the heart or other risk factors) or better and New York Heart Association Functional Classification II (slight limitation of physical activity, comfortable at rest, ordinary physical activity results in fatigue, palpitation, shortness of breath or chest pain), 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, unless the change in treatment was made only for toxicity
* 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 intravenous (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 prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of this investigational regimen

Primary outcomes:
measure: Maximum tolerated dose (Phase I)
timeFrame: Up to 14 days
measure: Recommended phase 2 dose (Phase I)
timeFrame: Up to 14 days
measure: Progression-free survival rate (Phase II)
timeFrame: Time from randomization to progression or death whichever occurs first, assessed up to 2 years
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: Time between the date of randomization and the date of patient death, assessed up to 2 years
measure: Two-year OS
timeFrame: At 2 years
measure: Overall response rate
timeFrame: Up to 2 years
measure: Disease control rate
timeFrame: Up to 2 years
measure: Pharmacokinetic markers of M3814
timeFrame: Up to 2 years
measure: Gene signature of tumor
timeFrame: Up to 2 years
Other outcomes:
measure: Gene signature of cell-free DNA from peripheral blood
timeFrame: Baseline and after treatment
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Irvine
country: United States
facility: UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
state: California
city: Irvine
country: United States
facility: City of Hope at Irvine Lennar
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: UCHealth University of Colorado Hospital
state: Colorado
city: Washington
country: United States
facility: Sibley Memorial Hospital
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Fairway
country: United States
facility: University of Kansas Clinical Research Center
state: Kansas
city: Hays
country: United States
facility: HaysMed
state: Kansas
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Lawrence
country: United States
facility: Lawrence Memorial Hospital
state: Kansas
city: Olathe
country: United States
facility: The University of Kansas Cancer Center - Olathe
state: Kansas
city: Overland Park
country: United States
facility: University of Kansas Cancer Center-Overland Park
state: Kansas
city: Pittsburg
country: United States
facility: Mercy Hospital Pittsburg
state: Kansas
city: Salina
country: United States
facility: Salina Regional Health Center
state: Kansas
city: Topeka
country: United States
facility: University of Kansas Health System Saint Francis Campus
state: Kansas
city: Westwood
country: United States
facility: University of Kansas Hospital-Westwood Cancer Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky/Markey Cancer Center
state: Kentucky
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Farmington Hills
country: United States
facility: Weisberg Cancer Treatment Center
state: Michigan
city: Kansas City
country: United States
facility: University Health Truman Medical Center
state: Missouri
city: Kansas City
country: United States
facility: University of Kansas Cancer Center - North
state: Missouri
city: Lee's Summit
country: United States
facility: University of Kansas Cancer Center - Lee's Summit
state: Missouri
city: North Kansas City
country: United States
facility: University of Kansas Cancer Center at North Kansas City Hospital
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
state: New Hampshire
city: Livingston
country: United States
facility: Saint Barnabas Medical Center
state: New Jersey
city: Long Branch
country: United States
facility: Monmouth Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center-Einstein Campus
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: NYP/Weill Cornell Medical Center
state: New York
city: Clemmons
country: United States
facility: Wake Forest University at Clemmons
state: North Carolina
city: Wilkesboro
country: United States
facility: Wake Forest Baptist Health - Wilkes Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
Study officials:
affiliation: JHU Sidney Kimmel Comprehensive Cancer Center LAO
name: Sarah L Davis
role: PRINCIPAL_INVESTIGATOR
References: