Afprøvning af tilføjelsen af et nyt lægemiddel mod kræft, M3814 (Peposertib), til strålebehandling for lokaliseret bugspytkirtelkræft
Et fase 1/2-studie af M3814 (Peposertib) i kombination med hypofraktioneret strålebehandling til behandling af lokalt avanceret pancreas-adenokarcinom
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.
Studieoversigt
Status
Detaljeret beskrivelse
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.
Undersøgelsestype
Tilmelding (Anslået)
Fase
- Fase 2
- Fase 1
Kontakter og lokationer
Studiesteder
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California
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Duarte, California, Forenede Stater, 91010
- City of Hope Comprehensive Cancer Center
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Irvine, California, Forenede Stater, 92618
- City of Hope at Irvine Lennar
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Irvine, California, Forenede Stater, 92612
- UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
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Orange, California, Forenede Stater, 92868
- UC Irvine Health/Chao Family Comprehensive Cancer Center
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Sacramento, California, Forenede Stater, 95817
- University of California Davis Comprehensive Cancer Center
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Colorado
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Aurora, Colorado, Forenede Stater, 80045
- UCHealth University of Colorado Hospital
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District of Columbia
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Washington D.C., District of Columbia, Forenede Stater, 20016
- Sibley Memorial Hospital
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Illinois
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Chicago, Illinois, Forenede Stater, 60611
- Northwestern University
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Kansas
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Fairway, Kansas, Forenede Stater, 66205
- University of Kansas Clinical Research Center
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Hays, Kansas, Forenede Stater, 67601
- HaysMed
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Kansas City, Kansas, Forenede Stater, 66160
- University of Kansas Cancer Center
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Lawrence, Kansas, Forenede Stater, 66044
- Lawrence Memorial Hospital
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Olathe, Kansas, Forenede Stater, 66061
- The University of Kansas Cancer Center - Olathe
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Overland Park, Kansas, Forenede Stater, 66210
- University of Kansas Cancer Center-Overland Park
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Pittsburg, Kansas, Forenede Stater, 66762
- Mercy Hospital Pittsburg
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Salina, Kansas, Forenede Stater, 67401
- Salina Regional Health Center
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Topeka, Kansas, Forenede Stater, 66606
- University of Kansas Health System Saint Francis Campus
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Westwood, Kansas, Forenede Stater, 66205
- University of Kansas Hospital-Westwood Cancer Center
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Kentucky
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Lexington, Kentucky, Forenede Stater, 40536
- University of Kentucky/Markey Cancer Center
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Michigan
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Detroit, Michigan, Forenede Stater, 48201
- Wayne State University/Karmanos Cancer Institute
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Farmington Hills, Michigan, Forenede Stater, 48334
- Weisberg Cancer Treatment Center
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Missouri
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Kansas City, Missouri, Forenede Stater, 64154
- University of Kansas Cancer Center - North
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Kansas City, Missouri, Forenede Stater, 64108
- University Health Truman Medical Center
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Lee's Summit, Missouri, Forenede Stater, 64064
- University of Kansas Cancer Center - Lee's Summit
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North Kansas City, Missouri, Forenede Stater, 64116
- University of Kansas Cancer Center at North Kansas City Hospital
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New Hampshire
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Lebanon, New Hampshire, Forenede Stater, 03756
- Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
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New Jersey
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Livingston, New Jersey, Forenede Stater, 07039
- Cooperman Barnabas Medical Center
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Long Branch, New Jersey, Forenede Stater, 07740
- Monmouth Medical Center
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New Brunswick, New Jersey, Forenede Stater, 08903
- Rutgers Cancer Institute of New Jersey
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New York
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Buffalo, New York, Forenede Stater, 14263
- Roswell Park Cancer Institute
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New York, New York, Forenede Stater, 10029
- Mount Sinai Hospital
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New York, New York, Forenede Stater, 10065
- NYP/Weill Cornell Medical Center
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New York, New York, Forenede Stater, 10016
- Laura and Isaac Perlmutter Cancer Center at NYU Langone
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The Bronx, New York, Forenede Stater, 10461
- Montefiore Medical Center-Einstein Campus
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The Bronx, New York, Forenede Stater, 10467
- Montefiore Medical Center - Moses Campus
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North Carolina
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Clemmons, North Carolina, Forenede Stater, 27012
- Wake Forest University at Clemmons
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Wilkesboro, North Carolina, Forenede Stater, 28659
- Wake Forest Baptist Health - Wilkes Medical Center
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Winston-Salem, North Carolina, Forenede Stater, 27157
- Wake Forest University Health Sciences
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Pennsylvania
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Pittsburgh, Pennsylvania, Forenede Stater, 15232
- UPMC Hillman Cancer Center
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Tennessee
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Nashville, Tennessee, Forenede Stater, 37232
- Vanderbilt University/Ingram Cancer Center
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Utah
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Salt Lake City, Utah, Forenede Stater, 84112
- Huntsman Cancer Institute/University of Utah
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Virginia
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Richmond, Virginia, Forenede Stater, 23298
- VCU Massey Comprehensive Cancer Center
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Wisconsin
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Madison, Wisconsin, Forenede Stater, 53792
- University of Wisconsin Carbone Cancer Center - University Hospital
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Madison, Wisconsin, Forenede Stater, 53718
- University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
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Deltagelseskriterier
Berettigelseskriterier
Aldre berettiget til at studere
Tager imod sunde frivillige
Køn, der er berettiget til at studere
Beskrivelse
Inclusion Criteria:
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Patients must have pathologically confirmed pancreatic adenocarcinoma. Patients with alternative or mixed histologies (i.e., squamous, neuroendocrine, acinar, colloid) are not eligible
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Received 4-6 months of induction chemotherapy with fluorouracil, irinotecan, leucovorin and oxaliplatin (FOLFIRINOX), fluorouracil, liposomal irinotecan, leucovorin, oxaliplatin (NALIRIFOX), or gemcitabine/Abraxane, as per standard of care
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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:
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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
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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
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Unreconstructible superior mesenteric vein or portal vein due to tumor involvement or occlusion (can be due to tumor or bland thrombus)
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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
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Measurable disease per response evaluation criteria in solid tumors (RECIST) version (v)1.1
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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
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Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
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Leukocytes >= 4,000/mcL
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Absolute neutrophil count >= 1.5 x 10^9/L.
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Hemoglobin >= 9 g/dL
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Platelets >= 100 x 10^9/L
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Total bilirubin =< 2.0 x institutional upper limit of normal (ULN)
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Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x institutional ULN
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Creatinine =< 1.5 x institutional ULN
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Glomerular filtration rate (GFR) >= 51 mL/min/1.73 m^2
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Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
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For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
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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
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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.
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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
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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:
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Patients who have completed induction chemotherapy less than 2 weeks or more than 8 weeks prior to study enrollment
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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
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Patients who are receiving any other investigational agents
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History of allergic reactions attributed to compounds of similar chemical or biologic composition to M3814 (peposertib)
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Evidence of distant metastatic disease
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More than 1 line of chemotherapy for the treatment of localized pancreatic cancer, unless the change in treatment was made only for toxicity
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Prior abdominal radiation
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Active inflammatory bowel disease or connective tissue disease
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Inability to swallow oral medications or gastrointestinal disease limiting absorption of oral agents
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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
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Patients who cannot discontinue concomitant medications or herbal supplements that are strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5, CYP2C9, and CYP2C19. Concomitant use of substrates with a narrow therapeutic index that are metabolized by CYP1A2, CYP2B6, CYP2C8, and CYP3A4/5 are also excluded.
- Use caution with other substrates of CYP3A4/5, CYP1A2, CYP2B6, CYP2C8 and substrates of P-gp, BCRP, OCT1, OAT3, OATP1B1, OATP1B3, MATE1, and MATE-2K with a narrow therapeutic index. Close monitoring is advised.
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. (Patient Drug Interactions Handout and Wallet Card) should be provided to patients
- 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
Studieplan
Hvordan er undersøgelsen tilrettelagt?
Design detaljer
- Primært formål: Behandling
- Tildeling: Randomiseret
- Interventionel model: Parallel tildeling
- Maskning: Enkelt
Våben og indgreb
Deltagergruppe / Arm |
Intervention / Behandling |
|---|---|
|
Eksperimentel: Phase I (hypofractionated radiation therapy, M3814)
Patients in Phase I 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. Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo CT and MRI during screening and on study. |
Undergo blood sample collection
Andre navne:
Undergo CT
Andre navne:
Undergo MRI
Andre navne:
Undergo hypofractionated radiation therapy
Andre navne:
Given PO
Andre navne:
Undergo tissue collection
Andre navne:
|
|
Eksperimentel: Phase II Group I (hypofractionated radiation therapy M3814)
Patients in Phase II 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. Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo CT and MRI during screening and on study. |
Undergo blood sample collection
Andre navne:
Undergo CT
Andre navne:
Undergo MRI
Andre navne:
Undergo hypofractionated radiation therapy
Andre navne:
Given PO
Andre navne:
Undergo tissue collection
Andre navne:
|
|
Placebo komparator: Phase II Group II(hypofractionated radiation therapy, placebo)
Patients in Phase II 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 CT and MRI during screening and on study. |
Undergo blood sample collection
Andre navne:
Undergo CT
Andre navne:
Undergo MRI
Andre navne:
Given PO Undergo hypofractionated radiation therapy
Andre navne:
Undergo tissue collection
Andre navne:
|
Hvad måler undersøgelsen?
Primære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
|
Maksimal tolereret dosis (fase I)
Tidsramme: Op til 14 dage
|
Op til 14 dage
|
|
|
Anbefalet fase 2 dosis (fase I)
Tidsramme: Op til 14 dage
|
Op til 14 dage
|
|
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Progression-free survival rate (Phase II)
Tidsramme: Time from randomization to progression or death whichever occurs first, assessed up to 2 years
|
The 95% confidence intervals will be provided. |
Time from randomization to progression or death whichever occurs first, assessed up to 2 years
|
Sekundære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
|
Overall survival (OS)
Tidsramme: Time between the date of randomization and the date of patient death, assessed up to 2 years
|
Will be analyzed using a log-rank test to test for differences between the treatment groups in survival experience. The proportion of patients who survive through 2 years (i.e. the 2-year OS rate) will be compared between arms using Kaplan-Meier estimates. |
Time between the date of randomization and the date of patient death, assessed up to 2 years
|
|
Two-year OS
Tidsramme: At 2 years
|
Defined as the rate of patient survival at 2 years following completion of study treatment (based on Kaplan-Meier method). |
At 2 years
|
|
Overall response rate
Tidsramme: Up to 2 years
|
Defined as the rate of complete or partial response by imaging following study treatment as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Will be summarized and compared between arms. |
Up to 2 years
|
|
Disease control rate
Tidsramme: Up to 2 years
|
Defined as rate of stable disease, complete or partial response by imaging as assessed by RECIST v1.1. Will be summarized and compared between arms. |
Up to 2 years
|
|
Pharmacokinetic markers of M3814
Tidsramme: Up to 2 years
|
M3814 concentration time data will be analyzed non-compartmentally and reported descriptively. |
Up to 2 years
|
|
Gene signature of tumor
Tidsramme: Up to 2 years
|
Defined according to whole exome sequencing and ribonucleic acid sequencing, with a focus on deoxyribonucleic acid (DNA) damage repair signatures. Will be reported descriptively. |
Up to 2 years
|
Andre resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
|
Gene signature of cell-free DNA from peripheral blood
Tidsramme: Baseline and after treatment
|
Results of cell-free DNA analysis will be compared pre- and post-treatment and reported descriptively. |
Baseline and after treatment
|
Samarbejdspartnere og efterforskere
Sponsor
Efterforskere
- Ledende efterforsker: Sarah L Davis, JHU Sidney Kimmel Comprehensive Cancer Center LAO
Datoer for undersøgelser
Studer store datoer
Studiestart (Faktiske)
Primær færdiggørelse (Anslået)
Studieafslutning (Anslået)
Datoer for studieregistrering
Først indsendt
Først indsendt, der opfyldte QC-kriterier
Først opslået (Faktiske)
Opdateringer af undersøgelsesjournaler
Sidste opdatering sendt (Faktiske)
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
Sidst verificeret
Mere information
Begreber relateret til denne undersøgelse
Yderligere relevante MeSH-vilkår
- Sygdomme i det endokrine system
- Neoplasmer efter sted
- Neoplasmer
- Neoplasmer i fordøjelsessystemet
- Sygdomme i fordøjelsessystemet
- Neoplasmer i endokrine kirtler
- Pancreassygdomme
- Bugspytkirtel neoplasmer
- Undersøgelsesteknikker
- Terapeutik
- Kliniske laboratorieteknikker
- Diagnostiske teknikker og procedurer
- Diagnose
- Kirurgiske procedurer, operative
- Cytologiske teknikker
- Cytodiagnose
- Fysiske fænomener
- Diagnostiske teknikker, kirurgisk
- Kemiteknikker, analytisk
- Spektrumanalyse
- Strålebehandling
- Dosisfraktionering, stråling
- Strålebehandlingsdosering
- Stråling
- Biopsi
- Håndtering af eksemplar
- Magnetisk resonansspektroskopi
- Strålingsdosishypofraktionering
- Peposertib
Andre undersøgelses-id-numre
- NCI-2019-07645
- UM1CA186691 (U.S. NIH-bevilling/kontrakt)
- NCI-2019-07645 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- 10366 (Anden identifikator: CTEP)
- 10366 (Anden identifikator: JHU Sidney Kimmel Comprehensive Cancer Center LAO)
Plan for individuelle deltagerdata (IPD)
Planlægger du at dele individuelle deltagerdata (IPD)?
IPD-planbeskrivelse
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
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