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Testare la combinazione del nuovo farmaco antitumorale Peposertib con Avelumab e radioterapia per tumori solidi avanzati/metastatici e neoplasie epatobiliari

1 ottobre 2026 aggiornato da: National Cancer Institute (NCI)

Uno studio di fase I/II su M3814 e Avelumab in combinazione con radiazioni ipofrazionate in pazienti con tumori solidi avanzati/metastatici e neoplasie epatobiliari

This phase I/II trial studies the best dose and side effects of peposertib and to see how well it works with avelumab and hypofractionated radiation therapy in treating patients with solid tumors and hepatobiliary malignancies that have spread to other places in the body (advanced/metastatic). Peposertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. 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 peposertib in combination with avelumab and hypofractionated radiation therapy may work better than other standard chemotherapy, hormonal, targeted, or immunotherapy medicines available in treating patients with solid tumors and hepatobiliary malignancies.

Panoramica dello studio

Stato

Attivo, non reclutante

Condizioni

Intervento / Trattamento

Descrizione dettagliata

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, peposertib (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 within 12 weeks following initiation of study treatment. (Phase II)

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. (Phase I) II. To characterize the pharmacokinetic (PK) profile of peposertib (M3814) in combination with avelumab. (Phase I) III. To determine the efficacy and safety of the combination of hypofractionated radiation, peposertib (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 and pKAP1 immunofluorescence (IFA) with beta CATN segmentation assay. (Phase II) V. To characterize the pharmacokinetic (PK) profiles of peposertib (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 8 fractions of hypofractionated radiation therapy (RT) every day (QD) 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. Patients also undergo computed tomography (CT), biopsy, and collection of blood samples during screening and on study.

PHASE II: Patients with advanced/metastatic cholangiocarcinoma/gallbladder cancer are randomized to 1 of 2 arms.

ARM A: Patients undergo 8 fractions of hypofractionated RT QD 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. Patients also undergo CT, biopsy, and collection of blood samples during screening and on study.

ARM B: Patients undergo 8 fractions of hypofractionated RT QD 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. Patients also undergo CT, biopsy, and collection of blood samples during screening and on study

After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, every 6 months for year 2, then annually thereafter.

Tipo di studio

Interventistico

Iscrizione (Stimato)

103

Fase

  • Fase 2
  • Fase 1

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Luoghi di studio

  • Stati Uniti
    • California
      • Duarte, California, Stati Uniti, 91010
        • City of Hope Comprehensive Cancer Center
      • Irvine, California, Stati Uniti, 92612
        • UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
      • La Jolla, California, Stati Uniti, 92093
        • UC San Diego Moores Cancer Center
      • Orange, California, Stati Uniti, 92868
        • UC Irvine Health/Chao Family Comprehensive Cancer Center
      • Sacramento, California, Stati Uniti, 95817
        • University of California Davis Comprehensive Cancer Center
    • Colorado
      • Aurora, Colorado, Stati Uniti, 80045
        • UCHealth University of Colorado Hospital
    • Connecticut
      • Derby, Connecticut, Stati Uniti, 06418
        • Smilow Cancer Hospital-Derby Care Center
      • Fairfield, Connecticut, Stati Uniti, 06824
        • Smilow Cancer Hospital Care Center-Fairfield
      • Glastonbury, Connecticut, Stati Uniti, 06033
        • Smilow Cancer Hospital Care Center at Glastonbury
      • Greenwich, Connecticut, Stati Uniti, 06830
        • Smilow Cancer Hospital Care Center at Greenwich
      • Guilford, Connecticut, Stati Uniti, 06437
        • Smilow Cancer Hospital Care Center - Guilford
      • Hartford, Connecticut, Stati Uniti, 06105
        • Smilow Cancer Hospital Care Center at Saint Francis
      • New Haven, Connecticut, Stati Uniti, 06520
        • Yale University
      • New Haven, Connecticut, Stati Uniti, 06510
        • Smilow Cancer Center/Yale-New Haven Hospital
      • North Haven, Connecticut, Stati Uniti, 06473
        • Yale-New Haven Hospital North Haven Medical Center
      • Stamford, Connecticut, Stati Uniti, 06902
        • Smilow Cancer Hospital Care Center at Long Ridge
      • Torrington, Connecticut, Stati Uniti, 06790
        • Smilow Cancer Hospital-Torrington Care Center
      • Trumbull, Connecticut, Stati Uniti, 06611
        • Smilow Cancer Hospital Care Center-Trumbull
      • Waterbury, Connecticut, Stati Uniti, 06708
        • Smilow Cancer Hospital-Waterbury Care Center
      • Waterford, Connecticut, Stati Uniti, 06385
        • Smilow Cancer Hospital Care Center - Waterford
    • District of Columbia
      • Washington D.C., District of Columbia, Stati Uniti, 20007
        • MedStar Georgetown University Hospital
      • Washington D.C., District of Columbia, Stati Uniti, 20016
        • Sibley Memorial Hospital
    • Florida
      • Aventura, Florida, Stati Uniti, 33180
        • UM Sylvester Comprehensive Cancer Center at Aventura
      • Coral Gables, Florida, Stati Uniti, 33146
        • UM Sylvester Comprehensive Cancer Center at Coral Gables
      • Deerfield Beach, Florida, Stati Uniti, 33442
        • UM Sylvester Comprehensive Cancer Center at Deerfield Beach
      • Miami, Florida, Stati Uniti, 33136
        • University of Miami Miller School of Medicine-Sylvester Cancer Center
      • Miami, Florida, Stati Uniti, 33176
        • UM Sylvester Comprehensive Cancer Center at Kendall
      • Plantation, Florida, Stati Uniti, 33324
        • UM Sylvester Comprehensive Cancer Center at Plantation
    • Georgia
      • Atlanta, Georgia, Stati Uniti, 30308
        • Emory University Hospital Midtown
      • Atlanta, Georgia, Stati Uniti, 30322
        • Emory University Hospital/Winship Cancer Institute
      • Atlanta, Georgia, Stati Uniti, 30342
        • Emory Saint Joseph's Hospital
    • Illinois
      • Chicago, Illinois, Stati Uniti, 60611
        • Northwestern University
    • Michigan
      • Detroit, Michigan, Stati Uniti, 48201
        • Wayne State University/Karmanos Cancer Institute
      • Farmington Hills, Michigan, Stati Uniti, 48334
        • Weisberg Cancer Treatment Center
    • New Jersey
      • New Brunswick, New Jersey, Stati Uniti, 08903
        • Rutgers Cancer Institute of New Jersey
    • New York
      • New York, New York, Stati Uniti, 10032
        • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
      • New York, New York, Stati Uniti, 10065
        • NYP/Weill Cornell Medical Center
      • New York, New York, Stati Uniti, 10016
        • Laura and Isaac Perlmutter Cancer Center at NYU Langone
      • New York, New York, Stati Uniti, 10016
        • Bellevue Hospital Center
    • Pennsylvania
      • Pittsburgh, Pennsylvania, Stati Uniti, 15232
        • UPMC Hillman Cancer Center
    • Rhode Island
      • Westerly, Rhode Island, Stati Uniti, 02891
        • Smilow Cancer Hospital Care Center - Westerly
    • Tennessee
      • Nashville, Tennessee, Stati Uniti, 37232
        • Vanderbilt University/Ingram Cancer Center
    • Utah
      • Salt Lake City, Utah, Stati Uniti, 84112
        • Huntsman Cancer Institute/University of Utah
    • Virginia
      • Richmond, Virginia, Stati Uniti, 23298
        • VCU Massey Comprehensive Cancer Center
    • Wisconsin
      • Madison, Wisconsin, Stati Uniti, 53792
        • University of Wisconsin Carbone Cancer Center - University Hospital
      • Madison, Wisconsin, Stati Uniti, 53718
        • University of Wisconsin Carbone Cancer Center - Eastpark Medical Center

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

18 anni e precedenti (Adulto, Adulto più anziano)

Accetta volontari sani

No

Sessi ammissibili allo studio

Tutto

Descrizione

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 gemcitabine, cisplatin, and durvalumab/pembrolizumab

  • Age >= 18 years

    • Because no dosing or adverse event data are currently available on the use of peposertib (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 and pKAP1 IFA with beta CATN segmentation 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. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The effects of peposertib (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 peposertib (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 peposertib (M3814) and avelumab, breastfeeding should be discontinued if the mother is treated with peposertib (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 peposertib (M3814) and avelumab, 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, 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 peposertib (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 peposertib (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 peposertib (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 peposertib (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 peposertib (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 peposertib (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 peposertib (M3814) and avelumab. These must be discontinued >= 5 days prior to starting peposertib (M3814) and avelumab. Patients do not need to discontinue calcium carbonate. H2 blockers are allowed provided they are taken at least 2 hours after peposertib (M3814) dose

  • Patients receiving sorivudine or any chemically related analogues (such as brivudine) and not able to discontinue prior to starting peposertib (M3814) and avelumab are excluded

  • Pregnant and lactating women are excluded from this study because peposertib (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 peposertib (M3814) and avelumab, breastfeeding should be discontinued if the mother is treated with peposertib (M3814) and avelumab

  • Patients who have received live vaccination within 30 days before starting peposertib (M3814) and avelumab

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Trattamento
  • Assegnazione: Randomizzato
  • Modello interventistico: Assegnazione parallela
  • Mascheramento: Nessuno (etichetta aperta)

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Comparatore attivo: Arm A (hypofractionated RT, avelumab)

Patients undergo 8 fractions of hypofractionated RT QD 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. Patients also undergo biopsy, CT, and collection of blood on the trial.
Procedura: Biospecimen Collection

Undergo collection of blood samples

Altri nomi:
  • Raccolta di campioni biologici
  • Biocampione raccolto
  • Raccolta di campioni
  • Raccolta campione
Procedura: Computed Tomography

Undergo CT scan

Altri nomi:
  • CT
  • GATTO
  • TAC
  • Tomografia assiale computerizzata
  • Tomografia computerizzata
  • tomografia
  • Tomografia assiale computerizzata (procedura)
  • Scansione tomografia computerizzata (CT).
  • Scansione CAT diagnostica
  • Tipo di servizio di scansione CAT diagnostica
Procedura: Biopsy Procedure

Undergo biopsy of tumor

Altri nomi:
  • Bx
  • BIOPSY_TYPE
  • Biopsia
Droga: Avelumab

Given IV

Altri nomi:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C
Radiazione: Hypofractionated Radiation Therapy

Undergo hypofractionated RT

Altri nomi:
  • Radioterapia ipofrazionata
  • ipofrazionamento
  • Radiazione, ipofrazionata
  • Ipofrazionato
Sperimentale: Arm B (hypofractionated RT, peposertib, avelumab)

Patients undergo 8 fractions of hypofractionated RT QD 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. Patients also undergo biopsy, CT, and collection of blood on the trial.
Procedura: Biospecimen Collection

Undergo collection of blood samples

Altri nomi:
  • Raccolta di campioni biologici
  • Biocampione raccolto
  • Raccolta di campioni
  • Raccolta campione
Procedura: Computed Tomography

Undergo CT scan

Altri nomi:
  • CT
  • GATTO
  • TAC
  • Tomografia assiale computerizzata
  • Tomografia computerizzata
  • tomografia
  • Tomografia assiale computerizzata (procedura)
  • Scansione tomografia computerizzata (CT).
  • Scansione CAT diagnostica
  • Tipo di servizio di scansione CAT diagnostica
Droga: Avelumab

Given IV

Altri nomi:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C
Radiazione: Hypofractionated Radiation Therapy

Undergo hypofractionated RT

Altri nomi:
  • Radioterapia ipofrazionata
  • ipofrazionamento
  • Radiazione, ipofrazionata
  • Ipofrazionato
Droga: Peposertib

Given PO

Altri nomi:
  • MSC2490484A
  • 3-piridazinametanolo, alfa-(2-cloro-4-fluoro-5-(7-(4-morfolinil)-4-chinazolinil)fenil)-6-metossi-, (alfaS)-
  • M3814
  • M-3814
  • MSC 2490484A
  • MSC-2490484A
  • Nedisertib
Sperimentale: Phase I (hypofractionated RT, peposertib, avelumab)

Patients with advanced/metastatic malignant solid tumors undergo 8 fractions of hypofractionated RT QD 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. Patients also undergo CT, biopsy, and collection of blood samples during screening and on study.
Procedura: Biospecimen Collection

Undergo collection of blood samples

Altri nomi:
  • Raccolta di campioni biologici
  • Biocampione raccolto
  • Raccolta di campioni
  • Raccolta campione
Procedura: Computed Tomography

Undergo CT scan

Altri nomi:
  • CT
  • GATTO
  • TAC
  • Tomografia assiale computerizzata
  • Tomografia computerizzata
  • tomografia
  • Tomografia assiale computerizzata (procedura)
  • Scansione tomografia computerizzata (CT).
  • Scansione CAT diagnostica
  • Tipo di servizio di scansione CAT diagnostica
Procedura: Biopsy Procedure

Undergo biopsy of tumor

Altri nomi:
  • Bx
  • BIOPSY_TYPE
  • Biopsia
Droga: Avelumab

Given IV

Altri nomi:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C
Radiazione: Hypofractionated Radiation Therapy

Undergo hypofractionated RT

Altri nomi:
  • Radioterapia ipofrazionata
  • ipofrazionamento
  • Radiazione, ipofrazionata
  • Ipofrazionato
Droga: Peposertib

Given PO

Altri nomi:
  • MSC2490484A
  • 3-piridazinametanolo, alfa-(2-cloro-4-fluoro-5-(7-(4-morfolinil)-4-chinazolinil)fenil)-6-metossi-, (alfaS)-
  • M3814
  • M-3814
  • MSC 2490484A
  • MSC-2490484A
  • Nedisertib

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Maximum tolerated doses and recommended phase 2 dose of peposertib (M3814) in combination with hypofractionated radiation and avelumab (Phase 1)
Lasso di tempo: Up to 28 days

Will be determined by the occurrence of dose-limiting toxicities defined as the occurrence of one or more grade 3 adverse events that delays treatment for more than 7 days, or any grade 4-5 adverse events.
Up to 28 days
Objective response rate (Phase 2)
Lasso di tempo: Within 12 weeks following initiation of study treatment

Defined as best overall response (compete response [CR] and partial response [PR] in non-irradiated lesions as opposed to stable disease [SD] or progressive disease) within 12 weeks following initiation of study treatment by Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Within 12 weeks following initiation of study treatment

Misure di risultato secondarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Pharmacokinetics of avelumab (Phase 1)
Lasso di tempo: Day 7: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours; Day 21: predose, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours

Will determine concentrations of plasma avelumab using enzyme-linked immunosorbent assay.
Day 7: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours; Day 21: predose, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours
Pharmacokinetics of M3814 (Phase 1)
Lasso di tempo: Day 21: predose

Will determine concentrations of plasma M3814 using liquid chromatography-mass spectrometry (MS)/MS.
Day 21: predose
Disease control rate (Phase 2)
Lasso di tempo: Up to 12 months

Defined as proportion of patients achieving a CR, PR, or SD in non-irradiated by RECIST 1.1 criteria. Will be analyzed by Kaplan-Meier estimates.
Up to 12 months
Progression free survival (PFS) (Phase 2)
Lasso di tempo: From randomization until disease progression or death, assessed up to 12 months

Will be analyzed by Kaplan-Meier estimates.
From randomization until disease progression or death, assessed up to 12 months
PFS outside the irradiated field (Phase 2)
Lasso di tempo: From randomization until disease progression outside the irradiated field or death, assessed up to 12 months

Will be analyzed by Kaplan-Meier estimates.
From randomization until disease progression outside the irradiated field or death, assessed up to 12 months
Overall survival (Phase 2)
Lasso di tempo: From randomization until death from any cause, assessed up to 12 months

Will be analyzed by Kaplan-Meier estimates.
From randomization until death from any cause, assessed up to 12 months
Incidence of adverse events (Phase 2)
Lasso di tempo: Up to 12 months

Defined by Common Terminology Criteria for Adverse Events version 5.0.
Up to 12 months
Pharmacokinetics of M3814 and avelumab (trough levels) (Phase 2)
Lasso di tempo: M3814 and avelumab: Day 21 (Predose)

Correlated with pharmacodynamics (e.g. toxicity). Will compare trough values between patients with and without toxicity, and/or response if warranted, with non-parametric testing.
M3814 and avelumab: Day 21 (Predose)
Defects in deoxyribonucleic acid (DNA) damage repair
Lasso di tempo: Up to 12 months

Assessed by the gamma H2AX phosphorylated (p)NBS1 multiplex immunofluorescence assay (IFA). The association of baseline DNA repair defects, scored as present or absent, with the response rate to treatment will be evaluated using Fisher's exact test.
Up to 12 months
Differential response to therapy (Phase 2)
Lasso di tempo: Up to 12 months

Assessed by the gamma H2AX pNBS1 multiplex IFA. The association of baseline DNA repair defects, scored as present or absent, with the response rate to treatment will be evaluated using Fisher's exact test.
Up to 12 months

Altre misure di risultato

Misura del risultato
Misura Descrizione
Lasso di tempo
Tumor mutation burden
Lasso di tempo: Baseline

Assessed by whole exome sequencing (WES). Correlates will be summarized using descriptive statistics. The association of tumor mutation scored as high or low, with response rates to treatment will be evaluated using Fisher's exact test.
Baseline
Tumor mutation burden
Lasso di tempo: Baseline

Assessed by ribonucleic acid sequencing (RNAseq). Correlates will be summarized using descriptive statistics. The association of tumor mutation scored as high or low, with response rates to treatment will be evaluated using Fisher's exact test.
Baseline
Tumor pattern
Lasso di tempo: Baseline

Assessed by WES. Correlates will be summarized using descriptive statistics. The association of tumor mutation scored as high or low, with response rates to treatment will be evaluated using Fisher's exact test.
Baseline
Tumor pattern
Lasso di tempo: Baseline

Assessed by RNAseq. Correlates will be summarized using descriptive statistics. The association of tumor mutation scored as high or low, with response rates to treatment will be evaluated using Fisher's exact test.
Baseline
Neoantigen burden
Lasso di tempo: Up to 12 months

Assessed by WES. Correlates will be summarized using descriptive statistics. The association of neoantigen burdens, scored as high or low, with response rates to treatment will be evaluated using Fisher's exact test.
Up to 12 months
Neoantigen burden
Lasso di tempo: Up to 12 months

Assessed by RNAseq. Correlates will be summarized using descriptive statistics. The association of neoantigen burdens, scored as high or low, with response rates to treatment will be evaluated using Fisher's exact test.
Up to 12 months
Defects in DNA damage repair
Lasso di tempo: Baseline up to 12 months

Assessed by WES. Immune-response gene expressions will be measured pre- and post-therapy, and be compared using a paired t-test, or a Wilcoxon signed rank test where appropriate.
Baseline up to 12 months
Differential response to therapy
Lasso di tempo: Baseline up to 12 months

Assessed by WES. Immune-response gene expressions will be measured pre- and post-therapy, and be compared using a paired t-test, or a Wilcoxon signed rank test where appropriate.
Baseline up to 12 months
Tumor infiltrating lymphocyte quantification and characterization
Lasso di tempo: Up to 12 months

Assessed by multiplexed ion beam imaging in both the tumor and the host.
Up to 12 months
Circulating T lymphocyte quantification and characterization
Lasso di tempo: Up to 12 months

Assessed by mass cytometry in both the tumor and the host.
Up to 12 months
T cell receptor (TCR) clonality
Lasso di tempo: Up to 12 months

Assessed by TCR sequencing in both the tumor and the host.
Up to 12 months

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

National Cancer Institute (NCI)

Investigatori

  • Investigatore principale: Kristen R Spencer, Laura and Isaac Perlmutter Cancer Center at NYU

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio (Effettivo)

7 aprile 2020

Completamento primario (Stimato)

1 luglio 2027

Completamento dello studio (Stimato)

1 luglio 2027

Date di iscrizione allo studio

Primo inviato

15 agosto 2019

Primo inviato che soddisfa i criteri di controllo qualità

23 agosto 2019

Primo Inserito (Effettivo)

28 agosto 2019

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Effettivo)

2 ottobre 2026

Ultimo aggiornamento inviato che soddisfa i criteri QC

1 ottobre 2026

Ultimo verificato

1 settembre 2026

Maggiori informazioni

Termini relativi a questo studio

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • NCI-2019-05373
  • UM1CA186644 (Sovvenzione/contratto NIH degli Stati Uniti)
  • UM1CA186716 (Sovvenzione/contratto NIH degli Stati Uniti)
  • NCI-2019-05373 (Identificatore di registro: CTRP (Clinical Trial Reporting Program))
  • 052002
  • 10276 (Altro identificatore: Dana-Farber - Harvard Cancer Center LAO)
  • 10276 (Altro identificatore: CTEP)

Piano per i dati dei singoli partecipanti (IPD)

Hai intenzione di condividere i dati dei singoli partecipanti (IPD)?

SÌ

Descrizione del piano IPD

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.

Informazioni su farmaci e dispositivi, documenti di studio

Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti

Sì

Studia un dispositivo regolamentato dalla FDA degli Stati Uniti

No

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

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