Clinical Trials /

Testing the Combination of New Anti-cancer Drug Nedisertib With Avelumab and Radiation Therapy for Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies

NCT04068194

Description:

This phase I/II trial studies the best dose and side effects of nedisertib 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). Nedisertib 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 nedisertib 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.

Related Conditions:
  • Cholangiocarcinoma
  • Gallbladder Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Combination of New Anti-cancer Drug Nedisertib With Avelumab and Radiation Therapy for Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies
  • Official Title: A Phase I/II Study of M3814 and Avelumab in Combination With Hypofractionated Radiation in Patients With Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-05373
  • SECONDARY ID: NCI-2019-05373
  • SECONDARY ID: 10276
  • SECONDARY ID: 10276
  • SECONDARY ID: UM1CA186716
  • NCT ID: NCT04068194

Conditions

  • Advanced Cholangiocarcinoma
  • Advanced Gallbladder Carcinoma
  • Advanced Malignant Solid Neoplasm
  • Metastatic Cholangiocarcinoma
  • Metastatic Gallbladder Carcinoma
  • Metastatic Malignant Solid Neoplasm
  • Refractory Cholangiocarcinoma
  • Refractory Gallbladder Carcinoma
  • Refractory Malignant Solid Neoplasm
  • Stage III Gallbladder Cancer AJCC v8
  • Stage III Hilar Cholangiocarcinoma AJCC v8
  • Stage III Intrahepatic Cholangiocarcinoma AJCC v8
  • Stage IIIA Gallbladder Cancer AJCC v8
  • Stage IIIA Hilar Cholangiocarcinoma AJCC v8
  • Stage IIIA Intrahepatic Cholangiocarcinoma AJCC v8
  • Stage IIIB Gallbladder Cancer AJCC v8
  • Stage IIIB Hilar Cholangiocarcinoma AJCC v8
  • Stage IIIB Intrahepatic Cholangiocarcinoma AJCC v8
  • Stage IIIC Hilar Cholangiocarcinoma AJCC v8
  • Stage IV Gallbladder Cancer AJCC v8
  • Stage IV Hilar Cholangiocarcinoma AJCC v8
  • Stage IV Intrahepatic Cholangiocarcinoma AJCC v8
  • Stage IVA Gallbladder Cancer AJCC v8
  • Stage IVA Hilar Cholangiocarcinoma AJCC v8
  • Stage IVB Gallbladder Cancer AJCC v8
  • Stage IVB Hilar Cholangiocarcinoma AJCC v8

Interventions

DrugSynonymsArms
AvelumabBavencio, MSB-0010718C, MSB0010718CArm A (hypofractionated RT, avelumab)
Nedisertib3-Pyridazinemethanol, alpha-(2-Chloro-4-fluoro-5-(7-(4-morpholinyl)-4-quinazolinyl)phenyl)-6-methoxy-, (alphaS)-, M 3814, M-3814, M3814, MSC 2490484A, MSC-2490484A, MSC2490484AArm B (hypofractionated RT, nedisertib, avelumab)

Purpose

This phase I/II trial studies the best dose and side effects of nedisertib 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). Nedisertib 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 nedisertib 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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and tolerability and recommended phase 2 dose (RP2D) of nedisertib
      (M3814) in combination with hypofractionated radiation and avelumab in patients with
      advanced/metastatic solid tumors. (Phase I) II. To determine the efficacy of the combination
      of hypofractionated radiation, M3814, and avelumab as compared to the combination of
      hypofractionated radiation and avelumab in patients with advanced/metastatic hepatobiliary
      tumors by objective response rate (ORR) in non-irradiated lesions. (Phase II)

      SECONDARY OBJECTIVES:

      I. To observe and record anti-tumor activity. (Phase I) II. To characterize the
      pharmacokinetic (PK) profile of M3814 in combination with avelumab. (Phase I) III. To
      determine the efficacy of the combination of hypofractionated radiation, M3814, and avelumab
      as compared to hypofractionated radiation and avelumab by measurement of disease control rate
      (DCR), duration of response (DOR), progression free survival (PFS), PFS outside the
      irradiated field, and overall survival (OS) in patients with advanced/metastatic
      hepatobiliary tumors. (Phase II) IV. To determine if baseline deoxyribonucleic acid (DNA)
      repair defects inherent to some cholangiocarcinomas correlate with a more dramatic response
      to radiation compared to those without as measured by gamma H2AX phosphorylated (p)NBS1
      multiplex immunofluorescence (IFA) assay. (Phase II) V. To characterize the pharmacokinetic
      (PK) profiles of M3814 and avelumab. (Phase II)

      EXPLORATORY OBJECTIVES:

      I. To perform molecular profiling assays on malignant and normal tissues, including, but not
      limited to, whole exome sequencing (WES), ribonucleic acid (RNA) sequencing (RNAseq), mass
      cytometry (CyTOF), multiplexed ion beam imaging (MIBI), and T cell receptor sequencing in
      order to:

      Ia. Determine if baseline tumor mutation burden and pattern, and neoantigen burden correlate
      with response.

      Ib. Determine if combination therapy results in changes in the immune landscape in both the
      tumor and the host that correlate with response.

      Ic. 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 nedisertib followed by a phase II study.

      PHASE I:

      Patients with advanced/metastatic malignant solid tumors undergo 5 fractions of
      hypofractionated radiation therapy (RT) every other day (QOD) on days -10 to 0. Patients also
      receive nedisertib orally (PO) twice daily (BID) on days 7-28 of cycle 1 and on days 1-28 of
      subsequent cycles, and avelumab intravenously (IV) over 60 minutes on days 7 and 21. Cycles
      repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

      ARM A: Patients undergo 5 fractions of hypofractionated RT QOD on days -10 to 0. Patients
      also receive avelumab IV over 60 minutes on days 7 and 21. Cycles repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      ARM B: Patients undergo 5 fractions of hypofractionated RT QOD on days -10 to 0. Patients
      also receive nedisertib PO BID on days 7-28 of cycle 1 and on days 1-28 of subsequent cycles,
      and avelumab IV over 60 minutes on days 7 and 21. Cycles repeat every 28 days in the absence
      of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 90 days for
      up to 12 months.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (hypofractionated RT, avelumab)Active ComparatorPatients undergo 5 fractions of hypofractionated RT QOD on days -10 to 0. Patients also receive avelumab IV over 60 minutes on days 7 and 21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Avelumab
Arm B (hypofractionated RT, nedisertib, avelumab)ExperimentalPatients undergo 5 fractions of hypofractionated RT QOD on days -10 to 0. Patients also receive nedisertib PO BID on days 7-28 of cycle 1 and on days 1-28 of subsequent cycles, and avelumab IV over 60 minutes on days 7 and 21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Avelumab
  • Nedisertib

Eligibility Criteria

        Inclusion Criteria:

          -  PHASE 1: Patients must have a histologically confirmed advanced/metastatic solid tumor
             that has progressed on at least one prior standard of care therapy or for which no
             acceptable standard of care therapy exists, or in which the patient declines standard
             of care therapy (each patient that declines standard of care therapy will be
             documented in the case report form)

          -  PHASE 2: Patients must be willing to undergo fresh biopsies at baseline (as opposed to
             using archival tissue), in the event they are randomized to the gamma H2AX pNBS1
             multiplex IFA assay

          -  PHASE 2: Patients must have a histologically confirmed advanced/metastatic
             cholangiocarcinoma/gallbladder carcinoma that has progressed on at least 1 prior
             standard of care therapy or for which no acceptable standard of care therapy exists,
             or in which the patient declines standard of care therapy (each patient that declines
             standard of care therapy will be documented in the case report form). Patients with
             MSI-H or NTRK-fusion positive tumors who have not received approved treatment for
             these tumor types are excluded

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Patients with at least 1 index lesion to irradiate (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
             will be considered for radiation after consultation with study PI.

          -  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

          -  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]) =< 2.5x
             ULN or =< 5.0x 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) =< 1.5x ULN

               -  This applies only to patients not receiving therapeutic anticoagulation; patients
                  receiving therapeutic anticoagulation should be on a stable dose

          -  Participants must have the ability to swallow and retain oral medication and not have
             any clinically significant gastrointestinal abnormalities that might alter absorption

          -  Female patients of childbearing potential must have a negative urine or serum
             pregnancy test within 72 hours prior to receiving the first dose of study medication.
             If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
             test will be required. The effects of M3814 and avelumab on the developing human fetus
             are unknown and there is the potential for teratogenic or abortifacient effects. For
             this reason, women and men of child-bearing potential must agree to use adequate
             contraception (hormonal or barrier method of birth control; abstinence) prior to study
             entry, for the duration of study treatment, and for 6 months after completion of M3814
             and avelumab administration. Should a woman become pregnant or suspect she is pregnant
             while she or her partner is participating in this study, she should inform her
             treating physician immediately. Because there is an unknown but potential risk for
             adverse events in nursing infants secondary to treatment of the mother with M3814 and
             avelumab, breastfeeding should be discontinued if the mother is treated with M3814 and
             avelumab

          -  Ability to understand and the willingness to sign a written informed consent document.
             Participants with impaired decision-making capacity (IDMC) who have a close caregiver
             or legally authorized representative (LAR) and/or family member available will also be
             eligible

        Exclusion Criteria:

          -  Patients who have had chemotherapy, definitive radiation, biological cancer therapy,
             or investigational agent/device within 21 days of first planned dose of study therapy
             (within 14 days for palliative radiation). Previously irradiated lesions may be
             re-irradiated provided there is disease progression in the irradiated lesion and the
             prescribed radiation dosage can safely be re- administered

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e., have residual toxicities > Common Terminology Criteria for Adverse Events
             [CTCAE] grade 1) with the exception of alopecia or those which are not expected to be
             exacerbated by or interfere with study treatment as determined between the sponsor and
             the study investigator

          -  Patients who received prior immunotherapy

          -  Patients with untreated/uncontrolled central nervous system (CNS)/leptomeningeal
             disease. Patients with asymptomatic, treated CNS disease are eligible if the treating
             physician determines that immediate CNS specific treatment is not required and is
             unlikely to be required during the first cycle of therapy and the following criteria
             are met:

               -  Radiographic demonstration of clinical stability upon the completion of
                  CNS-directed therapy and no evidence of interim progression between the
                  completion of CNS-directed therapy and the screening radiographic study done >= 4
                  weeks from completion of radiotherapy and >= 2 weeks from discontinuation of
                  corticosteroids

               -  No stereotactic radiation or whole-brain radiation within 28 days prior to
                  randomization

          -  Patients with active autoimmune disease requiring systemic corticosteroids greater
             than the equivalent of prednisone 10 mg daily including but not limited to: systemic
             lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, colitis,
             vascular thrombosis associated with antiphospholipid syndrome, Wegener's
             granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple
             sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis, with the
             following exceptions:

               -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
                  replacement hormone are eligible

               -  Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are
                  eligible

               -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
                  dermatologic manifestations only who require only low potency topical steroids
                  (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%,
                  desonide 0.05%, alclometasone dipropionate 0.05%) are eligible

          -  Patients who 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, 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, recent
             ischemic myocardial infarction [MI] within 6 months, cardiac arrhythmia, recent
             transient ischemic attack [TIA or cerebrovascular accident (CVA)]) within 6 months

          -  Patients with serious active infection within 4 weeks prior to randomization (e.g.
             requiring hospitalization and/or intravenous [IV] antibiotics), signs/symptoms of
             infection within 2 weeks prior to randomization, or currently receiving oral or IV
             antibiotics for the treatment of infection. Patients receiving prophylactic
             antibiotics are eligible

          -  Patients with known chronic hepatitis B virus (HBV) infection must have an
             undetectable viral load on suppressive therapy if indicated. Patients with known
             chronic hepatitis C (HCV) infection must have been treated and cured. Patients who are
             currently on curative treatment are eligible if they have an undetectable HCV viral
             load

          -  Patients with known human immunodeficiency virus (HIV) are allowed on study provided
             they have:

               -  A stable regimen of highly active anti-retroviral therapy (HAART)

               -  No requirement for concurrent antibiotics or antifungal agents for the prevention
                  of opportunistic infection

               -  A CD4 count above 250 cells/mcL

               -  An undetectable HIV viral load on standard polymerase chain reaction (PCR)-based
                  testing

          -  Patients with history of idiopathic pulmonary fibrosis, pneumonitis (including drug
             induced), organizing pneumonia (e.g., bronchiolitis obliterans, cryptogenic organizing
             pneumonia), or evidence of active pneumonitis on screening chest computed tomography
             (CT) scan

          -  Patients with known concurrent malignancy that is expected to require active treatment
             within two years, or may interfere with the interpretation of the efficacy and safety
             outcomes of this study in the opinion of the treating investigator. Superficial
             bladder cancer, nonmelanoma skin cancers, and low-grade prostate cancer not requiring
             cytotoxic therapy should not exclude participation in this trial. Patients with
             chronic lymphocytic leukemia (CLL) may be enrolled if they do not require active
             chemotherapy and their hematologic, renal and hepatic function meets criteria
             previously mentioned

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to M3814 or avelumab

          -  Patients unable to discontinue medications or substances that are potent inhibitors,
             inducers or sensitive substrates of CYP3A4/5 or CYP2C19 prior to study treatment are
             ineligible. Medications or substances that are strong inhibitors of CYP3A4/5 or
             CYP2C19 must be discontinued at least 1 week prior to first M3814 dose. Strong
             inducers of CYP3A4/5 or CYP2C19 must be stopped at least 3 weeks prior to the first
             dose. Drugs mainly metabolized by CYP3A with a narrow therapeutic index as judged by
             the investigator must stop at least 1 day prior to first M3814 dose. Because the lists
             of these agents are constantly changing, it is important to regularly consult a
             frequently-updated medical reference. As part of the enrollment/informed consent
             procedures, the patient will be counseled on the risk of interactions with other
             agents, and what to do if new medications need to be prescribed or if the patient is
             considering a new over-the-counter medicine or herbal product. The primary elimination
             mechanism of avelumab is proteolytic degradation, thus there are no contraindicated
             medications with respect to avelumab

          -  Pregnant and lactating women are excluded from this study because M3814 and avelumab
             are agents with the potential for teratogenic or abortifacient effects. Because there
             is an unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with M3814 and avelumab, breastfeeding should be discontinued
             if the mother is treated with M3814 and avelumab

          -  Patients who have received live vaccination within 30 days before the study

          -  Patients who cannot discontinue concomitant H2 blockers or proton-pump inhibitors
             (PPIs) prior to starting M3814 and avelumab on day 7. These must be discontinued >= 5
             days prior to study treatment. Patients do not need to discontinue calcium carbonate

          -  Patients receiving sorivudine or any chemically related analogues (such as brivudine)
             and not able to discontinue prior to starting M3814 and avelumab on day 7 are excluded
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated doses and recommended phase 2 dose of nedisertib (M3814) in combination with hypofractionated radiation and avelumab (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Pharmacokinetics of avelumab (Phase 1)
Time Frame: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
Safety Issue:
Description:Will determine concentrations of plasma avelumab using enzyme-linked immunosorbent assay (ELISA).
Measure:Pharmacokinetics of M3814 (Phase 1)
Time Frame:Day 21: predose
Safety Issue:
Description:Will determine concentrations of plasma M3814 using liquid chromatography-mass spectrometry (LC-MS)/MS.
Measure:Disease control rate (DCR) (Phase 2)
Time Frame:Up to 12 months
Safety Issue:
Description: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.
Measure:Progression free survival (PFS) (Phase 2)
Time Frame:From randomization until disease progression or death, assessed up to 12 months
Safety Issue:
Description:Will be analyzed by Kaplan-Meier estimates.
Measure:PFS outside the irradiated field (Phase 2)
Time Frame:From randomization until disease progression outside the irradiated field or death, assessed up to 12 months
Safety Issue:
Description:Will be analyzed by Kaplan-Meier estimates.
Measure:Overall survival (OS) (Phase 2)
Time Frame:From randomization until death from any cause, assessed up to 12 months
Safety Issue:
Description:Will be analyzed by Kaplan-Meier estimates.
Measure:Incidence of adverse events (Phase 2)
Time Frame:Up to 12 months
Safety Issue:
Description:Defined by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.
Measure:Pharmacokinetics of M3814 and avelumab (trough levels) (Phase 2)
Time Frame:M3814 and avelumab: Day 21 (Predose)
Safety Issue:
Description: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.
Measure:Defects in deoxyribonucleic acid (DNA) damage repair
Time Frame:Up to 12 months
Safety Issue:
Description: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.
Measure:Differential response to therapy (Phase 2)
Time Frame:Up to 12 months
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

February 10, 2020