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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04068194
Recruitment Status : Not yet recruiting
First Posted : August 28, 2019
Last Update Posted : December 17, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Avelumab Radiation: Hypofractionated Radiation Therapy Drug: Nedisertib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 92 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : January 31, 2020
Estimated Primary Completion Date : February 28, 2021
Estimated Study Completion Date : February 28, 2021


Arm Intervention/treatment
Active Comparator: Arm A (hypofractionated RT, avelumab)
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.
Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Radiation: Hypofractionated Radiation Therapy
Undergo hypofractionated RT
Other Names:
  • Hypofractionated Radiotherapy
  • hypofractionation

Experimental: Arm B (hypofractionated RT, nedisertib, avelumab)
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.
Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Radiation: Hypofractionated Radiation Therapy
Undergo hypofractionated RT
Other Names:
  • Hypofractionated Radiotherapy
  • hypofractionation

Drug: Nedisertib
Given PO
Other Names:
  • 3-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
  • MSC2490484A




Primary Outcome Measures :
  1. 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 ]
    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.

  2. Objective response rate (ORR) (Phase 2) [ Time Frame: Up to 12 months ]
    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 [PD]) by Response Evaluation Criteria in Solid Tumors (RECIST 1.1).


Secondary Outcome Measures :
  1. 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 ]
    Will determine concentrations of plasma avelumab using enzyme-linked immunosorbent assay (ELISA).

  2. Pharmacokinetics of M3814 (Phase 1) [ Time Frame: Day 21: predose ]
    Will determine concentrations of plasma M3814 using liquid chromatography-mass spectrometry (LC-MS)/MS.

  3. Disease control rate (DCR) (Phase 2) [ Time Frame: 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.

  4. Progression free survival (PFS) (Phase 2) [ Time Frame: From randomization until disease progression or death, assessed up to 12 months ]
    Will be analyzed by Kaplan-Meier estimates.

  5. 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 ]
    Will be analyzed by Kaplan-Meier estimates.

  6. Overall survival (OS) (Phase 2) [ Time Frame: From randomization until death from any cause, assessed up to 12 months ]
    Will be analyzed by Kaplan-Meier estimates.

  7. Incidence of adverse events (Phase 2) [ Time Frame: Up to 12 months ]
    Defined by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.

  8. Pharmacokinetics of M3814 and avelumab (trough levels) (Phase 2) [ Time Frame: 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.

  9. Defects in deoxyribonucleic acid (DNA) damage repair [ Time Frame: 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.

  10. Differential response to therapy (Phase 2) [ Time Frame: 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.


Other Outcome Measures:
  1. Tumor mutation burden [ Time Frame: 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.

  2. Tumor mutation burden [ Time Frame: 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.

  3. Tumor pattern [ Time Frame: 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.

  4. Tumor pattern [ Time Frame: 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.

  5. Neoantigen burden [ Time Frame: 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.

  6. Neoantigen burden [ Time Frame: 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.

  7. Defects in DNA damage repair [ Time Frame: 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.

  8. Differential response to therapy [ Time Frame: 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.

  9. Tumor infiltrating lymphocyte (TILS) quantification and characterization [ Time Frame: Up to 12 months ]
    Assessed by multiplexed ion beam imaging (MIBI) in both the tumor and the host.

  10. Circulating T lymphocyte quantification and characterization [ Time Frame: Up to 12 months ]
    Assessed by by mass cytometry (CyTOF) in both the tumor and the host.

  11. T cell receptor (TCR) clonality [ Time Frame: Up to 12 months ]
    Assessed by TCR sequencing in both the tumor and the host.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Patients with at least 1 index lesion to irradiate
  • 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 =< 1.5x 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 > 1.5x institutional ULN

    • Calculate serum creatinine clearance using the standard Cockcroft-Gault formula
  • Serum total bilirubin =< 1.5x ULN or direct bilirubin =< ULN for participants with total bilirubin > 1.5x 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

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)
  • 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 recent solid tumor or bone marrow transplant
  • 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], cardiac arrhythmia, recent transient ischemic attack [TIA or cerebrovascular accident (CVA)])
  • 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). 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
  • Patients receiving sorivudine or any chemically related analogues (such as brivudine) are excluded

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04068194


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Kristen R Spencer Rutgers University - Cancer Institute of New Jersey LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04068194    
Other Study ID Numbers: NCI-2019-05373
NCI-2019-05373 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10276 ( Other Identifier: Rutgers University - Cancer Institute of New Jersey LAO )
10276 ( Other Identifier: CTEP )
UM1CA186716 ( U.S. NIH Grant/Contract )
First Posted: August 28, 2019    Key Record Dates
Last Update Posted: December 17, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Gallbladder Neoplasms
Klatskin Tumor
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Biliary Tract Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Gallbladder Diseases
Carcinoma
Cholangiocarcinoma
Adenocarcinoma
Biliary Tract Diseases
Digestive System Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs