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Neoadjuvant Immunotherapy in Brain Metastases

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: NCT04434560
Recruitment Status : Recruiting
First Posted : June 17, 2020
Last Update Posted : October 1, 2020
Sponsor:
Collaborators:
Bristol-Myers Squibb
Duke University
Information provided by (Responsible Party):
Sarah Sammons, MD, Duke University

Brief Summary:
The purpose of this phase 2 study is to assess the feasibility and efficacy of neoadjuvant immunotherapy in patients with previously untreated, surgically-resectable, solid tumor brain metastases. The primary objectives of this study are to 1) assess the feasibility of neoadjuvant ipilimumab and nivolumab treatment before surgery and stereotactic radiosurgery (SRS) in patients with solid tumor brain metastases as measured by the proportion of patients who have their surgery delayed or surgery never occurs, and 2) demonstrate that neoadjuvant immunotherapy will increase proliferation of circulating T-cells compared to baseline measurements. Exploratory objectives include describing patient progression free survival and overall survival, time to local and distant intracranial progression, the rate of radiation necrosis, and differences in immune expression profiles between patient arms.

Condition or disease Intervention/treatment Phase
Brain Metastases, Adult Drug: Nivolumab Drug: Ipilimumab Phase 2

Detailed Description:
Forty patients planned for standard of care resection of at least one solid tumor brain metastasis will be enrolled onto the study after providing informed consent. Primary tumor histology types are restricted to those known to extracranially respond to immunotherapy, and will include, but not be limited to, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC that is anaplastic lymphoma kinase positive (ALK+), epidermal growth factor receptor positive (EGFR+), and ROS negative, renal cell carcinoma (RCC), melanoma that is v-raf murine sarcoma viral oncogene homolog B1 negative (BRAF -), and triple negative breast cancer (TNBC) that is programmed death-ligand 1 positive (PD-L1 +). Participants will be randomized 1:1 (20 participants per arm) to either the neoadjuvant immunotherapy (arm 1) or standard of care (no neoadjuvant immunotherapy; arm 2). Patients in arm 1 will receive a single infusion of nivolumab at a dose of 3 mg/kg and ipilimumab at a dose of 1 mg/kg 7 days (±3 days) prior to surgical resection of their metastases. Approximately three weeks after resection, patients in both arms will then receive SRS per standard of care guidelines. After SRS, patients will continue on a maintenance treatment with an immunotherapy regimen at the discretion of the treating physician. Patients will be followed for up to 18 months after initiating study treatment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase II Trial of Surgery and Stereotactic Radiosurgery With and Without Neoadjuvant Nivolumab and Ipilimumab in Patients With Surgically-resectable, Solid Tumor Brain Metastases
Estimated Study Start Date : September 2020
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2023


Arm Intervention/treatment
Experimental: Arm with checkpoint
Arm 1 (arm with checkpoint) will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.
Drug: Nivolumab
Nivolumab will be given at the FDA-approved dose of 3 mg/kg.
Other Name: Opdivo

Drug: Ipilimumab
Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.
Other Name: Yervoy

No Intervention: Arm without checkpoint
Arm 2 (control arm without checkpoint) will proceed straight to surgical resection with no nivolumab/ipilimumab given prior to surgery.



Primary Outcome Measures :
  1. Proportion of patients that receive neoadjuvant ipilimumab and nivolumab prior to surgery and SRS [ Time Frame: 10 days ]
    Proportion of patients within the neoadjuvant treatment arm (Arm 1) who have their surgery delayed by more than 4 days or surgery never occurs as a direct or indirect result of ipilimumab and nivolumab treatment.

  2. Proliferation of circulating T-cells [ Time Frame: 7 days ]
    Mean fold-change between baseline and day 1 in Ki67 levels.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • 1. Patients must have 1 to 3 previously untreated, solid tumor brain metastases that are ≤4 cm in the largest direction. At least one of the metastases must be surgically resectable. All metastases must be planned for treatment with SRS. Primary tumor histology must be one of the following:

    1. Squamous NSCLC
    2. Non-squamous NSCLC that is ALK, EGFR, and ROS negative
    3. RCC
    4. Urothelial carcinoma
    5. Ovarian carcinoma
    6. Melanoma that is BRAF negative
    7. Triple negative breast cancer that is PD-L1 positive
    8. Other solid tumor histologies may be eligible at the discretion of the PI if there are plans to proceed onto a maintenance regimen including a standard of care regimen with immunotherapy
  • 2. Patient must be asymptomatic or minimally symptomatic, requiring the equivalent of ≤ 4 mg dexamethasone daily for at least 7 days prior to enrollment
  • 3. Patient or partner(s) meets one of the following criteria:

    1. Non-childbearing potential (i.e. not sexually active, physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile, or any male who has had a vasectomy). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Postmenopausal for purposes of this study is defined as 1 year without menses.; or
    2. Childbearing potential and agrees to use one of the following methods of birth control: approved hormonal contraceptives (e.g. birth control pills, patches, implants, or infusions), an intrauterine device, or a barrier method of contraception (e.g. a condom or diaphragm) used with spermicide.
  • 4. Age ≥ 18 years of age at the time of entry into the study
  • 5. Karnofsky Performance Score (KPS) ≥ 70
  • 6. Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal prior to resection
  • 7. Neutrophil count ≥ 1000 prior to resection
  • 8. Hemoglobin ≥ 9 g/dl prior to resection
  • 9. Platelet count ≥ 100,000/µl unsupported is necessary for eligibility on the study; however, because of risks of intracranial hemorrhage during resection, platelet count ≥ 125,000/µl is required for the patient to undergo resection, which can be attained with the help of platelet transfusion
  • 10. Creatinine ≤ 1.5 x ULN prior to resection
  • 11. A signed informed consent form approved by the Institutional Review Board (IRB) will be required for patient enrollment into the study. Patients must be able to read and understand the informed consent document and must sign the informed consent indicating that they are aware of the investigational nature of this study
  • 12. Ability to undergo MRI

Exclusion Criteria:

  • 1. Females who are pregnant or breast-feeding
  • 2. Patients with an impending, life-threatening cerebral herniation syndrome, based on the assessment of the study neurosurgeons or their designate
  • 3. Patients with severe, active co-morbidity, defined as follow:

    1. Patients with an active infection requiring intravenous treatment or having an unexplained febrile illness (Tmax > 99.5°F/37.5°C)
    2. Patients with known immunosuppressive disease or known uncontrolled human immunodeficiency virus infection
    3. Patients with unstable or severe intercurrent medical conditions such as severe heart disease (New York Heart Association Class 3 or 4)
  • 4. Patients who have not recovered from the toxic effects of prior chemo- and/or radiation therapy. Guidelines for this recovery period are dependent upon the specific therapeutic agent being used:
  • 5. Patients must not have received immunotherapy within 3 months prior to enrollment
  • 6. Patients on the equivalent of > 4 mg of dexamethasone ≤ 7 days before receiving study treatment
  • 7. Patients with prior, unrelated malignancy requiring current active treatment in the last 3 years with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin
  • 8. Patients with a known history of hypersensitivity to nivolumab, or any components of nivolumab
  • 9. Patients with a known history of hypersensitivity to ipilimumab, or any components of ipilimumab
  • 10. Patients with active autoimmune disease requiring systemic immunomodulatory treatment within the past 3 months.
  • 11. History and/or confirmed pneumonitis, or extensive bilateral lung disease on high resolution/spiral CT scan.

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): NCT04434560


Contacts
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Contact: Sarah Sammons, MD 919-668-5247 sarah.sammons@duke.edu
Contact: Stevie Threatt 919-684-5301 dukebrain1@dm.duke.edu

Locations
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United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Sarah Sammons, MD    919-668-5247    sarah.sammons@duke.edu   
Contact: Stevie Threatt    919-684-5301    dukebrain1@dm.duke.edu   
Principal Investigator: Sarah Sammons, MD         
Sponsors and Collaborators
Sarah Sammons, MD
Bristol-Myers Squibb
Duke University
Investigators
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Principal Investigator: Sarah Sammons, MD Duke University
Additional Information:
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Responsible Party: Sarah Sammons, MD, Assistant Professor of Medicine, Duke University
ClinicalTrials.gov Identifier: NCT04434560    
Other Study ID Numbers: Pro00103812
CA184-583 ( Other Identifier: Bristol Myers Squibb )
First Posted: June 17, 2020    Key Record Dates
Last Update Posted: October 1, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sarah Sammons, MD, Duke University:
Pro00103812
Sammons
Non-small-cell lung carcinoma
Renal cell carcinoma
Urothelial carcinoma
Melanoma
Ovarian carcinoma
Triple negative breast cancer
Solid tumor
Brain metastases
Nivolumab
Ipilimumab
Opdivo
Yervoy
Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplasms, Second Primary
Brain Neoplasms
Neoplastic Processes
Neoplasms
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents