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Brief Title: Neoadjuvant Immunotherapy in Brain Metastases

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

INTRODUCTION

  • Org Study ID: Pro00103812
  • Secondary ID: CA184-583
  • NTC ID: NCT04434560
  • Sponsor: Sarah Sammons, MD

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.

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.


  • Overall Status
    Recruiting
  • Start Date
    September 2020
  • Phase
    Phase 2
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Proportion of patients that receive neoadjuvant ipilimumab and nivolumab prior to surgery and SRS

Primary Outcome 1 - Timeframe: 10 days

Primary Outcome 2 - Measure: Proliferation of circulating T-cells

Primary Outcome 2 - Timeframe: 7 days

CONDITION

  • Brain Metastases
  • Adult

ELIGIBILITY


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.

Gender: All

Minimum Age: N/A

Maximum Age: 18 Years

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Sarah Sammons, MD

Role: Principal Investigator

Affiliation: Duke University

Overall Contact

Name: Sarah Sammons, MD

Phone: 919-668-5247

Email: sarah.sammons@duke.edu

LOCATION

Facility Status Contact
Facility: Duke University Medical Center
Durham, North Carolina 27710
United States 		Status: Recruiting Contact:
Sarah Sammons, MD
919-668-5247
sarah.sammons@duke.edu

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