Description:
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, and the rate of
radiation necrosis. The rate of radionecrosis will also be explored, as immune expression
profiles.
Title
- Brief Title: Neoadjuvant Immunotherapy in Brain Metastases
- Official Title: A Phase II Trial of Surgery and Stereotactic Radiosurgery With Neoadjuvant Nivolumab and Ipilimumab in Patients With Surgically-resectable, Solid Tumor Brain Metastases
Clinical Trial IDs
- ORG STUDY ID:
Pro00103812
- SECONDARY ID:
CA184-583
- NCT ID:
NCT04434560
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Nivolumab | Opdivo | Neoadjuvant Immunotherapy |
Ipilimumab | Yervoy | Neoadjuvant Immunotherapy |
Purpose
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, and the rate of
radiation necrosis. The rate of radionecrosis will also be explored, as immune expression
profiles.
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 without known anaplastic lymphoma kinase (ALK), epidermal growth factor
receptor (EGFR), and ROS mutation, renal cell carcinoma (RCC), melanoma, and triple negative
breast cancer (TNBC) that is programmed death-ligand 1 positive (PD-L1 +). All participants
will receive neoadjuvant immunotherapy and 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 will
then receive SRS per standard of care guidelines. Patients will be followed for 18 months
after initiating study treatment. Up to 20 participants will be recruited and treated. Blood
will be collected periodically during the study for correlative assessments.
Trial Arms
Name | Type | Description | Interventions |
---|
Neoadjuvant Immunotherapy | Experimental | Patients will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection. | |
Eligibility Criteria
Inclusion Criteria:
- 1. Patients must have at least 1 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 without known ALK, EGFR, and ROS mutation
3. RCC
4. Urothelial carcinoma
5. Ovarian carcinoma
6. Melanoma
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 they
are known to respond to immunotherapy containing regimens.
- 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 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
- 7. Patients with a known history of hypersensitivity to nivolumab, or any components
of nivolumab
- 8. Patients with a known history of hypersensitivity to ipilimumab, or any components
of ipilimumab
- 9. Patients with active autoimmune disease requiring systemic immunomodulatory
treatment within the past 3 months.
- 10. History and/or confirmed pneumonitis, or extensive bilateral lung disease on high
resolution/spiral CT scan.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Proportion of patients that receive neoadjuvant ipilimumab and nivolumab prior to surgery and SRS |
Time Frame: | 10 days |
Safety Issue: | |
Description: | Proportion of patients 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. |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Sarah Sammons, MD |
Trial Keywords
- 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
Last Updated
July 23, 2021