| Eligibility |
Inclusion Criteria:
- Age 18 years old or older on day of signing the informed consent.
- Histological confirmation of systemic cancer from melanoma.
- Surgery for metastatic brain lesions (i.e., MBM) is needed but not imminent. Imminent
defined as requiring emergent intervention. A multidisciplinary team, including at
least a neurosurgeon, radiation-oncologist, and neuro-oncologist, will determine the
appropriateness for resection via craniotomy and level of urgency for surgery of the
MBM.
- Resectable metastatic brain lesions (i.e., MBM) in whom surgical resection is a
reasonable therapeutic option. A resectable metastatic brain lesion is defined as a
lesion that is =10 mm in size of longest diameter and in a location outside of the
brainstem. (Other target lesions, i.e. those that are not resected but are followed
for response, can be =5 mm). A multidisciplinary team, including at least a
neurosurgeon, radiation-oncologist, and neuro-oncologist, will determine the
appropriateness for resection via craniotomy and level of urgency for surgery of the
MBM.
- Patient is on =3 mg/day dexamethasone or equivalent/day over pre-op period.
- Patient did not receive treatment with immunotherapy within 6 months prior to day 1 of
treatment on study.
- No treatment with dabrafenib and/or trametinib (BRAF MEKi) for 1 month.
- MRI with enhancing metastatic brain lesions (i.e., MBM) amenable to resection of
contrast-enhancing tumor (determined by neurosurgeon). A multidisciplinary team,
including at least a neurosurgeon, radiation-oncologist, and neuro-oncologist, will
determine the appropriateness for resection via craniotomy and level of urgency for
surgery of the MBM.
- Patient willing to undergo craniotomy and resection.
- Patient eligible for surgery in the 7-10 days after initial treatment.
- Patients who had prior surgical resection of MBM are eligible to enroll.
- Usual acceptable lab parameters, demonstrating adequate organ function as defined in
protocol. All screening labs should be performed within 21 days of treatment
initiation.
- Resting baseline O2 saturation by pulse oximetry of 92% or higher at rest.
- Be willing and able to provide written informed consent for the trial.
- Willing to provide tissue and blood samples for correlative research purposes.
- Has ECOG Performance Status (PS) of 0, 1 or 2.
- Adequate seizure prophylaxis in the pre- and perioperative period.
- Prior whole Brain radiation therapy (WBRT), single fraction radiation therapy (e.g.,
SRS), or multiple fraction radiation therapy (e.g., fSRT) to the brain is permitted.
- A negative serum pregnancy test must be documented at the screening visit.
Additionally, female patients must exhibit a negative urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of
study drug, therefore the screening pregnancy test may need to be repeated prior to
the start of study drug dosing. A urine pregnancy test can be used for this. A
pre-dosing urine pregnancy test must be performed prior to each dose during study
phase. A urine pregnancy test will also be conducted at End of Treatment Visit.
- Female patients of childbearing potential must be willing to use an adequate method of
contraception as outlined in Section 13.1.2 Contraception Guidance for Female
Participants of Child Bearing Potential. Contraception, for the duration of treatment
and an additional 5 months after the last dose of the study drug. Abstinence is
acceptable if this is the usual lifestyle and preferred contraception for the patient.
- Male patients of childbearing potential who are sexually active with Women of Child
Bearing Potential do not require contraception.
- Patients with an LVEF >50% within the last 6 months prior to start of study treatment.
If Patient's LVEF <50% they can be re-assessed. If an LVEF assessment has not been
completed within the last 6 months it would require an LVEF assessment.
Exclusion Criteria:
- Under 18 years old.
- Patient is on > 3 mg of dexamethasone/day or equivalent/day
- Has a metastatic brain lesion (or all brain lesions) that is (are) unresectable.
Unresectable defined as located in the brainstem or measuring <10 mm in longest
diameter. Note, patients with multiple metastatic brain lesions that include
non-targetable lesions of <10 mm are allowed to enroll in the study as long as they
have at least 1 lesion that is =10 mm in size of longest diameter.
- Has ECOG Performance Status of >2.
- Has clear evidence of leptomeningeal disease.
- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment, or has not recovered (i.e., =
Grade 1 or at baseline) from AEs due to a previously administered agent.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment. Physiologic doses of steroid therapy (= 3 mg/day dexamethasone equivalents)
by the time of first dose of treatment are allowed.
- Has a known history of active Bacillus Tuberculosis.
- Hypersensitivity to either Nivolumab, Ipilimumab, or Relatlimab or any of its
excipients.
- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., = Grade 1 or at baseline) from adverse events
(AEs) due to agents administered more than 4 weeks earlier.
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., = Grade 1 or at
baseline) from AEs due to a previously administered agent. Note: Patients with = Grade
2 neuropathy are an exception to this criterion and may qualify for the study. Note:
If patient received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy.
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.
- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with the use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment. Patients with vitiligo or resolved childhood asthma/atopy
would be an exception to this rule. Patients that require intermittent use of
bronchodilators or local steroid injections would not be excluded from the study.
Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome will
not be excluded from the study.
- Has a prior history of life-threatening toxicity related to prior immune therapy
(i.e., anti-CTLA-4 or anti- PD-1/PD-L1 treatment or any other antibody or drug
specifically targeting T-cell co-stimulation or immune checkpoint pathways) except
those that are unlikely to re-occur with standard countermeasures (i.e., hormone
replacement after adrenal crisis).
- Has prior treatment with Relatlimab or any other LAG-3 targeted agent at least 6
months prior to signing informed consent.
- Other than the medications explicitly stated in the exclusion criteria or elsewhere in
the protocol, other medications or prior treatments are allowed.
- Has known history of, or any evidence of active, interstitial lung disease or
noninfectious pneumonitis requiring corticosteroid therapy.
- Has history of myocarditis
- Has documented LVEF <50% within 6 months prior to start of study treatment and unable
to be re-assessed with an LVEF >50%.
- Has an active infection requiring systemic therapy.
- Had major surgical procedure, open biopsy, or significant traumatic injury within 21
days prior to day 1 of treatment on study.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the patient's
participation for the full duration of the trial, or is not in the best interest of
the patient to participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant, breastfeeding, or expecting to conceive children within the projected
duration of the trial, starting with the pre-screening or screening visit through 5
months after the last dose of study drug. Patients must not have a positive pregnancy
test at enrollment or prior to administration of study medication. Male patients of
childbearing potential who are sexually active with Women of Child Bearing Potential
do not require contraception.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-LAG-3
agent within 6 months prior to day 1 of treatment on study.
- Patients with prior focal radiation to the lesion planned for resection will be
excluded from the study, as distinguishing radiation necrosis from progression cannot
be definitely performed until after surgery.
- Has a known history of a positive test for Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies), or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV
must be performed at sites where mandated locally.
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected). Patients must not have any positive test result for
hepatitis B virus or hepatitis C virus indicating presence of virus, eg, Hepatitis B
surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C antibody
(anti-HCV) positive (except if HCV-RNA negative).
- Has received a live / attenuated vaccine within 30 days of first treatment.
Inactivated vaccines are permitted.
- Has received treatment with botanical preparations (e.g., herbal supplements or
traditional Chinese medicines) intended for general health support or to treat the
disease under study within 2 weeks prior to treatment.
- Participants must not be prisoners or involuntarily incarcerated.
- Participants must not be compulsorily detained for treatment of either a psychiatric
or physical (e.g., infectious disease) illness.
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