Trial Title:
Pilot Study of Nivolumab w/Ipilimumab or Relatlimab in Surgically Resectable Melanoma Brain Metastases
NCT ID:
NCT05704933
Condition:
Metastatic Melanoma
Metastasis to Brain
Conditions: Official terms:
Melanoma
Neoplasm Metastasis
Brain Neoplasms
Nivolumab
Ipilimumab
Relatlimab
Study type:
Interventional
Study phase:
Early Phase 1
Overall status:
Active, not recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Nivolumab
Description:
Nivolumab is a monoclonal antibody o PD-1 protein, which is normally express on the
surface of activated T cells. The interaction of PD-1 with its ligand (PD-L1) on T cells
decreases their cytotoxic activity, helping protect normal cells in the setting of
chronic inflammation. Tumor cells can utilize mechanisms to evade T cell mediated
cytotoxicity by expressing PD-L1 on their surface or on the surface of T cells. Nivo, by
blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2, allows T cells to
remain active.
Arm group label:
Pre-Surgery Nivolumab + Ipilimumab
Other name:
Opdivo
Intervention type:
Drug
Intervention name:
Ipilimumab
Description:
Ipilimumab is a recombinant, human antibody to CTLA-4.[18-20] CTLA-4 regulates T cell
activation by binding with CD80 or CD86 with higher affinity than CD28, resulting in
blockage of the co-stimulation signal and preventing further T cell activation. Blockade
of CTLA-4 results in further T cell activation.
Arm group label:
Pre-Surgery Nivolumab + Ipilimumab
Other name:
Yervoy
Intervention type:
Drug
Intervention name:
Nivolumab + Relatlimab
Description:
Opdualag (Nivolumab and Relatlimab-rmbw) is a human monoclonal antibody to LAG-3,
currently under investigation.[6] Relatlimab is an antibody (IgG4 isotype) that has a
stabilizing hinge mutation for attenuated Fc receptor binding to decrease or get rid of
the possibility of antibody-mediated and/or complement-mediated target cell killing. Rela
binds to an epitope on LAG-3 with high affinity and specificity, with subsequent blockade
of LAG-3 and its interaction with its ligand, MHC class II. This antibody displays
compelling in vitro functional activity in reversing LAG-3 that facilitates inhibition of
an antigen-specific murine T cell hybridoma overexpressing human LAG-3 . Relatlimab was
also shown to improve the activation of human T cells in superantigen stimulation assays
when added either alone or in combination with Nivolumab.
Arm group label:
Pre-Surgery Nivolumab + Relatlimab(Opdualag)
Other name:
Opdualag
Intervention type:
Procedure
Intervention name:
Standard of Care Craniotomy
Description:
Participants will undergo craniotomy for surgical resection of melanoma brain metastases.
Arm group label:
Pre-Surgery Nivolumab + Ipilimumab
Arm group label:
Pre-Surgery Nivolumab + Relatlimab(Opdualag)
Summary:
The purpose of this pilot study is to determine the safety and feasibility of giving a
single dose of Nivolumab with Ipilimumab or Relatlimab in participants with brain
metastases from melanoma who can undergo surgery for removal of their brain metastases 7-
10 days after receiving the study drug.
Criteria for eligibility:
Criteria:
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 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 will determine the
appropriateness for resection via craniotomy and level of urgency for surgery of the
MBM.
- Patient is on ≤4 mg/day dexamethasone or equivalent/day over pre-op period.
- Patients treated with prior monotherapy with PD-1/PD-L1 are permitted.
- Treatment with BRAF MEK inhibitors (BRAF MEKi) (for example, dabrafenib /
trametinib) is permitted as long as has been at least five half-lives or one week
prior to study treatment, whichever is shorter.
- MRI with enhancing metastatic brain lesions (i.e., MBM) amenable to resection of
contrast-enhancing tumor (determined by neurosurgeon). A multidisciplinary team 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.
- 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.
Exclusion Criteria:
- 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 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 five
half-lives, whichever is shorter, 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 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 or CTLA-4
targeted agent within 3 months prior to day 1 of treatment.
- 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Moffitt Cancer Center
Address:
City:
Tampa
Zip:
33612
Country:
United States
Facility:
Name:
M.D. Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Start date:
June 6, 2023
Completion date:
June 2025
Lead sponsor:
Agency:
H. Lee Moffitt Cancer Center and Research Institute
Agency class:
Other
Collaborator:
Agency:
Bristol-Myers Squibb
Agency class:
Industry
Source:
H. Lee Moffitt Cancer Center and Research Institute
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05704933
https://www.moffitt.org/clinical-trials-research/clinical-trials/
