Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Malignant Neoplasm in the Brain, Metastatic Melanoma, Pathologic Stage IV Cutaneous Melanoma AJCC v8
Conditions
Brief summary
This phase II trial studies the side effects and how well low dose ipilimumab works in combination with pembrolizumab in treating patients with melanoma that has spread to the brain. Immunotherapy with monoclonal antibodies, such as ipilimumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Detailed description
PRIMARY OBJECTIVE: I. To assess clinical benefit rate (CBR), defined as complete response (CR) + partial response (PR) + stable disease (SD) \> 6 months, in the brain in subjects with melanoma brain metastasis (MBM) per modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria who are treatment naive to anti-PD-1 agents in the metastatic setting (prior adjuvant anti-PD1 allowed). SECONDARY OBJECTIVES: I. To assess clinical benefit rate (CBR) in the brain in subjects with MBM per modified RECIST 1.1 in patients who previously progressed on PD-1 inhibitors. II. To assess overall survival (OS) and progression free survival (PFS). III. To evaluate the brain-specific safety and tolerability of the combination regimen in subjects with or without stereotactic radiotherapy (SRT) received prior to study entry, or on study. IV. To evaluate cytokine levels and changes in the T-cell population in the cerebrospinal fluid (CSF) and blood in patients treated with combination low dose ipilimumab and pembrolizumab. V. To assess changes in relative apparent diffusion coefficient as measured by magnetic resonance imaging (MRI) as an early predictor of response. VI. To assess changes in circulating cfDNA (cell-free deoxyribonucleic acid) as determinants of response and/or markers of early progression. VII. To evaluate molecular and immunological changes in extracranial lesions. OUTLINE: Patients receive ipilimumab intravenously (IV) over 90 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles for ipilimumab and up to 35 cycles for pembrolizumab in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 6 weeks for the first year, and then every 12 weeks thereafter.
Interventions
BIOLOGICALIpilimumab
Given IV
BIOLOGICALPembrolizumab
Given IV
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Life expectancy \> 12 weeks. * Subjects must have signed and dated an IRB/IEC (Institutional Review Board/Independent Ethics Committee) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care. * Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study. * Histologically confirmed malignant melanoma with measurable metastases in the brain (\>= 0.5 cm). * At least one measurable intracranial target lesion, which previously was not treated with local therapy (no prior stereotactic radiosurgery \[SRS\] to this lesion). Largest diameter of \>= 0.5 cm, but =\< 3 cm as determined by contrast-enhanced MRI. * Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks are preferred) OR at least 4 unstained slides with an associated pathology report for testing of tumor PD-L1 expression: * Tumor tissue should be of good quality based on total and viable tumor content. * Patients who do not have tissue specimens may undergo a biopsy during the screening period. Acceptable samples include core-needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. * Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable. * However, if repeat biopsy is not feasible, and no archival tissue available patient still may be enrolled * Prior stereotactic radiotherapy (SRT) and prior excision of up to 5 MBM is permitted if there has been complete recovery, with no neurologic sequelae, and measurable lesions remain. Growth or change in a lesion previously irradiated will not be considered measurable. Regrowth in cavity of previously excised lesion will not be considered measurable. Note: Any prior SRT to brain lesions or prior excision must have occurred \>= 2 weeks before the start of dosing for this study. * Prior radiation to non-central nervous system (non-CNS) is allowed, and does not require a washout period for treatment initiation. * Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy in the 10 days prior to beginning protocol therapy. * ECOG (Eastern Cooperative Oncology Group) performance status =\< 1. * Absolute neutrophil count \>= 1500/uL. * Platelets \>= 100,000/uL. * Hemoglobin \>= 9.0 g/dL or \>= 5.6 mmol/L. * Creatinine =\< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance \>= 30 L/min with creatinine levels \> 1.5 x institutional ULN. GFR (glomerular filtration rate) can also be used in place of creatinine or CrCl (creatinine clearance). * Total bilirubin =\< 1.5 ULN OR direct bilirubin =\< ULN for participants with total bilirubin levels \> 1.5 x ULN. * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 2.5 x ULN (=\< 5 x ULN for participants with liver metastases). * International normalized ratio (INR) OR prothrombin time (PT) and activated partial thromboplastin time (aPTT) =\< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. * Women of child-bearing potential (WOCBP) must not be breastfeeding and must have a negative pregnancy test within 3 days prior to initiation of dosing. She must agree to use an acceptable method of birth control from the time of the negative pregnancy test up to 120 days after the last dose of study drug. WOCBP must agree to adhere to the contraceptive guidance in the protocol. Note: A female participant is eligible to participate if she is not a woman of childbearing potential as defined by the protocol. * Fertile men must agree to use an acceptable method of birth control as described in the protocol while on study drug and up to 120 days after the last dose of study drug and also refrain from donating sperm during this period. * All associated toxicity from previous or concurrent cancer therapy must be resolved (to =\< grade 1 or baseline) prior to study treatment administration. * Steroids for physiological replacement are allowed.
Exclusion criteria
* History of known leptomeningeal involvement (lumbar puncture not required). * Previous stereotactic or highly conformal radiotherapy within 2 weeks before the start of dosing for this study. Note the stereotactic radiotherapy field must not have included the brain index lesion(s). * Subjects previously treated with SRT \> 5 lesions in the brain * Brain lesion size \> 3 cm. * Prior checkpoint inhibitor therapy. Allowable prior therapy: Approved adjuvant therapies, which may include molecularly-targeted agents, IFN-·, and ipilimumab. * Patients who received ipilimumab as adjuvant or neoadjuvant therapy must have a 6 month washout before receiving any dosing on this study. * Cohort A: Prior anti-PD in the adjuvant setting is allowed, but washout period is 6 months. * For Cohort B: Patients with unresectable metastatic melanoma who received either anti-PD-1 or PDL-1 in the past are eligible. Washout period a minimum 3 weeks. * Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. * Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled. * Subject has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. Note: The time requirement does not apply to participants who underwent successful treatment of superficial bladder cancer, in situ cervical cancer, or other in-situ cancers. Subjects with a completely treated prior malignancy and no evidence of disease for \>= 2 years are eligible. * Skin cancer exclusion: Please note that basal cell carcinoma and squamous cell carcinoma is exempt from needing resection prior to treatment. (Resection can be completed after the start of treatment). * Has a known history of or is positive for hepatitis B (hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (hepatitis C virus \[HCV\] ribonucleic acid (RNA) \[qualitative\] is detected). Note: Without known history, testing needs to be performed to determine eligibility. Hepatitis C antibody (Ab) testing is allowed for screening purposes in countries where HCV RNA is not part of standard of care. * Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority. * The use of corticosteroids is not allowed for 10 days prior to initiation of therapy (based upon 5 times the expected half-life of dexamethasone) except patients who are taking steroids for physiological replacement. If alternative corticosteroid therapy has been used, consultation with the sponsor medical monitor is required to determine the washout period prior to initiating study treatment. * Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study initiation. Inhaled or topical steroids, and adrenal replacement steroid doses \> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. * Subjects with history of life-threatening toxicity related to prior ipilimumab adjuvant therapy except those that are unlikely to re-occur with standard countermeasures (e.g. hormone replacement after adrenal crisis). * Major surgical procedure, open biopsy (excluding skin cancer resection), or significant traumatic injury within 14 days of initiating study drug (unless the wound has healed) or anticipation of the need for major surgery during the study. * Non-healing wound, ulcer, or bone fracture. * Women who are breast-feeding or pregnant. * Uncontrolled intercurrent illness (i.e., active infection \>= grade 2) or concurrent condition that, in the opinion of the Investigator, would interfere with the study endpoints or the subject's ability to participate. * History of clinically significant cardiac disease or congestive heart failure \> New York Heart Association (NYHA) class 2. Subjects must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months. * Investigational drug use within 14 days (or 5 half-lives, whichever is longer) of the first dose of ipilimumab and pembrolizumab. * Has a history of non-infectious pneumonitis that required steroids or current pneumonitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) in PD-1 naïve Patients | Baseline to 2 years | clinical benefit rate (CBR), defined as CR + PR + SD \> 6 months, in the brain in subjects with MBM per modified RECIST 1.1 criteria who are treatment naïve to anti-PD-1 agents in metastatic setting (prior adjuvant anti-PD1 allowed). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CBR for Patients Who Progressed on PD-1 Inhibitors | Baseline to 2 years | Assess CBR in the brain in subjects with MBM per modified RECIST 1.1 in patients who previously progressed on PD-1 inhibitors. |
| Overall Survival (OS) & Progression-free Survival (PFS) | Baseline to 2 years | Assess OS and PFS. |
| Brain-specific Safety and Tolerability | Baseline to 2 years | Evaluate the brain-specific safety and tolerability of the combination regimen in subjects with or without SRT received prior to study entry, or on study. |
Countries
United States
Participant flow
Recruitment details
Low Dose Ipilimumab in Combination with Pembrolizumab in Metastatic Melanoma patients with brain metastases
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Treatment Naïve Ipilimumab 1 mg/kg IV q3 wks (up to 4 doses) & Pembrolizumab 200 mg IV q3 wks (up to 35 doses) | 20 |
| Cohort B: Previously Progressed on PD-1 Inhibitors Ipilimumab 1 mg/kg IV q3 wks (up to 4 doses) & Pembrolizumab 200 mg IV q3 wks (up to 35 doses) | 4 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 9 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort A: Treatment Naïve | Cohort B: Previously Progressed on PD-1 Inhibitors | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 3 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 1 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 4 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 4 Participants | 23 Participants |
| Region of Enrollment United States | 20 participants | 4 participants | 24 participants |
| Sex: Female, Male Female | 9 Participants | 0 Participants | 9 Participants |
| Sex: Female, Male Male | 11 Participants | 4 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 20 | 3 / 4 |
| other Total, other adverse events | 20 / 20 | 4 / 4 |
| serious Total, serious adverse events | 10 / 20 | 1 / 4 |
Outcome results
Primary
Clinical Benefit Rate (CBR) in PD-1 naïve Patients
clinical benefit rate (CBR), defined as CR + PR + SD \> 6 months, in the brain in subjects with MBM per modified RECIST 1.1 criteria who are treatment naïve to anti-PD-1 agents in metastatic setting (prior adjuvant anti-PD1 allowed).
Time frame: Baseline to 2 years
Population: For Cohort B- as these patients were not PD-1 naïve, there is no data to be entered in this section. The CBR for this cohort is listed under Secondary outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Treatment Naïve | Clinical Benefit Rate (CBR) in PD-1 naïve Patients | 68.4 percentage of participants |
Secondary
Brain-specific Safety and Tolerability
Evaluate the brain-specific safety and tolerability of the combination regimen in subjects with or without SRT received prior to study entry, or on study.
Time frame: Baseline to 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Treatment Naïve | Brain-specific Safety and Tolerability | Treatment related grade 3 or 4 AEs | 5 Participants |
| Cohort A: Treatment Naïve | Brain-specific Safety and Tolerability | CNS concerns | 0 Participants |
| Cohort B: Previously Progressed on PD-1 Inhibitors | Brain-specific Safety and Tolerability | CNS concerns | 0 Participants |
| Cohort B: Previously Progressed on PD-1 Inhibitors | Brain-specific Safety and Tolerability | Treatment related grade 3 or 4 AEs | 0 Participants |
Secondary
CBR for Patients Who Progressed on PD-1 Inhibitors
Assess CBR in the brain in subjects with MBM per modified RECIST 1.1 in patients who previously progressed on PD-1 inhibitors.
Time frame: Baseline to 2 years
Population: This metric only applies to Cohort B, as this objective only looks ONLY at the patients who are PD-1 refractory (Cohort B by definition)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort B: Previously Progressed on PD-1 Inhibitors | CBR for Patients Who Progressed on PD-1 Inhibitors | 1 Participants |
Secondary
Overall Survival (OS) & Progression-free Survival (PFS)
Assess OS and PFS.
Time frame: Baseline to 2 years
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A: Treatment Naïve | Overall Survival (OS) & Progression-free Survival (PFS) | PFS | 11.8 months |
| Cohort A: Treatment Naïve | Overall Survival (OS) & Progression-free Survival (PFS) | OS | NA months |
| Cohort B: Previously Progressed on PD-1 Inhibitors | Overall Survival (OS) & Progression-free Survival (PFS) | PFS | 1.4 months |
| Cohort B: Previously Progressed on PD-1 Inhibitors | Overall Survival (OS) & Progression-free Survival (PFS) | OS | 11.0 months |