CA-4948 in Combination with Pembrolizumab Following Stereotactic Radiosurgery to Improve Treatment of Patients with Melanoma Brain Metastases

Inclusion Criteria

• Patients must have radiographic or histologically confirmed melanoma brain metastasis (MBM) and be planning to undergo SRS for treatment, the decision on SRS should be based on institutional standards and location characteristics. A maximal number of lesions allowed at initial SRS should be determined by institutional standard but the all lesions must measure =< 3.0 cm in maximal extent, and total volume to be treated must measure < 30 mL on the contrast-enhanced diagnostic magnetic resonance imaging (MRI) brain scan. Patients must be asymptomatic from their brain metastases at conclusion of SRS therapy prior to starting study drug
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥ 2 cm) by chest x-ray or as ≥ 10 mm (≥ 1 cm) with CT scan, MRI, or calipers by clinical exam, via Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. See protocol document for the evaluation of measurable disease
• Patients may be either treatment-naïve or currently on therapy for systemic disease as long as there is exhibited control of systemic disease at time of MBM development. If currently on therapy, patients must have at least stable disease (SD) systemically per RECIST criteria at the time of MBM diagnosis, ie no evidence of progression on most recent systemic surveillance scan. If MBM diagnosis coincides with initial diagnosis, patients may be treatment-naïve with systemic disease. * In patients naïve to treatment, the choice of initial therapy will be left up to the treating physician. If in their clinical judgement, single agent aPD1 plus SRS is deemed the appropriate therapy then these patients may proceed to enrollment and inclusion of CA-4948 with their regimen. If in the treating physician’s judgement, patient would benefit from use of combination immunotherapy with CTLA-4/aPD1 therapy, then patient must complete induction with CTLA-4/aPD1 therapy and proceed to maintenance aPD1 therapy prior to enrollment. The timing of SRS in these patients should coincide with the conclusion of induction dual agent therapy (either during or following last cycle of CTLA-4/aPD1 therapy) to then allow for a 3-week washout from last dose of CTLA-4 inhibitor exposure received prior to starting on study drug with CA-4948 and pembrolizumab. ** Completion of induction is defined as either completing the planned 4 doses of CTLA-4/aPD1 therapy or if the CTLA-4 inhibitor is discontinued after any of the initial 3 doses of therapy due to toxicity. In the event for stopping due to toxicity, then patients may still be eligible for study inclusion as long as this toxicity would not prevent them from continuing on aPD1 therapy as planned systemic treatment and no other rules for exclusion have been met below. In these patients, the timing of SRS should be consistent as above and the washout period from time of last CTLA-4 inhibitor must be at least 3 weeks prior to initiating on study drug. If a longer period of washout is required due to toxicity and safe resumption of immunotherapy, patients may still be enrolled as long as they meet the timing requirements from time of SRS to initiation of therapy as outlined below. * In patient who develop MBM while previously having received treatment for metastatic melanoma at other systemic locations, previous treatment with dual checkpoint inhibitor therapy (CTLA-4/aPD1 or LAG-3/aPD-1) or single agent immunotherapy therapy will be allowed, as long as at the time of SRS to these MBM lesions the patient is planned to receive aPD1 therapy as long as the above criteria are met and the patients systemic disease is displaying at least SD on last surveillance imaging performed. * SD is determined by clinician judgement at time of study enrollment. This is to be based on most recent systemic imaging surveillance done at the time of new MBM development. If this systemic imaging shows no significant growth in the previously identified lesions and no new lesions when compared to most recent previous systemic imaging then patients can be deemed as SD with isolated progression in the brain. For these patients, they may enroll on study and start SRS. In patients on systemic single agent aPD1 there is no washout necessary in this case and patients can start pembrolizumab and study drug at next scheduled cycle of treatment following completion of SRS as long as all other rules have been met for enrollment. * Previous oral BRAFi/MEKi treatment will also be allowed, as long as at the time of MBM treatment with SRS the patient is planned to initiate aPD1 therapy and not continue on BRAFi/MEKi. A washout period of 14 days from last dose of BRAFi/MEKi to initiation of study drug is required. * Treatment of symptomatic MBM with corticosteroids is allowed while receiving CA4948, but in order to start aPD1 therapy, patient must be on ≤ 10mg of oral prednisone daily or equivalent
• Patients must be tolerant of receiving MRI and cannot have intolerance to gadolinium contrast
• Age ≥ 18 years at time of informed consent. Because no dosing or adverse event data are currently available on the use of CA-4948 in combination with pembrolizumab in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 (Karnofsky ≥ 70%), if patients performance status is borderline with ≤ 1 to ≤ 2, special consideration can be made and discussed with study principal investigator (PI) for possible enrollment. These patients should be deemed to have a decrease in their performance status linked with an acute process that is expected to improve with initiation of therapy. This is to allow for patients who have initial decline from event that caused their brain metastasis presentation that is expected to improve with short course of steroid treatment and stereotactic radiosurgery. For those with borderline performance status that is not related to acutely reversible intracranial changes expected to improve than these patients will not be allowed
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L * Hemoglobin criterion must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• Coagulation prothrombin time (PT)/International Normalized Ration (INR) and adjusted partial prothrombin time (aPTT) ≤ 1.5 × upper limit of normal (ULN) unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic ranged of intended use for anticoagulants
• Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) OR direct bilirubin no lower than the ULN if total bilirubin > 1.5 × ULN
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 × institutional ULN (with confirmed liver metastases: AST and ALT ≤ 5 x ULN)
• Creatinine clearance (CrCl) ≤ 1.5 × ULN measured or calculated OR glomerular filtration rate (GFR) ≥ 30 mL/min based on modified Cockcroft and Gault formula for participants with creatinine levels > 1.5 × institutional upper limit of normal (ULN) * Creatinine clearance (CrCl) should be calculated per institutional standard
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Hepatitis B screening tests are not required unless known history of hepatitis B virus (HBV) infection as mandated by local health authority. Hepatitis B positive subjects participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with Hepatitis C virus (HCV) infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Female patients of childbearing potential must have a negative serum pregnancy test at screening and agree to use of highly effective methods of contraception throughout the study and for at least four months following the last dose of study treatment. A woman is considered fertile following menarche and until becoming post-menopausal unless permanently sterile. Women in the following categories are not considered women of child bearing potential (WOCBP) : * Premenarchal * Premenopausal female with 1 of the following: ** Documented hysterectomy ** Documented bilateral salpingectomy ** Documented bilateral oophorectomy * Postmenopausal female ** A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. ** A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with two folical stimulating hormone (FSH) measurements in the postmenopausal range is required. * Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• The effects of CA-4948 and pembrolizumab on the developing human fetus are unknown, and may have teratogenic effects, women of child-bearing potential and men with female partners must agree to use adequate contraception prior to study entry and for the duration of study participation and 4 months after completion of CA-4948 administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of CA-4948 administration. Men should also not donate sperm from first dose of therapy until 4 months after the last dose of treatment. Adequate contraception is defined as: * Use of a male condom plus partner use of a contraceptive method with a failure rate of < 1% per year as described in the protocol document when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant. * Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration
• Participants must have recovered from all adverse events (AEs) due to previous therapies to ≤ grade 1 or baseline with the exception of alopecia. Participants with ≤ grade 2 neuropathy may be eligible. Participants with endocrine-related AEs grade ≤ 2 requiring treatment or hormone replacement may be eligible
• Archival tumor tissue sample or newly obtained biopsy of a tumor lesion not previously irradiated has been provided. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. In the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication
• If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention
• Prior radiotherapy within 2 weeks of start of study intervention to sites other than the described SRS that patients are mandated to receive for inclusion. Participants must have recovered from all radiation-related toxicities, not require corticosteroids over ≤ 10mg of oral prednisone daily or equivalent, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
• Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. Messenger ribonucleic acid (mRNA) coronavirus (COVID)-1 vaccines are allowed
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded
• Has severe hypersensitivity (≥ grade 3) to pembrolizumab, CA-4948, or any of their excipients
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Has an active infection requiring systemic therapy, is patient is receiving oral antibiotics for localized infection with planned end date they may enroll on study as soon as duration is complete
• Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant 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 or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
• Has had an allogenic tissue/solid organ transplant
• Unable to discontinue medications contraindicated to CA-4948 or pembrolizumab
• Patients with uncontrolled intercurrent illness