Y-NM600 in Combination with Immune Checkpoint Inhibitors in Treating Patients with Metastatic Cancer

Inclusion Criteria

• Subject must be informed of the investigational nature of the study and must be able to sign a written informed consent
• Subjects with histologically or cytologically confirmed cancer
• Subjects must have metastatic disease of one of the following types: bile duct cancer, bladder cancer, cervical cancer, colorectal cancer, cutaneous squamous cell cancer, esophageal cancer, head and neck squamous cell carcinoma, kidney cancer, liver cancer, lung cancer, melanoma, merkel cell carcinoma, mesothelioma, stomach cancer, triple-negative breast cancer, or any solid cancer with mismatch repair deficiency
• Subjects must be under treatment with one of the following standard-of-care anti-PD-1 or anti-PD-L1 therapies that is Food and Drug Administration (FDA) approved for the patient’s specific type of metastatic cancer: Pembrolizumab (Keytruda; anti-PD-1 antibody), nivolumab (Opdivo; anti-PD-1 antibody), atezolizumab (Tecentriq, anti-PD-L1 antibody), avelumab (Bavencio; anti-PD-L1 antibody), durvalumab (Imfinzi; anti-PD-L1 antibody), cemiplimab (Libtayo; anti-PD-1 antibody), dostarlimab (Jemperli; anti-PD-1 antibody). The patient must also have iUPD (immune unconfirmed progressive disease) after most recent imaging studies and be eligible to continue anti-PD-1 or anti-PD-L1 therapy, per the treating physician * For the purposes of this study, patients will be considered to have iUPD if they have been on treatment with anti-PD-1 or anti-PD-L1 therapy for any duration of time and, on their most recent standard-of-care imaging, been observed to have evidence of progression when the most recent scans prior to those did not show evidence of progression. Evidence of progression in this context will be defined as a 20% or greater increase in the sum of diameters of up to 5 lesions (these lesions will be identified as representative of the distribution of the patient’s metastatic disease by the treating physician), the appearance of a new lesion, or the unequivocal progression of any lesion * Subjects with iUPD standardly continue on anti-PD-1 or anti-PD-L1 therapy if the treating physician determines they do not have worsening performance status, clinically relevant increase in disease-related symptoms, or requirement of intensified management of disease-related symptoms. To be eligible for study, a subject’s treating physician must determine that it is in the patient’s best interest to continue on their current immune checkpoint inhibition regimen for additional treatment cycles until the subject’s next scheduled standard-of-care imaging assessment. Treating physicians making this decision should generally do so if they feel the subject has no available better alternative treatment approach * In addition to anti-PD-1 or anti-PD-L1 therapy, patients may also be under treatment with and may continue to receive ipilimumab (Yervoy; anti-CTLA4 antibody) or tremelimumab (Imjuno; anti-CTLA4 antibody) during this study. However, subjects must have been found to have iUPD while on the immune checkpoint therapy regimen that they receive during this study (i.e., subject’s treating physician must determine that it is in the subject’s best interest to stay on the current regimen of immune checkpoint inhibition until the subject’s next standard of care imaging evaluation)
• Subjects must have received and shown evidence of progression or iUPD on at least one front-line therapy for metastatic disease. This can include the immune checkpoint inhibitor they are currently taking
• Subjects must have at least one evaluable (measurable) tumor that is radiographically detectable
• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 – 2
• Subjects must have a life expectancy of at least 6 months
• People who could become pregnant have a confirmed negative urine pregnancy test within 7 days prior to receiving Y-NM600
• Subjects must use a medically acceptable method of birth control such as an oral, implantable, injectable, or transdermal hormonal contraceptive, an intrauterine device (IUD), a double barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or total abstinence during the study participation and for 6 months after last dose of study drug. Participants who are postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) are not considered to be people who could become pregnant
• Participants who are not surgically or medically sterile agree to use an acceptable method of contraception. Participants who could impregnante their sexual partners must abstain from intercourse for three weeks after Y-NM600 treatment and agree to use condoms at least 2 months after the last dose of this drug. Total abstinence for the same study period is an acceptable alternative
• The subject has adequate renal function as defined by Cockcroft-Gault calculated creatinine clearance > 60 ml/min
• Total bilirubin =< 1.5 times the upper limit of normal (ULN)
• Aspartate transaminase (AST) and alanine transaminase (ALT) =< 3.0 times the ULN
• An absolute neutrophil count (ANC) >= 2000 /uL (without granulocyte-macrophage colony-stimulating factor [GM-CSF] injection or transfusion in the prior 7 days)
• Hemoglobin >= 8 g/dL (without GM-CSF injection or transfusion in the prior 7 days)
• Platelets >= 100,000 /uL, or, if full-dose anticoagulation therapy is used, platelets >= 150,000 /uL are required (without GM-CSF injection or transfusion in the prior 7 days)
• Lymphocytes >= 1000 /uL (without GM-CSF injection or transfusion in the prior 7 days)
• For phase 1a, subject must be willing to undergo 2 core needle biopsies that are accessible via ultrasound and/or clinical biopsy
• Adequate uptake of 86Y-NM600 (3x red bone marrow) on PET CT imaging as determined by nuclear medicine
• No grade 2 toxicities new compared to baseline and unrelated or unlikely related to disease or any known cause other than 86Y-NM600 were noted through day 7 after 86Y-NM600 infusion
• No grade >= 3 toxicities new compared to baseline were noted through day 7 after 86Y-NM600 infusion

Exclusion Criteria

• Other concurrent severe and/or uncontrolled concomitant medical or psychiatric conditions (e.g., active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol, per investigator discretion
• The subject is taking strong inducers or inhibitors of CYP450 enzymes or drug transporters that cannot be held from at least 30 days prior to administration of 86Y-NM600 through the final 90Y-NM600 infusion without any expected adverse events. Examples include: clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, phenobarbital, phenytoin, rifampicin, and glucocorticoids
• Chemotherapy, radiotherapy, or major surgery within 3 weeks prior to study enrollment (this will be > 5 weeks prior to 90Y-NM600 therapy). * For patients receiving prior radiation therapy, the dose to tumor, kidneys, liver, and bone marrow must be recorded, if available
• The subject is pregnant, breastfeeding, or expecting to conceive or could impregnate someone within the projected duration of the trial, starting with the screening visit through 6 months after the last dose of trial treatment
• Any ongoing or active infection, including active tuberculosis, hepatitis B or C, or known infection with the human immunodeficiency virus (HIV) that is not well controlled (undetectable viral load by polymerase chain reaction [PCR]) by anti-retroviral therapy
• Concurrent treatment with any other systemic anti-cancer or investigational agents other than an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody. Subjects cannot be receiving concomitant chemotherapy, experimental therapy or any other therapy not otherwise outlined by the trial for the purposes of anti-cancer treatment. * Palliative external beam radiation therapy may be delivered to patients during this study if deemed necessary and safe by the treating physician. * Subjects can be receiving dual immune checkpoint inhibition with an anti-CTLA-4 antibody in addition to an anti-PD-1 or anti-PD-L1 therapy
• Patients with a history of or concurrent second primary malignancy within 2 years to study enrollment are excluded, with the exception of patients who have had definitive treatment of a primary skin basal cell, skin squamous cell carcinomas, or localized low or intermediate risk prostate cancer – these subjects are eligible 3 months after completion of definitive treatment for that prior cancer
• Subjects that have had total body or hemibody irradiation, or have had prior systemic radioisotope therapy (except for benign thyroid disease)
• Any condition requiring the use of immunosuppression, excluding rheumatologic conditions or endocrine conditions treated with stable doses of corticosteroids (equivalent to prednisone 10 mg daily)
• Ongoing hemodialysis or peritoneal dialysis
• Any known medical condition that predisposes the subject to uncontrolled bleeding such as hemophilia or clotting factor deficiencies
• Subjects with known genetic conditions causing pre-disposition to radiation therapy (RT) toxicity (i.e.: Li-Fraumeni, ataxia telangiectasia mutated [ATM] deficiency, active scleroderma, active inflammatory bowel disease, active systemic lupus)
• Patients with an implanted defibrillator or with an implanted pacemaker and pacemaker dependency for rate or rhythm control
• Patients with repeated demonstration on two electrocardiogram (EKGs) of a QT corrected by the Fridericia formula (QTcF) interval > 470 milliseconds or use of medications known to prolong the QT/corrected QT (QTc) interval (https://www.uspharmacist.com/article/drug-induced-qt-prolongation)
• Subjects who cannot provide independent, legal, informed consent