Participants with metastatic cancer who are taking anti-PD-1 or anti-PD-L1 therapy will be enrolled to assess the safety of and find the optimal dose for radioactive imaging agents and to explore whether these agents will make current drug therapies work better. Up to 60 participants will be enrolled and can expect to be on study for up to 9 months.

This is a safety study of 86Y-NM600 and 90Y-NM600 and a dose finding study for 90Y-NM600 in patients with metastatic cancers who are receiving anti-PD-1 or anti-PD-L1 therapy and have immune-unconfirmed progressive disease (iUPD). The imaging agent 86Y-NM600 will be injected, and serial positron-emission tomography (PET)/computed tomography (CT) imaging will be performed to enable dosimetry calculations that will be used to determine eligibility for 90Y-NM600.

Phase 1a of the study (dose finding) will enroll 6-24 participants into a 3x3 dose finding plan where 3 participants start at Level 1 (below) and the number of participants with dose limiting toxicities (DLTs) will inform the next 3 participants:

• 0/3 Escalate to next higher dose level*
• 1/3 Accrue additional 3 patients at current dose level
• 1/3 + 0/3 Escalate to next higher dose level*
• 1/3 + ≥ 1/3 End phase 1a or de-escalate to dose level -1 if at dose level 1
• ≥ 2/3 End phase 1a or de-escalate to dose level -1 if at dose level 1

Dosing Plan:

• Level -1: 20 millicurie (mCi) x 1
• Level 1: 35 mCi x1
• Level 2: 70 mCi x1
• Level 3: 105 mCi x1
• Level 4: 140 mCi x1

Phase 1b (expansion cohort) may enroll up to an additional 36 participants (18 into a single dose cohort, 18 into a multi-dose cohort) with metastatic cancer.

The primary endpoints are to determine the safety of administering 86Y-NM600 for imaging and 90Y-NM600 for delivering radiation in patients with iUPD metastatic cancer who are receiving standard-of-care anti-PD-1 or anti-PD-L1 therapy.

Inclusion Criteria:

1. Participant must be informed of the investigational nature of the study and must be able to sign a written informed consent.

2. Participants with histologically or cytologically confirmed squamous cell carcinoma thought to originate from the head and neck region (HNC).

3. Participants 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.

4. Participants must be under treatment with one of the following standard-of-care anti-PD-1 or anti-PD-L1 therapies that is 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.

   1. 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 percent 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.
   2. Participants 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 participant'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.
   3. 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, participants must have been found to have iUPD while on the immune checkpoint therapy regimen that they receive during this study (i.e., participant's treating physician must determine that it is in the participant's best interest to stay on the current regimen of immune checkpoint inhibition until the subject's next standard of care imaging evaluation).

5. Participants 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.

6. Participants must have at least one evaluable (measurable) tumor that is radiographically detectable.

7. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2.

8. Participants must have a life expectancy of at least 6 months.

9. People who could become pregnant have a confirmed negative urine pregnancy test within 7 days prior to receiving Y-NM600.

10. Participants 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.

11. Participants who are not surgically or medically sterile agree to use an acceptable method of contraception. Participants who could impregnate 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.

12. The participant has adequate renal function as defined by Cockcroft-Gault calculated creatinine clearance >60 ml/min

13. The subject has adequate hepatic function as defined by:

    1. total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
    2. aspartate transaminase (AST) and alanine transaminase (ALT) less than or equal to 3.0 times the ULN

14. The participant has adequate hematologic function without Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) injection or transfusion in the prior 7 days, as evidenced by:

    1. an absolute neutrophil count (ANC) greater than or equal to 2000 / μL
    2. hemoglobin greater than or equal to 8 g/dL
    3. platelets greater than or equal to 100,000 / μL, or, if full-dose anticoagulation therapy is used, platelets greater than or equal to 150,000 / μL are required.
    4. lymphocytes greater than or equal to 1000 / μL

15. For phase 1a, participant must be willing to undergo 2 core needle biopsies that are accessible via ultrasound and/or clinical biopsy.

16. Adequate uptake of 86Y-NM600 (3x red bone marrow) on PET CT imaging as determined by Nuclear Medicine.

17. 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.

18. No grade greater than or equal to 3 toxicities new compared to baseline were noted through day 7 after 86Y-NM600 infusion.

Exclusion Criteria:

1. 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.

2. The participant 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.

3. Chemotherapy, radiotherapy, or major surgery within 3 weeks prior to study enrollment (this will be greater than 5 weeks prior to 90Y-NM600 therapy).

   a. For patients receiving prior radiation therapy, the dose to tumor, kidneys, liver, and bone marrow must be recorded, if available.

4. The participant 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.

5. 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 PCR) by anti-retroviral therapy.

6. 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.

   b. Palliative external beam radiation therapy may be delivered to patients during this study if deemed necessary and safe by the treating physician.

   c. Participants 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.

7. 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.

8. Participants that have had total body or hemibody irradiation, or have had prior systemic radioisotope therapy (except for benign thyroid disease)

9. 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)

10. Ongoing hemodialysis or peritoneal dialysis

11. Any known medical condition that predisposes the subject to uncontrolled bleeding such as hemophilia or clotting factor deficiencies

12. Participants with known genetic conditions causing pre-disposition to RT toxicity (i.e.: Li-Fraumeni, ataxia telangiectasia mutated (ATM) deficiency, active scleroderma, active inflammatory bowel disease, active systemic lupus)

13. Patients with an implanted defibrillator or with an implanted pacemaker and pacemaker dependency for rate or rhythm control

14. Patients with repeated demonstration on two EKGs of a QTcF interval greater than 470 milliseconds or use of medications known to prolong the QT/QTc interval

15. Participants who cannot provide independent, legal, informed consent