Plinabulin in Combination With Radiation/Immunotherapy in Patients With Select Advanced Cancers After Progression on PD-1 or PD-L1 Targeted Antibodies

This phase Ib/II trial studies the side effects and best dose of plinabulin in combination with radiation therapy and immunotherapy in patients with select cancers that have spread to other places in the body (advanced) after progression on PD-1 or PD-L1 targeted antibodies. Plinabulin blocks tumor growth by targeting both new and existing blood vessels going to the tumor as well as killing tumor cells. Immunotherapy may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving plinabulin in combination with radiation therapy and immunotherapy may work better in treating advanced cancers.

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of plinabulin when administered in combination with radiation/immunotherapy regimen in subjects with select advanced solid malignancies after progression on anti-PD-1/PD-L1 monoclonal antibody (mAb).

II. To assess the objective tumor response rate (complete response + partial response).

SECONDARY OBJECTIVES:

I. To assess disease control rate (complete response, partial response + stable disease).

II. To determine progression-free survival (PFS). III. To assess overall survival.

EXPLORATORY OBJECTIVES:

I. To analyze the gene mutation density within each sample. II. To assess T-cell receptor (TCR) sequencing in tumor tissue and peripheral blood, pre- and post- treatment.

III. To perform imaging mass flow cytometry (CyTOF) and/or single cell ribonucleic acid sequencing (RNAseq) analysis on tumor tissue: Immune phenotyping, including dendritic cell (DC), T cells, tumor-associated macrophage (TAM)s, pre and post treatment.

IV. To conduct phenotyping analysis of immune cells from peripheral blood using multicolor flow cytometry.

V. To evaluate dendritic cell activation from whole blood upon the treatment. VI. To explore general predictive and response biomarker measurements from the collected biomarkers.

OUTLINE: This is a phase Ib, dose-escalation study of plinabulin followed by a phase II study. Patients are randomized to 1 of 2 arms.

ARM A: Patients undergo radiation therapy on days 1-3, 1-4, or 1-5 of cycle 1. Patients may undergo additional radiation in cycle 2 at the discretion of treating physician. Patients receive plinabulin intravenously (IV) over 30-60 minutes on days 1 and 4 of cycle 1, days 1 and 4 of cycle 2 (if receiving radiation therapy in cycle 2), and day 1 and or 15 (any day receiving immunotherapy) of subsequent cycles. Patients also receive immunotherapy consisting of either: avelumab IV over 1 hour on days 1 and 15; atezolizumab over 30-60 minutes on day 1; durvalumab IV over 1 hour on days 1 and 15; nivolumab IV over 30-60 min on days 1 and 15; or pembrolizumab IV over 30 min on day 1. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients undergo radiation therapy on days 1-3, 1-4, or 1-5 of cycle 1. Patients may undergo additional radiation in cycle 2 at the discretion of treating physician. Patients also receive immunotherapy consisting of either: avelumab IV over 1 hour on days 1 and 15; atezolizumab over 30-60 minutes on day 1; durvalumab IV over 1 hour on days 1 and 15; nivolumab IV over 30-60 min on days 1 and 15; or pembrolizumab IV over 30 min on day 1. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 months.

Eligibility Criteria:
Inclusion Criteria:

* Subjects must have one of seven histologically or cytologically confirmed malignant neoplasms (non-small cell lung cancer, small cell lung cancer, renal cell cancer, bladder cancer, Merkle cell cancer, microsatellite instability high (MSI-H) cancer (any histology), and melanoma) progressed on previous anti-PD-1/PD-L1 mAb treatment +/- chemotherapy or anti-CTLA4 requiring further treatment
* At least one lesion is amenable to radiation
* At least one additional non-contiguous lesion that has not been irradiated amenable to radiographic evaluation
* Have measurable disease based on immune-related response criteria (immune-related Response Evaluation Criteria In Solid Tumors \[RECIST\])
* Tissue must be newly obtained as a core needle biopsy (not fine-needle aspiration \[FNA\]) of the lesion being evaluated
* Age \>= 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Subjects must be recovered from any prior major surgery. The major surgery must be performed at least 4 weeks prior to consent date
* Platelets \>= 100 x 10\^9/L

  * Transfusions and growth factors are allowed
* Hemoglobin \>= 9 g/dL

  * Transfusions and growth factors are allowed
* Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L

  * Transfusions and growth factors are allowed
* White blood cell (WBC) \>= 3 x 10\^9/L

  * Transfusions and growth factors are allowed
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x upper limit of normal (ULN) (=\< 1.5 x ULN if alkaline phosphatase is \> 2.5 x ULN) (In the expansion cohort, subjects with known liver involvement may have ALT =\< 5 x ULN)
* Alkaline phosphatase \< 4 x ULN
* Total bilirubin =\< 1 x ULN (In the expansion cohort, subjects with Gilbert's syndrome \[hereditary indirect hyperbilirubinemia\] who must have a total bilirubin of =\< 3 x ULN)
* Albumin \>= 3 g/dL
* Renal function defined as a calculated or measured glomerular filtration rate (GFR) \>= 30 mL/min and Cockcroft-Gault equation
* The patient has recovered to grade =\< 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0) from the effects of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or other targeted therapies, with the exception of alopecia. The exceptions for such effects are allowed lab values of =\< grade 2 specified elsewhere in these inclusion criteria
* Subjects must give informed consent according to the rules and regulations of the individual participating sites
* Negative urine pregnancy test in women of child bearing potential within 7 days of first dose of treatment and subjects of child-bearing potential must agree to use effective contraception during and for 5 months following the last dose of atezolizumab or nivolumab, and for 4 months after the last dose of pembrolizumab, and for 3 months after last dose of durvalumab and avelumab, and for 3 months after your last dose of plinabulin. A woman of childbearing potential is defined as a premenopausal female capable of becoming pregnant. This includes women on oral, injectable or mechanical contraception; women who are single and women whose male sexual partners have been vasectomized or whose male sexual partners have received or are utilizing mechanical contraceptive devices

Exclusion Criteria:

* Evidence of complete or partial bowel obstruction
* Subjects with primary central nervous system (CNS) tumor or CNS tumor involvement. However, subjects with metastatic CNS tumors may participate in this study if the patient is:

  * \> 4 weeks from prior therapy completion
  * Clinically stable with respect to the CNS tumor at the time of study entry
  * Not receiving steroid therapy in treating CNS tumor or CNS tumor involvement
  * Not receiving anti-convulsive medications (that were started for brain metastases)
* Need of total parenteral nutrition
* Allergic to any of anti-PD-1/PD-L1 monoclonal antibody (mAb) intended to receive
* Prior exposure to plinabulin
* Pregnancy or lactation
* Radiation (except planned or ongoing palliative radiation to bone outside of the region of measurable disease) =\< 3 weeks prior to study drug administration date
* Chemotherapy, or immunotherapy or any other systemic anticancer therapy =\< 3 weeks prior to study drug administration date except anti-PD-1/PD-L1 mAb mono or combination therapy
* Diagnosis or recurrence of invasive cancer other than the present cancer within 3 years (except basal or squamous cell carcinoma of the skin that has been definitively treated)
* Major surgery within four weeks before consent date
* Unstable cardiovascular function or active cardiac disease:

  * Symptomatic ischemia (chest pain of cardiac origin),or
  * Uncontrolled clinically significant conduction abnormalities (e.g. ventricular tachycardia on antiarrhythmics are excluded; 1st degree AV block or asymptomatic Left anterior fascicular block (LAFB)/ right bundle branch block (RBBB) will not be excluded),or
  * Congestive heart failure (CHF) of New York Heart Association (NYHA) class \>= 3, or
  * Myocardial infarction (MI) within 3 months of consent date
* Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to the first dose. Active infection with concurrent treatment is acceptable only if the patient is clinically stable
* Subject is known to be positive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C
* Significantly diseased (as determined by the PI or treating physician) or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea. Presence of ileus or other significant gastrointestinal disorder known to predispose to ileus or chronic bowel hypomotility
* Treatment with an investigational anti-cancer study drug within 3 weeks prior to study drug administration date
* Concurrent therapy with approved or investigational anticancer therapeutics
* Medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
* Men whose partner is a woman of child-bearing potential, (i.e. biologically able to conceive), and who is not employing two forms of highly effective contraception. Highly effective contraception (e.g. male condom with spermicide, diaphragm with spermicide, intra-uterine device) must be used by both sexes during the study and must be continued for 5 months following the last dose of atezolizumab or nivolumab, for 4 months after the last dose of pembrolizumab, and for 3 months after last dose of durvalumab and avelumab, and for 3 months after your last dose of plinabulin. Women of child-bearing potential is defined as sexually mature women who are not surgically sterile or who have not been naturally postmenopausal for at least 12 consecutive months (e.g., who has had menses any time in the preceding 12 consecutive months)