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.
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)
