This is a single center, open-label phase IIA study that investigates the preliminary
efficacy of Trans-arterial Tirapazamine Embolization (TATE) treatment of liver cancer
followed by a PD-1 checkpoint inhibitor (either nivolumab or pembrolizumab). Patients with
four types of cancers will be enrolled, hepatocellular carcinoma (HCC), metastatic colorectal
cancer (mCRC), metastatic gastric cancer and advanced non-small cell lung cancer. All
enrolled patients need to have liver lesions.
The goal of the study is to investigate whether tumor necrosis induced by Trans-arterial
Tirapazamine Embolization (TATE) treatment can boost anti-tumor immunity and enhance the
therapeutic efficacy of immune checkpoint inhibitor. Patients with advanced liver cancers
(primary HCC or metastatic liver cancer derived from colorectal, gastric and NSCLC) will be
enrolled in the study. Liver lesions will be treated with up to 4 TATE treatments for optimal
debulking, which also serve as a vaccination process toward tumor. Lesion not treated with
TATE will be used for monitoring the response toward a PD-1 inhibitor (either Nivolumab or
Pembrolizumab per investigator decision). If a patient subsequently develops an "escape" to
the PD-1 inhibitor, patient can have another 2 TATE treatments of the escaped tumor lesion.
Dosing of the PD-1 inhibitor is per standard FDA-approved dosing schedule and continues until
progressive disease. The efficacy will be assessed by the response rate (RR) using RECIST and
irRC for the non-TATE treated lesion, and compared with the historic RR of the PD-1 inhibitor
in HCC (~16%) and mCRC (almost 0% for those without mismatch repair defect), advanced gastric
cancer (15%) and metastatic NSCLC who failed to respond to an immune checkpoint inhibitor.
Inclusion Criteria:
1. Patients with either a confirmed diagnosis of (1) metastatic colorectal cancer in
liver based on histopathology of either a prior resection of primary lesion or a
biopsied liver metastatic lesion; (2) advanced HCC (BCLC-stage C) with a
characteristic 3 or 4-phase CT or dynamic contrast enhanced MRI finding showing
arterial uptake followed by "washout" of contrast in the venous-delayed phases per
American Association for the Study of Liver Disease (AASLD) criteria; (3) metastatic
gastric cancer; (4) metastatic NSCLC without EGFR or ALK mutation.
2. Patients between ages 18 and 80
3. If HCC patients, they should have progressive disease (PD) on intolerant of or
refusing sorafenib. If mCRC, they should have received at least one regimen of
5-fluouracil based systemic chemotherapy such as FOLFOX, FOLFIRI, CAPOX, or XELOX,
with or without a VEGF or EGFR receptor inhibitor. For patients with metastatic
gastric cancer, they should have failed at least one line of systemic chemotherapy.
For patients with NSCLC, they should have been treated with a PD-1 inhibitor (either
with or without chemotherapy) for at least 4 months but are not able to achieve a
response.
4. Patients with at least two liver tumor lesions with at least one with a diameter of 2
cm or bigger, which is amendable for (super-)selective TATE as the target lesion.
Alternatively, patients with one intra-hepatic lesion of 2 cm or bigger and exhapetic
lesion(s) are also acceptable.
5. ECOG score 2 or less
6. Child-Pugh scores 5-7
7. Patients should have measurable disease by contrast CT or contrast-enhanced MRI.
8. All prior chemotherapy must be at least 4 weeks prior to TATE and free from
treatment-related toxicity. No gap is needed for prior PD-1 checkpoint inhibitors in
NSCLC patients.
9. Patients have normal organ function: Hemoglobin ≥ 8.5 gm/dL, Platelets ≥ 50,000 /µL,
Creatinine ≤ 2 mg/dL, AST and ALT < 10 X upper normal limit of the current
institution; bilirubin < 3.0 mg/dL
10. Patients are able to understand and willing to sign the informed consent.
11. Men and women of child-bearing age need to commit to using two methods of
contraception simultaneously to avoid pregnancy.
Exclusion Criteria:
1. Patients who have had a liver or any organ transplantation
2. Patients who take any immune or bone marrow suppressive agents including any systemic
corticosteroid that exceed an equivalent of 10 mg prednisone per day within 2 weeks
from the study treatment. Inhalation or topical steroids are allowed.
3. Patients who have received any checkpoint inhibitor, including ipilimumab, nivolumab,
pembrolizumab or others.
4. Patients who have major medical problems such as severe cardiac, pulmonary (COPD
requiring constant oxygen), or non-healing ulceration.
5. Patients with a history of autoimmune disease (e.g., rheumatoid arthritis, Addison's
syndrome, multiple sclerosis, uveitis, systemic lupus erythematosus or Wegener's
granulomatosis). Patients with vitiligo or alopecia are allowed. Patients with Graves
disease or psoriasis not requiring systemic treatment within the past 2 years are
allowed.
6. Patients who have any clinical evidence of hypoxia with O2 saturation less than 92% on
room air.
7. Patients with evidence of significant arterial insufficiency or microangiopathy in any
organ due to any reason, which could lead to distal extremity hypoxia, as evidenced by
any gangrenous change in distal limbs or requiring resection for this reason.
8. Patients with major gastrointestinal bleeding in the prior 2 months of enrollment.
9. Patients who are pregnant or lactating.
10. Patients with QTc interval > 480 msec or those known to have congenital long QTc
syndrome.
11. Patients who have received live, attenuated vaccine within 28 days prior to the first
dose of PD-1 inhibitor.
