Clinical Trials /

Combination of TATE and PD-1 Inhibitor in Liver Cancer

NCT03259867

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
  • Gastric Carcinoma
  • Hepatocellular Carcinoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination of TATE and PD-1 Inhibitor in Liver Cancer
  • Official Title: Phase IIA Single-Arm Study of Treatment of Patients With Advanced Liver Cancer With a Combination of TATE (Transarterial Tirapazamine Embolization) Followed by an Anti-PD-1 Monoclonal Antibody

Clinical Trial IDs

  • ORG STUDY ID: LT-004
  • NCT ID: NCT03259867

Conditions

  • Hepatocellular Carcinoma
  • Colorectal Neoplasms
  • Gastric Cancer
  • Lung Cancer

Interventions

DrugSynonymsArms
Opdivo Injectable Product or Keytruda Injectable ProductHepatocellular carcinoma

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Hepatocellular carcinomaExperimentalPD-1 inhibitor (either Opdivo 240 mg Q2W IV or Keytruda 200 mg Q3W IV) starts at day 1, and continues until progression. TATE treatment starts at day 8 for debulking up to 4 cycles. If escape lesion appears, two more TATE treatments can be given. Tirapazamine dose at 35 mg flat dose given before embolization.
  • Opdivo Injectable Product or Keytruda Injectable Product
Colorectal cancerExperimentalPD-1 inhibitor (Keytruda 200 mg Q3W IV) starts at day 1, and continues until progression. TATE treatment starts at day 8 for debulking up to 4 cycles. If escape lesion appears, two more TATE treatments can be given. Tirapazamine dose at 35 mg flat dose given before embolization.
  • Opdivo Injectable Product or Keytruda Injectable Product
Gastric cancerExperimentalPD-1 inhibitor (Keytruda 200 mg Q3W IV) starts at day 1, and continues until progression. TATE treatment starts at day 8 for debulking up to 4 cycles. If escape lesion appears, two more TATE treatments can be given. Tirapazamine dose at 35 mg flat dose given before embolization.
  • Opdivo Injectable Product or Keytruda Injectable Product
NSCLCExperimentalPD-1 inhibitor (Keytruda 200 mg Q3W IV) starts at day 1, and continues until progression. TATE treatment starts at day 8 for debulking up to 4 cycles. If escape lesion appears, two more TATE treatments can be given. Tirapazamine dose at 35 mg flat dose given before embolization.
  • Opdivo Injectable Product or Keytruda Injectable Product

Eligibility Criteria

        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.
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate
Time Frame:up to 24 months
Safety Issue:
Description:Objective response rate in non-TATE treated lesion

Secondary Outcome Measures

Measure:Overall Response rate
Time Frame:up to 24 months
Safety Issue:
Description:All tumor lesions
Measure:Duration of Response
Time Frame:up to 24 months
Safety Issue:
Description:All tumor lesions
Measure:Progression Free Survival
Time Frame:up to 24 months
Safety Issue:
Description:From randomization to disease progression or death
Measure:Overall survival
Time Frame:through study completion, an average of 3 years
Safety Issue:
Description:From randomization to death

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Teclison Ltd.

Trial Keywords

  • Hepatocellular carcinoma
  • Colorectal cancer
  • Immune checkpoint inhibitor
  • Gastric cancer
  • Non-small cell lung cancer

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