Combination of TATE and PD-1 Inhibitor in Liver Cancer (TATE-PD1)

• ClinicalTrials.gov Identifier: NCT03259867
• Recruitment Status: Active, not recruiting
• First Posted: August 24, 2017
• Last Update Posted: September 11, 2019
• Sponsor: Teclison Ltd.
• Information provided by (Responsible Party): Teclison Ltd.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hepatocellular Carcinoma; Colorectal Neoplasms; Gastric Cancer; Lung Cancer	Drug: Opdivo Injectable Product or Keytruda Injectable Product; Combination Product: Trans-arterial tirapazamine embolization	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 80 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: One arm for HCC, CRC, gastric cancer and NSCLC each. All enrolled patients will receive the same treatment with TATE and a PD-1 inhibitor until disease progression
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: July 1, 2017
• Estimated Primary Completion Date: October 30, 2020
• Estimated Study Completion Date: December 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Hepatocellular carcinoma; PD-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.	Drug: Opdivo Injectable Product or Keytruda Injectable Product; a PD-1 immune check inhibitor per Investigator decision; Combination Product: Trans-arterial tirapazamine embolization; Embolization with Lipiodol and Gelfoam
Experimental: Colorectal cancer; PD-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.	Drug: Opdivo Injectable Product or Keytruda Injectable Product; a PD-1 immune check inhibitor per Investigator decision; Combination Product: Trans-arterial tirapazamine embolization; Embolization with Lipiodol and Gelfoam
Experimental: Gastric cancer; PD-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.	Drug: Opdivo Injectable Product or Keytruda Injectable Product; a PD-1 immune check inhibitor per Investigator decision; Combination Product: Trans-arterial tirapazamine embolization; Embolization with Lipiodol and Gelfoam
Experimental: NSCLC; PD-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.	Drug: Opdivo Injectable Product or Keytruda Injectable Product; a PD-1 immune check inhibitor per Investigator decision; Combination Product: Trans-arterial tirapazamine embolization; Embolization with Lipiodol and Gelfoam

Outcome Measures

Primary Outcome Measures :

1. Response rate [ Time Frame: up to 24 months ]
   Objective response rate in non-TATE treated lesion

Secondary Outcome Measures :

1. Overall Response rate [ Time Frame: up to 24 months ]
   All tumor lesions
2. Duration of Response [ Time Frame: up to 24 months ]
   All tumor lesions
3. Progression Free Survival [ Time Frame: up to 24 months ]
   From randomization to disease progression or death
4. Overall survival [ Time Frame: through study completion, an average of 3 years ]
   From randomization to death

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, California

University of California, Irvine

Orange, California, United States, 92868

Sponsors and Collaborators

Teclison Ltd.

Investigators

• Principal Investigator: Nadine Abi-Jaoudeh, MD; UC Irvine Medical Center

More Information

• Responsible Party: Teclison Ltd.
• ClinicalTrials.gov Identifier: NCT03259867
• Other Study ID Numbers: LT-004
• First Posted: August 24, 2017
• Last Update Posted: September 11, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Teclison Ltd.:

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

Additional relevant MeSH terms:

Carcinoma, Hepatocellular; Stomach Neoplasms; Liver Neoplasms; Colorectal Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Gastrointestinal Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Intestinal Neoplasms; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Pembrolizumab; Tirapazamine; Antineoplastic Agents, Immunological; Antineoplastic Agents