Neoplasms

Digestive System Diseases

All Conditions

Skin and Connective Tissue Diseases

Gland and Hormone Related Diseases

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Esophageal Neoplasms

Breast Neoplasms

Adenocarcinoma

Pancreatic Neoplasms

Stomach Neoplasms

Neoplasm Metastasis

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Liver Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Neoplastic Processes

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Stomach Diseases

Pancreatic Diseases

Esophageal Cancer

Pancreatic Cancer

Ovarian Cancer

Stomach Cancer

Ovarian Epithelial Cancer

Hematinics

All Drugs and Chemicals

Gastrointestinal Agents

Liver Extracts

Pancrelipase

Pancreatin

TKM-080301

Protein Kinase Inhibitors

Enzyme Inhibitors

Udo Rudloff, M.D.

Background:

Cancer in the liver can start in the liver (e.g., primary liver cancer or hepatocellular cancer) or spread to the liver from cancers in other parts of the body (e.g. colon, pancreas, gastric, breast, ovarian, esophageal cancers, cancer with metastases to the liver.) People who have tumors that can be removed by surgery live longer than those whose cancer cannot be removed. Chemotherapy can shrink some tumors in the liver, which also helps people to live longer, and sometimes chemotherapy can shrink tumors enough that they can be removed by surgery. However, most chemotherapy drugs do not work well on tumors in the liver. In this study we are testing a new drug, TKM-080301, given directly into the cancer blood supply in the liver circulation, to see if it will cause tumors to shrink.

Objectives:

- To test the safety and effectiveness of TKM-080301 for cancer in the liver that has not responded to standard treatments.

Eligibility:

- Individuals at least 18 years of age who have inoperable cancer that has started in or spread to the liver.

Design:

* Participants will be screened with a medical history and physical exam. They will also have blood tests, and imaging studies.
* Participants will have a liver angiogram (type of X-ray study) to look at the blood flow in the liver and to place a catheter for delivery of the TKM080301.
* Participants will have a single dose of TKM-080301 given directly into the liver. After the drug has been given, the catheter will be removed. They will have frequent blood tests and keep a diary to record side effects.
* Participants may have two more doses, each dose given 2 weeks apart. {Before each dose, participants will have another angiogram and catheter placement.}They may also have liver biopsies to study the tumors.
* Two weeks after the third treatment (one full course), participants will have a physical exam, blood tests, and imaging studies. If the tumor is shrinking, they may have up to three more courses of the study drug.
* Participants will have follow up visits every 3 months for 2 years after the last course and then every 6 months as required.

BACKGROUND:

- Metastatic liver disease is a life-limiting factor for patients with a variety of cancers. For

unresectable liver metastases, the 5-year survival is \< 5%.

* For selected histologies the 5-year survival of resectable hepatic metastases ranges from 20-60%, suggesting that control of liver metastases could result in prolonged survival.
* Phase I through III trials have shown that Hepatic Arterial Infusion (HAI) is safe. However, agents used thus far in HAI have limited efficacy.
* TKM-080301 is a lipid nanoparticle (LNP) formulation containing siRNA against the PLK1 (polo-like kinase-1) gene product. More specifically, TKM-080301 is a type of LNP formulation, referred to as SNALP (Stable Nucleic Acid Lipid Particles). PLK1 has been validated as a molecular target and a prognostic factor in a variety of cancers. Inhibition of PLK1 activity in proliferating cancer cells rapidly induces mitotic arrest and apoptosis.
* This study will offer HAI with TKM-080301 to patients with unresectable and/or life threatening primary liver cancer or liver metastases.

OBJECTIVES:

Primary Objective:

- To evaluate feasibility of administering TKM-080301 via HAI and to characterize the pharmacokinetics (PK) and pharmacodynamics of TKM-080301 administered by HAI.

Secondary Objectives:

* To establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of TKM-080301.
* To evaluate response rate using RECIST, PET and EASL criteria.
* To evaluate the conversion rate from unresectable to resectable disease.

ELIGIBILITY:

* Patients with unresectable colorectal, pancreas, gastric, breast, ovarian and esophageal cancers with hepatic metastases; or primary liver cancer patients who have demonstrated progressive disease following standard of care treatment.
* 18 years old or greater with an ECOG 0-2
* Laboratory and physical examination parameters within acceptable limits by standard of practice guidelines prior to surgery or chemotherapy.

DESIGN:

- This is a dose escalation phase-I study testing HAI of TKM-080301 for patients with

unresectable colorectal, pancreas, gastric, breast, ovarian and esophageal cancers with hepatic metastases, or primary liver cancers.

* Up to 54 patients who meet eligibility criteria will receive HAI with TKM-080301.
* Initial dose will be 4 mg/m(2); treatment will be given every 2 weeks for up to 12 doses.
* Patients will be evaluated every 6 weeks. Patients whose tumors become resectable will be offered this option; patients who show progressive disease will be taken off treatment. All patients will be followed for survival.

TKM 080301 for Primary or Secondary Liver Cancer

A Phase 1 Dose Escalation Study of Hepatic Intra-Arterial Administration of TKM 080301 (Lipid Nanoparticles Containing siRNA Against the PLK1 Gene Product) in Patients With Colorectal, Pancreas, Gastric, Breast, Ovarian and Esophageal Cancers With Hepatic

National Cancer Institute (NCI)

Infections

Carcinoma

Adenoviridae Infections

Antineoplastic Agents

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Vascular Biogenics (VB)-111 and nivolumab

1E13 or 0.7E13 VP via intravenous (IV) infusion on Day 1 of cycle 1 and continue every 6 weeks

Vascular Biogenics (VB)-111

240 mg of nivolumab via intravenous (IV) infusion on Day 1 of each cycle starting on cycle 2 and continue every 2 weeks

Tim F Greten, M.D.

Background:

Gastrointestinal cancer is one of the most common cancers worldwide. Researchers think an unmet need exists to understand and improve treatment options. They want to see if a combination of drugs can help people with metastatic colorectal cancer.

Objective:

To see if using a combination of Vascular Biogenics (VB)-111 and nivolumab is safe and will cause colorectal tumors to shrink.

Eligibility:

People ages 18 and older with microsatellite stable colorectal cancer that has spread to the liver

Design:

Participants must consent to sample collection protocol 11C0112.

Participants will be screened with:

Blood tests

Scans

Tumor samples. If these are not available, participants will have a biopsy.

Before they start treatment and with every treatment cycle, participants will have:

Physical exams

Blood tests

Heart tests

Before they start treatment and every 4 cycles, participants will have computed tomography (CT) or magnetic resonance imaging (MRI) scans. For these, they will lie in a machine that takes pictures of the body. For the MRI, a soft padding or coil will be placed around their head.

Participants will have biopsies before they start therapy. They will have them again after 2 6 weeks on study.

On day 1 of 14-day cycles, participants will get one or both study drugs by vein.

After they finish treatment, participants will have monthly visits for 3 months. They will have a physical exam and blood tests.

If participants stop treatment for reasons other than their disease getting worse, they will have scans about every 8 weeks. This will continue until their disease gets worse.

Participants will be contacted by phone or email every 6 months. This will continue for life.

...

Background:

* Immune based approaches in gastrointestinal (GI) cancers have unfortunately- with the notable exception of immune checkpoint inhibition in microsatellite instable (MSI-H) disease and gastric cancer-been largely unsuccessful. The reasons for this are unclear but no doubt relate to the fact that in advanced disease GI cancer appears to be less immunogenic, as evidenced by the lack of infiltrating lymphocytes with advancing T stage as well as an immunosuppressive tumor micro-environment.
* Vascular Biogenics (VB)-111 is an anti-angiogenic agent comprising of a nonreplicating E1 deleted adenovirus type 5 which contains a modified murine preproendothelin (PPE) promoter and Fas-chimera transgene
* VB-111 has been tested and shows promise in glioblastoma, ovarian and thyroid tumors
* Nivolumab is a human monoclonal antibody directed against programmed cell death protein 1 (PD-1).
* The aim of this study is to study the effects of VB-111 in colorectal cancer (CRC) and to evaluate whether the antitumor immunity induced by VB-111 therapy can be enhanced by PD-1 inhibition.

Objectives:

* To determine the safety and tolerability of VB-111 in combination with nivolumab in patients with refractory, metastatic CRC
* To determine Best Overall Response (BOR) (partial response (PR) + complete response (CR)) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) of combined treatment of VB-111 and nivolumab in patients with refractory, metastatic CRC.

Eligibility:

* Histopathological confirmation of colorectal cancer metastatic to the liver
* Patients must have progressed on \> 2 lines of standard of care chemotherapy for colorectal cancer or been intolerant of chemotherapy or refused prior chemotherapy.
* Patient's tumors must be documented to be microsatellite stable (MSS).
* Patients must have at least 1 focus of metastatic disease that is amenable to pre-and on-treatment biopsies and be willing to undergo this.
* All patients enrolled will be required to have measurable disease by RECIST v 1.1 criteria.

Design:

* The proposed study is a phase II study of VB-111 in combination with immune checkpoint inhibition (nivolumab) in patients with metastatic CRC
* Treatment will be delivered in cycles consisting of 2 weeks with VB-111 given every 6 weeks and nivolumab given every 2-week until progression or unacceptable toxicity.
* Disease status evaluation will be done every 8 (+/- 1) weeks after the start of study therapy.

VB-111 in Combination With Nivolumab in People With Metastatic Colorectal Cancer (mCRC)

Phase II Trial of VB-111 in Combination With Nivolumab in Patients With Metastatic Colorectal Cancer (mCRC).

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v5.0. Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.

Best overall response is defined as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.

Progression-free survival was assessed by the Kaplan-Meier technique with GraphPad Prism 9.3.1 for Windows (GraphPad, San Diego, CA) to calculate these values, and the median PFS will be reported along with 95% confidence interval. PFS is defined as the time between the first day of treatment to the day of disease progression. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.

Overall survival was assessed by the Kaplan-Meier technique with GraphPad Prism 9.3.1 for Windows (GraphPad, San Diego, CA) to calculate these values, and the median OS will be reported along with 95% confidence intervals. Overall survival is the time between the first day of treatment to the day of death.

6-month progression-free survival was assessed by the Kaplan-Meier technique with GraphPad Prism 9.3.1 for Windows (GraphPad, San Diego, CA) to calculate these values, and the median PFS will be reported along with 95% confidence interval. PFS is defined as the time between the first day of treatment to the day of disease progression. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.

Principal Investigator

Participants with colorectal cancers metastasized to the liver who received Vascular Biogenics (VB)-111 and nivolimab. Second biopsy: Cycle 2 Day 1. VB-111 will be given on Day 1 of cycle 1 and continue every 3 cycles (cycles 4, 7, 10 and so on) at a flat dose of 1x10\^13 or 0.7x10\^13 viral particles (VP). Nivolumab will be given on day 1 of every cycle starting at cycle 2 at a flat dose of 240 mg. Nivolumab will be administered over approximately 30-60 minutes via intravenous infusion.

Colorectal Cancers Metastasized to the Liver

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Tim F. Greten

Activated partial thromboplastin time prolonged

Anorexia

Chills

Diarrhea

Fatigue

Fever

Flu like symptoms

Headache

Hypoxia

Lymphocyte count decreased

Mucositis oral

Nausea

Platelet count decreased

Respiratory, thoracic and mediastinal disorders - Other, tachypnea

Sinus tachycardia

White blood cell decreased

Vomiting

Grade 1 Possibly Related

Grade 1 Probably Related

Grade 1 Definitely Related

Grade 2 Possibly Related

Grade 2 Probably Related

Grade 2 Definitely Related

Grade 3 Possibly Related

Grade 3 Probably Related

Grade 3 Definitely Related

Grade 4 Possibly Related

Grade 4 Probably Related

Grade 4 Definitely Related

Grade 5 is death related to adverse event.

Grade 5 Possibly Related

Grade 5 Probably Related

Grade 5 Definitely Related

One participant never treated with study drugs.

Number of Participants With Grade 1, Grade 2, Grade 3, Grade 4, and/or Grade 5 Adverse Events That Are Possibly, Probably and/or Definitely Related to Drug

Complete Response

Partial Response

Progressive Disease

Stable Disease

Best Overall Response (BOR)

Median Progression-free Survival (PFS)

Median Overall Survival (OS)

One participant not analyzed as they never received study drug.

6-month Progression-free Survival (PFS)

One participant never received study drugs.

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

Participants with colorectal cancers metastasized to the liver who received Vascular Biogenics (VB)-111 and nivolimab. Second biopsy: Cycle 2 Day 1. VB-111 will be given on Day 1 of cycle 1 and continue every 3 cycles (cycles 4, 7, 10 and so on) at a flat dose of 1x10\^13 or 0.7x10\^13 viral particles (VP). Nivolumab will be given on day 1 of every cycle starting at cycle 2 at a flat dose of 240 mg. Nivolumab will be administered over approximately 30-60 minutes via intravenous infusion.

TAC = Treatment Assignment Code

Drug Administration

TAC 1 - Second Biopsy Cycle 2 Day 1

TAC 2 - Second Biopsy Cycle 4 Day 1

Disease Progression

Anti-Inflammatory Agents

Antiemetics

Micronutrients

Irinotecan

Dexamethasone

Cetuximab

Leucovorin

Fluorouracil

Oxaliplatin

Dexamethasone acetate

Panitumumab

Floxuridine

Topoisomerase I Inhibitors

HAIP chemotherapy + Systemic chemotherapy

implanted Medtronic SynchroMed II Pump with codman 3000 Constant Flow Pump Catheter

Codman 3000 constant flow pump catheter

HAIP will be filled with mixture of Floxuridine and Dexamethasone. Pump will perfuse drugs to liver for 14 days. Floxuridine (0.12 mg/kg X pump volume X pump flow rate),Dexamethasone (1 mg/day X pump volume (30) X pump flow rate)

FUDR-Dex

2000 mg/m2, IV 46-hour infusion of 5-Fluorouracil + 400 mg/m2, IV of Leucovorin

HAIP installation

cetuximab

implanted Medtronic SynchroMed II Pump with Codman 3000 Constant Flow Pump Catheter

Medtronic SynchroMed II Pump

Kathleen M Smith, R.N.

Jonathan M Hernandez, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Many people with colorectal cancer get liver metastases. Standard treatment for this is a combination of chemotherapy drugs. Directing the chemotherapy to the liver may be effective. A device that does this a pump that delivers drugs over 2 weeks at constant rate into the hepatic artery. The person s body temperature causes the drug to flow from the pump. Researchers want to see if this helps people with colorectal metastases to the liver.

Objective:

To study the effectiveness of a hepatic artery infusion pump at treating colorectal metastases to the liver.

Eligibility:

Adults at least 18 years old with colorectal metastases to the liver

Design:

Participants will be screened with:

Medical history

Physical exam

Heart, blood, and urine tests

Scans

Participants will stay in the hospital a few days. A small plastic tube (catheter) will be inserted in an artery into the liver. The catheter will be attached to the pump. That will lie under the skin on the abdomen. It will be small and participants will be able to feel it.

Participants will get treatment in 28-day cycles.

Every Day 1, they will have physical exam, symptom review, and blood tests.

Every 2 weeks, they will come to the clinic to get chemotherapy by a catheter or port.

Every 12 weeks, they will have a scan.

Tissue samples may be taken during the study.

When they finish the drug, participants may have the pump removed. They will repeat the Day 1 tests. They will be called every 6 months to see how they are doing.

Background:

* Nearly 60% of patients with colorectal cancers will develop liver metastases over the course of their disease.
* Of patients with metastatic colorectal cancer, the liver will be the sole site of recurrence or the survival-limiting site of disease for 20%.
* Liver directed therapy, which has taken many forms over the last several decades, is a potential means to prolong survival for properly selected patients and delay progression at that site.
* Hepatic artery infusion of floxuridine (FUDR) via an implantable hepatic artery infusion pump (HAIP) induces objective clinical response rates of nearly 50% in heavily pre-treated patients with metastatic colorectal cancer to the liver.
* The identification of patients likely to respond to HAIP and those likely to suffer pumprelated adverse events is currently unknown, and has limited the wide-spread adoption of this otherwise well tolerated intervention.

Objective:

* To assess the safety of hepatic artery infusion therapy using the Medtronic pump with the Codman catheter.
* To determine the response rate in patients with unresectable metastatic colorectal cancer treated with HAIP chemotherapy as measured by RECIST.

Eligibility:

* Histologically or cytologically confirmed colorectal adenocarcinoma metastatic to the liver.
* Patients with liver metastases not amenable to resection to No Evidence of Disease (NED) in one stage.
* Patients must have received systemic chemotherapy.
* Age greater than or equal to 18 years.

Design:

- Single arm, Phase II study of HAIP chemotherapy.

Hepatic Artery Infusion Pump Chemotherapy With Floxuridine and Dexamethasone in Combination With Systemic Chemotherapy for Patients With Colorectal Cancer Metastatic to the Liver

A Single-Arm Phase II Study of Hepatic Artery Infusion Pump Chemotherapy With Floxuridine and Dexamethasone in Combination With Systemic Chemotherapy for Patients With Colorectal Cancer Metastatic to the Liver

.All IPD recorded in the medical record will be shared with intramural investigators upon request.

The fraction of patients who experience a PR or CR using the study treatment

Median amount of time subject survives after therapy

The fraction of patients whose tumors in liver shrunk after therapy

The fraction of patients whose tumors outside liver shrunk after therapy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
TKM 080301 for Primary or Secondary Liver Cancer	NCT01437007	Colorectal Canc... Pancreas Cancer... Gastric Cancer ... Breast Cancer W... Ovarian Cancer ...	TKM-080301	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
VB-111 in Combination With Nivolumab in People With Metastatic Colorectal Cancer (mCRC)	NCT04166383	Metastatic Colo... Colorectal Neop... Colorectal Carc... Colorectal Canc... Colorectal Tumo...	Vascular Biogen... Nivolumab	18 Years -	National Institutes of Health Clinical Center (CC)
Hepatic Artery Infusion Pump Chemotherapy With Floxuridine and Dexamethasone in Combination With Systemic Chemotherapy for Patients With Colorectal Cancer Metastatic to the Liver	NCT03366155	Colorectal Canc... Liver Metastase... Colorectal Aden... Colorectal Canc... Colorectal Carc...	Codman 3000 con... Panitumumab FUDR-Dex Oxaliplatin 5FU Irinotecan HAIP installati... cetuximab Medtronic Synch...	18 Years -	National Institutes of Health Clinical Center (CC)
Hepatic Artery Infusion Pump Chemotherapy With Floxuridine and Dexamethasone in Combination With Systemic Chemotherapy for Patients With Colorectal Cancer Metastatic to the Liver	NCT03366155	Colorectal Canc... Liver Metastase... Colorectal Aden... Colorectal Canc... Colorectal Carc...	Codman 3000 con... Panitumumab FUDR-Dex Oxaliplatin 5FU Irinotecan HAIP installati... cetuximab Medtronic Synch...	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for colorectal cancer with hepatic metastases