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)

Inflammatory Breast Neoplasms

Breast Diseases

Skin Diseases

Inflammatory Breast Cancer

A complete treatment cycle defined as 28 days or 4 weeks (+/- 2 days). Patients receive a single daily oral dose of 500 mg of dovitinib for 5 consecutive days, followed by a 2-day rest period (5 days on/2 days off schedule).

500 mg by mouth for 5 consecutive days, followed by a 2-day rest period (5 days on/2 days off schedule) for every 28 day cycle.

Dovitinib

Vicente Valero, MD

The goal of this clinical research study is to learn if dovitinib can help to control inflammatory breast cancer. The safety of this drug will also be studied.

The Study Drug:

Dovitinib is designed bind to a protein on the surface of cancer cells called the FGF receptor. This may slow the growth of cancer cells or kill cancer cells.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take dovitinib by mouth each day for 5 days and have a 2-day rest period (5 days on/2 days off schedule). The first dose of each week is Day 1. You should take dovitinib in the morning with a glass (about 8 ounces) of water at least 1 hour before or at least 2 hours after eating. It is important that you take the study drug at about the same time every day.

If you forget to take a dose of the study drug as scheduled, or take a dose during your 2-day rest period, you should follow the guidelines below or call your study staff:

* If you take a dose on Day 6, then you will rest on Day 7 and start taking the drug on Day 1.
* If you take a dose on Day 7, then you will skip Day 1 the next schedule and start dosing on Day 2.
* If you take a dose on Day 6 and Day 7, then you will skip Days 1 and 2 of the next schedule and start dosing on Day 3.
* If you missed a dose on Days 1, 2, 3, or 4, you should restart the next dosing day and rest on Days 6 and 7.
* If you missed a dose on Day 5, you should rest on Days 6 and 7, and restart dosing on Day 1 of the next week.

You should not take additional medications including over-the-counter products and herbal/alternative medications during the study without asking your doctor. It is important to avoid medications that are known to cause liver side effects.

If you experience intolerable side effects, the study doctor may give you drugs to help control the side effects.

You should store the study drug at room temperature and out of direct sunlight. The study drug should also be kept away from children.

About every 4 weeks, you will need to bring back your empty or partially used bottles of study drug.

During Treatment:

At every visit, you will be asked if you have had any side effects.

Before each Cycle:

* You will have a physical exam, including measurement of your vital signs.
* Your performance status will be recorded.
* Blood (about 2 tablespoons) will be drawn for routine tests.

Cycle 1, around Days 8 and 22:

° Blood (about 1 tablespoon) will be drawn to check your liver function.

Cycle 2 around Day 8:

° Blood (about 1 tablespoon) will be drawn to check your liver function.

Every 2 cycles (before Cycles 3, 5, 7, and so on):

* If the doctor thinks it is needed, photographs will be taken of your skin and any areas affected by inflammatory breast cancer.
* If the doctor thinks it is needed, you will have x-rays, a CT scan of the chest and/or abdomen, and/or a bone scan.

Before Cycle 3:

* If the doctor thinks it is needed, you will have a positron emission computed tomography (PET/CT) scan to check the status of the disease.
* Blood (about 2 tablespoons) will be drawn for biomarker testing.

You will also have a one-time blood draw (about 1 tablespoon) to measure the level of the study drug in your blood. This sample may be drawn on Days 12 or 26 of Cycle 1, before Cycle 2, or on Day 12 of Cycle 2.

If the doctor thinks it is needed, any of these tests and procedures may be performed earlier. If the doctor thinks it is needed, you will have an ECG, ECHO, or MUGA scan to check your heart function.

Length of Study:

You may remain on study for as long as you are benefiting. You will be taken off study treatment if the disease gets worse or you experience intolerable side effects.

Your participation on the study will be over once you have completed the end-of-treatment visit.

End-of-Treatment Visit:

After you are off study, you will have a end-of-treatment visit within 14 days after the last study visit.

* You will be asked if you have had any side effects.
* You will have a physical exam, including measurement of your vital signs.
* Your performance status will be recorded.
* Blood (about 1 tablespoon) will be drawn for routine tests.
* If the doctor thinks it is needed, photographs will be taken of your skin and any areas affected by inflammatory breast cancer.
* If the doctor thinks it is needed, you will have x-rays, a CT scan of the chest and/or abdomen, and/or a bone scan.
* If the doctor thinks it is needed, you will have an ECG and ECHO or MUGA scan to check your heart function.
* If the doctor thinks it is needed, you will have a PET/CT scan to check the status of the disease.

Follow-up Visits:

You will be called or e-mailed every 3 months for up to 1 year and asked how you are doing.

This is an investigational study. Dovitinib is not FDA approved or commercially available. At this time, dovitinib is only being used in research.

Up to 33 patients will take part in this study. All will be enrolled at MD Anderson.

TKI258 for Metastatic Inflammatory Breast Cancer Patients

A Phase II Study of TKI258 (Dovitinib Lactate) as Salvage Therapy in Patients With Stage IV HER2-negative Inflammatory Breast Cancer (IBC) and Local or Distant Relapse

Number of participants experiencing CR, PR or SD as defined by Response Evaluation Criteria In Solid Tumors (RECIST). Response is anyone who experiences SD, CR or PR in first 6 months. CR: Disappearance clinical evidence active tumor by evaluation, mammogram \& ultrasound. No symptoms or evidence of residual invasive tumor, including no residual tumor in axillary lymph nodes. PR: 50%/\> decrease for minimum 4 weeks in measurable lesion determined by product of perpendicular diameters of lesion. Every lesion should not regress to qualify as PR; however, if lesion progresses or if new lesions appear, response cannot be classified as PR. Minor Response \[MR\]: Decreases in tumor masses insufficient to qualify as partial remission, i.e. \<50%. SD: Between MR \& PD. PD: Increase 25% measured lesion from baseline. New lesions constitutes increasing disease. Mixed responses consid

Safety analysis evaluated by grading each adverse event according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and reporting the type, frequency and severity in a summary format. Full AE reporting can be found in the Adverse Event Section.

Novartis

M.D. Anderson Cancer Center

Dovitinib 500 mg single oral dose for 5 consecutive days, followed by a 2-day rest period (5 days on/2 days off schedule) for every 28 day cycle.

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

United States

Region of Enrollment

Vicente Valero, MD/Professor, Breast Medical Oncology

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD)

Three participants were not evaluable for response due to early departure from study.

Overall Response (Complete Response [CR], Partial Response [PR] or Stable Disease [SD]) of Participants

Grade 3 & 4: Fatigue

Grade 3 & 4: Pain

Safety Analysis of Dovitinib: Most Frequently Reported Treatment-related Adverse Event (AEs)

Overall Study

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Antineoplastic Agents

Gemcitabine

Capecitabine

Paclitaxel

Albumin-Bound Paclitaxel

Cisplatin

Tubulin Modulators

Antimitotic Agents

Antimetabolites

cisplatin at 30 mg/m2 on days 1 and 15, nab-paclitaxel at the RP2D on days 1 and 15, capecitabine at 1250 mg/ m2 days 1-28, gemcitabine at 800 mg/ m2 on days 1 and 15 every 4 weeks

gemcitabine at 1000 mg/ m2 on days 1, 8 and 15 every 4 weeks + nab-paclitaxel at 125 mg/ m2 on days 1, 8 and 15 every 4 weeks

cisplatin

capecitabine

gemcitabine at 800 mg/ m2 on days 1 and 15 in arm A; at 1000 mg/m2 on days 1, 8 and 15 in arm B

gemcitabine

nab-paclitaxel at the recommended phase II dose day 1 and 15 in arm A; at 125 mg/m2 on days 1, 8 and 15 in arm B

nab-paclitaxel

Michele Reni, MD

Four-drug combo yielded a statistically significant improvement in progression-free survival and overall survival compared to gemcitabine in patients with advanced pancreatic adenocarcinoma. Nab-Paclitaxel showed promising antitumor activity in patients with pancreatic cancer. Given the synergism of taxanes with gemcitabine, fluoropyrimidines and platinating agents the role of nab-Paclitaxel in a 4-drug regimen will be explored.

The aim of this trial is to determine the recommended dose of nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine, PAXG regimen (Phase I), and to evaluate the feasibility and the activity of the PAXG regimen in patients with stage III and IV pancreatic cancer.

OBJECTIVES: PHASE I: to determine the recommended phase 2 dose of nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine.

PHASE II: to evaluate the feasibility and the activity of the PAXG regimen in terms of 6-months progression-free survival in patients with stage III and IV pancreatic cancer.

OUTLINE Phase I - dose finding single institution trial, followed by a randomized open label multicenter phase II trial.

Phase II: Patients will be stratified by stage (III vs IV) and CA19.9 level (\< 10 x ULN versus \>10 x ULN); Patients will be randomly assigned to receive PAXG (arm A) or gemcitabine-nab-paclitaxel regimen (arm B).

Treatment plan (phase II):

Arm A: PAXG every 4 weeks (1 cycle): cisplatin at 30 mg/m2 on days 1 and 15, nab-paclitaxel at the RP2D on days 1 and 15, capecitabine at 1250 mg/ m2 days 1-28, gemcitabine at 800 mg/ m2 on days 1 and 15.

Arm B: Gemcitabine + nab-paclitaxel every 4 weeks (1 cycle): gemcitabine at 1000 mg/m2 on days 1, 8 and 15; nab-paclitaxel at 125 mg/mq on days 1, 8 and 15.

Treatment will be administered for a maximum of 6 cycles or until there is a clinical benefit.

A Phase I-II Study of PAXG in Stage III-IV Pancreatic Adenocarcinoma

Dose Limiting Toxicity definition: DLT will be defined as any of the following events attributable to the administered study drugs:

* Hematologic toxicity

  * Grade ≥ 4 neutropenia lasting 7 days or more
  * Grade ≥ 3 febrile neutropenia or fever of unknown origin ≥ 38.5°C
  * Grade 4 thrombocytopenia
  * Grade 3 thrombocytopenia which required transfusions
* Nausea or vomiting Grade ≥ 3 nausea or vomiting despite maximal antiemetic therapy
* Diarrhea Grade ≥ 3 diarrhea despite optimal management of the event
* Neurological toxicity Any Grade ≥ 2 neurological toxicity
* Other non-hematologic toxicity Any grade ≥ 3 toxicities or representing a shift by 2 grades from baseline (in case of abnormal baseline)
* Failure to recover Failure to recover to grade ≤ 1 toxicity (except alopecia) or to baseline values after delaying the initiation of next cycle by \> 2 weeks.

rate of progression-free patients at 6 months from randomization

rate of resectable patients at at time of CT evaluation and multidisciplinary assessment after 4 and 6 months from treatment start

contrast enhanced CT scan tumor assessment

IRCCS San Raffaele

Principal Investigator

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)
TKI258 for Metastatic Inflammatory Breast Cancer Patients	NCT01262027	Breast Cancer	Dovitinib	18 Years -	M.D. Anderson Cancer Center
A Phase I-II Study of PAXG in Stage III-IV Pancreatic Adenocarcinoma	NCT01730222	Pancreatic Canc...	cisplatin capecitabine gemcitabine nab-paclitaxel	18 Years - 75 Years	IRCCS San Raffaele
A Phase I-II Study of PAXG in Stage III-IV Pancreatic Adenocarcinoma	NCT01730222	Pancreatic Canc...	cisplatin capecitabine gemcitabine nab-paclitaxel	18 Years - 75 Years	IRCCS San Raffaele
A Phase I-II Study of PAXG in Stage III-IV Pancreatic Adenocarcinoma	NCT01730222	Pancreatic Canc...	cisplatin capecitabine gemcitabine nab-paclitaxel	18 Years - 75 Years	IRCCS San Raffaele

Spots Global Cancer Trial Database for stage iv disease