Neoplasms

Digestive System Diseases

All Conditions

Symptoms and General Pathology

Colorectal Neoplasms

Diarrhea

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Signs and Symptoms, Digestive

Micronutrients

All Drugs and Chemicals

Antineoplastic Agents

Leucovorin

Fluorouracil

Irinotecan

PHY906

Wayne D Brenckman, Jr., MD

The triple combination chemotherapy of irinotecan, 5-fluorouracil and leucovorin (CPT-11/5-FU/LV or Saltz regimen) is the treatment of choice for patients with advanced colorectal cancer. Severe diarrhea, unfortunately, is a side effect of such treatment. Preclinical studies have indicated that the botanical drug PHY906 can reduce such diarrhea without compromising the effectiveness of the chemotherapy. The primary purpose of this clinical study is to evaluate the safety, tolerability and minimum effective dose of PHY906 when administered in conjunction with the Saltz regimen.

CPT-11/5-FU/LV is an active combination agent in the treatment of colorectal cancer, but one of its dose-limiting toxicities is diarrhea. PHY906 has been shown to reduce the severity of CPT-11-induced toxicity without compromising antitumor efficacy in in vivo animal models. Additionally, there has been a long historical experience in the Far East demonstrating safety of PHY906 in humans. Thus, we are conducting this double-blind, placebo-controlled study to evaluate the safety and tolerability of PHY906. This dose escalation study will also examine the effect of PHY906 (1.2, 2.4, and 3.6 g/day) on the pharmacokinetics of CPT-11 and 5-FU after concomitant administration with CPT-11, 5-FU, and LV, and on the severity of CPT-11-induced toxicities such as diarrhea.

Safety Study of the Chemotherapy Modulator PHY906 in Patients With Advanced Colorectal Cancer

A Phase I/IIA, Multicenter, Double-Blind, Randomized, Placebo-Controlled, Crossover, Dose Escalation, Safety Study of the Chemotherapy Modulator PHY906 in Patients With Advanced Colorectal Cancer

PhytoCeutica

Skin and Connective Tissue Diseases

Gland and Hormone Related Diseases

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Breast Neoplasms

Pancreatic Neoplasms

Neoplasm Metastasis

Nerve Sheath Neoplasms

Neurofibrosarcoma

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Peripheral Nervous System Diseases

Neuromuscular Diseases

Fibrosarcoma

Neoplasms, Fibrous Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Sarcoma

Neurofibromatoses

Neurofibroma

Pancreatic Cancer

Malignant Peripheral Nerve Sheath Tumor

Soft Tissue Sarcoma

Neurofibromatosis

Escalating/de-escalation doses of metarrestin

Phase IA: Loading dose on Day 1 of Cycle 1 for Dose Levels 1-7. Loading dose on Days 1 and 3 of Cycle 1 for Dose Levels 8-11. After the loading dose on Day 1 or Days 1 and 3 of Cycle 1, continue on Mondays-Wednesdays-Fridays of every following cycle. Phase IB: PO according to the dose and schedule estimated during Phase IA

Metarrestin

Murielle Hogu

Udo Rudloff, M.D.

Joaquina Baranda, MD

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

Background:

Metastasis is the spread of cancer from one organ to a nonadjacent organ. It causes 90% of cancer deaths. No treatment specifically prevents or reduces metastasis. Researchers hope a new drug can help. It stops cancer cells from growing and spreading further and possibly shrink cancer lesions in distant organs.

Objective:

To find a safe dose of metarrestin and to see if this dose shrinks tumors.

Eligibility:

Adults age 18 and older with pancreatic cancer, breast cancer, or a solid tumor that has not been cured by standard therapies. Also, children age 12-17 with a solid tumor (other than a muscle tumor) with no standard therapy options.

Design:

Participants will be screened with:

* blood tests
* physical exam
* documentation of disease confirmation or tumor biopsy
* electrocardiogram to evaluate the heart
* review of their medicines and their ability to do their normal activities

Participants will take metarrestin by mouth until they cannot tolerate it or stop to benefit from it. They will keep a medicine diary.

Participants will visit the Clinical Center. During the first month there are two brief hospital stays required with visits weekly or every other week thereafter. They will repeat some of the screening tests. They will fill out questionnaires. They will have tests of their cognitive function. They will have an electroencephalogram to record brain activity. They will have a computed tomography (CT) scan or magnetic resonance imaging (MRI). A CT is a series of X-rays of the body. An MRI uses magnets and radio waves to take pictures of the body.

Adult participants may have tumor biopsies.

Participants will have a follow-up visit 30 days after treatment ends. Then they will have follow-up phone calls or emails every 6 months for the rest of their life or until the study ends.

Background:

Metarrestin is a first-in-class investigational agent targeting the peri-nucleolar compartment (PNC), a marker of genome organization associated with metastasis.

Preclinical studies have shown that metarrestin effectively suppresses metastasis and extends overall survival in different cancer models.

Multi-species allometric scaling and good laboratory practice (GLP) toxicology and toxicokinetic studies indicate that metarrestin administered at a calculated safe maximum recommended starting dose (MRSD) to human subjects is predicted to afford intratumoral exposure levels within the therapeutic range observed preclinically.

Objectives:

Phase IA: To determine the maximum tolerated dose (MTD) of metarrestin.

Phase IB: To determine the Objective Response Rate (ORR) according to Evaluation Criteria (RECIST 1.1) in patients treated with metarrestin at the MTD.

Eligibility:

Adult subjects with any advanced solid tumors (Cohort IA), or pancreatic, colorectal, or breast tumors (Cohort IB1).

OR

Pediatric subjects age 12 and older with solid tumors other than rhabdomyosarcoma (RMS) including embryonal, alveolar, spindle cell/sclerosing, and pleomorphic subtypes of RMS (Cohort IB2).

Patients must have progressed on prior standard chemotherapeutic therapy.

Design:

This is first-in-human Phase I trial to investigate the safety and clinical activity of metarrestin in subjects with metastatic solid tumors.

During Phase IA MTD of metarrestin will be estimated in adult patients with solid tumors.

During Phase IB adult patients with breast, colorectal, or pancreatic cancer and pediatric patients with solid organ cancer will be treated at dose level of estimated MTD.

Patients will receive treatment in cycles consisting of 28 (+7/- 2) days.

Metarrestin will be administered PO until progression or unacceptable toxicity

Metarrestin (ML-246) in Subjects With Metastatic Solid Tumors

First-in-Human Phase I Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological and Clinical Activity of Metarrestin (ML-246) in Subjects With Metastatic Solid Tumors

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

Fraction of objective responses determined and reported as the ORR

The ORR rate will be determined by dividing the number of patients with an objective response by the number of evaluable patients who are treated at the MTD for cohort Phase IB1

The pharmacokinetic (PK) profile of metarrestin will be derived from single dose and multiple dose PK measures for each dose level collecting the standard pharmacokinetic parameters

Median amount of time subject survives without disease progression after treatment

Kaplan-Meier curves beginning at the date of response will be used and will be determined in all responding patients treated on the Phase IB expansion cohorts

The fraction of patients who can tolerate the dose

All treatment-related AEs will be captured, and for each grade, the number and type of AE per dose level will be descriptively described in Cohort 1B1

All treatment-related AEs will be captured, and for each grade, the number and type of AE per dose level will be descriptively described

National Cancer Institute (NCI)

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Lymphosarcoma

Hematinics

Vitamins

Eniluracil

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Antidotes

Protective Agents

Folic Acid

Vitamin B Complex

Trace Elements

Enzyme Inhibitors

Folate

Vitamin B9

5-Fluorouracil

Ethynyluracil

This is a dose escalation study.

During the first period of this study, an initial pharmacological assessment of fluorouracil administered intravenously along with oral leucovorin calcium is made. Leucovorin calcium is given orally bid on days 1-3. Fluorouracil is given as a 24 hour infusion on day 2.

After a 2 week rest period and resolution of any toxicities experienced during the first period of treatment, patients are given an escalating dose of fluorouracil with fixed doses of leucovorin calcium and ethynyluracil. Ethynyluracil and leucovorin calcium are given bid orally on days 1-3 of each week. Fluorouracil is given bid orally on day 2 of each week. Treatment is repeated for three weeks followed by a one week rest period.

3 to 6 patients are enrolled at each dose level. Dose escalation proceeds until the maximum tolerated dose (MTD) is determined. MTD is defined as the dose preceding that at which 2 or more patients experience dose limiting toxicity.

The primary purpose of this Phase I protocol is to develop an orally administered regimen of fluorouracil (5-FU) given with fixed doses of leucovorin (LV) and 776C85 (GW776), a mechanism-based inhibitor of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme involved in the catabolism of 5-FU. In the presence of 776C85, 5-FU is cleared by renal mechanisms. The schedule employed is intended to mimic the pharmacologic profile associated with a 24 hour weekly continuous infusion of 5-FU without the need for an indwelling central venous catheter. The target population is adult cancer patients with solid tumors.

The first week, each patient will receive a single dose of 5-FU given by 24 hour continuous IV infusion at its recommended Phase II dose with low-dose oral LV. In the third week, the patient will begin 776C85 (GW776) and LV PO on days 1, 2, 3 at fixed doses. Oral 5-FU will be given on day 2, and the dose will be escalated in successive cohorts of patients. Treatment will be repeated weekly for three weeks, followed by a one week break. The dose of 5-FU will be adjusted according to individual tolerance. Cohorts of three patients will be entered at each dose level of 5-FU, which will be escalated until dose-limiting toxicity is seen (guidelines are outlined in the following schema). Treatment will be continued indefinitely until evidence of disease progression, provided the patient is tolerating therapy and wishes to continue.

Biochemical monitoring suggests that there is profound and sustained inhibition of DPD with a single dose of 20 mg PO 776C85 days 1-3 each week for three of four weeks. Once the MTD has been defined for the once daily dosing on days 1, 2, 3 schedule, a simplified schedule will be evaluated in which a single dose of 776C85 on day 1 in the evening, with oral leucovorin days 1 and 2, and 5-FU given day 2 as a single dose.

Since the pharmaceutical company has decided to go with a combined tablet of eniluracil/5-FU for future studies, the new schedule will be oral leucovorin on days 1 \& 2, with 776C85 and 5-FU both given day 2 as a single dose.

A Phase I Trial of 5-Fluorouracil Given With 776C85 (GW776) and Low-Dose Leucovorin in Adult Patients With Solid Tumors

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma

Adenocarcinoma

Stomach Neoplasms

Genital Diseases, Female

Stomach Diseases

Genital Diseases

Adenocarcinoma, Scirrhous

Linitis Plastica

Neoplasms, Glandular and Epithelial

Stomach Cancer

TKI258 is dosed on a flat scale of 500 mg, to be administered orally on a 5 days on / 2 days off dosing schedule which will be repeated every week.

TKI258

Novartis Pharmaceuticals

This is a prospective, open-label, single-arm, non-randomized, multi-center, phase II proof of concept (PoC) study with a two-stage design and Bayesian interim monitoring to evaluate efficacy and safety of single agent TKI258 in adult patients with scirrhous gastric carcinoma (SGC) that have progressed after one or two prior systemic treatments.

A Phase II Study to Evaluate Efficacy and Safety of Dovitinib (TKI258) in Advanced Scirrhous Gastric Carcinoma Patients

A Single-arm, Multi-center, Phase II Study to Evaluate Efficacy and Safety of Dovitinib (TKI258) in Adult Patients With Advanced Scirrhous Gastric Carcinoma That Have Progressed After One or Two Prior Systemic Treatments

Eight-week DCR is defined as the proportion of patients with best overall response of CR, PR or SD at the end of Week 8 as per local investigator's assessment.

TTP is defined as the time from the start date of study treatment to the date of event defined as the first documented progression or death due to underlying cancer as per local investigator's assessment.

ORR is defined as the proportion of patients with best overall response of CR or PR as per local investigator's assessment.

PFS is defined as the time from the start date of study treatment to the date of event defined as the first documented progression or death due to any cause as per local investigator's assessment.

OS is defined as the time from the start date of study treatment to the date of death from any cause.

Eight-week DCR is as defined above. An independent central review of the radiological data will be performed and the results will be used for secondary supportive analyses.

TTP as defined above. An independent central review of the radiological data will be performed and the results will be used for secondary supportive analyses.

Safety will be measured in terms of type, frequency and severity of adverse events according to CTCAE v4.03.

Pharmacokinetics (PK) of TKI258 at each scheduled time point of single dose and steady dose.

ORR as defined above. An independent central review of the radiological data will be performed and the results will be used for secondary supportive analyses.

PFS as defined above. An independent central review of the radiological data will be performed and the results will be used for secondary supportive analyses.

Vinorelbine

Tubulin Modulators

Antimitotic Agents

vinorelbine tartrate

George Tidmarsh, MD, PhD

The purpose of this study is to determine the safety of oral administration of vinorelbine once daily for at least 7 days. The study will be conducted in subjects with a non-hematologic malignancy for which there are no currently accepted therapies.

Safety Study of Oral Vinorelbine in Subjects With Non-Hematologic Malignancies

A Phase 1 Study of the Safety, Pharmacokinetics, and Biological Activity of Metronomic Dosing With Orally Administered Vinorelbine Tablets in Subjects With Non-Hematologic Malignancies For Which There Are No Currently Accepted Therapies

Metronome Therapeutics

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Anti-Infective Agents

Sirolimus

Temsirolimus

MTOR Inhibitors

Oral tablet, single dose on Day 1, followed by a 48 hour - 7 day washout and then either twice daily alternate days dosing from multiple dose day 1 onwards or twice daily dosing for 21 days from multiple dose day 1 onwards followed by 7 days no treatment. Cycles of 28 days.

AZD8055

Ian Smith, MD

To investigate the safety and tolerability of AZD8055 intermittent dosing schedules when given orally to patients with advanced solid malignancies and lymphomas. Two intermittent dosing schedules will be explored with increasing doses until a maximum tolerated dose is determined for each schedule.

Preliminary Anti-tumour Activity of mTor Kinase Inhibitor in Advanced Tumours

A Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of the m-Tor Kinase Inhibitor AZD8055 Using Intermittent Dosing Schedules in Patients With Advanced Solid Malignancies and Lymphomas

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety Study of the Chemotherapy Modulator PHY906 in Patients With Advanced Colorectal Cancer	NCT00036517	Colorectal Neop... Diarrhea	PHY906	18 Years - 75 Years	PhytoCeutica
Metarrestin (ML-246) in Subjects With Metastatic Solid Tumors	NCT04222413	Advanced Solid ... Metastatic Panc... Pediatric Solid... Advanced Breast... Malignant Perip... Colorectal Neop...	Metarrestin	12 Years - 120 Years	National Institutes of Health Clinical Center (CC)
A Phase I Trial of 5-Fluorouracil Given With 776C85 (GW776) and Low-Dose Leucovorin in Adult Patients With Solid Tumors	NCT00001579	Lymphoma Neoplasms	5-Fluorouracil Ethynyluracil Leucovorin	-	National Institutes of Health Clinical Center (CC)
A Phase II Study to Evaluate Efficacy and Safety of Dovitinib (TKI258) in Advanced Scirrhous Gastric Carcinoma Patients	NCT01576380	Adenocarcinoma,... Linitis Plastic... Stomach Neoplas... Stomach Disease... Neoplasms by Si... Neoplasms	TKI258	20 Years -	Novartis
Safety Study of Oral Vinorelbine in Subjects With Non-Hematologic Malignancies	NCT00641160	Nonhematologic ...	vinorelbine tar... vinorelbine tar... vinorelbine tar...	18 Years -	Metronome Therapeutics
A Phase II Study to Evaluate Efficacy and Safety of Dovitinib (TKI258) in Advanced Scirrhous Gastric Carcinoma Patients	NCT01576380	Adenocarcinoma,... Linitis Plastic... Stomach Neoplas... Stomach Disease... Neoplasms by Si... Neoplasms	TKI258	20 Years -	Novartis
Preliminary Anti-tumour Activity of mTor Kinase Inhibitor in Advanced Tumours	NCT01194193	Cancer Advanced Solid ... Lymphomas	AZD8055	18 Years -	AstraZeneca
Metarrestin (ML-246) in Subjects With Metastatic Solid Tumors	NCT04222413	Advanced Solid ... Metastatic Panc... Pediatric Solid... Advanced Breast... Malignant Perip... Colorectal Neop...	Metarrestin	12 Years - 120 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for oral administration