Neoplasms

Digestive System Diseases

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Gastrointestinal Stromal Tumors

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Amino Acids

All Drugs and Chemicals

Tyrosine

Children with measurable localized or metastatic wt-GIST

Adults with measurable localized or metastatic wt-GIST

Vandetanib administered orally once per day continuously using a 28 day cycle until disease progression or unacceptable toxicity

Vandetanib

Brigitte C Widemann, M.D.

Background:

-Some people with wild-type gastrointestinal stromal tumors (WT-GIST) have a deficiency in one of their proteins called succinate dehydrogenase (SDH). Vandetanib is a cancer drug that has been approved to treat thyroid cancer and has been used with some success in other tumors that have a similar loss of SDH. Researchers want to see if this drug can also decrease tumor growth in people with WT-GIST.

Objectives:

-To test whether the study drug will benefit people with WT-GIST.

Eligibility:

-Adults and children 3 years old and older with WT-GIST.

Design:

* Researchers will test participants tumor tissue to confirm it is the wild type of GIST.
* Participants will be screened with a medical history, physical exam, and blood tests. They will also have electrical recording of the heart (Eastern Cooperative Oncology Group (ECOG)) and scans of the tumor.
* Participants will take the study drug in 28-day cycles. Their doctor will decide how many cycles they can complete.

  * They will take the study drug once every day and record it in a diary.
  * On Day 14, they will also visit their doctor to look for side effects.
* Before cycles 2, 3 and 4, participants will have a physical exam, urine tests, blood pressure check, and blood tests. These tests will then be done periodically for as long as they are in the study.
* Before cycle 4, scans will be done to check the size of the cancer. Most of these will be repeated every 3-6 cycles.
* When they stop taking the study drug, participants will return to the clinic for a physical exam and blood tests.

Background:

* Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract, resistant to cytotoxic chemotherapy and radiation therapy. KIT and platelet derived growth factor receptor alpha (PDGFRA) mutations have been identified as tumor initiating events in 85% of adult patients with GIST, but 85% of GISTs in pediatric patients lack KIT and PDGFRA mutations (wild-type) and imatinib is not as effective in eliciting objective responses.
* Recent work in the Pediatric and Wild-Type (wt) GIST Clinic at the National Cancer Institute (NCI) led to the identification of succinate dehydrogenase (SDH) germline mutations in 12% patients with wt-GIST (6/34). SDH protein expression evaluated using immunohistochemistry (IHC) was markedly decreased or absent in 18/18 patients with pediatric wt-GIST. Thus the majority of wt-GIST are SDH-deficient. Vandetanib (ZACTIMA; ZD6474; AstraZeneca) is an oral small molecule antineoplastic drug that inhibits vascular endothelial growth factor receptor 2 (VEGFR2), estimated glomerular filtration rate (EGFR), and rearranged during transfection (RET)-dependent signaling. Preliminary preclinical data demonstrate marked growth inhibition of SDH-mutant/deficient renal cell carcinoma cell lines when treated with vandetanib.

Objective(s):

-Primary: To assess the clinical activity (radiographic response Response Evaluation Criteria in Solid Tumors (RECIST v1.1) of vandetanib in children and adults with wt-GIST using RECIST (v1.1).

Eligibility:

-Adults and children with measurable localized or metastatic wt-GIST confirmed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory will be eligible for trial participation. Patients must have measurable disease by RECISTv1.1 and adequate organ function.

Design:

* This phase II trial will determine whether daily oral vandetanib is active in patients with wt-GIST. Vandetanib activity will be assessed primarily by radiographic response of measurable disease using RECISTv1.1.
* Vandetanib will be administered orally once daily continuously in the absence of toxicity or disease progression, using a 28-day cycle.
* Patients will be carefully monitored for toxicity and response. A small, optimal two-stage phase II design with a target response rate of 25% will be used. Nine evaluable patients will be enrolled initially. If 1 or more of the first 9 have a response, then accrual would continue until a total of 24 patients have enrolled. If there are 3 or more responses in 24 (12.5% or more) patients, then this would be sufficiently interesting activity to warrant further study.

Phase II Trial of Vandetanib in Children and Adults With Wild-Type Gastrointestinal Stromal Tumors

Phase II Trial of Vandetanib (ZD6474, Caprelsa(R) in Children and Adults With Wild-Type Gastrointestinal Stromal Tumors

Clinical activity will be assessed primarily by radiographic response of measurable disease using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete Response is disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease 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); (Note: the appearance of one or more new lesions is also considered progressions). Stable Disease is neither sufficient shrinkage to qualify for Partial Response nor sufficient increase to qualify for Progressive Disease, taking as reference the smallest sum diameters while on study.

The count of participants with serious and non-serious adverse events was assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). 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.

Overall survival is defined as the date of on-study to the date of death from any cause or last follow up.

Progression free survival is defined as the time interval from start of treatment to documented evidence of disease progression. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and 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). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

The maximum standardized uptake value (SUVmax) was used to measure the uptake of FDG-PET by the Gastrointestinal Tumors.

National Cancer Institute (NCI)

Principal Investigator

Initially patients 18 years and older at the time of enrollment on this study will start vandetanib at a fixed dose of 200 mg once daily (QD) for cycles 1, 2, and 3. One cycle = 28 days. If vandetanib was tolerated at 200mg daily the dose was increased to 300mg daily. Because of excessive toxicity at the 300mg daily dose the study was amended to maintain a dose of 200mg daily in patients 18 years and older after cycle 3.

200 mg Vandetanib Adult

Patients 18 years and older at the time of enrollment on this study will start vandetanib at a fixed dose of 200 mg once daily (QD) for cycles 1, 2, and 3. One cycle = 28 days.

If Vandetanib was well tolerated: Cycles ≥4: 300 mg/dose

300 mg Vandetanib Adult

Patients younger than 18 years of age at the time of enrollment were started at a dose of 100 mg/m\^2 based on a dosing nomogram with a planned increase in the dose to 150mg/m\^2/day after the third cycle if the drug was tolerated. One cycle = 28 days.

Dose Level 100mg/m^2 Vandetanib Pediatric

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Not meeting definition for Hispanic or Latino

Mexican, Puerto Rican, Cuban, Central or So. Amer.

Black or African American

White

Asian

Race/Ethnicity, Customized

United States

Region of Enrollment

Dr. Brigitte Widemann

Number of Participants With a Clinical Activity-radiographic Response

Count of Participants With Serious and Non-serious Adverse Events

Percentage of Participants Overall Survival

Progression Free-Survival

Baseline

Day 3-6 of cycle 1

Data were only collected from patients \>/= 15 years of age.

Maximum Standardized Uptake Value (SUVmax) on Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)

Overall Study

Symptoms and General Pathology

Recurrence

Sarcoma

Soft Tissue Sarcoma

Antineoplastic Agents

Tyrosine Kinase Inhibitors

Imatinib Mesylate

Protein Kinase Inhibitors

Enzyme Inhibitors

1 year of adjuvant imatinib mesylate 400 mg/day orally

3 years of adjuvant imatinib mesylate 400 mg/day orally

imatinib 400 mg/day orally qd for 12 months

imatinib mesylate

imatinib 400 mg/d orally qd for 36 months

imatinib

Heikki Joensuu, M.D.

In this study, patients who have been diagnosed with gastrointestinal stromal tumor (GIST) will be randomly allocated in a 1:1 ratio to receive imatinib (Gleevec) either for 12 or for 36 months following surgery. The study participants are required to have a histologically verified GIST with a high risk of GIST recurrence despite complete removal of all macroscopic GIST tissue at surgery. The high/very high risk of recurrence is defined as one of the following: 1) the largest tumor diameter is over 10 cm; 2) the mitosis count is high (over 10 mitoses per 50 high power microscope fields, HPFs); 3) the largest tumor diameter over 5 cm and the mitosis count is over 5/50 HPFs; 4) tumor spillage has taken place into the abdominal cavity at the time of surgery or following spontaneous tumor rupture. All study participants will receive imatinib 400 mg/day orally, but the duration of imatinib administration will be determined randomly (either for 12 or for 36 months). The study participants will be followed up using blood tests and computed tomography (or MRI) of the abdomen. The computed tomography examinations will be performed at 6 month intervals for a median of 5 years. A total of 280 patients will be entered into the study. The study hypothesis is that adjuvant imatinib may prevent some of the GIST recurrences, and that there may be a difference in the rate of GIST recurrence between the two groups.

This is an open-label, randomized, prospective, phase III, multicenter study carried out in the Nordic countries and in Germany. Following macroscopically complete surgery, the study participants will be allocated to receive imatinib either for 12 or for 36 months. At randomization, the patients are stratified into 2 strata: 1) local disease (1 GIST tumor); 2) intra-abdominal implants or resectable intra-abdominal/hepatic metastases, or intra-abdominal spillage is present, or R1 surgery has been carried out (microscopic disease has been left behind). The imatinib dose is 400 mg/day administered with food. Imatinib dose adjustments are made as per protocol.

Medical history, current medication, weight, height, and ECOG performance status are recorded prior to study entry. Physical examination, blood cell counts, blood biochemistry, pregnancy test, chest X-ray or CT, and CT or MRI of the abdomen and pelvis are carried out/measured prior to study entry. FDG-PET is an optional staging examination. Research serum samples are collected for banking prior to initiating imatinib and at 6-month intervals during the study. Tumor tissue is reviewed centrally to confirm the histological diagnosis of GIST, and KIT and PDGFRA gene mutation analyses will be performed from stored GIST tissue.

The study participants are monitored during adjuvant treatment and following adjuvant treatment. Physical examination, weight and ECOG performance status are assessed at 4- to 26-week intervals. Adverse events are collected using structured forms at the times of the evaluation visits. Blood cell counts and blood biochemistry are measured at 2- to 6-week intervals during imatinib therapy, and at 6-month intervals following completion of adjuvant therapy. CT or MRI examinations of the abdomen and pelvis are performed at 6-month intervals during the study.

Study Comparing 12 Months Versus 36 Months of Imatinib in the Treatment of Gastrointestinal Stromal Tumor (GIST)

Short (12 Months) Versus Long (36 Months) Duration of Adjuvant Treatment With the Tyrosine Kinase Inhibitor Imatinib Mesylate of Operable GIST With a High Risk of Recurrence

Scandinavian Sarcoma Group

Carcinoma

Cholangiocarcinoma

Liver Neoplasms

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Bile Duct Cancer

Biliary Tract Cancer

Intrahepatic Cholangiocarcinoma

Crouzon Syndrome

Jackson-Weiss Syndrome

Pfeiffer Syndrome

Hematinics

Liver Extracts

Mitogens

Patients who received derazantinib orally at dose levels from 25 mg every other day (QOD) - 200 mg daily (QD) on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

Patients who received derazantinib orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

Patients who received derazantinib orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

Patients who received derazantinib orally at the recommended phase 2 dose of 300 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

Derazantinib was administered orally at dose levels from 25 mg QOD - 200 mg QD on a 28-day schedule.

Derazantinib low dose range

Derazantinib was administered orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule.

Derazantinib middle dose range

Derazantinib was administered orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule.

Derazantinib high dose range

Derazantinib was administered orally at the recommended phase 2 dose of 300 mg QD on a 28-day schedule.

Derazantinib at recommended phase 2 dose (RP2D)

Marc Engelhardt, MD

This was an open-label, Phase 1/2, dose escalation and signal finding study of derazantinib administered to patients with advanced solid tumors (Part 1; Dose Escalation/Food-effect Cohorts) or with advanced solid tumors with FGFR genetic aberrations, including iCCA with FGFR2 gene fusion (Part 2; Expanded Cohort, signal finding).

Phase 1/2 Study of Derazantinib (ARQ 087) in Adult Subjects With Advanced Solid Tumors With FGFR Genetic Alterations

A Phase 1/2 Study of ARQ 087 in Adult Subjects With Advanced Solid Tumors With FGFR Genetic Alterations, Including Intrahepatic Cholangiocarcinoma With FGFR2 Gene Fusion

Adverse events were graded for severity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. CTCAE is classifying AEs and their associated severity from Grade 1 (Mild AE), Grade 2 (Moderate AE), Grade 3 (Severe or medically significant but not immediately life-threatening), Grade 4 (Life-threatening consequences) to Grade 5 (Death related to AE)

The number of patients with an objective tumor response, which included those with either a complete response (CR) or a partial response (PR) based on RECIST v1.1 guidelines which defines criteria for the radiological assessment in tumor response.

The objective response rate (ORR) was defined as the proportion of patients with a CR or PR.

The number of patients with tumor disease control, which included those with either a complete or partial tumor response, or a stable disease (SD) based on RECIST v1.1 guidelines which defines criteria for the radiological assessment in tumor response. The disease control rate (DCR) was defined as the proportion of patients with CR, PR or SD.

PFS was calculated as the time from the date of first dose until documented radiographic disease progression or death from any cause, whichever occurred first. Disease progression is measured according to a specified radiologic increase in tumor size.

ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)

Basilea Pharmaceutica

Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Patients who received derazantinib orally at dose levels from 25 mg QOD - 200 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

Derazantinib 25 mg QOD - 200 mg QD - Low Dose Group

Derazantinib 250 mg QOD - 325 mg QD -Middle Dose Group

Derazantinib 400 mg QOD - 425 mg QD - High Dose Group

Derazantinib 300 mg QD - Expanded Cohort Group

Derazantinib 250 mg QOD - 325 mg QD - Middle Dose Group

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Safety Population (patients who received any amount of derazantinib)

Study Director

The safety population included all subjects who received at least one dose of derazantinib.

Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs)

Evaluable Population: patients who received at least one cycle of study treatment and had at least one postbaseline tumor evaluation.

Proportion of Patients With an Objective Tumor Response Per RECIST 1.1

Patients who received derazantinib orally at the recommended phase 2 dose of 300 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria .

Proportion of Patients With Disease Control Per RECIST 1.1

Progression-free Survival (PFS)

Subjects who received derazantinib orally at dose levels from 25 mg QOD - 200 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

Subjects who received derazantinib orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

Subjects who received derazantinib orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

Subjects who received derazantinib orally at the recommended phase 2 dose of 300 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase II Trial of Vandetanib in Children and Adults With Wild-Type Gastrointestinal Stromal Tumors	NCT02015065	GIST	Vandetanib	3 Years - 99 Years	National Institutes of Health Clinical Center (CC)
Study Comparing 12 Months Versus 36 Months of Imatinib in the Treatment of Gastrointestinal Stromal Tumor (GIST)	NCT00116935	Sarcoma	imatinib mesyla... imatinib imatinib	18 Years -	Scandinavian Sarcoma Group
Study Comparing 12 Months Versus 36 Months of Imatinib in the Treatment of Gastrointestinal Stromal Tumor (GIST)	NCT00116935	Sarcoma	imatinib mesyla... imatinib imatinib	18 Years -	Scandinavian Sarcoma Group
Phase 1/2 Study of Derazantinib (ARQ 087) in Adult Subjects With Advanced Solid Tumors With FGFR Genetic Alterations	NCT01752920	Solid Tumor	Derazantinib lo... Derazantinib mi... Derazantinib hi... Derazantinib at...	18 Years -	Basilea Pharmaceutica

Spots Global Cancer Trial Database for receptor tyrosine kinase