Study of JI-101 in Patients With Advanced Low Grade Endocrine Tumors, Ovarian Cancers or K-RAS Mutant Colon Cancers
Primary Purpose
Cancer, Neuroendocrine, Ovarian Cancer
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
JI-101
Everolimus
Sponsored by
About this trial
This is an interventional treatment trial for Cancer focused on measuring Low grade endocrine tumors, ovarian cancers, K-RAS mutant colon cancers
Eligibility Criteria
Inclusion Criteria:
- Male or female, ≥18 years of age
- For the Pharmacokinetic Drug Interaction Study: Histologically or cytologically confirmed advanced solid tumors that are refractory to all standard of care therapy or for whom no standard therapy is available, or for whom other standard therapies the patient has denied. For the Pharmacodynamic Study: Histologically or cytologically confirmed metastatic/advanced ovarian carcinoma or metastatic/advanced KRAS mutant colorectal cancer or metastatic/advanced Head and neck squamous cell cancer (HNSCC) that are refractory to all standard therapies therapy or for whom no standard therapy is available, or for whom other standard therapies the patient has denied.
- At least one measurable tumor as defined by RECIST
- Minimum of 4 weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy
- Eastern Cooperative Oncology Group (ECOG) of 0 to 2
- Organ &marrow function as defined in the protocol.
- No evidence of preexisting uncontrolled hypertension as documented by two baseline blood pressure readings taken at least 1 hour apart
- Clinically euthyroid
- Normal range cardiac function
- For female patients of child-bearing potential, a negative serum pregnancy test at Screening.
- Current use of an acceptable form of double-barrier birth control
- Have provided written informed consent
Exclusion Criteria:
- Known brain or other central nervous system metastases metastases that are not stable for 3 months or longer
- Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation.
- Major surgery, radiotherapy, chemotherapy, or cytokine therapy within 28 days of Study Day 0;
- History of intratumoral bleeding or evidence of bleeding diathesis or coagulopathy
- Female patients who are pregnant, planning a pregnancy, or who are breastfeeding
- Known allergy or hypersensitivity to JI-101 or everolimus or any component of the investigational products
- Use of an investigational drug/device/biologic within 28 days of Study Day 0
- Current drug or alcohol abuse or history of drug or alcohol abuse within the past two years
- Known history of or serologic positivity for the Hepatitis B Virus (HBV), or the Hepatitis C Virus (HCV), or for the human immunodeficiency virus (HIV)
- History of cardiac abnormalities
- Gastrointestinal (GI) abnormalities
- Use of concomitant medications that prolong the QT/QTc interval within 14 days prior to Study Day 0
- History of cerebrovascular accident including transient ischemic attack within the past 6 months
- History of pulmonary embolism or deep vein thrombosis within the past 6 months
- History of significant retinopathy or any progressive eye disease that could lead to severe loss of visual acuity or visual field loss during the study period
- Treatment with heparin or heparin analogs
- Inability or unwillingness to meet the requirements of the study
- Other current active malignancy or history of malignancy within the past five years, except for cervical carcinoma in situ, basal cell carcinoma that has been surgically removed, or prostate cancer that is being managed with watchful waiting.
- Any clinically significant abnormal finding at screening that the investigator judges would interfere with study participation
Sites / Locations
- Huntsman Cancer Institute
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Pharmacokinetic Arm
Pharmacodynamic arm
Arm Description
Patients going on Pharmacokinetic arm will receive JI-101 & Everolimus (4 patients only)
Patients going on the Pharmacodynamic study will receive JI-101 only.
Outcomes
Primary Outcome Measures
Effect of JI 101 on Pharmacokinetics Area Under Curve (AUC) (0-inf) of RAD001
Determine the mean percent change that JI-101 has on the peak concentration as determined by calculating the AUC (0-inf) of RAD001 in the presence and absence of JI-101
Effect of RAD001 on Pharmacokinetics AUC(0-inf) of JI-101
Determine the mean percent change that RAD001 has on the peak concentration as determined by calculating the AUC (0-inf) of JI101 in the presence and absence of RAD001
Progression Free-Survival in the Ovarian Cancer Cohort
progression-free survival at 2 months. We define progression as using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), to detect a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Tumor Response in the Ovarian Cancer Cohort
Response Rate determined by the sum of patients achieving complete or partial response to JI-101 as defined by Response Evaluation Criteria in Solid Tumors
Secondary Outcome Measures
Safety and Tolerability of JI-101
Number of patients experiencing a grade 2 or higher Adverse Event related to JI101
Tumor Response
Response Rate determined by the sum of patients achieving complete or partial response to JI-101 as defined by Response Evaluation Criteria in Solid Tumors. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Full Information
NCT ID
NCT01149434
First Posted
June 22, 2010
Last Updated
September 24, 2014
Sponsor
University of Utah
Collaborators
Jubilant Innovation Ltd.
1. Study Identification
Unique Protocol Identification Number
NCT01149434
Brief Title
Study of JI-101 in Patients With Advanced Low Grade Endocrine Tumors, Ovarian Cancers or K-RAS Mutant Colon Cancers
Official Title
Drug- Drug Interaction Study of JI-101 & Everolimus in Advanced Solid Tumors, Expansion Pharmacodynamic Study of JI-101 in Advanced Low Grade Endocrine Tumors, Ovarian Cancers or K-RAS Mutant Colon Cancers
Study Type
Interventional
2. Study Status
Record Verification Date
September 2014
Overall Recruitment Status
Terminated
Why Stopped
Lack of drug efficacy
Study Start Date
September 2010 (undefined)
Primary Completion Date
August 2012 (Actual)
Study Completion Date
August 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Utah
Collaborators
Jubilant Innovation Ltd.
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The study consists of two parts: Drug Interaction (Pharmacokinetic) Phase and Pharmacodynamic Phase
The primary study objective for the Drug Interaction Study is to determine the pharmacokinetic interactions between RAD001 and JI-101.
The primary study objective for the Pharmacodynamic Study is progression-free survival at 2 moths, evaluated separately in each of the three cohorts.
These will include a determination of tumor response using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria and an assessment of ephrinB4 expression in blood samples.
Secondary objectives are to determine safety and tolerability of JI-101. The investigational products are everolimus (42-O-(2-hydroxyethyl) rapamycin) and JI-101 (1-[1-(2-amino-pyridin-4-ylmethyl)-1H-indol-4-yl]-3-(5-bromo-2 methoxy-phenyl)-urea)
Eligible patients meeting all study entry criteria will be enrolled in the study. For the Drug Interaction study, patients with solid tumors will receive a single dose (10 mg) of Everolimus by mouth on Day 1 and Day 8 and JI-101 capsules (200 mg) by mouth on Day 8 and Day 15. For the Pharmacodynamic Study, all patients will receive JI-101 capsules by mouth (200 mg BID) for 28 day treatment cycles.
Detailed Description
This is a multi-center, non-randomized, open-label study to evaluate the safety and efficacy of RAD001 and JI-101 in patients with solid tumors.
Patients will complete all Screening evaluations within 21 days of Study Cycle 1Day 1. All patients will provide written Informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization before any procedures or assessments are initiated for the purposes of the protocol.
For the Drug Interaction Study, Everolimus will be administered to eligible patients at Cycle 1 Day 1 and blood will be drawn for pharmacokinetic analyses prior to dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after dosing. On Day 8, Everolimus and JI-101 will be administered and blood will be drawn for pharmacokinetic analyses prior to dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after dosing. On Day 15, JI-101 will be administered and blood will be drawn for pharmacokinetic analyses prior to dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after dosing. Patients will continue to receive JI-101(200 mg BID) for 28 day treatment cycles. Patients in the Drug Interaction Study will also receive CT scans prior to screening and every 2 treatment cycles.
For the Pharmacodynamic Study, JI-101 will be dispensed to eligible patients at Cycle 1 Day 1. JI-101 will be administered (200 mg BID) for 28 day treatment cycles. PET and CT scans will be performed prior to commencing treatment if it is standard of care. A CT scan will be performed otherwise. Patients will return to the study site every 2 cycles to complete safety assessments with radiologic tumor assessments (CT and/or PET). Adverse events will be monitored following the first administration of investigational product for the duration of the patient's participation in this study. Archival tissue will be collected for detection of mutations in relevant pathways and development of assays to study modulation of pathways that are targeted by JI-101.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cancer, Neuroendocrine, Ovarian Cancer, Colon Cancer
Keywords
Low grade endocrine tumors, ovarian cancers, K-RAS mutant colon cancers
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
19 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Pharmacokinetic Arm
Arm Type
Experimental
Arm Description
Patients going on Pharmacokinetic arm will receive JI-101 & Everolimus (4 patients only)
Arm Title
Pharmacodynamic arm
Arm Type
Experimental
Arm Description
Patients going on the Pharmacodynamic study will receive JI-101 only.
Intervention Type
Drug
Intervention Name(s)
JI-101
Intervention Description
JI-101 inhibits angiogenesis, and subsequently tumor growth, by inhibiting three receptor tyrosine kinases: VEGF Receptor Type 2 (VEGFR 2), platelet derived growth factor receptor beta (PDGFR β and Ephrin B4 (EphB4). JI-101 selectively inhibits kinases critical for all three stages of tumor angiogenesis.
Intervention Type
Drug
Intervention Name(s)
Everolimus
Other Intervention Name(s)
RAD001
Intervention Description
Everolimus is a signal transduction inhibitor that selectively inhibits mTOR (mammalian target of rapamycin), a key and highly conserved serine-threonine kinase, that is present in all cells and is a central regulator of protein synthesis and ultimately cell growth, cell proliferation, angiogenesis, and cell survival. mTOR is the only currently known target of everolimus (1).
Primary Outcome Measure Information:
Title
Effect of JI 101 on Pharmacokinetics Area Under Curve (AUC) (0-inf) of RAD001
Description
Determine the mean percent change that JI-101 has on the peak concentration as determined by calculating the AUC (0-inf) of RAD001 in the presence and absence of JI-101
Time Frame
pre-dose and at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after dosing (Cycle 1 Day 1 for RAD001 alone and Cycle 1 Day 8 for RAD001 + JI-101
Title
Effect of RAD001 on Pharmacokinetics AUC(0-inf) of JI-101
Description
Determine the mean percent change that RAD001 has on the peak concentration as determined by calculating the AUC (0-inf) of JI101 in the presence and absence of RAD001
Time Frame
pre-dose and at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after dosing (Cycle 1 Day 8 for RAD001 + JI101 and Cycle 1 Day 15 for JI-101 alone
Title
Progression Free-Survival in the Ovarian Cancer Cohort
Description
progression-free survival at 2 months. We define progression as using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), to detect a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame
2 months
Title
Tumor Response in the Ovarian Cancer Cohort
Description
Response Rate determined by the sum of patients achieving complete or partial response to JI-101 as defined by Response Evaluation Criteria in Solid Tumors
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Safety and Tolerability of JI-101
Description
Number of patients experiencing a grade 2 or higher Adverse Event related to JI101
Time Frame
2 years
Title
Tumor Response
Description
Response Rate determined by the sum of patients achieving complete or partial response to JI-101 as defined by Response Evaluation Criteria in Solid Tumors. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time Frame
2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female, ≥18 years of age
For the Pharmacokinetic Drug Interaction Study: Histologically or cytologically confirmed advanced solid tumors that are refractory to all standard of care therapy or for whom no standard therapy is available, or for whom other standard therapies the patient has denied. For the Pharmacodynamic Study: Histologically or cytologically confirmed metastatic/advanced ovarian carcinoma or metastatic/advanced KRAS mutant colorectal cancer or metastatic/advanced Head and neck squamous cell cancer (HNSCC) that are refractory to all standard therapies therapy or for whom no standard therapy is available, or for whom other standard therapies the patient has denied.
At least one measurable tumor as defined by RECIST
Minimum of 4 weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy
Eastern Cooperative Oncology Group (ECOG) of 0 to 2
Organ &marrow function as defined in the protocol.
No evidence of preexisting uncontrolled hypertension as documented by two baseline blood pressure readings taken at least 1 hour apart
Clinically euthyroid
Normal range cardiac function
For female patients of child-bearing potential, a negative serum pregnancy test at Screening.
Current use of an acceptable form of double-barrier birth control
Have provided written informed consent
Exclusion Criteria:
Known brain or other central nervous system metastases metastases that are not stable for 3 months or longer
Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation.
Major surgery, radiotherapy, chemotherapy, or cytokine therapy within 28 days of Study Day 0;
History of intratumoral bleeding or evidence of bleeding diathesis or coagulopathy
Female patients who are pregnant, planning a pregnancy, or who are breastfeeding
Known allergy or hypersensitivity to JI-101 or everolimus or any component of the investigational products
Use of an investigational drug/device/biologic within 28 days of Study Day 0
Current drug or alcohol abuse or history of drug or alcohol abuse within the past two years
Known history of or serologic positivity for the Hepatitis B Virus (HBV), or the Hepatitis C Virus (HCV), or for the human immunodeficiency virus (HIV)
History of cardiac abnormalities
Gastrointestinal (GI) abnormalities
Use of concomitant medications that prolong the QT/QTc interval within 14 days prior to Study Day 0
History of cerebrovascular accident including transient ischemic attack within the past 6 months
History of pulmonary embolism or deep vein thrombosis within the past 6 months
History of significant retinopathy or any progressive eye disease that could lead to severe loss of visual acuity or visual field loss during the study period
Treatment with heparin or heparin analogs
Inability or unwillingness to meet the requirements of the study
Other current active malignancy or history of malignancy within the past five years, except for cervical carcinoma in situ, basal cell carcinoma that has been surgically removed, or prostate cancer that is being managed with watchful waiting.
Any clinically significant abnormal finding at screening that the investigator judges would interfere with study participation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sunil Sharma, MD
Organizational Affiliation
Huntsman Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Huntsman Cancer Institute
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Study of JI-101 in Patients With Advanced Low Grade Endocrine Tumors, Ovarian Cancers or K-RAS Mutant Colon Cancers
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