Study of JI-101 in Patients With Advanced Low Grade Endocrine Tumors, Ovarian Cancers or K-RAS Mutant Colon Cancers

NCT01149434 | Terminated Phase 1 Results DMC

• 1 other identifier: HCI43102
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

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.

Conditions

Cancer; Neuroendocrine; Ovarian Cancer; Colon Cancer

Keywords

Low grade endocrine tumors; ovarian cancers; K-RAS mutant colon cancers

Outcome Measures

Primary Outcomes (4)

• 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

  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

• 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

  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

• 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.

  2 months

• 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

  2 years

Secondary Outcomes (2)

• Safety and Tolerability of JI-101

  2 years

• Tumor Response

  2 years

Study Arms (2)

Pharmacokinetic Arm

EXPERIMENTAL

Patients going on Pharmacokinetic arm will receive JI-101 \& Everolimus (4 patients only)

Drug: JI-101; Drug: Everolimus

Pharmacodynamic arm

EXPERIMENTAL

Patients going on the Pharmacodynamic study will receive JI-101 only.

Drug: JI-101

Interventions

JI-101 DRUG

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.

Pharmacodynamic arm; Pharmacokinetic Arm

Everolimus DRUG

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).

Also known as: RAD001

Pharmacokinetic Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Utah: lead
• Jubilant Innovation Ltd.: collaborator

Study Sites (1)

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

MeSH Terms

Conditions

Neoplasms; Ovarian Neoplasms; Colonic Neoplasms

Interventions

1-(1-(2-amino-pyridin-4-ylmethyl)-1H-indol-4-yl)-3-(5-bromo-2-methoxyphenyl)urea; Everolimus

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Sunil Sharma, MD
• Organization: Huntsman Cancer Institute Unversity of Utah

sunil.sharma@hci.utah.edu

801-585-0255

Study Officials

• Sunil Sharma, MD

  Huntsman Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 22, 2010
• First Posted: June 23, 2010
• Study Start: September 1, 2010
• Primary Completion: August 1, 2012
• Study Completion: August 1, 2012
• Last Updated: October 6, 2014
• Results First Posted: September 25, 2014

Record last verified: 2014-09

Locations

US (1)