VEGFR/PDGFR Dual Kinase Inhibitor X-82 and Everolimus for Treating Patients With Pancreatic Neuroendocrine Tumors

NCT01784861 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: 201303150
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 2

Brief Summary

This study is to evaluate the combination of an investigational drug X-82 with everolimus in the treatment of pancreatic neuroendocrine tumors.

Conditions

Adenocarcinoma; Pancreatic Neoplasms

Outcome Measures

Primary Outcomes (4)

• Number of Participants With Dose Limiting Toxicities - Phase I

  Tolerability of X-82 in combination with everolimus will be determined by NCI Common Terminology Criteria for Adverse Events (CTCAE version 4.0)

  Completion of 1st cycle for all patients in Phase I portion of study (completed in approximately 20 months)

• Overall Toxicities - Phase I

  -Toxicities will be graded by the NCI Common Terminology Criteria for Adverse Events (CTCAE version 4.0)

  30 days after completion of treatment (estimated to be 13 months)

• Recommended Phase II Dose of X-82

  Completion of 1st cycle for all patients in Phase I portion of study (completed in approximately 20 months)

• Objective Response Rate (Complete Response + Partial Response) - Phase II

  Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

  Through completion of treatment (estimated to be 12 months)

Secondary Outcomes (4)

• Disease Stabilization Rate - Phase II

  Through completion of treatment (estimated to be 12 months)

• Progression Free Survival (PFS) - Phase II

  Up to 3 years

• Overall Survival - Phase II

  Up to 3 years

• Number of Participants With Toxicity - Phase II

  Through 30 days after completion of treatment (estimated to be 13 months)

Study Arms (6)

Phase I Dose Level 0: X-82 + Everolimus

EXPERIMENTAL

* X-82 100 mg by mouth once daily * Everolimus 10mg by mouth once daily for each cycle * Everolimus and X-82 should be taken at the same time every day * 28 days =1 cycle

Drug: X-82; Drug: Everolimus

Phase I Dose Level 1: X-82 + Everolimus

EXPERIMENTAL

* X-82 150 mg by mouth once daily * Everolimus 10mg by mouth once daily for each cycle * Everolimus and X-82 should be taken at the same time every day * 28 days =1 cycle

Drug: X-82; Drug: Everolimus

Phase I Dose Level 2: X-82 + Everolimus

EXPERIMENTAL

* X-82 200 mg by mouth once daily * Everolimus 10mg by mouth once daily for each cycle * Everolimus and X-82 should be taken at the same time every day * 28 days =1 cycle

Drug: X-82; Drug: Everolimus

Phase II: X-82 + Everolimus

EXPERIMENTAL

* X-82 (dose determined by Phase I portion to be 300 mg) mg by mouth once daily * Everolimus 10mg by mouth once daily for each cycle * 28 days =1 cycle

Drug: X-82; Drug: Everolimus

Phase I Dose Level 3: X-82 + Everolimus

EXPERIMENTAL

* X-82 300 mg by mouth once daily * Everolimus 10mg by mouth once daily for each cycle * Everolimus and X-82 should be taken at the same time every day * 28 days =1 cycle

Drug: X-82; Drug: Everolimus

Phase I Dose Level 4: X-82 + Everolimus

EXPERIMENTAL

* Everolimus 10mg by mouth once daily for each cycle MUST BE TAKEN FIRST * X-82 400 mg by mouth once daily 2 HOURS AFTER everolimus dose * 28 days =1 cycle

Drug: X-82; Drug: Everolimus

Interventions

X-82 DRUG

Also known as: Afinitor®, Afinitor Disperz®

Phase I Dose Level 0: X-82 + Everolimus; Phase I Dose Level 1: X-82 + Everolimus; Phase I Dose Level 2: X-82 + Everolimus; Phase I Dose Level 3: X-82 + Everolimus; Phase I Dose Level 4: X-82 + Everolimus; Phase II: X-82 + Everolimus

Everolimus DRUG

Also known as: Zortress®, RAD001

Phase I Dose Level 0: X-82 + Everolimus; Phase I Dose Level 1: X-82 + Everolimus; Phase I Dose Level 2: X-82 + Everolimus; Phase I Dose Level 3: X-82 + Everolimus; Phase I Dose Level 4: X-82 + Everolimus; Phase II: X-82 + Everolimus

Eligibility Criteria

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

You may qualify if:

• Phase I Patients: Histologic documentation of a solid malignancy and has exhausted available standard medical treatments or has no standard treatments currently available. This includes primary brain tumors.
• PK Expansion Patients: Histologic documentation of locally unresectable or metastatic renal cell carcinoma not currently amenable to surgery, radiation, or other therapy with curative intent.
• Measurable or nonmeasurable disease per RECIST 1.1 criteria.
• ECOG performance status of 0-1
• At least 18 years of age.
• Normal bone marrow and organ function as defined below:
• Granulocytes ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• Hemoglobin ≥9 g/dL
• Creatinine ≤ 1.5 x ULN
• Bilirubin ≤ 1.5 x ULN
• AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present)
• Urine protein ≤ 1+ OR urine protein to creatinine ratio ≤ 1; if UPC ratio is \> 1 on urinalysis, then 24-hour urine collection for protein must be obtained and level must be \< 1,000 mg for patient enrollment.
• QTcF \< 450 ms.
• Normal LVEF.

You may not qualify if:

• Active or severe liver disease (acute or chronic hepatitis, cirrhosis).
• Patients currently receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization).
• Receiving any other investigational agent(s) within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug. A minimum of 10 days between termination of the investigational drug and administration of study drug is required.
• Any radiotherapy or immunotherapy within the last 3 weeks (limited palliative radiation is allowed ≥2 weeks). Chemotherapy regimens with delayed toxicity within the last 4 weeks (or within the last 6 weeks for prior nitrosourea or mitomycin C). Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last 2 weeks.
• Major surgery within the last 4 weeks; minor surgery within the last 2 weeks.
• Immunization with any attenuated live vaccine within 1 week prior to registration.
• Concurrent condition resulting in immune compromise, including chronic treatment with corticosteroids or other immunosuppressive agents.
• History of allergic reactions attributed to, or intolerance of, or other significant toxicity with, compounds of similar chemical or biologic composition to X-82 or everolimus.
• Patients with fasting serum cholesterol \> 300 mg/dL OR \> 7.75 mmol/L AND fasting triglycerides \> 2.5 x ULN who would need to initiate lipid lowering medications.
• Concomitant use of drugs with a risk of causing prolonged QTc and/or Torsades de Pointes, or patients with a history of risk factors for Torsades de Pointes (e.g., familial long QT syndrome, heart failure, left ventricular hypertrophy, slow heart rate (\<45 beats per minute)).
• Concomitant use of herbal medications (i.e. St. John's wort, Kava, ephedra (ma huang), ginkgo biloba) at least 7 days prior to the first dose of study drug and throughout participation in the trial.
• Concomitant use of any drug which is a moderate or strong CYP3A4 inhibitor or strong CYP3A4 inducer.
• Patients with known CNS metastases, unless metastases are treated and stable and the patients do not require systemic steroids.
• Treatment with therapeutic doses of coumarin-type anticoagulants (maximum daily dose of 1 mg allowed for port line patency permitted). Low molecular weight heparin (LMWH) will be allowed.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, inadequately controlled hypertension, uncontrolled diabetes mellitus, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or cerebrovascular accident or transient ischemic attack within 6 months of starting study drugs, or psychiatric illness/social situations that would limit compliance with study requirements.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Tyrogenex: collaborator

Study Sites (2)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Related Publications (1)

• Pedersen KS, Grierson PM, Picus J, Lockhart AC, Roth BJ, Liu J, Morton A, Chan E, Huffman J, Liang C, Wang-Gillam A, Tan B. Vorolanib (X-82), an oral anti-VEGFR/PDGFR/CSF1R tyrosine kinase inhibitor, with everolimus in solid tumors: results of a phase I study. Invest New Drugs. 2021 Oct;39(5):1298-1305. doi: 10.1007/s10637-021-01093-7. Epub 2021 Mar 18.

  PMID: 33738668 DERIVED

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Adenocarcinoma; Pancreatic Neoplasms

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Benjamin Tan, M.D.
• Organization: Washington University School of Medicine

btan@wustl.edu

314-362-5740

Study Officials

• Benjamin Tan, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: February 4, 2013
• First Posted: February 6, 2013
• Study Start: May 3, 2013
• Primary Completion: August 19, 2020
• Study Completion: August 19, 2020
• Last Updated: July 8, 2021
• Results First Posted: June 10, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)