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AdenocarcinomaPhase 1/2NCT01784861

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

A Phase 1/2 study testing X-82 and Everolimus in people with Adenocarcinoma and Pancreatic Neoplasms, run by Washington University School of Medicine at 2 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial summary

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

Who is it for?
Ages 18 years and older
Conditions the study is for
Adenocarcinoma, Pancreatic Neoplasms
What is being tested?
X-82 and Everolimus
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
23 participants
Where
2 sitesUnited States
Study dates
3 May 2013to 19 Aug 2020
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Phase I and PK Expansion Cohort Inclusion Criteria
  • 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.
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  • 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.
  • Recovery from any major or minor surgeries.
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
  • Ability to swallow and retain oral medication.
  • Able to understand and willing to sign written informed consent document.
  • Phase II Inclusion Criteria
  • Histologic documentation of well differentiated or moderately differentiated locally unresectable or metastatic pancreatic neuroendocrine tumor from either a primary or metastatic site with documented disease progression ≤ 12 months prior to enrollment whose disease is not currently amenable to surgery, radiation, or other modality therapy with curative intent. If different histologic classification schemes are used, equivalent histologic classifications (for example "grade 1," "low grade," or "intermediate grade") are allowed. There must be histologic documentation of a pancreatic primary site or clinical evidence of a pancreatic neuroendocrine primary tumor as determined by the treating physician. Documentation from a metastatic site is sufficient if there is clinical evidence of a pancreatic primary site. In the case of discordant pathology, patient eligibility will be determined by the PI after review of available records. Patients with neuroendocrine tumors (e.g., gastrinoma, VIPoma) in whom a pancreatic or peripancreatic primary site is strongly suspected are also eligible.
  • Evidence of measurable disease per RECIST 1.1. Measurable disease is defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 2 cm with conventional techniques or as ≥ 1 cm with spiral CT scan.
  • There is no limit on the number of prior chemotherapy regimens allowed. Any prior treatment (with the exception of lanreotide or octreotide) must be completed at least 4 weeks prior to initiation of treatment.
  • Prior treatment with embolization or ablative therapies is allowed if measurable disease remains outside of the treated area or if there is definite progression of the treated lesions. There is no limit on the number of prior procedures.
  • 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
  • ALT and AST ≤ 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.
  • Patients with fasting serum cholesterol > 300 mg/dL OR > 7.75 mmol/L AND fasting triglycerides > 2.5 x ULN should initiate lipid lowering medications.
  • Recovery from any major or minor surgeries. Patient must be 4 weeks post-major surgery and 2 weeks post-minor surgery.
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
  • Ability to swallow and retain oral medication.
  • Able to understand and willing to sign written informed consent document.

Who cannot join

  • Phase I and PK Expansion Cohort Exclusion Criteria
  • 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.
Show all 47Show fewer
  • 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.
  • Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of the study drugs.
  • Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol.
  • Pregnant or breastfeeding.
  • Known HIV-positivity on combination antiretroviral because of the potential for pharmacokinetic interactions with X-82 or everolimus. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  • Phase II Exclusion Criteria
  • Poorly differentiated neuroendocrine carcinoma or small cell carcinoma.
  • Prior treatment with everolimus, other mTOR inhibitors, or anti-VEGF drug (sunitinib, bevacizumab).
  • Patients currently receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization).
  • Major surgery < 4 weeks from the start of treatment.
  • Minor surgery < 2 weeks from the start of treatment. (Insertion of a vascular access device is not considered major or minor surgery.)
  • Any radiotherapy or immunotherapy within the last 21 days (limited palliative radiation is allowed ≥2 weeks). Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity 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.
  • 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.
  • Active or severe liver disease (acute or chronic hepatitis, cirrhosis).
  • Positive anti-HBV. HBV seropositive patients (HBsAg positive) are eligible if they are closely monitored for evidence of active HBV infection by HBV DNA testing, and they must agree to receive suppressive therapy with lamivudine or other HBV-suppressive therapy until at least 4 weeks after the last dose of everolimus. Patients who are anti-HCV positive are eligible provided that hepatitis C viral load (hepatitis C RNA) is undetectable.
  • Clinical evidence of brain metastases or carcinomatous meningitis.
  • History of GI perforation within 12 months prior to registration or presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of the study drugs.
  • History of clinically significant bleeding episodes.
  • Current NYHA class II, III, or IV congestive heart failure (see Appendix C) or symptomatic heart failure within 60 days prior to the start of study drugs.
  • Symptomatic arterial peripheral vascular disease.
  • History of aortic aneurysm, aortic dissection, angina, myocardial infarction, stroke, transient ischemic attack, or other arterial thrombotic events within 6 months of registration. Patients on therapeutic non-coumarin anticoagulation are eligible provided that they are on a stable dose of anticoagulants.
  • Uncontrolled diabetes mellitus or inadequately controlled hypertension.
  • 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.
  • History of allergic reactions or intolerance of, or other significant toxicity with, attributed to compounds of similar chemical or biologic composition to X-82 or everolimus.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol
  • Pregnant or breastfeeding.
  • Known HIV-positivity on combination antiretroviral because of the potential for pharmacokinetic interactions with X-82 or everolimus. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Vanderbilt University

    Nashville, Tennessee, 37232

  • Washington University School of Medicine

    St Louis, Missouri, 63110

Other trials in United States

About this study

Official title: A Phase I/II Study of X-82, an Oral Anti-VEGFR Tyrosine Kinase Inhibitor, With Everolimus for Patients With Pancreatic Neuroendocrine Tumors

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

Being tested
X-82, Everolimus
Medical subject headings
Adenocarcinoma, Pancreatic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • X-82Drug

    Also called Afinitor®, Afinitor Disperz®

  • EverolimusDrug

    Also called Zortress®, RAD001

Study groups in NCT01784861
Study groupRoleWhat they receive
Phase I Dose Level 0: X-82 + EverolimusExperimental* 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
Receives: Drug: X-82; Drug: Everolimus
Phase I Dose Level 1: X-82 + EverolimusExperimental* 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
Receives: Drug: X-82; Drug: Everolimus
Phase I Dose Level 2: X-82 + EverolimusExperimental* 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
Receives: Drug: X-82; Drug: Everolimus
Phase II: X-82 + EverolimusExperimental* 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
Receives: Drug: X-82; Drug: Everolimus
Phase I Dose Level 3: X-82 + EverolimusExperimental* 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
Receives: Drug: X-82; Drug: Everolimus
Phase I Dose Level 4: X-82 + EverolimusExperimental* 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
Receives: Drug: X-82; Drug: Everolimus

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

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

  2. Overall Toxicities - Phase I

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

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

  3. Recommended Phase II Dose of X-82

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

  4. 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.

    Measured: Through completion of treatment (estimated to be 12 months)

Secondary outcomes (4)

  1. Disease Stabilization Rate - Phase II

    • Disease stabilization rate is defined as the proportion of patients achieving a best overall response of complete response, partial response, or stable disease.
    • 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.
    • Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.

    Measured: Through completion of treatment (estimated to be 12 months)

  2. Progression Free Survival (PFS) - Phase II

    • PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
    • Progressive Disease (PD): 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. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

    Measured: Up to 3 years

  3. Overall Survival - Phase II

    Start of the treatment until death.

    Measured: Up to 3 years

  4. Number of Participants With Toxicity - Phase II

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

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Feb 2013 (estimated)
  2. Study start3 May 2013
  3. Primary completion19 Aug 2020
  4. Study completion19 Aug 2020

Why it stopped: Pharmaceutical company decision

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
23 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01784861
Sponsor's protocol ID
201303150
Status last verified
Jun 2021
First submitted
4 Feb 2013
Last updated
8 Jul 2021
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 33738668

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing X-82 and Everolimus in people with Adenocarcinoma and Pancreatic Neoplasms, run by Washington University School of Medicine at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 42 inclusion and 47 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 8 Jul 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Jun 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Dose Limiting Toxicities - Phase I (time frame: Completion of 1st cycle for all patients in Phase I portion of study (completed in approximately 20 months)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01784861, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jul 2021.

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