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

Sponsor
Washington University School of Medicine (Other)
Overall Status
Terminated
CT.gov ID
NCT01784861
Collaborator
Tyrogenex (Industry)
23
Enrollment
2
Locations
6
Arms
87.6
Actual Duration (Months)
11.5
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
23 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
May 3, 2013
Actual Primary Completion Date :
Aug 19, 2020
Actual Study Completion Date :
Aug 19, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Phase I Dose Level 0: X-82 + Everolimus

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
Other Names:
  • Afinitor®
  • Afinitor Disperz®

    • Drug: Everolimus
    Other Names:
  • Zortress®
  • RAD001

    		•
    Experimental: Phase I Dose Level 1: X-82 + Everolimus

    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
    Other Names:
  • Afinitor®
  • Afinitor Disperz®

    • Drug: Everolimus
    Other Names:
  • Zortress®
  • RAD001

    		•
    Experimental: Phase I Dose Level 2: X-82 + Everolimus

    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
    Other Names:
  • Afinitor®
  • Afinitor Disperz®

    • Drug: Everolimus
    Other Names:
  • Zortress®
  • RAD001

    		•
    Experimental: Phase II: X-82 + Everolimus

    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
    Other Names:
  • Afinitor®
  • Afinitor Disperz®

    • Drug: Everolimus
    Other Names:
  • Zortress®
  • RAD001

    		•
    Experimental: Phase I Dose Level 3: X-82 + Everolimus

    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
    Other Names:
  • Afinitor®
  • Afinitor Disperz®

    • Drug: Everolimus
    Other Names:
  • Zortress®
  • RAD001

    		•
    Experimental: Phase I Dose Level 4: X-82 + Everolimus

    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
    Other Names:
  • Afinitor®
  • Afinitor Disperz®

    • Drug: Everolimus
    Other Names:
  • Zortress®
  • RAD001

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Dose Limiting Toxicities - Phase I [Completion of 1st cycle for all patients in Phase I portion of study (completed in approximately 20 months)]

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

    2. Overall Toxicities - Phase I [30 days after completion of treatment (estimated to be 13 months)]

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

    3. 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)]

    4. Objective Response Rate (Complete Response + Partial Response) - Phase II [Through completion of treatment (estimated to be 12 months)]

      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.

    Secondary Outcome Measures

    1. Disease Stabilization Rate - Phase II [Through completion of treatment (estimated to be 12 months)]

      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.

    2. Progression Free Survival (PFS) - Phase II [Up to 3 years]

      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.

    3. Overall Survival - Phase II [Up to 3 years]

      Start of the treatment until death.

    4. Number of Participants With Toxicity - Phase II [Through 30 days after completion of treatment (estimated to be 13 months)]

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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    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.

    • 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.

    Exclusion Criteria:

    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.

    • 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Washington University School of Medicine Saint Louis Missouri United States 63110
    2 Vanderbilt University Nashville Tennessee United States 37232

    Sponsors and Collaborators

    • Washington University School of Medicine
    • Tyrogenex

    Investigators

    • Principal Investigator: Benjamin Tan, M.D., Washington University School of Medicine

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Washington University School of Medicine
    ClinicalTrials.gov Identifier:
    NCT01784861
    Other Study ID Numbers:
    • 201303150
    First Posted:
    Feb 6, 2013
    Last Update Posted:
    Jul 8, 2021
    Last Verified:
    Jun 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Neuroendocrine Tumors
    Pancreatic Neoplasms
    Everolimus

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title 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
    Arm/Group Description 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 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 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 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 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 X-82 Everolimus 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
    Period Title: Overall Study
    STARTED 3 3 4 8 3 2
    COMPLETED 3 3 3 3 2 1
    NOT COMPLETED 0 0 1 5 1 1

    Baseline Characteristics

    Arm/Group Title 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 Total
    Arm/Group Description 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 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 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 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 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 X-82 Everolimus 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 Total of all reporting groups
    Overall Participants 3 3 4 8 3 2 23
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    71
    61
    53
    53
    59
    64.5
    59
    Sex: Female, Male (Count of Participants)
    Female
    1
    33.3%
    3
    100%
    3
    75%
    2
    25%
    2
    66.7%
    0
    0%
    11
    47.8%
    Male
    2
    66.7%
    0
    0%
    1
    25%
    6
    75%
    1
    33.3%
    2
    100%
    12
    52.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Not Hispanic or Latino
    2
    66.7%
    2
    66.7%
    4
    100%
    8
    100%
    2
    66.7%
    1
    50%
    19
    82.6%
    Unknown or Not Reported
    1
    33.3%
    1
    33.3%
    0
    0%
    0
    0%
    1
    33.3%
    1
    50%
    4
    17.4%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    2
    66.7%
    2
    66.7%
    1
    25%
    0
    0%
    1
    33.3%
    0
    0%
    6
    26.1%
    White
    1
    33.3%
    1
    33.3%
    3
    75%
    8
    100%
    1
    33.3%
    2
    100%
    16
    69.6%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    1
    4.3%
    Region of Enrollment (participants) [Number]
    United States
    3
    100%
    3
    100%
    4
    100%
    8
    100%
    3
    100%
    2
    100%
    23
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Dose Limiting Toxicities - Phase I
    Description Tolerability of X-82 in combination with everolimus will be determined by NCI Common Terminology Criteria for Adverse Events (CTCAE version 4.0)
    Time Frame Completion of 1st cycle for all patients in Phase I portion of study (completed in approximately 20 months)

    Outcome Measure Data

    Analysis Population Description
    -1 participant in Phase I Dose Level 2 was not evaluable for this outcome measure because they received less than one cycle of treatment. 1 participant in Phase I Dose Level 3 was not evaluable for this outcome measure because they received less than one cycle of treatment. 1 participant in Phase I Dose Level 3 was not evaluable for this outcome measure because they didn't receive any treatment.
    Arm/Group Title 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
    Arm/Group Description 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 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 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 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 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 X-82 Everolimus 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
    Measure Participants 3 3 3 6 3 0
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    2. Primary Outcome
    Title Overall Toxicities - Phase I
    Description -Toxicities will be graded by the NCI Common Terminology Criteria for Adverse Events (CTCAE version 4.0)
    Time Frame 30 days after completion of treatment (estimated to be 13 months)

    Outcome Measure Data

    Analysis Population Description
    Phase II is zero analyzed because this outcome measure is for Phase I participants only.
    Arm/Group Title 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
    Arm/Group Description 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 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 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 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 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 X-82 Everolimus 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
    Measure Participants 3 3 4 8 3 0
    Anemia
    0
    0%
    1
    33.3%
    0
    0%
    1
    12.5%
    0
    0%
    Hearing impaired
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Peripheral vision/depth perception impairment
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    Abdominal distension
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    Abdominal pain
    1
    33.3%
    0
    0%
    1
    25%
    5
    62.5%
    2
    66.7%
    Colonic fistula
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Constipation
    0
    0%
    1
    33.3%
    1
    25%
    1
    12.5%
    0
    0%
    Diarrhea
    2
    66.7%
    2
    66.7%
    2
    50%
    3
    37.5%
    2
    66.7%
    Dry mouth
    0
    0%
    0
    0%
    0
    0%
    2
    25%
    0
    0%
    Dyspepsia
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    Flatulence
    0
    0%
    0
    0%
    1
    25%
    1
    12.5%
    0
    0%
    Hemorrhoids
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Intra-abdominal hemorrhage
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    1
    33.3%
    Loss of taste
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Mucositis oral
    2
    66.7%
    2
    66.7%
    2
    50%
    4
    50%
    2
    66.7%
    Nausea
    1
    33.3%
    1
    33.3%
    1
    25%
    3
    37.5%
    1
    33.3%
    Rectal fissure
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Stomach pain
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    Taste changes
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    Vomiting
    1
    33.3%
    1
    33.3%
    1
    25%
    2
    25%
    1
    33.3%
    Chills
    0
    0%
    1
    33.3%
    1
    25%
    3
    37.5%
    0
    0%
    Edema face
    0
    0%
    0
    0%
    0
    0%
    4
    50%
    0
    0%
    Edema limbs
    0
    0%
    1
    33.3%
    2
    50%
    3
    37.5%
    1
    33.3%
    Fatigue
    1
    33.3%
    2
    66.7%
    3
    75%
    5
    62.5%
    2
    66.7%
    Fever
    0
    0%
    1
    33.3%
    0
    0%
    2
    25%
    0
    0%
    Pain
    0
    0%
    0
    0%
    2
    50%
    0
    0%
    1
    33.3%
    Cold sores
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    Elevated lactate dehydrogenase total
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    Oral thrush
    0
    0%
    2
    66.7%
    0
    0%
    0
    0%
    0
    0%
    Peritoneal infection
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    Sinusitis
    0
    0%
    1
    33.3%
    0
    0%
    2
    25%
    0
    0%
    Upper respiratory infection
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Urinary tract infection
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Bruising
    0
    0%
    0
    0%
    0
    0%
    2
    25%
    0
    0%
    Slow wound healing
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Alkaline phosphatase increased
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Blood bilirubin increased
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Creatinine increased
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    1
    33.3%
    Neutrophil count decreased
    0
    0%
    0
    0%
    2
    50%
    3
    37.5%
    0
    0%
    Platelet count decreased
    0
    0%
    0
    0%
    0
    0%
    4
    50%
    0
    0%
    Weight loss
    1
    33.3%
    0
    0%
    1
    25%
    1
    12.5%
    0
    0%
    Anorexia
    1
    33.3%
    1
    33.3%
    3
    75%
    3
    37.5%
    3
    100%
    Dehydration
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    2
    66.7%
    Hypernatremia
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    Hypertriglyceridemia
    0
    0%
    0
    0%
    0
    0%
    2
    25%
    1
    33.3%
    Hypophosphatemia
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Arthralgia
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    1
    33.3%
    Back pain
    0
    0%
    1
    33.3%
    1
    25%
    2
    25%
    0
    0%
    Flank pain
    0
    0%
    1
    33.3%
    1
    25%
    1
    12.5%
    0
    0%
    Myalgia
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Pain to extremity
    0
    0%
    0
    0%
    0
    0%
    2
    25%
    0
    0%
    Aphasia
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Dizziness
    1
    33.3%
    1
    33.3%
    0
    0%
    2
    25%
    1
    33.3%
    Dysgeusia
    0
    0%
    0
    0%
    0
    0%
    2
    25%
    1
    33.3%
    Headache
    1
    33.3%
    0
    0%
    0
    0%
    3
    37.5%
    1
    33.3%
    Tremor
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    Trigeminal nerve disorder
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    Anxiety
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    Confusion
    0
    0%
    1
    33.3%
    0
    0%
    1
    12.5%
    0
    0%
    Depression
    0
    0%
    0
    0%
    1
    25%
    1
    12.5%
    0
    0%
    Insomnia
    1
    33.3%
    0
    0%
    0
    0%
    3
    37.5%
    1
    33.3%
    Libido decreased
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Mood swings
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Hematuria
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    Urinary frequency
    0
    0%
    0
    0%
    0
    0%
    2
    25%
    0
    0%
    Testicular pain
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Cough
    0
    0%
    0
    0%
    2
    50%
    2
    25%
    1
    33.3%
    Dyspnea
    1
    33.3%
    1
    33.3%
    1
    25%
    1
    12.5%
    1
    33.3%
    Epistaxis
    0
    0%
    0
    0%
    1
    25%
    3
    37.5%
    0
    0%
    Hiccups
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hypoxia
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    Nasal congestion
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Sore throat
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    Alopecia
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    Hair color changes
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    Pruritis
    0
    0%
    0
    0%
    0
    0%
    2
    25%
    0
    0%
    Rash acneiform
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    1
    33.3%
    Rash maculo-papular
    0
    0%
    1
    33.3%
    2
    50%
    2
    25%
    1
    33.3%
    Skin hypopigmentation
    0
    0%
    1
    33.3%
    1
    25%
    0
    0%
    0
    0%
    Skin thinning
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Hot flashes
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    Hypertension
    0
    0%
    0
    0%
    1
    25%
    1
    12.5%
    0
    0%
    Dysphagia
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    Hypovolemia
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    Intraperitoneal bleeding
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    Night sweats
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Thromboembolic event
    0
    0%
    1
    33.3%
    0
    0%
    1
    12.5%
    0
    0%
    Lung infection
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    Pancreas infection
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    Sepsis
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    Diabetic ketoacidosis
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    Stroke
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Pleural effusion
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    Mesenteric ischemia
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    3. Primary Outcome
    Title Recommended Phase II Dose of X-82
    Description
    Time Frame Completion of 1st cycle for all patients in Phase I portion of study (completed in approximately 20 months)

    Outcome Measure Data

    Analysis Population Description
    This was the recommended Phase II dose because there were concerns about the ability to maintain the 400 mg daily dosing level for multiple cycles without significant toxicity.
    Arm/Group Title Phase I All Dose Levels: X-82 + Everolimus Phase II: X-82 + Everolimus
    Arm/Group Description X-82 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 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
    Measure Participants 21 0
    Number [mg]
    300
    4. Primary Outcome
    Title Objective Response Rate (Complete Response + Partial Response) - Phase II
    Description 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.
    Time Frame Through completion of treatment (estimated to be 12 months)

    Outcome Measure Data

    Analysis Population Description
    Phase I participants are not evaluable for this outcome measure. One participant in the Phase II portion of the study was not evaluable because the treating physician removed the participant from the treatment prior to receiving the end of cycle 3 imaging.
    Arm/Group Title 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
    Arm/Group Description 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 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 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 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 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 X-82 Everolimus 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
    Measure Participants 0 0 0 0 0 1
    Count of Participants [Participants]
    0
    0%
    5. Secondary Outcome
    Title Disease Stabilization Rate - Phase II
    Description 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.
    Time Frame Through completion of treatment (estimated to be 12 months)

    Outcome Measure Data

    Analysis Population Description
    Phase I participants are not evaluable for this outcome measure. One participant in the Phase II portion of the study was not evaluable because the treating physician removed the participant from the treatment prior to receiving the end of cycle 3 imaging.
    Arm/Group Title 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
    Arm/Group Description 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 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 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 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 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 X-82 Everolimus 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
    Measure Participants 0 0 0 0 0 1
    Count of Participants [Participants]
    1
    33.3%
    6. Secondary Outcome
    Title Progression Free Survival (PFS) - Phase II
    Description 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.
    Time Frame Up to 3 years

    Outcome Measure Data

    Analysis Population Description
    Phase I participants are not evaluable for this outcome measure.
    Arm/Group Title 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
    Arm/Group Description 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 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 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 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 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 X-82 Everolimus 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
    Measure Participants 0 0 0 0 0 2
    Median (Full Range) [days]
    183
    7. Secondary Outcome
    Title Overall Survival - Phase II
    Description Start of the treatment until death.
    Time Frame Up to 3 years

    Outcome Measure Data

    Analysis Population Description
    Phase I participants are not evaluable for this outcome measure.
    Arm/Group Title 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
    Arm/Group Description 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 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 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 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 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 X-82 Everolimus 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
    Measure Participants 0 0 0 0 0 2
    Median (Full Range) [days]
    115
    8. Secondary Outcome
    Title Number of Participants With Toxicity - Phase II
    Description Toxicity will be graded by NCI Common Terminology Criteria for Adverse Events (CTCAE version 4.0)
    Time Frame Through 30 days after completion of treatment (estimated to be 13 months)

    Outcome Measure Data

    Analysis Population Description
    Phase I participants are not evaluable for this outcome measure.
    Arm/Group Title 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
    Arm/Group Description 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 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 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 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 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 X-82 Everolimus 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
    Measure Participants 0 0 0 0 0 2
    Diarrhea
    2
    66.7%
    Mucositis oral
    1
    33.3%
    Nausea
    1
    33.3%
    Vomiting
    1
    33.3%
    Chest pain
    1
    33.3%
    Edema limbs
    1
    33.3%
    Hematoma
    1
    33.3%
    Mouth sores
    1
    33.3%
    Creatinine increased
    1
    33.3%
    Platelet count decreased
    1
    33.3%
    Hip pain
    1
    33.3%
    Leg cramps
    1
    33.3%
    Dizziness
    1
    33.3%
    Headache
    1
    33.3%
    Allergic rhinitis
    1
    33.3%
    Rash acneiform
    1
    33.3%
    Rash maculo-papular
    1
    33.3%
    Hypertension
    1
    33.3%

    Adverse Events

    Time Frame Adverse events were followed from start of treatment through 30 days following end of treatment. All-cause mortality was followed from start of treatment through completion of follow-up.
    Adverse Event Reporting Description
    Arm/Group Title 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
    Arm/Group Description 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 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 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 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 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 X-82 Everolimus 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
    All Cause Mortality
    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
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/3 (100%) 3/3 (100%) 4/4 (100%) 5/8 (62.5%) 2/3 (66.7%) 2/2 (100%)
    Serious Adverse Events
    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
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/3 (66.7%) 2/3 (66.7%) 0/4 (0%) 2/8 (25%) 2/3 (66.7%) 2/2 (100%)
    Blood and lymphatic system disorders
    Anemia 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Gastrointestinal disorders
    Abdominal pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 1/3 (33.3%) 0/2 (0%)
    Colonic fistula 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Diarrhea 1/3 (33.3%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Dysphagia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 1/3 (33.3%) 0/2 (0%)
    Intra-abdominal hemorrhage 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 1/3 (33.3%) 0/2 (0%)
    Nausea 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Vomiting 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    General disorders
    Hematoma 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 1/2 (50%)
    Non-cardiac chest pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 1/2 (50%)
    Pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 1/3 (33.3%) 0/2 (0%)
    Infections and infestations
    Lung infection 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 1/3 (33.3%) 0/2 (0%)
    Oral thrush 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Pancreas infection 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 1/3 (33.3%) 0/2 (0%)
    Peritoneal infection 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Sepsis 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Sinusitis 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Metabolism and nutrition disorders
    Dehydration 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 1/3 (33.3%) 0/2 (0%)
    Diabetic ketoacidosis 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Nervous system disorders
    Dizziness 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 1/3 (33.3%) 0/2 (0%)
    Leukoencephalopathy 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 1/2 (50%)
    Stroke 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Respiratory, thoracic and mediastinal disorders
    Hypoxia 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Pleural effusion 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Vascular disorders
    Hypovolemia 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Intraperitoneal bleeding 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Mesenteric ischemia 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Other (Not Including Serious) Adverse Events
    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
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/3 (100%) 3/3 (100%) 4/4 (100%) 8/8 (100%) 3/3 (100%) 2/2 (100%)
    Blood and lymphatic system disorders
    Anemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Cardiac disorders
    Chest pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 1/2 (50%)
    Ear and labyrinth disorders
    Hearing impaired 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Eye disorders
    Peripheral vision/depth perception impairment 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Gastrointestinal disorders
    Abdominal distension 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Abdominal pain 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 4/8 (50%) 1/3 (33.3%) 0/2 (0%)
    Colonic fistula 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Constipation 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Diarrhea 1/3 (33.3%) 1/3 (33.3%) 2/4 (50%) 3/8 (37.5%) 2/3 (66.7%) 2/2 (100%)
    Dry mouth 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/8 (25%) 0/3 (0%) 0/2 (0%)
    Dyspepsia 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Flatulence 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Hemorrhoids 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Intra-abdominal hemorrhage 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Loss of taste 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Mucositis oral 2/3 (66.7%) 2/3 (66.7%) 2/4 (50%) 4/8 (50%) 2/3 (66.7%) 1/2 (50%)
    Nausea 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 3/8 (37.5%) 1/3 (33.3%) 1/2 (50%)
    Rectal fissure 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Stomach pain 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Taste changes 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Vomiting 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 2/8 (25%) 1/3 (33.3%) 1/2 (50%)
    General disorders
    Chills 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 3/8 (37.5%) 0/3 (0%) 0/2 (0%)
    Edema face 0/3 (0%) 0/3 (0%) 0/4 (0%) 4/8 (50%) 0/3 (0%) 0/2 (0%)
    Edema limbs 0/3 (0%) 1/3 (33.3%) 2/4 (50%) 3/8 (37.5%) 1/3 (33.3%) 1/2 (50%)
    Fatigue 1/3 (33.3%) 2/3 (66.7%) 3/4 (75%) 5/8 (62.5%) 2/3 (66.7%) 0/2 (0%)
    Fever 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 2/8 (25%) 0/3 (0%) 0/2 (0%)
    Pain 0/3 (0%) 0/3 (0%) 2/4 (50%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Infections and infestations
    Cold sores 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Elevated lactate dehydrogenase total 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 1/3 (33.3%) 0/2 (0%)
    Mouth sores 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 1/2 (50%)
    Sinusitis 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/8 (25%) 0/3 (0%) 0/2 (0%)
    Upper respiratory infection 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Urinary tract infection 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Injury, poisoning and procedural complications
    Bruising 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/8 (25%) 0/3 (0%) 0/2 (0%)
    Slow wound healing 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Investigations
    Alkaline phosphatase increased 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Blood bilirubin increased 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Creatinine increased 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 1/3 (33.3%) 1/2 (50%)
    Neutrophil count decreased 0/3 (0%) 0/3 (0%) 2/4 (50%) 3/8 (37.5%) 0/3 (0%) 0/2 (0%)
    Platelet count decreased 0/3 (0%) 0/3 (0%) 0/4 (0%) 4/8 (50%) 0/3 (0%) 1/2 (50%)
    Weight loss 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Metabolism and nutrition disorders
    Anorexia 1/3 (33.3%) 1/3 (33.3%) 3/4 (75%) 3/8 (37.5%) 3/3 (100%) 0/2 (0%)
    Dehydration 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Hypernatremia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 1/3 (33.3%) 0/2 (0%)
    Hypertriglyceridemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/8 (25%) 1/3 (33.3%) 0/2 (0%)
    Hypophosphatemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/8 (0%) 1/3 (33.3%) 0/2 (0%)
    Back pain 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 2/8 (25%) 0/3 (0%) 0/2 (0%)
    Flank pain 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Hip pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 1/2 (50%)
    Leg cramps 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 1/2 (50%)
    Myalgia 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Pain to extremity 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/8 (25%) 0/3 (0%) 0/2 (0%)
    Nervous system disorders
    Aphasia 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Dizziness 1/3 (33.3%) 1/3 (33.3%) 0/4 (0%) 2/8 (25%) 0/3 (0%) 1/2 (50%)
    Dysgeusia 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/8 (25%) 1/3 (33.3%) 0/2 (0%)
    Headache 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 3/8 (37.5%) 1/3 (33.3%) 1/2 (50%)
    Tremor 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Trigeminal nerve disorder 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Psychiatric disorders
    Anxiety 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Confusion 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Depression 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Insomnia 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 3/8 (37.5%) 1/3 (33.3%) 0/2 (0%)
    Libido decreased 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Mood swings 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Renal and urinary disorders
    Hematuria 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Urinary frequency 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/8 (25%) 0/3 (0%) 0/2 (0%)
    Reproductive system and breast disorders
    Testicular pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 1/2 (50%)
    Cough 0/3 (0%) 0/3 (0%) 2/4 (50%) 2/8 (25%) 1/3 (33.3%) 0/2 (0%)
    Dyspnea 1/3 (33.3%) 1/3 (33.3%) 1/4 (25%) 1/8 (12.5%) 1/3 (33.3%) 0/2 (0%)
    Epistaxis 0/3 (0%) 0/3 (0%) 1/4 (25%) 3/8 (37.5%) 0/3 (0%) 0/2 (0%)
    Hiccups 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Nasal congestion 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Sore throat 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Hair color changes 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Pruritis 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/8 (25%) 0/3 (0%) 0/2 (0%)
    Rash acneiform 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 1/3 (33.3%) 1/2 (50%)
    Rash maculo-papular 0/3 (0%) 1/3 (33.3%) 2/4 (50%) 2/8 (25%) 1/3 (33.3%) 1/2 (50%)
    Skin hypopigmentation 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Skin thinning 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)
    Vascular disorders
    Hot flashes 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 1/3 (33.3%) 0/2 (0%)
    Hypertension 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/8 (12.5%) 0/3 (0%) 1/2 (50%)
    Night sweats 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/8 (0%) 0/3 (0%) 0/2 (0%)
    Thromboembolic event 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/8 (12.5%) 0/3 (0%) 0/2 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Benjamin Tan, M.D.
    Organization Washington University School of Medicine
    Phone 314-362-5740
    Email btan@wustl.edu
    Responsible Party:
    Washington University School of Medicine
    ClinicalTrials.gov Identifier:
    NCT01784861
    Other Study ID Numbers:
    • 201303150
    First Posted:
    Feb 6, 2013
    Last Update Posted:
    Jul 8, 2021
    Last Verified:
    Jun 1, 2021