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Vorolanib (X-82) Combined With Checkpoint Inhibitors in Patients With Solid Tumors

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ClinicalTrials.gov Identifier: NCT03511222
Recruitment Status : Recruiting
First Posted : April 27, 2018
Last Update Posted : April 12, 2019
Sponsor:
Collaborator:
Xcovery Holding Company, LLC
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
The investigators hypothesize that vorolanib in combination with checkpoint inhibitors (pembrolizumab for gastric/gastroesophageal (GE) junction cancers and nivolumab for hepatocellular carcinoma (HCC)) may improve immunotherapy efficacy by overcoming treatment resistance of checkpoint inhibitors in gastrointestinal (GI) cancers.

Condition or disease Intervention/treatment Phase
Solid Tumor Hepatocellular Carcinoma Gastric Cancer Gastroesophageal Junction Adenocarcinoma Drug: Vorolanib Drug: Nivolumab Drug: Pembrolizumab Procedure: Peripheral blood draw Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase IB Trial of Vorolanib (X-82) Combined With Checkpoint Inhibitors in Patients With Solid Tumors
Actual Study Start Date : September 11, 2018
Estimated Primary Completion Date : October 31, 2019
Estimated Study Completion Date : March 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dose Escalation: Vorolanib + Nivolumab
  • Vorolanib is an oral drug which will be administered daily on an outpatient basis at the assigned dose level.
  • Patients receiving nivolumab will get it on an outpatient basis as a 30-minute intravenous infusion at a dose of 480 mg on Day 1 of each 28-day cycle
  • In light of immunotherapy approach, treatment beyond progression is allowed as long as patient has clinical stability. Patients can stay on the regimen unless excessive toxicity or clinical or radiographic disease progression per RECIST
Drug: Vorolanib
Patients should take vorolanib at approximately the same time every day with food.
Other Name: X-82

Drug: Nivolumab
Standard of care
Other Name: Opdivo

Experimental: Dose Escalation: Vorolanib + Pembrolizumab
  • Vorolanib is an oral drug which will be administered daily on an outpatient basis at the assigned dose level
  • Patients receiving pembrolizumab will get it on an outpatient basis as a 30-minute (-5/+10 minutes) intravenous infusion at a dose of 200 mg on Day 1 of each 21-day cycle
  • In light of immunotherapy approach, treatment beyond progression is allowed as long as patient has clinical stability. Patients can stay on the regimen unless excessive toxicity or clinical or radiographic disease progression per RECIST
Drug: Vorolanib
Patients should take vorolanib at approximately the same time every day with food.
Other Name: X-82

Drug: Pembrolizumab
Standard of care
Other Name: Keytruda

Experimental: Dose Expansion: Vorolanib + Pembrolizumab (HCC)
  • Vorolanib is an oral drug which will be administered daily on an outpatient basis at recommended phase II dose
  • Patients receiving pembrolizumab will get it on an outpatient basis as a 30-minute (-5/+10 minutes) intravenous infusion at a dose of 200 mg on Day 1 of each 21-day cycle
  • In light of immunotherapy approach, treatment beyond progression is allowed as long as patient has clinical stability. Patients can stay on the regimen unless excessive toxicity or clinical or radiographic disease progression per RECIST
Drug: Vorolanib
Patients should take vorolanib at approximately the same time every day with food.
Other Name: X-82

Drug: Pembrolizumab
Standard of care
Other Name: Keytruda

Procedure: Peripheral blood draw
  • Only performed in 20 participants from the Expansion Cohorts
  • Baseline and Day 1 of each cycle

Experimental: Dose Expansion: Vorolanib + Nivolumab (Gastric or GE Junction)
  • Vorolanib is an oral drug which will be administered daily on an outpatient basis at recommended phase II dose
  • Patients receiving nivolumab will get it on an outpatient basis as a 30-minute intravenous infusion at a dose of 480 mg on Day 1 of each 28-day cycle
  • In light of immunotherapy approach, treatment beyond progression is allowed as long as patient has clinical stability. Patients can stay on the regimen unless excessive toxicity or clinical or radiographic disease progression per RECIST
Drug: Vorolanib
Patients should take vorolanib at approximately the same time every day with food.
Other Name: X-82

Drug: Nivolumab
Standard of care
Other Name: Opdivo

Procedure: Peripheral blood draw
  • Only performed in 20 participants from the Expansion Cohorts
  • Baseline and Day 1 of each cycle




Primary Outcome Measures :
  1. Recommended phase II dose (RP2D) of vorolanib plus pembrolizumab [ Time Frame: Completion of enrollment to Dose Escalation cohorts (estimated to be 13 months) ]
    -The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle. Dose escalations will proceed for both nivolumab and pembrolizumab until the MTD or highest dose level (level 2), which is defined as RP2D.

  2. Recommended phase II dose (RP2D) of vorolanib plus nivolumab [ Time Frame: Completion of enrollment to Dose Escalation cohorts (estimated to be 13 months) ]
    -The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle. Dose escalations will proceed for both nivolumab and pembrolizumab until the MTD or highest dose level (level 2), which is defined as RP2D.


Secondary Outcome Measures :
  1. Safety and toxicity of vorolanib plus pembrolizumab as measured by the number and type of adverse events experienced by participant [ Time Frame: 30 days after completion of treatment (estimated to be 7 months) ]
    -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.

  2. Safety and toxicity of vorolanib plus nivolumab as measured by the number and type of adverse events experienced by participant [ Time Frame: 30 days after completion of treatment (estimated to be 7 months) ]
    -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.

  3. Objective response rate (ORR) [ Time Frame: Through completion of treatment (estimated to be 6 months) ]
    • ORR = complete response + partial response)
    • Complete response: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Normalization of tumor mark level.
    • Partial response: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

  4. Optimal duration of treatment regimen [ Time Frame: Through completion of treatment (estimated to be 6 months) ]
  5. Overall survival (OS) [ Time Frame: Through 1 year after completion of treatment (estimated to be 18 months) ]
    -Overall survival (OS) is defined as the date from treatment to death or last follow-up.

  6. Progression-free survival (PFS) [ Time Frame: Through 1 year after completion of treatment (estimated to be 18 months) ]
    • Progression-free survival (PFS) is defined as the time from the date of treatment to the date of progression or last follow-up
    • 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. (Note: the appearance of one or more new lesions is also considered progressions).

  7. Immune-related progression-free survival (irPFS) [ Time Frame: Through 1 year after completion of treatment (estimated to be 18 months) ]
    • Immune-related PFS (irPFS) is defined as the time from the date of treatment to the date of immune-related progression or last follow-up.
    • Immune-related measurements are measured using iRECIST



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Dose escalation cohort: histologically or cytologically confirmed diagnosis of a solid tumor that can be treated with either pembrolizumab or nivolumab as part of standard of care or whom no standard of therapy exists except pembrolizumab or nivolumab
  • Expansion cohort (gastric or GE junction): histologically or cytologically confirmed diagnosis of advanced gastric cancer or GE junction with positive PD-L1 (threshold of positivity CPS ≥ 1) whose disease progressed on or after two or more prior systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu targeted therapy, refused chemotherapy, or were not candidates for chemotherapy.
  • Expansion cohort (HCC): histologically or cytologically confirmed diagnosis of hepatocellular carcinoma who are Child-Pugh Class A and who were previously treated with sorafenib or refused sorafenib.
  • 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 ≥ 10 mm with CT scan.
  • At least 18 years of age.
  • ECOG performance status ≤ 1
  • Normal bone marrow and organ function as defined below:

    • Leukocytes ≥ 2,000/mcL
    • Absolute neutrophil count ≥ 1,500/mcL
    • Platelets ≥ 100,000/mcL
    • Hemoglobin ≥ 9.0 g/dL
    • Total bilirubin ≤ 1.5 x IULN
    • AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN (≤ 5 x IULN for patients with liver metastases or hepatocellular carcinoma (HCC))
    • Creatinine ≤ 1.5 x IULN OR measured or calculated creatinine clearance ≥ 50 mL/min for patients with creatinine levels > 1.5 x IULN
    • Urine protein ≤1+ or urine protein to creatinine ratio ≤ 1; if UPC ratio is >1 on urinalysis, then 24-hour urine collection from protein must be obtained and level must be <1,000 mg for patient enrollment.
    • aPTT and either INR or PT ≤ 1.5 x ILUN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
  • Patients receiving therapeutic non-Coumadin anticoagulation are eligible, provided they are on a stable dose (per investigator judgment) of anticoagulant.
  • Patients with treated/stable brain metastases, defined as patients who have received prior therapy for their brain metastases and whose CNS disease is radiographically stable at study entry, are eligible. Patients with clinically evident CNS hemorrhage on scans are excluded.
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 31 weeks after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
  • Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

  • Presence of a concurrent active, incurable malignancy that may alter the outcome of the treatment for disease under treatment as determined by the treating physician.
  • Receiving any other investigational agents within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug.
  • Prior PD-1 or PD-L1 inhibitor therapy, or prior therapy with anti-PD-L2 or anti-CTLA-4 inhibitor, or any other drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorolanib, nivolumab or pembrolizumab (as applicable), any monoclonal antibody, or other agents used in the study.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection.
  • Has a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses ≤ 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). A brief course of corticosteroids for prophylaxis (e.g. contrast dye allergy) or for treatment of non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by contact allergens) is permitted.
  • Toxicities from prior therapy must have resolved to G1 or less prior to the first dose of study drug except those deemed not clinically significant per PI.
  • Active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. This includes but is not limited to: history of immune-related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome. Patients with vitiligo or endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome, and psoriasis controlled with topical medication, and patients with positive serology, such as antinuclear antibodies (ANA) or anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible. Patients with type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger (precipitating event) are eligible.
  • Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
  • History of clinically significant bleeding.
  • Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, GI obstruction, and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study.
  • Inability to swallow or retain oral medications or the presence of active GI disease or other conditions that will interfere significantly with the absorption, distribution, metabolism, or excretion of vorolanib.
  • Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 24 hours of study entry.
  • Active hepatitis B or hepatitis C. Note: no testing for hepatitis B or C is required unless mandated by local health authority.
  • Has a known history of active tuberculosis.
  • Known HIV-positivity.
  • Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live attenuated vaccines and are not allowed.
  • Major surgery within the last 4 weeks; minor surgery within the last 2 weeks.
  • Any radiotherapy within 3 weeks except palliative stereotactic body radiation therapy (SBRT) within 2 weeks.
  • Chemotherapy regimen given on every 3-week schedule within the last 3 weeks. Chemotherapy given on the weekly basis with limited potential for delayed toxicity within the last 2 weeks.
  • Concurrent use of any medications or substances (e.g. herbal supplement or food) known to be a strong inhibitor or strong inducer of CYP3A4. .
  • Symptomatic arterial peripheral vascular disease or significant cardiovascular disease or condition including:

    • Congestive heart failure (CHF) currently requiring therapy.
    • Class III or IV cardiovascular disease according to the New York Heart Association (NYHA) Functional Criteria.
    • Need for antiarrhythmic medical therapy for a ventricular arrhythmia.
    • Severe conduction disturbance (e.g. 3rd degree heart block).
    • Unstable angina pectoris (i.e. last episode ≤ 6 months prior to first dose of protocol-indicated treatment).
    • Uncontrolled (per investigator judgment) hypertension.
    • Myocardial infarction within 6 months prior to starting trial treatment.
    • QTcF >450 ms in men, or >470 ms in women.
  • Deep vein thrombosis or pulmonary embolism ≤ 4 weeks before first dose of protocol-indicated treatment, unless adequately treated and stable.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03511222


Contacts
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Contact: Andrea Wang-Gillam, M.D., Ph.D. 314-362-5740 awang-gillam@wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Andrea Wang-Gillam, M.D., Ph.D.         
Principal Investigator: Andrea Wang-Gillam, M.D., Ph.D.         
Sub-Investigator: Manik Amin, M.D.         
Sub-Investigator: George Ansstas, M.D.         
Sub-Investigator: Olivia Aranha, M.D.         
Sub-Investigator: Salman Chaudhry, M.D.         
Sub-Investigator: Eric Knoche, M.D.         
Sub-Investigator: Kian-Huat Lim, M.D.         
Sub-Investigator: Peter Oppelt, M.D.         
Sub-Investigator: Russell Pachynski, M.D.         
Sub-Investigator: Haeseong Park, M.D.         
Sub-Investigator: Katrina Pedersen, M.D.         
Sub-Investigator: Timothy Rearden, M.D.         
Sub-Investigator: Caron Rigden, M.D.         
Sub-Investigator: Anna Roshal, M.D.         
Sub-Investigator: Rama Suresh, M.D.         
Sub-Investigator: Benjamin Tan, M.D.         
Sub-Investigator: Nikolaos Trikalinos, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
Xcovery Holding Company, LLC
Investigators
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Principal Investigator: Andrea Wang-Gillam, M.D., Ph.D. Washington University School of Medicine

Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03511222     History of Changes
Other Study ID Numbers: 201806087
First Posted: April 27, 2018    Key Record Dates
Last Update Posted: April 12, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma, Hepatocellular
Esophageal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Gastrointestinal Neoplasms
Head and Neck Neoplasms
Esophageal Diseases
Gastrointestinal Diseases
Pembrolizumab
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents