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

NCT03511222 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: 201806087
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Solid Tumor; Hepatocellular Carcinoma; Gastric Cancer; Gastroesophageal Junction Adenocarcinoma

Outcome Measures

Primary Outcomes (2)

• Recommended phase II dose (RP2D) of vorolanib plus pembrolizumab

  -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.

  Completion of enrollment to Dose Escalation cohorts (estimated to be 13 months)

• Recommended phase II dose (RP2D) of vorolanib plus nivolumab

  -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.

  Completion of enrollment to Dose Escalation cohorts (estimated to be 13 months)

Secondary Outcomes (2)

• Safety and toxicity of vorolanib plus pembrolizumab as measured by the number and type of adverse events experienced by participant

  30 days after completion of treatment (estimated to be 7 months)

• Safety and toxicity of vorolanib plus nivolumab as measured by the number and type of adverse events experienced by participant

  30 days after completion of treatment (estimated to be 7 months)

Study Arms (3)

Dose Escalation: Vorolanib + Nivolumab

EXPERIMENTAL

* 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; Drug: Nivolumab

Dose Escalation: Vorolanib + Pembrolizumab

EXPERIMENTAL

* 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; Drug: Pembrolizumab

Vorolanib + Nivolumab (Small Cell Lung Cancer)

EXPERIMENTAL

* Vorolanib is an oral drug which will be administered daily on an outpatient basis at 300 mg daily * 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; Drug: Nivolumab

Interventions

Vorolanib DRUG

Patients should take vorolanib at approximately the same time every day with food.

Also known as: X-82

Dose Escalation: Vorolanib + Nivolumab; Dose Escalation: Vorolanib + Pembrolizumab; Vorolanib + Nivolumab (Small Cell Lung Cancer)

Nivolumab DRUG

Standard of care

Also known as: Opdivo

Dose Escalation: Vorolanib + Nivolumab; Vorolanib + Nivolumab (Small Cell Lung Cancer)

Pembrolizumab DRUG

Standard of care

Also known as: Keytruda

Dose Escalation: Vorolanib + Pembrolizumab

Eligibility Criteria

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

You may qualify if:

• 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
• SCLC cohort: histologically or cytologically confirmed diagnosis of small cell lung cancer whose disease progressed on platinum-based chemotherapy or refused chemotherapy
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Xcovery Holdings, Inc.: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (1)

• Bagegni NA, Park H, Kraft K, O-Toole M, Gao F, Waqar SN, Ratner L, Morgensztern D, Devarakonda S, Amin M, Baggstrom MQ, Liang C, Selvaggi G, Wang-Gillam A. Phase 1b trial of anti-VEGF/PDGFR vorolanib combined with immune checkpoint inhibitors in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2022 Apr;89(4):487-497. doi: 10.1007/s00280-022-04406-6. Epub 2022 Mar 5.

  PMID: 35247086 DERIVED

Related Links

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

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Stomach Neoplasms

Interventions

vorolanib; Nivolumab; pembrolizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; 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; Gastrointestinal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Nusayba A Bagegni, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: April 18, 2018
• First Posted: April 27, 2018
• Study Start: September 11, 2018
• Primary Completion: August 15, 2019
• Study Completion: May 28, 2020
• Last Updated: July 29, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)