Clinical Trials /

Phase I/II Eval Safety & Prelim Activity Nivolumab Comb W/Vorolanib Pts W/Refractory Thoracic Tumors

NCT03583086

Description:

This is a two-agent, open-label, non-randomized, Phase 1/2 dose escalation and dose expansion study of combinatorial oral vorolanib plus infusional nivolumab in patients with Non-Small Cell Lung Cancer naïve to checkpoint inhibitor therapy, Non-Small Cell Lung Cancer who have progressed on checkpoint inhibitor therapy, Small Cell Lung Cancer ( who have progressed on platinum-based chemotherapy, and thymic carcinoma.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
  • Thymic Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I/II Eval Safety & Prelim Activity Nivolumab Comb W/Vorolanib Pts W/Refractory Thoracic Tumors
  • Official Title: Phase 1/2 Study to Evaluate the Safety and Preliminary Activity of Nivolumab in Combination With Vorolanib in Patients With Refractory Thoracic Tumors

Clinical Trial IDs

  • ORG STUDY ID: VICC THO 1802
  • SECONDARY ID: CA209-982
  • NCT ID: NCT03583086

Conditions

  • Thymic Carcinoma
  • Non-small Cell Lung Cancer
  • Refractory Thoracic Tumors

Interventions

DrugSynonymsArms
VEGFR/PDGFR Dual Kinase Inhibitor X-82Treatment (vorolanib, nivolumab)
NivolumabTreatment (vorolanib, nivolumab)

Purpose

This phase I/II trial studies the side effects and best does of VEGFR/PDGFR dual kinase inhibitor X-82 (vorolanib) when given in combination with nivolumab in treating participants with non-small cell lung cancer and thoracic tumors that aren't responding to treatment. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Vorolanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab and vorolanib may work better in treating participants with non-small cell lung cancer and thoracic tum

Detailed Description

      Primary Objectives:

        -  Phase I: To assess the safety of nivolumab and vorolanib in combination in patients with
           refractory NSCLC naïve to checkpoint inhibitor therapy, NSCLC progressed on prior
           checkpoint inhibitor therapy, and thymic carcinoma.

        -  Phase II: To evaluate the response rate of combination nivolumab and vorolanib in
           patients with refractory NSCLC naïve to checkpoint inhibitor therapy, NSCLC progressed
           on prior checkpoint inhibitor therapy, and thymic carcinoma.

      Secondary Objectives:

        -  Phase I: To assess antitumor activity as measured by response rate for this novel
           combination.

        -  Phase II: To assess, safety, progression free survival and overall survival

      Exploratory Objectives:

      • To assess the effects of combinatorial treatment on specific pharmacodynamic and
      pharmacogenetic biomarkers including PD-L1 expression and tumor mutation burden.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (vorolanib, nivolumab)ExperimentalParticipants receive vorolanib PO QD on days 1-56 and nivolumab IV over 60 minutes every 2 weeks on days 1, 15, 29, and 43. Courses repeat every 56 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • VEGFR/PDGFR Dual Kinase Inhibitor X-82

Eligibility Criteria

        Inclusion Criteria:

          -  Signed and dated written informed consent.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  Having progressed on at least one prior line of therapy, histologically or
             cytologically confirmed diagnosis of one of the following:

               -  Dose escalation and expansion cohorts:

                    -  Checkpoint inhibitor naive non-small cell lung cancer patients must have
                       progressed on front-line therapy cytotoxic chemotherapy and may have
                       received up to two prior treatment regimens provided no regimens included an
                       anti-PD1 or PD-L1 agent or an oral VEGF TKI. Prior bevacizumab or
                       ramucirumab is allowed.

                    -  Progressed on checkpoint inhibitor non-small cell lung cancer patients must
                       have progressed on front-line checkpoint inhibitor therapy and may have
                       received up to two prior treatment regimens provided no regimens included an
                       oral VEGF TKI. Prior bevacizumab or ramucirumab is allowed.

                    -  Thymic carcinoma patients must not be eligible for surgical resection at the
                       time of enrollment and may have received any number of prior lines of
                       therapy provided no regimens included an anti-PD1 or PD-L1 agent or an oral
                       VEGF TKI. Prior bevacizumab or ramucirumab is allowed.

          -  At least one measurable lesion as defined by Response Evaluation Criteria in Solid
             Tumors (RECIST) 1.1 which can be followed by computed tomography (CT) or magnetic
             resonance imaging (MRI).

          -  Absolute neutrophil count (ANC) >= 1,500/uL within 14 days prior to first dose of
             protocol-indicated treatment.

          -  Platelets >= 100,000/uL within 14 days prior to first dose of protocol-indicated
             treatment.

          -  Hemoglobin >= 9.0 g/dL within 14 days prior to first dose of protocol-indicated
             treatment.

          -  Serum creatinine =< 1.5 times institutional upper limit of normal (ULN), or calculated
             creatinine clearance >= 40 mL/min (per the Cockcroft-Gault formula) within 14 days
             prior to first dose of protocol-indicated treatment.

          -  Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who must have
             total bilirubin < 3.0 mg/dL) within 14 days prior to first dose of protocol-indicated
             treatment.

          -  Alanine aminotransferase and aspartate aminotransferase =< 2.5 x ULN, (=< 5.0 x ULN
             with documented liver metastases) within 14 days prior to first dose of
             protocol-indicated treatment.

          -  Women must not be breastfeeding.

          -  Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
             within 24 hours prior to receiving first dose of protocol-indicated treatment.

               -  WOCBP is defined as any female who has experienced menarche who has not undergone
                  surgical sterilization (hysterectomy or bilateral oophorectomy) or is not
                  postmenopausal.

               -  Menopause is defined clinically as 12 months of amenorrhea in a woman over 45
                  years of age in the absence of other biological or physiological causes.

               -  If menopausal status is considered for the purpose of evaluating childbearing
                  potential, women < 62 years of age must have a documented serum follicle
                  stimulating hormone (FSH) level within laboratory reference range for
                  postmenopausal women, in order to be considered postmenopausal and not of
                  childbearing potential.

          -  Women of childbearing potential must agree to follow instructions for acceptable
             contraception from the time of signing consent, and for 23 weeks after their last dose
             of protocol-indicated treatment.

          -  Men not azoospermic who are sexually active with WOCBP must agree to follow
             instructions for acceptable contraception, from the time of signing consent, and for
             31 weeks after their last dose of protocol-indicated treatment.

        Exclusion Criteria:

          -  =< 28 days before first dose of protocol-indicated treatment:

               -  Anti-cancer treatment with bevacizumab.

               -  Major surgery requiring general anesthesia or significant traumatic injury.

          -  =< 14 days before first dose of protocol-indicated treatment:

               -  Anti-cancer therapy with an approved or investigational agent (including
                  chemotherapy, hormonal therapy, targeted therapy, immunotherapy, or biological
                  therapy).

               -  Radiosurgery or radiotherapy. (Note: A tumor lesion situated in a previously
                  irradiated area is considered a measurable/target lesion only if subsequent
                  disease progression has been documented in the lesion.)

               -  Initiation of a new erythropoietin, darbepoietin, and/or bisphosphonate therapy.

               -  Minor surgery. (Note: Placement of a vascular access device is not considered
                  minor or major surgery.)

               -  Serious or uncontrolled infection.

               -  Infection requiring parenteral antibiotics. (Note: Patients with a non-serious
                  infection under active treatment and controlled with oral antibiotics initiated
                  at least 10 days prior to initiation of protocol-indicated treatment are not
                  excluded - e.g. urinary tract infection controlled with oral antibiotics.)

               -  Unexplained fever > 38.0 degree Celsius (C).

          -  =< 7 days before first dose of protocol-indicated treatment: * Receipt of granulocyte
             colony‐stimulating factor (G-CSF) or granulocyte‐macrophage colony stimulating factor
             (GM-CSF).

          -  Concurrent use of any medications or substances (e.g. herbal supplement or food) known
             to be a strong inhibitor or strong inducer of CYP3A4.

             * Although corticosteroids are considered to be strong inducers of CYP3A4, physiologic
             replacement doses of corticosteroids =< 10 mg daily prednisone or equivalent are
             allowed.

          -  Inadequate recovery from toxicity attributed to prior anti-cancer therapy.

             * With the exception of alopecia, fatigue, or peripheral neuropathy, patients must
             have recovered to =< grade 1 (National Cancer Institute-Common Terminology Criteria
             for Adverse Events [NCI-CTCAE] version [v] 4.03) residual toxicity prior to first dose
             of protocol-indicated treatment.

          -  Known history of allergy or intolerance which, in the opinion of the investigator, was
             an unacceptable adverse reaction attributed by the investigator to any prior
             anti-neoplastic therapy specifically targeting vascular endothelial growth factor or
             the VEGF receptor - i.e. pazopanib (Votrient), bevacizumab (Avastin), sorafenib
             (Nexavar), sunitinib (Sutent), axitinib (Inlyta), etc.

          -  Known history of allergy or intolerance which, in the opinion of the investigator, was
             an unacceptable adverse reaction attributed by the investigator to any prior
             anti-neoplastic therapy specifically targeting T-cell costimulation or immune
             checkpoint pathways - i.e. nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab
             (Tecentriq), ipilimumab (Yervoy), etc.

          -  Non-healing wounds on any part of the body.

          -  Known or suspected clinically significant active bleeding.

          -  Inability to swallow oral medication; or the presence of a poorly controlled
             gastrointestinal disorder that could significantly affect the absorption of oral study
             drug - e.g. Crohn's disease, ulcerative colitis, chronic diarrhea (defined as > 4
             loose stools per day), malabsorption, or bowel obstruction.

          -  NSCLC patients with radiographic evidence of major airway or blood vessel invasion by
             cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis (>= one
             teaspoon) within the preceding 2 months.

          -  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.

               -  Fridericia's correction formula (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.

             * Patients receiving therapeutic non-coumarin anticoagulation are eligible, provided
             they are on a stable dose (per investigator judgment) of anticoagulant.

          -  Patients with active interstitial lung disease and non-infectious pneumonitis or a
             history of active interstitial lung disease or pneumonitis requiring treatment with
             steroids or that may interfere with the detection or management of suspected
             drug-related pulmonary toxicity. Patients with lung cancer with a remote history of
             pneumonitis following chemo-radiation treatment that has resolved are allowed.

             * Note: Patients with chronic obstructive pulmonary disease (COPD) whose disease is
             controlled (per investigator judgment) at trial entry are not excluded.

          -  Central nervous system (CNS) metastasis, unless asymptomatic and stable with no change
             in CNS disease status for at least two (2) weeks prior to initiating
             protocol-indicated treatment.

             * Anticonvulsant and/or corticosteroid prophylaxis (=< 10 mg/day prednisone or
             equivalent daily) will be allowed if patient is on a stable or decreasing dose of such
             treatment for at least 14 days prior to initiating protocol-indicated treatment.

          -  Any condition requiring systemic treatment with either corticosteroids (> 10 mg/day
             prednisone or equivalent daily) or other immunosuppressive medications within 14 days
             prior to initiating protocol-indicated treatment.

             * In the absence of active autoimmune disease: Subjects are permitted the use of
             corticosteroids with minimal systemic absorption (e.g. topical, ocular,
             intra-articular, intranasal, and inhalational) =< 10 mg/day prednisone or equivalent
             daily; and physiologic replacement doses of systemic corticosteroids =< 10 mg/day
             prednisone or equivalent daily (e.g. hormone replacement therapy needed in patients
             with hypophysitis).

          -  Active, known or suspected autoimmune disease.

             * Subjects with type I diabetes mellitus; hypothyroidism only requiring hormone
             replacement; skin disorders such as vitiligo, psoriasis or alopecia not requiring
             systemic treatment; or conditions not expected by the investigator to recur in the
             absence of an external trigger are permitted to enroll.

          -  Uncontrolled (per investigator judgment) type I or type II diabetes mellitus.

          -  Known positive test for human immunodeficiency virus (HIV) or known acquired
             immunodeficiency syndrome (AIDS).

          -  Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic
             infection.

             * Hepatitis B and C testing required =< 28 days prior to initiating protocol-indicated
             treatment, including at least: hepatitis B surface antigen (HBV sAg); and hepatitis C
             virus antibody (HCV Ab) or hepatitis C virus ribonucleic acid (HCV RNA).

          -  Solid tumor transplantation.

          -  Immunization with any attenuated live vaccine within 1 week prior to initiating
             protocol-indicated treatment.

          -  Active second malignancy or history of a previous second malignancy within the last 3
             years.

             * Exceptions include the following permitted conditions - provided a complete
             remission was achieved at least 3 years prior to initiating protocol-indicated
             treatment and no additional therapy (with the exception of allowable
             anti-estrogen/androgen therapy or bisphosphonates) is ongoing or required during the
             trial period: non-melanoma skin cancers (e.g. basal or squamous cell); superficial
             bladder cancer; or carcinoma in situ of the prostate, cervix, or breast.

          -  Known psychiatric condition, social circumstance, or other medical condition
             reasonably judged by the investigator to unacceptably increase the risk of study
             participation; or to prohibit the understanding or rendering of informed consent or
             anticipated compliance with and interpretation of scheduled visits, treatment
             schedule, laboratory tests and other study requirements.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase II recommended combination dose per Common Terminology Criteria for Adverse Events (CTCAE) criteria version 4.03
Time Frame:At 28 days
Safety Issue:
Description:Antitumor activity will be assessed by objective response rate.

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:Up to 2 years
Safety Issue:
Description:Duration of Response (DOR) will also be assessed using Kaplan-Meier (KM) product-limit method. Median value of DOR, along with two-sided 95% CI using Brookmeyer and Crowley method will be reported.
Measure:Overall survival
Time Frame:At 1 year
Safety Issue:
Description:
Measure:Objective response rate as related to PD-L1 status measured as < 1%, 1-49%, and > 50%.
Time Frame:At 1 year
Safety Issue:
Description:Summarized by binomial response rate and their corresponding two-sided 95% exact CIs using Clopper-Pearson method.
Measure:Disease control rate
Time Frame:Up to 2 years
Safety Issue:
Description:Summarized by binomial response rate and their corresponding two-sided 95% exact CIs using the Clopper-Pearson method.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Vanderbilt-Ingram Cancer Center

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