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

NCT03583086 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: VICC THO 1802CA209-982
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 7

Brief Summary

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.

Conditions

Thymic Carcinoma; Non-small Cell Lung Cancer; Refractory Thoracic Tumors; Small-Cell Lung Cancer

Outcome Measures

Primary Outcomes (6)

• Recommended Phase II Combination Dose in Phase I (Per Common Terminology Criteria for Adverse Events (CTCAE) Criteria Version 5)

  Maximum tolerated dose for vorolanib daily combined with 240mg nivolumab every 2 weeks based on 3+3 dose escalation design. When 2 out of 6 patients at one dose experienced dose limiting toxicity, lower dose will be used. We have specified the phase I and phase II populations as study arms; note outcome measures are then distinct for each arm, with the phase I arm intended to assess safety (MTD), and the phase 2 arm intended to assess efficacy, as typical for phase I-II studies. Thus, for each outcome, only the phase I cohort is included in the analysis population, or only the phase II cohort is including in the analysis population, as relevant to the outcome measure.

  At 28 days

• Objective Response Rate in Phase II.

  Antitumor activity will be assessed by objective response rate. Best response is determined as complete response(CR), partial response(PR), stable disease and progressive disease based on per Response Evaluation Criteria in Solid Tumors (RECIST). Objective response rate is the percentage of patients who had a CR or PR. We have specified the phase I and phase II populations as study arms; note outcome measures are then distinct for each arm, with the phase I arm intended to assess safety (MTD), and the phase 2 arm intended to assess efficacy, as typical for phase I-II studies. Thus, for each outcome, only the phase I cohort is included in the analysis population, or only the phase II cohort is including in the analysis population, as relevant to the outcome measure.

  Up to 1 year.

• Progression Free Survival in Phase II

  Antitumor activity will be assessed by progression free survival. Progression is termined per Response Evaluation Criteria in Solid Tumors (RECIST). Progression free survival (PFS) is defined as time from on treatment to disease progression or death (whicever comes first). Those without progression and alive were censored at last follow up. Kaplan-meier method is used to estimate the median survival time. We have specified the phase I and phase II populations as study arms; note outcome measures are then distinct for each arm, with the phase I arm intended to assess safety (MTD), and the phase 2 arm intended to assess efficacy, as typical for phase I-II studies. Thus, for each outcome, only the phase I cohort is included in the analysis population, or only the phase II cohort is including in the analysis population, as relevant to the outcome measure.

  Up to 1 year.

• Duration of Response in Phase II.

  Duration of best response among patients who responsed to the treatment. Best response per Response Evaluation Criteria in Solid Tumors (RECIST). The duration of response was estimated from the first date of best overall response of a complete (CR) or partial response (PR) to the date of disease progression or death, using the Kaplan-Meier method. We have specified the phase I and phase II populations as study arms; note outcome measures are then distinct for each arm, with the phase I arm intended to assess safety (MTD), and the phase 2 arm intended to assess efficacy, as typical for phase I-II studies. Thus, for each outcome, only the phase I cohort is included in the analysis population, or only the phase II cohort is including in the analysis population, as relevant to the outcome measure.

  Up to 1 year

• Disease Control Rate in Phase II. Best Response Per Response Evaluation Criteria in Solid Tumors (RECIST)

  Antitumor activity will be assessed by disease control rate. Best response (complete response,CR; partial response, PR;stable disease , SD; or progression,PD) per Response Evaluation Criteria in Solid Tumors (RECIST). Disease control rate is the percentage of patients who had a CR,PR or SD. We have specified the phase I and phase II populations as study arms; note outcome measures are then distinct for each arm, with the phase I arm intended to assess safety (MTD), and the phase 2 arm intended to assess efficacy, as typical for phase I-II studies. Thus, for each outcome, only the phase I cohort is included in the analysis population, or only the phase II cohort is including in the analysis population, as relevant to the outcome measure.

  Up to 1 year

• Overall Survival in Phase II.

  Antitumor activity will be assessed by overall survival. Overall survial is defined as the time from on treatment to death. Those alive were censored at last follow up. Kaplan-meier method is used to estimate the median overall survival time. We have specified the phase I and phase II populations as study arms; note outcome measures are then distinct for each arm, with the phase I arm intended to assess safety (MTD), and the phase 2 arm intended to assess efficacy, as typical for phase I-II studies. Thus, for each outcome, only the phase I cohort is included in the analysis population, or only the phase II cohort is including in the analysis population, as relevant to the outcome measure.

  Up to 2 years.

Other Outcomes (1)

• Correlation Between Biomarkers and Response for Phase II Patients

  Up to 1 year

Study Arms (6)

Escalation

EXPERIMENTAL

Participants receive vorolanib PO QD on days 1-56 and nivolumab IV over 30 minutes every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) for the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression.

Drug: Vorolanib; Biological: Nivolumab

Dose Expansion - Non Small-Cell-Lung Cancer Acquired Resistance

EXPERIMENTAL

Participants receive vorolanib PO QD on days 1-56 and nivolumab IV over 30 minutes every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) for the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression.

Drug: Vorolanib; Biological: Nivolumab

Dose Expansion - Non Small-Cell-Lung Cancer Naive

EXPERIMENTAL

Participants receive vorolanib PO QD on days 1-56 and nivolumab IV over 30 minutes every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) for the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression.

Drug: Vorolanib; Biological: Nivolumab

Dose Expansion - Non Small-Cell-Lung Cancer Primary Refractory

EXPERIMENTAL

Participants receive vorolanib PO QD on days 1-56 and nivolumab IV over 30 minutes every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) for the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression.

Drug: Vorolanib; Biological: Nivolumab

Dose Expansion - Small Cell Lung Cancer - Progressed on Platinum-based Chemotherapy

EXPERIMENTAL

Participants receive vorolanib PO QD on days 1-56 and nivolumab IV over 30 minutes every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) for the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression.

Drug: Vorolanib; Biological: Nivolumab

Dose Expansion - Thymic Carcinoma

EXPERIMENTAL

Participants receive vorolanib PO QD on days 1-56 and nivolumab IV over 30 minutes every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) for the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression.

Drug: Vorolanib; Biological: Nivolumab

Interventions

Vorolanib DRUG

Given by mouth

Dose Expansion - Non Small-Cell-Lung Cancer Acquired Resistance; Dose Expansion - Non Small-Cell-Lung Cancer Naive; Dose Expansion - Non Small-Cell-Lung Cancer Primary Refractory; Dose Expansion - Small Cell Lung Cancer - Progressed on Platinum-based Chemotherapy; Dose Expansion - Thymic Carcinoma; Escalation

Nivolumab BIOLOGICAL

Given by IV

Dose Expansion - Non Small-Cell-Lung Cancer Acquired Resistance; Dose Expansion - Non Small-Cell-Lung Cancer Naive; Dose Expansion - Non Small-Cell-Lung Cancer Primary Refractory; Dose Expansion - Small Cell Lung Cancer - Progressed on Platinum-based Chemotherapy; Dose Expansion - Thymic Carcinoma; Escalation

Eligibility Criteria

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

You may qualify if:

• Signed and dated written informed consent.
• Male or female ≥ 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Having progressed on at least one prior line of therapy, or refused chemotherapy, histologically or cytologically confirmed diagnosis of one of the following:
• Dose Escalation and Expansion Cohorts:
• Checkpoint Inhibitor Naïve Non-Small Cell Lung Cancer patients must have progressed on front-line cytotoxic chemotherapy or have refused chemotherapy and may have received up to three prior treatment regimens for stage IV disease 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 or second checkpoint inhibitor therapy and may have received up to three prior treatment regimens for stage IV disease provided no regimens included an oral VEGF TKI. Prior bevacizumab or ramucirumab is allowed.
• Patients with EGFR, ALK, ROS1 and BRAF NSCLC must have progressed on an oral TKI and may have received an unlimited number of prior regimens.
• 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.
• Small Cell Lung Cancer patients must have progressed on platinum-based chemotherapy and may have received up to three prior lines of therapy for stage IV disease provided no prior regimen included an oral VEGF TKI; prior regimens can include an anti-PD-1 or PD-L1 agent.
• At least one measureable lesion as defined by RECIST 1.1 which can be followed by CT or MRI.
• Adequate organ function prior to first dose of protocol-indicated treatment, including:
• Absolute neutrophil count (ANC) ≥ 1,500/µL
• Platelets ≥ 100,000/µL
• Hemoglobin ≥ 9.0 g/dL

You may not qualify if:

• ≤ 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 measureable/target lesion only if subsequent disease progression has been documented in the lesion.)
• Initiation of a new erythropoietin, darbepoietin, and/or bisphosphonate therapy. (See Section 9.3.)
• 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 ºC.
• ≤ 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). (See Section 9.3.)
• 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 (Section 9).

Sponsors & Collaborators

• Vanderbilt-Ingram Cancer Center: lead
• Bristol-Myers Squibb: collaborator
• Xcovery Holdings, Inc.: collaborator

Study Sites (7)

Stanford Cancer Institute

Palo Alto, California, 94304, United States

Location

Winship Cancer Institute, Emory University

Atlanta, Georgia, 30322, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Providence Cancer Institute Franz Clinic

Portland, Oregon, 97213, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

Baptist Clinical Research Institute

Memphis, Tennessee, 38120, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

MeSH Terms

Conditions

Thymoma; Carcinoma, Non-Small-Cell Lung; Small Cell Lung Carcinoma

Interventions

vorolanib; Nivolumab

Condition Hierarchy (Ancestors)

Neoplasms, Complex and Mixed; Neoplasms by Histologic Type; Neoplasms; Thymus Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lymphatic Diseases; Hemic and Lymphatic Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Teresa Melton
• Organization: Vanderbilt-Ingram Cancer Center

teresa.melton@vumc.org

6159367423

Study Officials

• Kathryn Beckermann, MD

  Vanderbilt-Ingram Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 26, 2018
• First Posted: July 11, 2018
• Study Start: July 10, 2018
• Primary Completion: February 21, 2024
• Study Completion: April 27, 2024
• Last Updated: October 8, 2024
• Results First Posted: October 8, 2024

Record last verified: 2024-09

Locations

US (7)