Non-small Cell Lung Cancer, Refractory Thoracic Tumors, Small-Cell Lung Cancer, Thymic Carcinoma
Conditions
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.
Detailed description
Primary Objectives: * Phase I: To assess the safety and tolerability of nivolumab and vorolanib in combination in patients with refractory non small cell lung cancer naïve to checkpoint inhibitor therapy, non small cell lung cancer progressed on prior checkpoint inhibitor therapy considered primary refractory, non small cell lung cancer progressed on prior checkpoint inhibitor therapy considered acquired resistance, small cell lung cancer progressed on platinum-based chemotherapy, and thymic carcinoma. * Phase II: To evaluate the efficacy as measured by response to the combination nivolumab and vorolanib in patients with refractory non small cell lung cancer naïve to checkpoint inhibitor therapy, non small cell lung cancer progressed on prior checkpoint inhibitor therapy considered primary refractory, non small cell lung cancer progressed on prior checkpoint inhibitor therapy considered acquired resistance, small cell lung cancer progressed on platinum-based chemotherapy, and thymic carcinoma as compared to historical controls. 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.
Interventions
DRUGVorolanib
Given by mouth
BIOLOGICALNivolumab
Given by IV
Sponsors
Bristol-Myers Squibb
Xcovery Holdings, Inc.
Vanderbilt-Ingram Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 * Serum creatinine ≤ 1.5 times institutional upper limit of normal (ULN), or calculated creatinine clearance ≥ 40 mL/min (per the Cockcroft-Gault formula) * Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who must have total bilirubin \< 3.0 mg/dL) * Alanine aminotransferase and aspartate aminotransferase ≤ 2.5 x ULN, (≤ 5.0 x ULN with documented liver metastases) * Women must not be breastfeeding. * Women of childbearing potential must have a negative serum pregnancy test within 24 hours prior to receiving first dose of protocol-indicated treatment. * Women of childbearing potential 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 Appendix 5 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 women of childbearing potential must agree to follow instructions for acceptable contraception (Appendix 5), 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 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). * 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 (NCI-CTCAE v5.0) residual toxicity prior to first dose of protocol-indicated treatment. * Patients requiring replacement therapy (e.g. prednisone or thyroid replacement therapy) for endocrine disorders from prior checkpoint inhibitor therapy are allowed * 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. * 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. * 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) that is uncontrolled on current therapy. * Class III or IV cardiovascular disease according to the New York Heart Association (NYHA) Functional Criteria. * Uncontrolled 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. * 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 (\> 3 months ago) 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. * 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; or endocrine disorders requiring hormone replacement even if due to prior immunotherapy; 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 active Hepatitis B or Hepatitis C 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 RNA (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 2 years that could in the opinion of the investigator interfere with their assessment of study treatment. * Exceptions include the following permitted conditions - provided a complete remission was achieved at least 2 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival in Phase II | Up to 1 year. | 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. |
| Recommended Phase II Combination Dose in Phase I (Per Common Terminology Criteria for Adverse Events (CTCAE) Criteria Version 5) | At 28 days | 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. |
| Objective Response Rate in Phase II. | Up to 1 year. | 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. |
| Overall Survival in Phase II. | Up to 2 years. | 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. |
| Duration of Response in Phase II. | Up to 1 year | 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. |
| Disease Control Rate in Phase II. Best Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Up to 1 year | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Correlation Between Biomarkers and Response for Phase II Patients | Up to 1 year | Antitumor activity will be assessed by correlation between the biomarkers and clinical outcomes. This is a exploratory end point. To assess the effects of combinatorial treatment on specific pharmacodynamic and pharmacogenetic biomarkers, including but not limited to circulating levels of serum CSF1 and VEGF, protein expression using CyTOF, and multiplex immunofluorescence. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Escalation Level 1 (Vorolanib 200+Nivolumab 240mg) 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.
Vorolanib: Given by mouth
Nivolumab: Given by IV | 3 |
| Escalation Level 2 (Vorolanib 300+Nivolumab 240mg) 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. | 7 |
| Dose Expansion - Non Small-Cell-Lung Cancer Acquired Resistance Participants receive vorolanib 200mg PO QD on days 1-56 and nivolumab 240mg 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.
Vorolanib: Given by mouth
Nivolumab: Given by IV | 19 |
| Dose Expansion - Non Small-Cell-Lung Cancer Naive Participants receive vorolanib 200mg PO QD on days 1-56 and nivolumab 240mg 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.
Vorolanib: Given by mouth
Nivolumab: Given by IV | 15 |
| Dose Expansion - Non Small-Cell-Lung Cancer Primary Refractory Participants receive vorolanib 200mg PO QD on days 1-56 and nivolumab 240mg 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.
Vorolanib: Given by mouth
Nivolumab: Given by IV | 17 |
| Dose Expansion - Small Cell Lung Cancer - Progressed on Platinum-based Chemotherapy Participants receive vorolanib 200mg PO QD on days 1-56 and nivolumab 240mg 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.
Vorolanib: Given by mouth
Nivolumab: Given by IV | 18 |
| Dose Expansion - Thymic Carcinoma Participants receive vorolanib 200mg PO QD on days 1-56 and nivolumab 240mg 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.
Vorolanib: Given by mouth
Nivolumab: Given by IV | 9 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Death | 2 | 6 | 12 | 10 | 14 | 14 | 4 |
| Overall Study | Declining Performance Status | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Disease progression | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Refused follow-up | 0 | 0 | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Still on study | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Undergoing radiation therapy | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Escalation Level 2 (Vorolanib 300+Nivolumab 240mg) | 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 | Escalation Level 1 (Vorolanib 200+Nivolumab 240mg) | Dose Expansion - Small Cell Lung Cancer - Progressed on Platinum-based Chemotherapy | Dose Expansion - Thymic Carcinoma |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 46 Participants | 3 Participants | 10 Participants | 10 Participants | 9 Participants | 3 Participants | 8 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants | 4 Participants | 9 Participants | 5 Participants | 8 Participants | 0 Participants | 10 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 77 Participants | 7 Participants | 16 Participants | 15 Participants | 12 Participants | 3 Participants | 16 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 0 Participants | 1 Participants | 0 Participants | 5 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 0 Participants | 1 Participants | 4 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 70 Participants | 7 Participants | 17 Participants | 10 Participants | 13 Participants | 3 Participants | 15 Participants | 5 Participants |
| Region of Enrollment United States | 88 participants | 7 participants | 19 participants | 15 participants | 17 participants | 3 participants | 18 participants | 9 participants |
| Sex: Female, Male Female | 38 Participants | 5 Participants | 6 Participants | 9 Participants | 9 Participants | 0 Participants | 7 Participants | 2 Participants |
| Sex: Female, Male Male | 50 Participants | 2 Participants | 13 Participants | 6 Participants | 8 Participants | 3 Participants | 11 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 6 / 7 | 13 / 19 | 12 / 15 | 14 / 17 | 14 / 18 | 4 / 9 |
| other Total, other adverse events | 3 / 3 | 7 / 7 | 19 / 19 | 15 / 15 | 17 / 17 | 18 / 18 | 9 / 9 |
| serious Total, serious adverse events | 3 / 3 | 6 / 7 | 9 / 19 | 10 / 15 | 9 / 17 | 5 / 18 | 6 / 9 |
Outcome results
Primary
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.
Time frame: Up to 1 year
Population: Patients who received 200mg vorolanib daily with 240mg nivolumab every two weeks and were available for measurement of tumor response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escalation | Disease Control Rate in Phase II. Best Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | 44.4 percentage of participants |
| Dose Expansion - Non Small-Cell-Lung Cancer Naive | Disease Control Rate in Phase II. Best Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | 53.3 percentage of participants |
| Dose Expansion - Non Small-Cell-Lung Cancer Primary Refractory | Disease Control Rate in Phase II. Best Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | 52.9 percentage of participants |
| Dose Expansion - Small Cell Lung Cancer - Progressed on Platinum-based Chemotherapy | Disease Control Rate in Phase II. Best Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | 11.0 percentage of participants |
| Dose Expansion - Thymic Carcinoma | Disease Control Rate in Phase II. Best Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | 66.7 percentage of participants |
Primary
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.
Time frame: Up to 1 year
Population: Patients who received 200mg vorolanib daily with 240mg nivolumab every two weeks, were available for measurement of tumor response, and had partial or complete response. No patients in the Dose Expansion - Small Cell Lung Cancer - Progressed on Platinum-based Chemotherapy group had a partial or complete response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Escalation | Duration of Response in Phase II. | 2.7 months |
| Dose Expansion - Non Small-Cell-Lung Cancer Naive | Duration of Response in Phase II. | NA months |
| Dose Expansion - Non Small-Cell-Lung Cancer Primary Refractory | Duration of Response in Phase II. | 12.8 months |
| Dose Expansion - Small Cell Lung Cancer - Progressed on Platinum-based Chemotherapy | Duration of Response in Phase II. | NA months |
Primary
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.
Time frame: Up to 1 year.
Population: Patients who received 200mg vorolanib daily with 240mg nivolumab every two weeks and were available for measurement of tumor response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escalation | Objective Response Rate in Phase II. | 11.1 percentage of participants |
| Dose Expansion - Non Small-Cell-Lung Cancer Naive | Objective Response Rate in Phase II. | 33 percentage of participants |
| Dose Expansion - Non Small-Cell-Lung Cancer Primary Refractory | Objective Response Rate in Phase II. | 5.9 percentage of participants |
| Dose Expansion - Small Cell Lung Cancer - Progressed on Platinum-based Chemotherapy | Objective Response Rate in Phase II. | 0 percentage of participants |
| Dose Expansion - Thymic Carcinoma | Objective Response Rate in Phase II. | 11 percentage of participants |
Primary
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.
Time frame: Up to 2 years.
Population: Patients who received 200mg vorolanib daily with 240mg nivolumab every two weeks and were available for measurement of survival.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Escalation | Overall Survival in Phase II. | 10.81 months |
| Dose Expansion - Non Small-Cell-Lung Cancer Naive | Overall Survival in Phase II. | NA months |
| Dose Expansion - Non Small-Cell-Lung Cancer Primary Refractory | Overall Survival in Phase II. | 16.27 months |
| Dose Expansion - Small Cell Lung Cancer - Progressed on Platinum-based Chemotherapy | Overall Survival in Phase II. | 4.5 months |
| Dose Expansion - Thymic Carcinoma | Overall Survival in Phase II. | 21.06 months |
Primary
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.
Time frame: Up to 1 year.
Population: Patients who received 200mg vorolanib daily with 240mg nivolumab every two weeks and were available for measurement of tumor response(progression).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Escalation | Progression Free Survival in Phase II | 1.97 months |
| Dose Expansion - Non Small-Cell-Lung Cancer Naive | Progression Free Survival in Phase II | 7.16 months |
| Dose Expansion - Non Small-Cell-Lung Cancer Primary Refractory | Progression Free Survival in Phase II | 3.22 months |
| Dose Expansion - Small Cell Lung Cancer - Progressed on Platinum-based Chemotherapy | Progression Free Survival in Phase II | 1.36 months |
| Dose Expansion - Thymic Carcinoma | Progression Free Survival in Phase II | 9.1 months |
Primary
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.
Time frame: At 28 days
Population: 8 patients with NSCLC and 2 patients with TC who received vorolanib orally daily and 240mg nivolumab every 2 weeks, and had assessable results.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escalation | Recommended Phase II Combination Dose in Phase I (Per Common Terminology Criteria for Adverse Events (CTCAE) Criteria Version 5) | 200 mg |
Other Pre-specified
Correlation Between Biomarkers and Response for Phase II Patients
Antitumor activity will be assessed by correlation between the biomarkers and clinical outcomes. This is a exploratory end point. To assess the effects of combinatorial treatment on specific pharmacodynamic and pharmacogenetic biomarkers, including but not limited to circulating levels of serum CSF1 and VEGF, protein expression using CyTOF, and multiplex immunofluorescence.
Time frame: Up to 1 year