Summary

This phase I/II trial studies the side effects and best dose of vorolanib when given in combination with nivolumab in treating patients with non-small cell lung cancer and thoracic tumors that aren't responding to treatment (refractory). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer, and 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 patients with non-small cell lung cancer and thoracic tumors.

Objectives

PRIMARY OBJECTIVES:
I. To assess the safety and tolerability of nivolumab and vorolanib in combination in patients with non-small cell lung cancer (NSCLC) naive to checkpoint inhibitor therapy, NSCLC progressed on prior checkpoint inhibitor therapy considered primary refractory, NSCLC progressed on prior checkpoint inhibitor therapy considered acquired resistance, and thymic carcinoma. (Phase I)
II. To evaluate the efficacy as measured by response to the combination nivolumab and vorolanib in patients with refractory NSCLC naive to checkpoint inhibitor therapy, NSCLC progressed on prior checkpoint inhibitor therapy considered primary refractory, NSCLC progressed on prior checkpoint inhibitor therapy considered acquired resistance, small cell lung cancer, and thymic carcinoma as compared to historical controls. (Phase II)

SECONDARY OBJECTIVE:
I. To assess the effects of tumor PD-L1 status and tumor mutation burden (TMB) on the response to combinatorial treatment vorolanib and nivolumab. (Phase II)

EXPLORATORY OBJECTIVE:
I. To assess the effects of combinatorial treatment on specific pharmacodynamic and pharmacogenetic biomarkers.

OUTLINE: This is a phase I, dose-escalation study of vorolanib followed by a phase II study.

Patients receive vorolanib orally (PO) once daily (QD) on days 1-56 and nivolumab intravenously (IV) over 30 minutes every 2 weeks on days 1, 15, 29, and 43. Patients with no evidence of disease progression after cycle 2 receive nivolumab IV over 30 minutes on days 1 and 29. Cycles repeat every 56 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days, 100 days, and every 3 months for up to 2 years.

Eligibility

1. Signed and dated written informed consent.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
3. 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 naive 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 tyrosine kinase inhibitors (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.
4. 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).
5. Absolute neutrophil count (ANC) >= 1,500/uL
6. Platelets >= 100,000/uL
7. Hemoglobin >= 9.0 g/dL
8. Serum creatinine =< 1.5 times institutional upper limit of normal (ULN), or calculated creatinine clearance >= 40 mL/min (per the Cockcroft-Gault formula)
9. Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who must have total bilirubin < 3.0 mg/dL)
10. Alanine aminotransferase and aspartate aminotransferase =< 2.5 x ULN, (=< 5.0 x ULN with documented liver metastases)
11. Women must not be breastfeeding.
12. 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 < 55 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.
13. 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.
14. 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.