Nivolumab and BMS-813160 or BMS-986253 for the Treatment of Resectable Non-small Cell Lung Cancer or Liver cancer
This phase II trial studies how well nivolumab given together with BMS-813160 or BMS-986253 before surgery work in treating patients with non-small cell lung cancer or liver cancer that can be removed by surgery (resectable). 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. Immunotherapy with BMS-986253 and BMS-813160 may induce changes in body’s immune system and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab with BMS-813160 or BMS-986253 before surgery may work better in treating patients with non-small cell lung cancer or liver cancer compared to nivolumab alone.
Inclusion Criteria
- Histological diagnosis of NSCLC and HCC is required before initiation of treatment. Initial diagnosis of HCC may be made using standard-of-care radiographic parameters, however, pre-treatment core needle biopsies are mandatory for all cohorts. Patients can be consented, and pre-treatment and diagnostic biopsies can be done simultaneously if the imaging leaves little doubt in the investigator’s mind that the patient carries the required diagnosis (e.g. HCC); patients where the diagnosis is not appropriately confirmed will be considered screen-failures. HCC lesions must be T1b or larger, meaning 2 cm or larger, in order to be enrolled in this trial. The NSCLC cohort will enroll any patient with T1b or more advanced (> 1cm primary tumor). Both cohorts will enroll only patients whose tumor is deemed amenable to surgical or core needle biopsy by a multidisciplinary team including a medical oncologist and an interventionalist (radiologist, surgeon, pulmonologist or hepatologist)
- Patient must be willing and able to provide blood samples (12 green tops tubes, roughly 100mL) at the time points indicated in the study calendar
- Patient must be willing and able to undergo 200 cc blood draw (in lieu of previously planned leukaapheresis) upon recovery from surgery (roughly 6 weeks following surgery)
- Patient must be willing and able to have excisional or core needle biopsies (goal 3-6 biopsies, final number to be determined by the surgeon and radiologist performing the procedure as safe) of tumor prior to initiation of therapy, and of any recurrent disease at the time of recurrence/metastases is detected on imaging
- Eastern Cooperative Oncology Group (ECOG) 0-1. The exception will be patients carrying long term disability (such as cerebral palsy) where the disability is not acute nor progressive, and unlikely to significantly affect their response to therapy
- Patient is determined to be a surgical candidate for resection of their tumor by a multidisciplinary team including a surgeon and a medical oncologist
- Women of child-bearing potential and men must agree to use adequate contraception upon study entry, for the duration of study participation, and for 5 months following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy; or * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
- Ability to understand and the willingness to sign a written informed consent
- Absolute neutrophil count (ANC) >= 1,000 /mcL
- Platelets >= 75,000 /mcL
- Hemoglobin >= 9 g/dL
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 60 mL/min for patient with creatinine levels > 1.5 X institutional ULN. (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) * Creatinine clearance should be calculated per institutional standard ** If laboratory criteria are not met due to what the investigator determines to be a biologic cause (e.g. Gilbert’s syndrome causing elevated bilirubin or excessive muscle mass affecting creatinine) or drug-related cause (e.g. elevating in transaminases due to highly active antiretroviral therapy (HAART) therapy, elevated international normalized ratio (INR) due to anticoagulation) then the lab values will not be used to exclude patient from this trial. Similarly, for patients with elevated bilirubin due to biliary obstruction from tumor, this will not serve as an exclusion criteria. This determination will be made by principal investigator (PI)
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 ULN =< 3 X ULN for patients with HCC * If laboratory criteria are not met due to what the investigator determines to be a biologic cause (e.g. Gilbert’s syndrome causing elevated bilirubin or excessive muscle mass affecting creatinine) or drug-related cause (e.g. elevating in transaminases due to HAART therapy, elevated INR due to anticoagulation) then the lab values will not be used to exclude patient from this trial. Similarly, for patients with elevated bilirubin due to biliary obstruction from tumor, this will not serve as an exclusion criteria. This determination will be made by PI
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 X ULN OR =< 5 X ULN for patients with HCC * If laboratory criteria are not met due to what the investigator determines to be a biologic cause (e.g. Gilbert’s syndrome causing elevated bilirubin or excessive muscle mass affecting creatinine) or drug-related cause (e.g. elevating in transaminases due to HAART therapy, elevated INR due to anticoagulation) then the lab values will not be used to exclude patient from this trial. Similarly, for patients with elevated bilirubin due to biliary obstruction from tumor, this will not serve as an exclusion criteria. This determination will be made by PI
- Albumin >= 2.5 mg/dL * If laboratory criteria are not met due to what the investigator determines to be a biologic cause (e.g. Gilbert’s syndrome causing elevated bilirubin or excessive muscle mass affecting creatinine) or drug-related cause (e.g. elevating in transaminases due to HAART therapy, elevated INR due to anticoagulation) then the lab values will not be used to exclude patient from this trial. Similarly, for patients with elevated bilirubin due to biliary obstruction from tumor, this will not serve as an exclusion criteria. This determination will be made by PI
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT is within therapeutic range of intended use of anticoagulants * If laboratory criteria are not met due to what the investigator determines to be a biologic cause (e.g. Gilbert’s syndrome causing elevated bilirubin or excessive muscle mass affecting creatinine) or drug-related cause (e.g. elevating in transaminases due to HAART therapy, elevated INR due to anticoagulation) then the lab values will not be used to exclude patient from this trial. Similarly, for patients with elevated bilirubin due to biliary obstruction from tumor, this will not serve as an exclusion criteria. This determination will be made by PI
- Activated partial thromboplastin time (aPTT) =<1.5 X ULN unless patient is receiving anticoagulant therapy as long as PTT is within therapeutic range of intended use of anticoagulants * If laboratory criteria are not met due to what the investigator determines to be a biologic cause (e.g. Gilbert’s syndrome causing elevated bilirubin or excessive muscle mass affecting creatinine) or drug-related cause (e.g. elevating in transaminases due to HAART therapy, elevated INR due to anticoagulation) then the lab values will not be used to exclude patient from this trial. Similarly, for patients with elevated bilirubin due to biliary obstruction from tumor, this will not serve as an exclusion criteria. This determination will be made by PI
Exclusion Criteria
- Patients who have had chemotherapy or radiotherapy within 4 months prior to entering the study for a different primary tumor, nor can they have received locoregional therapy (radiation, chemoembolization, etc) for the target lesion that will be biopsied and subsequently resected. Previous therapy for a different cancer (a different primary) is acceptable
- Patients may not be receiving any other investigational agents
- Patients with metastatic disease, for whom the intent of surgery would not be curative
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring antibiotics (exception is a brief (=< 10 days) course of antibiotics to be completed before initiation of treatment), symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements
- Patients must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants
- Has a diagnosis of primary immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Patients on chronic steroids (more than 4 weeks at stable dose) equivalent to =< 10 mg prednisone will not be excluded
- Has active autoimmune disease that has required systemic treatment in the past 1 year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is acceptable
- Has a known additional malignancy that is progressing and/or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical or anal cancer, non-metastatic prostate cancer on stable dose of hormonal therapy without rising prostate specific antigen (PSA), and breast cancer whom have been treated with curative intent, who may be on hormonal therapy
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient’s participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
- Human immunodeficiency virus (HIV) positive with detectable viral load, or anyone not on stable anti-viral (HAART) regimen, or with < 200 CD4+ T cells/microliter in the peripheral blood
- Has known active hepatitis B (e.g., hepatitis B [HBV] detected by polymerase chain reaction [PCR] [< 200 IU/ml] or active hepatitis C (e.g., hepatitis C [HCV] ribonucleic acid [RNA] [qualitative] is detected). Patients recently started (> 14 day [d] from cycle 1 day 1 [C1D1]) antiviral therapy may go on to the trial, as this is standard to treat with antiviral therapy for 1-2 months ahead of surgical excision
- History of allogeneic hematopoietic cell transplantation or solid organ transplantation
- Documented allergic or hypersensitivity response to any protein therapeutics (e.g., recombinant proteins, vaccines, intravenous immune globulins, monoclonal antibodies, receptor trap) principle investigator believes that for one or multiple reasons the patient will be unable to comply with all study visits, or if they believe the trial is not clinically in the best interest of the patient
- Patients may not have prolonged QRS or corrected QC (QTc) (must have QRS < 120ms or QTc < 480ms) to be enrolled in an arm receiving BMS-813160)
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04123379.
PRIMARY OBJECTIVE:
I. To ascertain the clinical efficacy of neoadjuvant therapy on patients with resectable non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) lesions, as is measured on pathological evaluation of resected tumors, which serve as surrogates of clinical efficacy.
SECONDARY OBJECTIVES:
I. Time from first dose of therapy to surgery, measured as the time in days that elapses between the first dose of neoadjuvant therapy and surgical resection.
II. Safety and tolerability.
III. Radiographic response to therapy.
IV. Progression-free survival (PFS).
V. Overall survival (OS).
EXPLORATORY SCIENTIFIC OBJECTIVES:
I. Correlation of radiomics parameters and histologic response to therapy.
II. Creation of dynamic atlases documenting the evolution of a patient’s tumor microenvironment (TME), comparing pre-treatment biopsy and blood with tumor and blood taken from the patient prior to surgical resection. (Non-clinical objective)
OUTLINE:
Patients with non-small cell lung cancer are sequentially assigned to 1 of 2 cohorts.
COHORT A: Patients receive CCR2/CCR5 antagonist BMS-813160 (BMS-813160) orally (PO) twice daily (BID) on days 1-28 and nivolumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after the second dose of nivolumab, then after recovery, receive standard of care chemotherapy and 3 additional cycles of nivolumab in the absence of disease progression or unacceptable toxicity.
COHORT B: Patients receive anti-IL-8 monoclonal antibody HuMax-IL8 (BMS-986253) IV over 120-180 minutes on days 1 and 15 and nivolumab IV over 60 minutes on day 1. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after the second dose of nivolumab, then after recovery, receive standard of care chemotherapy and 3 additional cycles of nivolumab in the absence of disease progression or unacceptable toxicity.
Patients with hepatocellular carcinoma are sequentially assigned to 1 of 3 cohorts.
COHORT C: Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after the second dose of nivolumab, then after recovery, receive 3 additional cycles of nivolumab in the absence of disease progression or unacceptable toxicity.
COHORT D: Patients receive BMS-813160 PO BID on days 1-28 and nivolumab IV over 60 minutes on day 1. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after the second dose of nivolumab, then after recovery, receive 3 additional cycles of nivolumab in the absence of disease progression or unacceptable toxicity.
COHORT E: Patients receive BMS-986253 IV over 120-180 minutes on days 1 and 15 and nivolumab IV over 60 minutes on day 1. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after the second dose of nivolumab, then after recovery, receive 3 additional cycles of nivolumab in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, every 3-4 months for 2 years then every 12 months thereafter.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationIcahn School of Medicine at Mount Sinai
Principal InvestigatorThomas Urban Marron
- Primary ID19-1754
- Secondary IDsNCI-2019-07794
- ClinicalTrials.gov IDNCT04123379