Aldesleukin Prodrug NKTR-214 and Nivolumab in Treating Patients with Locally Advanced or Metastatic Sarcoma
This pilot phase II trial studies how well aldesleukin prodrug NKTR-214 and nivolumab work in treating patients with sarcoma that has spread from where it started to nearby tissue, lymph nodes, or other places in the body. Aldesleukin prodrug NKTR-214 is a modified (changed in the laboratory) form of a protein called interleukin-2 (or IL-2) that is normally made by the immune system. This protein is designed to trigger other cells in the immune system to start attacking sarcoma cells. 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. Giving aldesleukin prodrug NKTR-214 and nivolumab may work better in treating patients with sarcoma.
- Be capable, willing, and able to provide written informed consent/assent. For patients < 18 years of age, their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
- Be willing to comply with clinical trial instructions and requirements.
- Be willing to comply with clinical trial instructions and requirements, including mandatory biopsies.
- Patients >= 18 years must be willing to comply with the mandatory biopsies.
- Patients must have a histologically confirmed metastatic and/or locally advanced sarcoma by the enrolling institution.
- For histological specific cohorts, patients must have confirmed metastatic and/or locally advanced osteosarcoma, chondrosarcoma, undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high grade myxofibrosarcoma, vascular sarcoma, alveolar soft part sarcoma (ASPS), dedifferentiated/pleomorphic liposarcoma, small blue round cell/synovial, or leiomyosarcoma (LMS) by the enrolling institution
- Participants >= 16 years - Eastern Cooperative Oncology Group (ECOG) 0 or 1/Karnofsky performance status (KPS) 100-70%
- Participants 12-15 years - Lansky 100-70%
- Patients must have at least one prior line of systemic therapy (e.g. chemotherapy, immunotherapy, targeted or biological therapy) for their sarcoma if standard treatment is appropriate. Treatment naive patients may be enrolled if they have refused standard systemic treatment. Prior adjuvant therapy will not count provided it was completed more than 6 months previously.
- Presence of measurable disease per RECIST version (v)1.1; target lesions must not be chosen from a previously irradiated field unless there has been radiographically and/or pathologically documented tumor progression in that lesion prior to enrollment.
- On echocardiogram, documented left ventricular ejection fraction > 45%; patients may instead have a multigated acquisition (MUGA) scan instead of transthoracic echocardiogram (TTE).
- Absolute neutrophil count (ANC) >= 1,500/mcL.
- Platelets >= 100,000/mcL.
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L.
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated (creatinine clearance should be calculated per institutional standard) 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.
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 ULN.
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for patients with liver metastases.
- Albumin >= 2.5 mg/dL.
- International normalized ratio or prothrombin time =< 1.5 X ULN unless patient is receiving anticoagulant therapy as long as prothrombin time (PT) or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants.
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
- Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test at screening and =< 72 hours prior to day 1 of study treatment; if the urine pregnancy test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * A woman of childbearing potential is a sexually mature female who: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e. has had menses at any time in the preceding 24 consecutive months).
- Male patients with WOCBP partners and female patients of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 7 months (male participants) or 5 months (female participants) after the last dose of study medication * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
- History of unstable or deteriorating cardiac disease within the previous 6 months prior to screening including but not limited to the following: * Unstable angina or myocardial infarction * Congestive heart failure (New York Heart Association [NYHA] class III or IV) * Uncontrolled clinically significant arrhythmias.
- Evidence of clinically significant interstitial lung disease or has known history of, or any evidence of active, non-infectious pneumonitis.
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; patients with previously treated brain metastases may participate provided: * No current brain metastasis lesion greater than 2 cm. Patients with prior metastasis lesions greater than 2 cm that have been removed by surgical and/or radiotherapy may be enrolled if the lesion has been stable since surgery or radiotherapy. * No new or progressing brain metastasis of any size. * No stereotactic radiation or craniotomy within 4 weeks of cycle 1 day 1. * They are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment. * No clinically significant symptoms secondary to brain metastases. (This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.)
- Evidence of clinically significant immunosuppression such as the following: * Primary immunodeficiency state such as severe combined immunodeficiency disease * Concurrent opportunistic infection * Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 2 months prior to enrollment; (steroids for pre-medication for imaging studies are allowed).
- History or evidence of symptomatic autoimmune disease (e.g., pneumonitis, glomerulonephritis, vasculitis, or other), or history of active autoimmune disease that has required systemic treatment (i.e., use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) in past 2 years prior to enrollment; replacement therapy (e.g., thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment for autoimmune disease.
- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) disease.
- Patients known to be positive for active hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected).
- Prolonged Fridericia's corrected QT (QTcF) > 450 ms for men and > 470 ms for women at screening.
- Patients who have received a live vaccine within 30 days of the start date of the planned study therapy; Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.
- Has a known history of active TB (Bacillus tuberculosis).
- Is currently participating and receiving study therapy or using an investigational device or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 3 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: Patients with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- Hypersensitivity to nivolumab or any of its excipients.
- Hypersensitivity to NKTR-214 or any of its excipients.
- Need for > 2 antihypertensive medications for management of hypertension (including diuretics).
- Women who are pregnant or breast feeding.
Locations & Contacts
Contact: Sandra Pierina D'Angelo
Contact: Anthony P. Conley
Trial Objectives and Outline
I. To evaluate the efficacy of aldesleukin prodrug NKTR-214 (NKTR-214) in combination with nivolumab in patients with selected advanced bone or soft tissue sarcoma, as assessed by the best overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by 24 weeks.
I. To assess the safety and tolerability of NKTR-214 in combination with nivolumab in patients with select advanced bone or soft tissue sarcoma.
II. To evaluate the efficacy NKTR-214 in combination with nivolumab in patients with select advanced bone or soft tissue sarcoma, as assessed by ORR according to immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).
III. To determine the progression-free survival (PFS) at 24 weeks and median PFS according to RECIST 1.1 and to determine overall survival (OS) rate at 12 months and median OS for patients treated with NKTR-214 in combination with nivolumab.
I. To determine the baseline characteristics of sarcoma tumors (pre-treatment biopsy sample) evaluated in this study including the level PD-1/PD-L1 expression, presence of tumor infiltrating lymphocytes (TILs) and tumor antigens, gene expression profile, and the T-cell receptor clonality in tumor-infiltrating lymphocytes (TIL).
II. To assess the potential effect of NKTR-214 and nivolumab on selected biomarker expression measured in post-treatment tumor tissue and the association between these biomarkers (baseline level of expression and the change in biomarker level of expression following treatment) and clinical outcome, including characterization of PD-1/PD-L1 expression, tumor infiltrating lymphocytes (TILs) and tumor antigens, gene expression profiling, and characterization of T-cell receptor clonality in tumor-infiltrating lymphocytes (TIL).
III. To evaluate associations between selected biomarkers measured in serial peripheral blood and with clinical efficacy, including immunophenotyping and functional analyses, evaluation of serum levels of chemokines, cytokines and other immune mediators, and characterization of T-cell receptor clonality in peripheral blood.
IV. To evaluate the association between baseline tumor mutational burden and neoantigen production with clinical efficacy of the study therapy.
Patients receive aldesleukin prodrug NKTR-214 intravenously (IV) over 30 minutes and nivolumab IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with a partial response (PR) or complete response (CR) may receive treatment for up to 24 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up within 30 days and then every 12 weeks for up to 12 months.
Trial Phase & Type
Memorial Sloan Kettering Cancer Center
Sandra Pierina D'Angelo
Secondary IDs NCI-2017-01741
Clinicaltrials.gov ID NCT03282344