A PHASE 1/2, OPEN-LABEL, MULTICENTER, DOSE ESCALATION AND DOSE EXPANSION STUDY OF NKTR-214 IN SUBJECTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMOR MALIGNANCIES
The goal of this clinical research study is to find the highest tolerable dose of the study drug NKTR-214 that can be given to patients with advanced or recurrent solid tumors. Researchers also want to learn if NKTR-214 can help to control the disease. There are 2 parts to this study: Part 1 (dose escalation) and Part 2 (dose expansion). This is the first study using NKTR-214 in humans.
Disease Group: Melanoma
Treatment Agent: NKTR-214
Treatment Location: Both at MDACC & and Other Sites
Sponsor: NEKTAR THERAPEUTICS
Primary Objective • To evaluate the safety and tolerability, and define the MTD of NKTR-214. • To evaluate the efficacy of NKTR-214 by assessing the objective response rate (ORR) at the MTD or the dose below the MTD. Secondary Objectives • To evaluate the efficacy of NKTR-214 by assessing best overall response (BOR), progression-free survival (PFS), duration of response (DOR), clinical benefit rate (CBR), median time to response (MTR), and overall survival (OS). • To characterize the pharmacokinetic (PK) profile of NKTR-214 and relevant metabolites. • To assess the immunogenicity of NKTR-214. Exploratory Objectives • To assess the immunologic effect of NKTR-214 in tumor tissue on tumor-infiltrating lymphocytes (TIL). • To assess the immunologic effects of NKTR-214 in blood, including effects on cytokines, NK cells, T-cells, and other serum proteins and immune modulators.
IRB Review and Approval Date: 11/30/2015
Recruitment Status: Open
Projected Accrual: 100
1) Willing and able to provide written informed consent. (For Parts 1
2) Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) or recurrent solid tumor. (For Parts 1 and 2)
3) Male or female patients, age 18 years or older at the time of signing the informed consent (ICF). (For Parts 1 and 2)
4) Life expectancy >12 weeks. (For Parts 1 and 2)
5) Received no more than 2 prior lines of therapy or patient refuse non-curative standard of care, unless specified differently for a specific tumor type (patients must not have received interleukin-2 [IL-2] therapy within 12 months of Cycle-1 Day-1). (For Parts 1 and 2)
6) Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. (For Parts 1 and 2)
7) Measurable disease per RECIST v1.1. (For Parts 1 and 2)
8) Sample of archival tumor tissue and fresh baseline tumor biopsies (fresh baseline biopsy is defined as a biopsy specimen taken within 28 days prior to Cycle 1, Day 1) are required, except if inaccessible with Medical Monitor approval. Subjects must consent to allow acquisition of existing formalin-fixed paraffin-embedded (FFPE) material, either a block or unstained slides for performance of correlative studies. (For Parts 1 and 2)
9) Demonstrated adequate organ function, as defined below, within 14 days of treatment initiation: a.) WBC count >/= 2000/L (after at least 7 days without growth factor support or transfusion) b.) Absolute neutrophil count (ANC) >/= 1500/mL (after at least 7 days without growth factor support or transfusion) c.) Platelet count >/= 100x 103/µL (transfusions allowed) d.) Hemoglobin >/= 9.0 g/dL (transfusions allowed) e.) Serum creatinine </= 2 mg/dL (or glomerular filtration rate >/= 40 mL/min) f.) Aspartate aminotransferase (AST) and alanine transaminase (ALT) </= 3X upper limit of normal (ULN) g.) Total bilirubin within normal limits unless associated with hepatobiliary metastases or Gilbert’s syndrome, in that case total bilirubin </=2x ULN. (For Parts 1 and 2)
10) On stress echocardiogram, documented left ventricular ejection fraction >45% on cardiac stress test within 60 days prior to Cycle 1 Day 1. At the discretion of the Investigator, patients who are unable to perform a stress echocardiogram may instead have a multigated acquisition (MUGA) scan or transthoracic echocardiogram (TTE). (For Parts 1 and 2)
11) Oxygen saturation >/= 92% on room air. NSCLC patients may use supplemental oxygen. (For Parts 1 and 2)
12) Clinically significant toxic effect(s) of the most recent prior chemotherapy must be resolved to Grade 1 or less (except alopecia and sensory neuropathy). Immune-related AEs from previous therapy must be resolved to Grade 0 (except for endocrinopathies, or rash, which can be Grade 1). If the subject received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the intervention. (For Parts 1 and 2)
13) Women of childbearing potential must agree to use highly effective methods of birth control (defined as those, alone or in combination, that result in a low failure rate [i.e., < 1% per year] when used consistently and correctly, such as oral contraceptives, surgical sterilization, an intrauterine device, and/or 2-barrier methods [e.g., condom and cervical barrier such as a diaphragm]). Protections against pregnancy must be continued for at least 3 months after the last dose of study drug. All subjects must agree to use double-barrier contraception during participation in this study and for at least 3 months after the last dose of study drug. This criterion may be waived for male subjects who have had a vasectomy > 6 months before signing the ICF. (For Parts 1 and 2)
14) Patients with stable brain metastases may be enrolled, provided: a.) No prior brain metastasis lesion greater than 2 cm b.) No previous treatment wih steriotactic radiation or craniotomy within 4 weeks of Cycle 1 Day 1 c.) No new CNS lesions on repeat radiographic imaging 4 weeks or more from last treatment d.) No treatment with systemic steroids (> 10mg of prednisone daily or equivalent) within 2 weeks of Cycle 1 Day 1 e.) Clinically asymptomatic in screening. (For Parts 1 and 2)
15) Renal Cell Carcinoma (RCC): a.) Histologically confirmed diagnosis of unresectable or metastatic RCC with predominantly clear cell elements b.) Received no more than 1 prior line of therapy for RCC or patient refuses non-curative standard of care c.) Must not have received prior immunotherapy with immune-modulators including but not limited to checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-CTLA-4 antibody and any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways, indoleamine 2.3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, and cytokine therapies. (For expansion cohort only)
1) Use of an investigational agent or an investigational device within
28 days before administration of first dose of NKTR-214.
2) Females who are pregnant or breastfeeding.
3) Subjects who have an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease that requires systemic steroids or immunosuppressive agents. (Exceptions include any subject on 10 mg or less of prednisone or equivalent, subjects with vitiligo, hypothyroidism stable on hormone replacement, Type I diabetes, Graves' disease, Hashimoto's disease, alopecia areata, eczema, or with Medical Monitor approval.)
4) History of organ transplant that requires use of immune suppressive agents.
5) Use of Coumadin within 14 days of initiating NKTR-214. (Note: Low molecular weight heparin is allowed on the study).
6) Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis.
7) Active or history of Central nervous system (CNS) metastases).
8) Prior surgery or radiotherapy within 14 days of therapy. Subjects must have recovered from all radiation-related toxicities, not required corticosteroids and have not had radiation pneumonitis.
9) Subjects who have had < 28 days since the last chemotherapy, immunotherapy, biological therapy, or < 14 days from approved tyrosine kinase inhibitor (TKI) therapy (sunitinib, sorafenib, vemurafenib, dabrafenib, cobimetinib), or systemic or inhaled steroid therapy at doses greater than 10mg of prednisone or equivalent before administration of the first dose of study medication.
10) Active infection requiring systemic therapy.
11) Has known hepatitis B virus (HBV) infection (e.g. HBsAg reactive) or hepatitis C virus (HCV) e.g., HCV RNA qualitative is detected).
12) Has known immunodeficiency or active human immunodeficiency virus (HIV 1/2 antibodies).
13) Prolonged QTcF >450 milliseconds (ms) for men and >470 ms for women at Screening
14) History of unstable or deteriorating cardiac disease within the previous 6 months prior to screening including but not limited to the following: a.) Unstable angina or myocardial infarction b.) Congestive heart failure (New York Heart Association [NYHA] Class III or IV) c.) Uncontrolled clinically significant arrhythmias
15) Need for >2 antihypertensive medications for management of hypertension.
16) Known current drug or alcohol abuse.
17) Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the subject from adhering to the protocol