A Phase 1 Dose Escalation Study of BMS-982470 (Recombinant Interleukin-21, rIL-21) in Combination with BMS-936558 (Anti-PD-1) in Subjects with Advanced or Metastatic Solid Tumors
The purpose of this study is to determine the safety, tolerability, pharmacokinetics (PK), immunoregulatory (pharmacodynamic) activity, and preliminary antitumor activity of BMS-982470 (rIL-21) in combination with BMS-936558 (anti-PD-1) in subjects with advanced or metastatic solid tumors. The goal of this study is to demonstrate adequate safety and tolerability of the combination of BMS-936558 and BMS-982470 so as to permit further testing. Information gathered will inform the optimal dose and schedule for administration of BMS-982470 in combination with BMS-936558 in future studies.
Part 1 (Dose Escalation): Histologic or cytologic confirmation of locally advanced, non-resectable, or metastatic solid tumors unresponsive (not achieving a CR or PR) to at least 1 line of prior therapy. Part 2 (Cohort Expansion): Histologic or cytologic confirmation of locally advanced, non-resectable or metastatic RCC with a clear cell component unresponsive (not achieving a CR or PR) to at least 1 line of therapy, or NSCLC unresponsive (not achieving a CR or PR) to at least 1 line of therapy. Age greater than 18, ecog performace status 0, or 1. Presence of at least 1 non-irradiated lesion with measurable disease at baseline as assessed by computed tomography (CT) or magnetic resonance imaging (MRI). Women of childbearing potential and Men must use highly effective methods of birth control (i.e., double barrier) for the entire duration of the study including a minimum of 18 weeks after dosing has been completed. Adequate bone marrow, liver and remal function. No active central nervous system (CNS) metastases (including evidence of cerebral edema by CT scan or MRI, or progression from prior imaging study, any requirement for steroids, or clinical symptoms of/from CNS metastases) within 28 days of study enrollment. Subjects with known metastases must have a baseline imaging scan within 28 days of first study drug administration. No subjects with other concomitant malignancies, except adequately treated non-melanomatous cell skin cancers, superficial bladder cancer, or carcinoma in situ of the cervix or breast, are excluded unless a complete remission was achieved at least 2 years prior to study enrollment and no additional therapy is required or anticipated to be required during the study period. No prior therapy with the following is not permitted: BMS-936558 (or any other agent targeting PD-1); BMS-982470 (rIL-21); any agent specifically targeting T cell costimulation or checkpoint pathways such as, but not limited to, ipilimumab (Yervoyï??), anti-PD-L1, anti-PD-L2, or anti-CD137. No subjects with any active autoimmune disease or history of known or suspected autoimmune disease (see Appendix 3) except for subjects with vitiligo, resolved childhood asthma/atopy, or euthyroid patients with a history of Graveâ??s disease. Subjects with suspected autoimmune thyroid disorders must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid-stimulating immunoglobulin prior to randomization. Other individual cases may be considered upon discussion with the Medical Monitor. No uncontrolled or significant cardiac disease including, but not limited to, any of the following: i) Myocardial infarction within 6 months of study enrollment ii) Uncontrolled angina within 3 months of study enrollment iii) History (family or personal) of congenital long QT syndrome iv) Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) v) Controlled atrial fibrillation by itself is not an exclusion criterion vi) History of other clinically significant heart disease No history of prior organ allograft or allo bone marrow transplant. No HIV or any Hepatitis. No actice infection or known drug/alcohol abuse. No chemo, surgery, growth factors or investigational meds within 4 weeks of starting trial.
In Part 1, BMS-982470 will be administered at doses of 10, 30, 50, or 100 Î¼g/kg as an IV push on 1 of 2 schedules: Arm A- weekly during Weeks 1 through 4 of a 6-week cycle or Arm B -3 times per week during Weeks 1 and 3 of a 6-week cycle. In both arms above, BMS-936558 will be administered IV over one hour at a dose of 3 mg/kg once every 2 weeks during the 6-week cycle (i.e., during Weeks 1, 3, and 5). In Part 2, cohort expansion will be carried out at the dose selected in Part 1 for both treatment schedules. In both parts of the study, treatment can continue for up to 2 years with the potential for 1 additional year of therapy for subjects who become eligible for retreatment during the follow-up period.
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