2877 - REVEAL: A phase 1/2, open-label, multicenter, dose escalation and dose expansion study of NKTR-262 [TLR 7/8 agonist] plus NKTR-214 [CD122-biased agonist] with or without nivolumab (nivo) in patients (pts) with locally advanced or metastatic solid tumor malignancies

Background

Cancer treatments that couple pharmacological activation of tumor antigen presentation with activation and expansion of CD8⁺ T and NK cells in the tumor environment have the potential to induce an effective anti-tumor immune response in pts. NKTR-262 is a small molecule agonist of toll-like receptors (TLRs) 7/8 designed to be retained in the tumor micro-environment to activate antigen-presenting cells (eg, dendritic cells) to create new antigen-specific cytotoxic T cells. As a CD122-biased agonist, NKTR-214 monotherapy increases newly proliferative CD8⁺ T cells in tumors. NKTR-262 + NKTR-214 is expected to increase expansion of antigen-specific CD8⁺ T cells. In preclinical studies, a single intratumoral (IT) injection of NKTR-262 + IV NKTR-214 resulted in complete abscopal effects in tumor models (Kivimae, SITC ‘17). Preliminary clinical data show NKTR-214 + nivo enhances immune-stimulatory responses (Diab, SITC ‘17). The REVEAL trial will assess safety and anti-tumor activity of NKTR-262 + NKTR-214 with or without nivo for the treatment of selected cancers.

Trial design

Primary objectives of the phase 1 dose escalation are to identify the recommended phase 2 dose of the doublet, NKTR-262 + NKTR-214 and of the triplet, NKTR-262 + NKTR-214 + nivo. Secondary objectives include antitumor activity including ORR, PFS and OS. Pts will receive IT NKTR-262 at escalating doses q3w until biological response. The study will enroll eligible pts with advanced and/or metastatic melanoma, Merkel cell carcinoma, triple-negative breast cancer, ovarian carcinoma, renal cell carcinoma, colorectal cancer, urothelial carcinoma, or sarcoma. Eligibility includes measurable disease per RECIST 1.1 with at least 2 lesions (1 amenable to IT injection and biopsy collection). ∼48 pts will be enrolled in phase 1 and ∼345 pts in phase 2. Pts in the NKTR-262 + NKTR-214 cohorts will have progressed on prior approved therapies and pts in the NKTR-262 + NKTR-214 + nivo cohorts will be naïve to immunotherapy treatment. Trial is open and recruiting.

Clinical trial identification

NCT03435640.

Legal entity responsible for the study

Nektar Therapeutics, San Francisco, CA.

Funding

Nektar Therapeutics, San Francisco, CA.

Editorial Acknowledgement

Disclosure

A. Diab: Consulting or advisory role: Nektar, CureVac, Celgene; Travel, accommodations, expenses: Nektar Research funding (to institution): Nektar, Idera, Celgene, Pfizer. M. Marcondes: Employment: Nektar; Stock or Other Ownership: Nektar. M.A. Tagliaferri: Employment: Nektar; Leadership: Nektar; Stock and other ownership interests: Nektar; Consulting or advisory role (immediate family member): Bluebird Bio, Nektar; Patents, royalties, other intellectual property: Nektar; Travel, accommodations, expenses: Bluebird Bio, Nektar. U. Hoch, J. Zhang: Employment: Nektar Stock; Other ownership interests: Nektar. W. Rubas: Employment: Nektar (immediate family member): Pharm-Olam; Stock and other ownership Interests: Nektar. S. Kivimae: Employment: Nektar; Stock and other ownership interests: Nektar; Patents, royalties, other intellectual property: Nektar. E. Borazanci: Consulting or advisory role (an immediate family member): Teva, Biogen, Genzyme, Novartis consulting or advisory role: Fujifilm, Ipsen; Speakers' bureau (an immediate family member): Teva, Genzyme, Biogen, Novartis; Speakers' bureau: Ipsen, Taiho Pharmaceutical Research funding (to institution): Bristol-Myers Squibb, Pharmacyclics, Idera, Daiichi Sankyo, Minneamrita Therapeutics, Ambry Genetics, MabVax, Lilly, Samumed. S.P. D'Angelo: Consulting or advisory role: EMD Serono, Amgen, Nektar, Immune design, GlaxoSmithKline; Travel, accommodations, expenses: Adaptimmune, EMD Serono. All other authors have declared no conflicts of interest.