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Background Aberrant BCL2 control mechanisms are a defining characteristic of a variety of cancers including follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). PNT2258 is a 24-base, single-stranded, chemically unmodified phosphodiester DNA oligonucleotide encapsulated in a specialized liposome (SMARTICLES ® ) that has demonstrated antitumor activity against human cell lines and xenograft models that include NHL, prostate cancer and melanoma. The oligonucleotide sequence is designed to hybridize with genomic sequences that reside within 5'-untranscribed regulatory regions of the BCL2 gene to block transcription of BCL2 through a mechanism called DNA interference (DNAi). In a previously conducted phase I study, PNT2258 was safe and well tolerated at doses from 1 through 150 mg/m2 and PNT2258 showed evidence of BCL2-targeted effects on a variety of biomarkers. Methods This study is a multi-center, single-agent, pilot Phase II investigation of PNT2258 administered at a dose of 120 mg/m2 as a 3-hour IV infusion on days 1-5 of a 21-day cycle. Objectives included characterization of anti-tumor activity and safety data in patients (pts) with relapsed or refractory lymphoma undergoing treatment with PNT2258 for six cycles or until progressive disease or unacceptable toxicity. Adult pts with measureable disease that was FDG-PET positive at baseline were eligible. Additional criteria included ECOG PS ≤2, adequate bone marrow, renal and hepatic function, and prior treatment that included rituximab and cytotoxic chemotherapy. Standard CTCAE and Cheson criteria were used for evaluation. Patients were scanned with CT/PET at baseline, after 2 cycles and at study end. Details are at [ClinicalTrials.gov][1] under study number [NCT01733238][2]. Results To date, 10 pts (median age, 61 [range 40 - 74]) have been treated with PNT2258. Median number of prior therapies was 4 (2 - 8) and 100% of pts had baseline adenopathy >5 cm with the majority >10 cm. Antitumor activity was observed in 4 of 4 patients with FL, including 1 complete response, 1 partial response (with 80% reduction in tumor size from 20 cm to 4 cm), and 2 patients with stable disease (SD); both with tumor shrinkage at interim (i.e., end-of-cycle 2) scan. One patient each with mantle cell lymphoma (MCL) and bulky chronic lymphocytic leukemia (CLL) has exhibited SD at interim scan. Two pts exhibited progressive disease (1 each MCL and CLL). Seven of ten pts continue treatment and updated results will be presented. Toxicity occurring in ≥2 pts included grade 1 chills (n=2), diarrhea (n=2), grade 2 nausea (n=3), tumor pain (n=2) and hypotension (n=2). The single grade 3 toxicity occurring in ≥2 pts was nausea (n=2) and no grade 4 toxicity was noted. Additionally, tumor lysis syndrome has not been observed. Conclusions PNT2258 is a first-in-class DNAi consisting of a native, single-stranded, chemically unmodified DNA oligonucleotide delivered to a nuclear genomic target via a protective lipid nanoparticle, and the first to target the regulatory upstream region of the BCL2 gene. PNT2258 is well tolerated with an acceptable safety profile and shows significant single agent anti-tumor activity in pts with heavily treated relapsed NHL, particularly in pts with FL. Additional studies are planned. Disclosures: Gaylor: ProNAi Therapeutics, Inc.: Employment. Woolliscroft: ProNAi Therapeutics, Inc.: Employment. Rodrigueza: ProNAi Therapeutics, Inc.: Employment, Equity Ownership. Sooch: ProNAi Therapeutics, Inc.: Employment, Equity Ownership. Messmann: ProNAi Therapeutics, Inc.: Employment. Al-Katib: ProNAi Therapeutics, Inc.: Research Funding. [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01733238&atom=%2Fbloodjournal%2F122%2F21%2F88.atom

Background Aberrant BCL2 control mechanisms are a defining characteristic of a variety of cancers including follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). PNT2258 is a 24-base, single-stranded, chemically unmodified phosphodiester DNA oligonucleotide encapsulated in a specialized liposome (SMARTICLES®) that has demonstrated antitumor activity against human cell lines and xenograft models that include NHL, prostate cancer and melanoma. The oligonucleotide sequence is designed to hybridize with genomic sequences that reside within 5'-untranscribed regulatory regions of the BCL2 gene to block transcription of BCL2 through a mechanism called DNA interference (DNAi). In a previously conducted phase I study, PNT2258 was safe and well tolerated at doses from 1 through 150 mg/m2 and PNT2258 showed evidence of BCL2-targeted effects on a variety of biomarkers. Methods This study is a multi-center, single-agent, pilot Phase II investigation of PNT2258 administered at a dose of 120 mg/m2 as a 3-hour IV infusion on days 1-5 of a 21-day cycle. Objectives included characterization of anti-tumor activity and safety data in patients (pts) with relapsed or refractory lymphoma undergoing treatment with PNT2258 for six cycles or until progressive disease or unacceptable toxicity. Adult pts with measureable disease that was FDG-PET positive at baseline were eligible. Additional criteria included ECOG PS ≤2, adequate bone marrow, renal and hepatic function, and prior treatment that included rituximab and cytotoxic chemotherapy. Standard CTCAE and Cheson criteria were used for evaluation. Patients were scanned with CT/PET at baseline, after 2 cycles and at study end. Details are at ClinicalTrials.gov under study number NCT01733238. Results To date, 10 pts (median age, 61 [range 40 - 74]) have been treated with PNT2258. Median number of prior therapies was 4 (2 - 8) and 100% of pts had baseline adenopathy >5 cm with the majority >10 cm. Antitumor activity was observed in 4 of 4 patients with FL, including 1 complete response, 1 partial response (with 80% reduction in tumor size from 20 cm to 4 cm), and 2 patients with stable disease (SD); both with tumor shrinkage at interim (i.e., end-of-cycle 2) scan. One patient each with mantle cell lymphoma (MCL) and bulky chronic lymphocytic leukemia (CLL) has exhibited SD at interim scan. Two pts exhibited progressive disease (1 each MCL and CLL). Seven of ten pts continue treatment and updated results will be presented. Toxicity occurring in ≥2 pts included grade 1 chills (n=2), diarrhea (n=2), grade 2 nausea (n=3), tumor pain (n=2) and hypotension (n=2). The single grade 3 toxicity occurring in ≥2 pts was nausea (n=2) and no grade 4 toxicity was noted. Additionally, tumor lysis syndrome has not been observed. Conclusions PNT2258 is a first-in-class DNAi consisting of a native, single-stranded, chemically unmodified DNA oligonucleotide delivered to a nuclear genomic target via a protective lipid nanoparticle, and the first to target the regulatory upstream region of the BCL2 gene. PNT2258 is well tolerated with an acceptable safety profile and shows significant single agent anti-tumor activity in pts with heavily treated relapsed NHL, particularly in pts with FL. Additional studies are planned. Disclosures: Gaylor: ProNAi Therapeutics, Inc.: Employment. Woolliscroft:ProNAi Therapeutics, Inc.: Employment. Rodrigueza:ProNAi Therapeutics, Inc.: Employment, Equity Ownership. Sooch:ProNAi Therapeutics, Inc.: Employment, Equity Ownership. Messmann:ProNAi Therapeutics, Inc.: Employment. Al-Katib:ProNAi Therapeutics, Inc.: Research Funding.