On April 9, 2024 Syros Pharmaceuticals (NASDAQ:SYRS), a biopharmaceutical company committed to advancing new standards of care for the frontline treatment of hematologic malignancies, reported that the United States Food and Drug Administration (FDA) has granted Fast Track Designation to tamibarotene in combination with azacitidine and venetoclax for the treatment of newly diagnosed acute myeloid leukemia (AML) with RARA overexpression as detected by an FDA approved test in adults who are over age 75 years or who have comorbidities that preclude the use of intensive induction chemotherapy (Press release, Syros Pharmaceuticals, APR 9, 2024, View Source [SID1234641968]). Tamibarotene, an oral first-in-class selective retinoic acid receptor alpha (RARα) agonist, is currently being evaluated in combination with venetoclax and azacitidine for the treatment of newly diagnosed AML patients with RARA gene overexpression.

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"We are pleased to receive Fast Track designation for tamibarotene for the treatment of AML. This designation reflects the tremendous need for a safe and effective therapy, which can improve the clinical outcomes and prognosis among people diagnosed with AML, many of whom cannot tolerate intensive treatment," said David A. Roth, M.D., Chief Medical Officer of Syros Pharmaceuticals. "We are particularly encouraged to secure Fast Track designation following initial randomized data from a prespecified interim analysis of our ongoing SELECT-AML-1 clinical trial, in which treatment with our RARα agonist, tamibarotene, in combination with venetoclax and azacitidine resulted in a 100% CR/CRi rate compared with a 70% CR/CRi rate for the comparator of venetoclax and azacitidine. Additionally, tamibarotene in combination with venetoclax and azacitidine demonstrated no added toxicity relative to venetoclax and azacitidine alone. We look forward to sharing additional data from SELECT-AML-1 later this year, and to potentially accelerate the delivery of tamibarotene as a new frontline option for the approximately 30% of AML patients who are positive for RARA overexpression."

Fast Track is a process designed by the FDA to facilitate the development and expedite the review of drug candidates intended to treat serious conditions and for which nonclinical or clinical data demonstrate the potential to address unmet medical need. The purpose is to facilitate development and expedite review of drugs to treat serious and life-threatening conditions, to bring the approved products to patients earlier. A therapeutic candidate that receives Fast Track designation may be eligible for more frequent interactions with the FDA to discuss the therapeutic candidate’s development plan. Therapeutic candidates with Fast Track designation may also be eligible for priority review and accelerated approval if supported by clinical data.

Syros is evaluating tamibarotene in combination with venetoclax and azacitidine in newly diagnosed, unfit AML patients with RARA overexpression in the ongoing SELECT-AML-1 Phase 2 trial. In December 2023, Syros announced initial randomized data from SELECT-AML-1, demonstrating a 100% CR/CRi (complete response/complete response with incomplete hematologic recovery) rate in response-evaluable patients (nine of nine) treated with the triplet regimen of tamibarotene, venetoclax and azacitidine, as compared to 70% among patients (seven of ten) treated with venetoclax and azacitidine alone, with corresponding CR rates of 78% vs 30%, respectively. The median time to CR/CRi response was rapid; all patients treated with the triplet regimen achieved a CR/CRi by the end of cycle one. Consistent with prior clinical experience, tamibarotene in combination with approved doses of venetoclax and azacitidine was generally well tolerated, and the overall safety profile demonstrated no additive toxicities or new safety signals, and no evidence of increased myelosuppression compared to treatment with the doublet combination of venetoclax and azacitidine. Syros expects to report additional data from SELECT-AML-1 in 2024.

Syros is also evaluating tamibarotene in combination with azacitidine in newly diagnosed higher-risk myelodysplastic syndrome (MDS) patients with RARA overexpression in the SELECT-MDS-1 Phase 3 trial. As recently announced, enrollment to support the pivotal primary efficacy analysis was completed in the first quarter of 2024, and pivotal complete response data is expected by the middle of the fourth quarter of 2024. In January 2023, the FDA granted Fast Track Designation to tamibarotene for the treatment of HR-MDS patients with RARA overexpression.

On April 9, 2024 Brenus Pharma reported groundbreaking results during the American Association Cancer Research (AACR) (Free AACR Whitepaper) Annual meeting 2024 – San Diego (April 5-10) (Press release, Brenus Pharma, APR 9, 2024, View Source [SID1234641967]).

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"Efficacy of the STC-10101 a new allogeneic cancer vaccine in different colorectal cancer models" | Abstract 5003 View Source

This communication confirms the ability of Brenus’ next gen immunotherapy, STC-1010, to fight against resistant colorectal tumors with excellent tolerability.

Additionally, multi-omics analysis of STC-1010 batches confirmed consistent quality and batch-to-batch reproducibility, through standardized and scalable production.

STC-1010 was tested in several models extrapolating human conditions (ex-vivo; in-ovo,) using PBMCs from different donors. Results showed a significant immune response activation coupled with a massive and robust tumor killing that has been consistent with our 3 latest STC1010 batches manufactured. Metastasis reduction has also been shown with in-ovo model.

Results show the potential of STC-1010 in clinical settings to treat patients with colorectal cancer causing 9.7 million death per year.

On April 9, 2024 Synthekine Inc., an engineered cytokine therapeutics company, reported positive initial results from a Phase 1a/1b clinical trial of its α/β biased IL-2 partial agonist, STK-012, for the treatment of advanced solid tumors (Press release, Synthekine, APR 9, 2024, View Source [SID1234641966]). The data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 in San Diego. STK-012 is a first-in-class α/β-IL-2R biased partial agonist engineered to selectively stimulate CD25+ antigen-activated T cells, which are associated with potent anti-tumor activity, and avoid broad stimulation of other lymphocytes, such as natural killer (NK) cells, which are associated with IL-2 toxicity. In the results presented, which included 47 patients treated in Phase 1a dose escalation, STK-012 monotherapy demonstrated a favorable safety, efficacy, pharmacokinetic and pharmacodynamic profile.

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"The promise of IL-2 in the treatment of solid tumors has yet to be realized as IL-2 analogues developed to date have had limited efficacy and an unacceptable toxicity profile," said Naiyer Rizvi, M.D., chief medical officer of Synthekine. "We are excited to report multiple objective responses with STK-012 monotherapy, driven by robust induction of interferon‐gamma (IFNγ) and selective expansion of antigen activated T cells. At the same time, we do not see the severe toxicities typically associated with IL-2 treatments, such as hypotension, capillary leak syndrome (CLS), or transaminitis. We look forward to completing the dose expansion portion of this study to further evaluate its potential for patients."

Synthekine initiated the Phase 1b portion of its study in September 2023 after successfully completing the Phase 1a dose-escalation portion. The Phase 1b portion of the study includes dose expansion cohorts to evaluate STK-012 as monotherapy at the candidate recommended phase 2 dose (RP2D) in selected solid tumor types, including renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). Along with the Phase 1a results, Synthekine presented a case study on a subject with Stage IV ccRCC treated with STK-012 monotherapy in the ongoing Phase 1b portion of the study. The subject had 2 prior lines of therapy, including immune checkpoint inhibitor, before starting on STK-012 and went on to achieve a confirmed partial response with 85% reduction in target lesion size as best overall response.

The poster, titled "Initial results from a Phase 1a/1b study of STK-012, a first-in-class α/β IL-2 receptor biased partial agonist in advanced solid tumors (NCT05098132)," will be presented today at AACR (Free AACR Whitepaper) from 9 am to 12:30 pm PT. The poster will be on poster board 11 in the session "First-in-Human Phase I Clinical Trials 2." Following presentation at the meeting, the poster will be available on Synthekine’s website. For additional information about the trial, please visit www.clinicaltrials.gov using the identifier NCT05098132.

STK-012 Initial Phase 1a Monotherapy Dose Escalation Data

As of February 26th, 2024, 47 subjects were treated with STK-012 monotherapy at 7 dose levels across the 2 dosing schedules (QW and Q3W) in the Phase 1a
Majority of patients (60%) had three or more prior lines of therapy in the advanced setting and 79% had received prior immune checkpoint inhibitor (ICI)
Treatment-related adverse events (TRAEs) were reversible with standard management and mostly Grade 1 or 2 in severity
Most common TRAEs (≥10% of subjects) were maculopapular rash, fatigue, injection site reaction, nausea, diarrhea, pruritis, vomiting, and arthralgia
Based on observed PK (half-life of ~4 days), only the Q3W schedule was advanced beyond the 0.75 mg dose during the STK-012 monotherapy dose escalation
STK-012 demonstrated selectivity (pSTAT5 induction) for T cells that express IL-2Rα (CD25)
STK-012 demonstrated dose proportional increase in IFNγ and activated proliferating CD8 T cells
STK-012 showed limited expansion of NK cells and Tregs
Of 40 efficacy evaluable subjects, partial response (PR) was observed in 3 (RCC, NSCLC and HNSCC) and 12 had stable disease (SD) as their best overall response (BOR) by RECIST V1.1
In the subset of 15 subjects who were ICI refractory and minimally pretreated (≤ 2 prior lines), 3 had BOR of PR and 6 had BOR of SD
Durability of response was observed in multiple subjects

On April 9, 2024 Obsidian Therapeutics, Inc., a clinical-stage biotechnology company pioneering engineered cell and gene therapies, reported an update on its Phase 1 first-in-human study of OBX-115 tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced or metastatic melanoma, including 25-week median study follow-up safety data and newly detailed efficacy data, during a presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in San Diego, CA (Press release, Obsidian Therapeutics, APR 9, 2024, View Source [SID1234641965]). The poster, "OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy induced deepening and durable responses without interleukin 2 (IL2) in patients with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma," was presented by Rodabe N. Amaria, M.D., professor of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center and principal investigator of the study.

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The single-center study (NCT05470283) is evaluating the safety, tolerability, dosing, and efficacy of OBX-115 in patients with ICI-resistant metastatic melanoma. All 6 patients had disease that was primary-resistant to anti–PD-1 therapy, with a median of 2.5 (range, 1–5) lines of prior therapy.

OBX-115 was well-tolerated with a differentiated safety profile from non-engineered TIL cell therapy, which utilizes high-dose IL2:

No dose-limiting toxicities were observed
No Grade 4 or higher non-hematologic events were reported and 2 patients experienced limited Grade 3 events
No confirmed events of cytokine release syndrome, capillary leak syndrome, or ICANS were reported
OBX-115 induced consistently deepening and durable responses:

50% objective response rate and 33% complete response rate using investigator-assessed RECIST 1.1 criteria
All patients experienced tumor burden reduction and meaningful disease control for ≥12 weeks after infusion
All patients were alive and median PFS had not been reached, with 6-month PFS of 67%
Dr. Amaria stated, "The clinical safety and efficacy data from the first 6 patients treated with OBX-115 are promising and demonstrate a meaningful objective response rate. The results are particularly encouraging since OBX-115 is the first engineered TIL cell therapy not requiring IL2 co-administration. OBX-115 has the potential to drive durable responses in patients with ICI-resistant metastatic melanoma, without the well-described toxicity associated with IL2."

"We are highly encouraged by the promising OBX-115 data being shared today, which not only clinically validate Obsidian’s cytoDRiVE technology, but also demonstrate that OBX-115, with its positively differentiated safety profile, has the potential to further expand eligibility for TIL cell therapy and comprehensively address the unmet need in ICI-resistant advanced melanoma," commented Parameswaran Hari, M.D., Chief Development Officer of Obsidian.

In addition to the first-in-human study, Obsidian is actively enrolling patients with metastatic melanoma and NSCLC at multiple sites in its ongoing Phase 1/2 multicenter study. Additional details may be found at clinicaltrials.gov, using identifier: NCT06060613.

Obsidian also has 3 other poster presentations at AACR (Free AACR Whitepaper) 2024:

Title: Trial in progress: A Phase 1/2 study to investigate the safety and efficacy of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with immune checkpoint inhibitor (ICI)-resistant advanced or metastatic melanoma
Presenting Author: Sajeve S Thomas, Orlando Health Cancer Institute, Orlando, FL

Title: Tumor-infiltrating lymphocytes (TIL) engineered with membrane-bound IL15 (cytoTIL15 cells) exhibit pharmacologically regulatable signal transduction in cis and trans
Presenting Author: Rachel Burga, Obsidian Therapeutics, Inc., Cambridge, MA

Title: Tumor-infiltrating lymphocytes (TIL) engineered with regulatable membrane-bound IL15 (mbIL15) and LIGHT (TNFSF14) show enhanced efficacy in fibroblast-containing cold tumors
Presenting Author: Balazs Koscso, Obsidian Therapeutics, Inc., Cambridge, MA

About OBX-115

Obsidian’s lead investigational cytoTIL15 program, OBX-115, is a novel engineered tumor-derived autologous T cell immunotherapy (tumor-infiltrating lymphocyte [TIL] cell therapy) armored with pharmacologically regulatable membrane-bound IL15 (mbIL15). OBX-115 has the potential to become a meaningful therapeutic option for patients with advanced or metastatic melanoma and other solid tumors by leveraging the expected benefits of mbIL15 and Obsidian’s proprietary, differentiated manufacturing process to enhance persistence, antitumor activity, and clinical safety of TIL cell therapy. OBX-115 is being investigated in 2 ongoing and enrolling clinical trials in advanced or metastatic melanoma and NSCLC (NCT05470283 and NCT06060613).

On April 9, 2024 AffyImmune, a clinical-stage biopharmaceutical company committed to developing novel, first-in-class, affinity-tuned CAR T cell therapies, reported preclinical data on new indications for its lead program, AIC100, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 (Press release, AffyImmune Therapeutics, APR 9, 2024, View Source [SID1234641964]). The data showcases the efficacy of AIC100 in non-small cell lung cancer (NSCLC) and cervical cancer in preclinical models expressing cell surface ICAM-1.

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Affinity tuned AIC100 is expected to selectively bind and kill tumor cells expressing cell surface ICAM-1 while sparing healthy cells.

The preclinical studies demonstrated that AIC100 exhibited potent cytotoxic activity against ICAM-1-positive NSCLC and cervical cancer cell lines in vitro, resulting in 100% cell death within 72 hours. The investigational affinity-tuned CAR T candidate AIC100 also demonstrated remarkable efficacy in NSCLC and cervical cancer xenograft models, with the active arm showing a significant reduction in tumor size and an increase in survival compared to placebo.

"We are excited to share preclinical proof-of-concept data for our affinity-tuned CAR T program AIC100 in new solid tumor types. Advanced stage cervical cancer and NSCLC represent significant unmet medical needs, with patients experiencing poor outcomes and a 5-year survival rate ranging from approximately 10 to 20%," said Matt Britz, CEO, AffyImmune. "These preclinical data build on the potential for AIC100 to be a first-in-class targeted therapy for ICAM-1-positive solid tumors with significant unmet medical need."

"Advanced lung and cervical cancers continue to have unmet medical need despite our recent advances in targeted and immune therapy. There are few good options for patients who experience progression after initial therapy for metastatic disease," said Jorge J. Nieva, MD, Associate Professor of Clinical Medicine, Keck School of Medicine, University of Southern California. "This promising preclinical data presented at AACR (Free AACR Whitepaper) 2024 suggest that AIC100 could be a potential new option for patients with these ICAM-1-positive tumors."

AIC100 is currently in Phase 1 trials for anaplastic and poorly differentiated thyroid cancer (NCT04420754).