tilsotolimod (IMO-2125) / Aceragen - LARVOL DELTA

Phase III randomized trial evaluating tilsotolimod in combination with ipilimumab versus ipilimumab alone in patients with advanced refractory melanoma (ILLUMINATE 301). (ASCO 2024) - P3 | "Adding tilsotolimod to ipilimumab did not improve response or OS in patients with PD-1 refractory advanced melanoma. However, the results represent the largest prospective dataset reported to date on using ipilimumab in this setting and are a valuable addition to the knowledge base."

Clinical • Combination therapy • Late-breaking abstract • Metastases • P3 data • Melanoma • Oncology • Solid Tumor

Randomized, Open-Label, Phase III Study of Tilsotolimod in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced Refractory Melanoma (ILLUMINATE-301). (PubMed, J Clin Oncol) - P3 | "Combining IT tilsotolimod with ipilimumab did not significantly improve the ORR or OS compared with ipilimumab alone in patients with anti-PD-1 advanced refractory melanoma."

Journal • P3 data • Melanoma • Oncology • Solid Tumor

Tilsotolimod exploits the TLR9 pathway to promote antigen presentation and Type 1 IFN signaling in solid tumors: A Multicenter International Phase I/II trial (ILLUMINATE-101). (PubMed, Clin Cancer Res) - "Overall, tilsotolimod monotherapy was generally well tolerated and induced rapid, robust alterations in the tumor microenvironment."

Journal • P1/2 data • Immunology • Melanoma • Oncology • Solid Tumor

Intradermal IMO-2125 versus placebo as adjuvant treatment in patients with stage II pT3-4/cN0 melanoma: Interim efficacy and safety results of the randomized phase II INTRIM study (ESMO 2022) - P2 | "CPG7909, a Toll-like receptor-9 (TLR9) agonist, injected at the primary tumour excision site in patients with clinical stage I/II melanoma, was found to boost loco-regional and systemic anti-melanoma immunity. Conclusions Single-dose IMO-2125 has a reasonable safety profile and significantly reduces tumour positive SLN rates in pT3-T4 melanoma patients. Provided that SLN status accurately reflects future RFS, IMO-2125 has the potential to improve outcomes of early-stage melanoma patients."

Clinical • Late-breaking abstract • P2 data • Melanoma • Oncology • Solid Tumor

Phase 1b study of ABBV-368, tilsotolimod, budigalimab, and nab-paclitaxel in patients with recurrent/metastatic head and neck squamous cell carcinoma. (PubMed, J Immunother Cancer) - P1b | "The quadruple combination of ABBV-368, tilsotolimod, nab-paclitaxel, and budigalimab was well tolerated and demonstrated pharmacodynamic activity. Several patients had disease stabilization, but clinical responses were limited. Initial priming and T-cell immune activation were inadequate to overcome prior therapy resistance mechanisms including a hypothesized unfavorable tumor microenvironment. Future work investigating strategies to target this inhibitory tumor microenvironment with optimally scheduled immunotherapy combinations in selected patients and indications is urgently needed to improve patient outcomes."

IO biomarker • Journal • P1 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • IFNG

Erratum: Randomized, Open-Label, Phase III Study of Tilsotolimod in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced Refractory Melanoma (ILLUMINATE-301). (PubMed, J Clin Oncol) - No abstract available

Journal • P3 data • Melanoma • Oncology • Solid Tumor

Intradermal tilsotolimod versus placebo as adjuvant treatment in patients with stage II, pT3-4cN0 melanoma: recurrence-free survival data of the randomized double blinded phase II INTRIM study (EADO-WCM 2025) - "Background CPG7909, a Toll-like receptor-9 (TLR9) agonist, injected intradermally at the primary tumor excision site in patients with clinical stage I/II melanoma, was found to boost loco-regional and systemic anti-melanoma immunity...Upon establishing positive SLN status, i.e. stage III disease, 13% of the tilsotolimod-injected patients and 39% of the placebo patients were treated with adjuvant anti-PD1 (7 vs 20) or dabrafenib/trametinib (0 vs 1)...Tilsotolimod treatment was mainly associated with grade 1 and 2 injection site reactions (54%) and flu-like symptoms (46%). Conclusions Adjuvant single-dose tilsotolimod in patients with pT3-T4 cN0 melanoma has a favorable benefit-risk profile and demonstrates significant improvements over placebo in tumor-positive SLN rate and RFS, with a 69% reduction in the risk of recurrence or death after a median follow-up of 24 months."

Clinical • P2 data • Melanoma • Oncology • Solid Tumor

PRIMO: Intratumoral Tilsotolimod, a TLR-9 Agonist, Together With Intratumoral Ipilimumab and Intravenous Nivolumab in Patients With Advanced Cancers (clinicaltrials.gov) - P1 | N=25 | Terminated | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | N=72 ➔ 25 | Active, not recruiting ➔ Terminated; The part A of the trial has been completed according to the protocol. The part B has not been opened because of unfeasibility (experimental products not yet available).

Enrollment change • Metastases • Trial termination • Colorectal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology

Intradermal CpG/tilsotolimod treatment in pT3-4 cN0M0 melanoma: efficacy update of the randomized INTRIM trial (ITOC 2024) - No abstract available

Clinical • Melanoma • Oncology • Solid Tumor

Intratumoral (IT) Injection of the TLR9 agonist tilsotolimod (IMO-2125) in combination with ipilimumab (ipi) triggers durable responses in PD-1 inhibitor refractory metastatic melanoma (rMM): Results from a Multicenter, Phase 1/2 study (ESMO 2018) - P1/2; "IT tilsotolimod 8mg+ ipi is well tolerated and shows substantial clinical benefit and durable responses. The ORR of 38% compares favorably to ipi in this challenging population, leading to an ongoing global randomized Phase 3 study of tilsotolimod 8mg+ipi vs. ipi in aPD-1 rMM."

Clinical • Combination therapy • IO biomarker • P1/2 data • PD(L)-1 Biomarker • Melanoma

ILLUMINATE 301: A Randomized Phase 3 Comparison of IMO-2125 with Ipilimumab (ipi) versus Ipi Alone in Subjects with Anti PD 1 Refractory Melanoma (ESMO 2018) - P1/2, P3; "Enrollment is planned as 308 subjects at around 80 centers in 10 countries. It is currently recruiting in the US and Australia with study initiation ongoing in EU and Canada."

Clinical • P3 data • Brain Cancer • Melanoma

A Phase 1/2 trial of intratumoral (i.t.) IMO-2125 (IMO) in combination with checkpoint inhibitors (CPI) in PD-(L)1-refractory melanoma (ESMO 2017) - P1/2; "IMO + ipi is a viable strategy to revive the immune response in CPI-resistant tumors and shows preliminary clinical activity worthy of further development."

Checkpoint inhibition • Clinical • Combination therapy • P1/2 data • Melanoma

Intratumoral (i.t.) IMO-2125 (IMO), a TLR9 agonist, in combination with ipilimumab (ipi) in PD-(L)1 refractory melanoma (RM). (ASCO-SITC 2017) - P1/2; "Based on this we initiated a trial of IMO in combination with ipi or pembrolizumab (pem) in RM. The combination of IMO and ipi is tolerable and has activity in PD-1 refractory melanoma. Dose escalation is ongoing and a Phase 2 expansion with both combinations is planned. Updated safety, antitumor activity, PK, and biomarker data will be presented at the meeting."

Biomarker • Clinical • Biosimilar • Immunology • Melanoma • Oncology

A phase 2 study to evaluate the safety and efficacy of Intratumoral (IT) injection of the TLR9 agonist IMO-2125 (IMO) in combination with ipilimumab (ipi) in PD-1 inhibitor refractory melanoma. (ASCO 2018) - P1/2; "IMO + ipi is a robust strategy to revive the immune response in PD-1/L1resistant tumors and the demonstrated substantial clinical benefit including durable responses in this clinically challenging pt population. This data supports the initiation of a phase 3 study compared to ipi alone."

Clinical • Combination therapy • IO biomarker • P2 data • PD(L)-1 Biomarker • Melanoma

Triple combination of IMO-2125, epacadostat and anti-PD-1 antibody demonstrates maximal antitumor efficacy and eradicates large established tumors in preclinical models (AACR 2018) - P1/2; "NCT02644967Similar antitumor activities were also observed in a murine peritoneal model with NSCLC 3LL-C75.Combination of IMO-2125 with checkpoint inhibitors targeting IDO-1 and PD-1 induces maximal antitumor efficacy and eradicates large established tumors in preclinical models. A Phase 2 clinical trial of IMO-2125 in combination with ipilimumab in patients with metastatic melanoma is ongoing and a Phase 3 multi-center, global trial in the same population is initiating enrollment."

Preclinical • Melanoma • Non Small Cell Lung Cancer

Translational evidence of reactivated innate and adaptive immunity with intratumoral IMO-2125 in combination with systemic checkpoint inhibitors from a Phase I/II study in patients with anti-PD-1 refractory metastatic melanoma (AACR 2017) - "These results demonstrate that IMO-2125 with a checkpoint inhibitor is a viable strategy to revive the immune response in tumors that are refractory to PD-1 inhibitors. Further clinical evaluation of both the IMO-ipilimumab and IMO-pembrolizumab combination is planned in a Phase 2 expansion of the current trial."

Biomarker • Checkpoint inhibition • Clinical • P1/2 data • Biosimilar • Hematological Malignancies • Melanoma • Multiple Myeloma • Oncology

A Study to Determine the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of ABBV-368 Plus Tilsotolimod and Other Therapy Combinations in Participants With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P1b | N=30 | Completed | Sponsor: AbbVie | Active, not recruiting ➔ Completed

Trial completion • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

ILLUMINATE 301: A randomized phase III study of tilsotolimod in combination with ipilimumab compared with ipilimumab alone in patients with advanced melanoma following progression on or after anti-PD-1 therapy (ESMO 2019) - P1/2, P3; "Legal entity responsible for the study: Idera Pharmaceuticals, Inc. Funding: Idera Pharmaceuticals, Inc."

Clinical • Combination therapy • IO biomarker • P3 data • PD(L)-1 Biomarker • Brain Cancer • Melanoma • Oncology • Solid Tumor

Safety, efficacy, and immune effects of intratumoral tilsotolimod in patients with refractory solid tumours: Updated results from ILLUMINATE-101 (ESMO 2019) - P1b, P2; "Tilsotolimod was well tolerated and induced robust alterations in the tumor microenvironment, including immune checkpoint upregulation, activation of dendritic cells, and induction of Type 1 IFN signaling. A phase II study of tilsotolimod in combination with nivolumab and ipilimumab has been initiated for the treatment of multiple solid tumors (ILLUMINATE-206; NCT03865082). Clinical trial identification: NCT03052205."

Clinical • IO biomarker • PD(L)-1 Biomarker • Melanoma • Oncology • Solid Tumor

Intra-tumoral therapy to make a "cold" tumor "hot": the jury is still out. (PubMed, Clin Cancer Res) - "Tilsotolimod, an oligodeoxynucleotide TLR9 agonist, administered intra-tumorally, has been clinically evaluated. This compound has demonstrated the ability to induce changes within the tumor microenvironment, to convert non-inflamed cold tumors into inflamed hot tumors, with the hope that these tumors will be more responsive to immune checkpoint blockade."

Journal • Immune Modulation • Inflammation • Oncology

ILLUMINATE 204: A Phase 2 Study to Assess the Safety and Efficacy of IMO-2125 With 8 mg Ipilimumab in Patients With Metastatic Melanoma (clinicaltrials.gov) - P2 | N=53 | Completed | Sponsor: Idera Pharmaceuticals, Inc. | Phase classification: P1/2 ➔ P2

Combination therapy • Phase classification • Melanoma • Oncology • Solid Tumor • BRAF

"Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated anti-tumor activity in preclinical models." (,@VivekSubbiah)

Preclinical • Oncology

"Overall, tilsotolimod monotherapy was generally well tolerated and induced rapid, robust alterations in the tumor microenvironment." (,@VivekSubbiah)

Biomarker • Monotherapy • Tumor microenvironment • Oncology

Idera Pharmaceuticals Shares Positive Results from Investigator-Sponsored Trial in Melanoma Patients at Amsterdam UMC (GlobeNewswire) - P2 | N=214 | INTRIM (NCT04126876) | "Idera Pharmaceuticals, Inc...shared positive interim results from Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands, regarding its investigator-sponsored trial, INTRIM 1, involving tilsotolimod, Idera’s synthetic Toll-like receptor 9 agonist. Based on these results, the trial has been stopped early...Noting that there were more patients with ulcerated lesions in the placebo arm compared to the tilsotolimod arm, topline interim results of the respective SLN-positivity rates showed a 70% lower SLN+ rate among patients injected with tilsotolimod as compared to those injected with placebo; the placebo SLN+ rate was in the mid-40%s. Statistical significance exceeded the pre-specified p-value of 0.008. Adverse reactions included injection site reactions, malaise, fever and flu-like symptoms."

P2 data • Trial status • Melanoma • Oncology

Tilsotolimod: an investigational synthetic toll-like receptor 9 (TLR9) agonist for the treatment of refractory solid tumors and melanoma. (PubMed, Expert Opin Investig Drugs) - "With encouraging early clinical results demonstrating extensive TME immunomodulation and abscopal effects on distant tumor lesions, tilsotolimod has emerged as a potential candidate immunomodulatory agent with the possibility to augment currently available immunotherapy and provide novel avenues of treatment for patients with advanced refectory cancer. Tilsotolimod is a novel TLR-9 agonist in phase II and III clinical trials for advanced refractory cancer."

Journal • Immune Modulation • Immunology • Inflammation • Melanoma • Oncology • Solid Tumor