Clinical Trials

Date: 2018-03-12

Type of information: Initiation of development program

phase: 1-2

Announcement: presentation of results at the 59th American Society of Hematology (ASH) Annual Meeting

Company: Immune Design (USA - MA) Merck&Co (USA - NJ)

Product: G100 and pembrolizumab

Action mechanism:

• monoclonal antibody/immune checkpoint inhibitor/immunotherapy product/TLR4 agonist. Keytruda® (pembrolizumab - MK-3475) is an investigational, highly selective monoclonal anti-PD-1 antibody designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein. By blocking PD-1, MK-3475 enables activation of the immune system’s T-cells that target cancer by essentially releasing a brake on the immune system. Keytruda® is the first approved drug that blocks the PD-1 cellular pathway.
• G100 is a product candidate generated from Immune Design's GLAAS™ discovery platform, and includes a specific formulation of Glucopyranosyl Lipid A (GLA), a synthetic, toll-like Receptor-4 (TLR-4) agonist. G100 is part of Immune Design's intratumoral immune activation, or ‘Endogenous Antigen’ approach to treating cancer, which leverages the activation of dendritic cells, T cells and other immune cells in the tumor microenvironment to potentially create a robust immune response against the tumor's preexisting diverse set of antigens. Preclinical and clinical data have demonstrated the ability of G100 to activate dendritic cells in tumors and to increase antigen-dependent systemic humoral and cellular Th1 immune responses.

Disease: follicular lymphoma

Therapeutic area: Cancer - Oncology

Country: France, Spain, UK, USA

Trial details:

• This is a Phase 1/2 open label trial of G100 in patients with low grade NHL. G100 is composed of glucopranosyl lipid A in a stable emulsion and is a potent TLR4 (toll-like receptor-4) agonist. G100 will be administered by direct injection (intratumorally) into tumors of low grade NHL following standard low dose radiation therapy. Preclinical models and clinical studies in other cancers such as Merkel cell carcinoma have demonstrated that G100 administered in this manner can alter the tumor microenvironment, activate dendritic cells, T cells and other immune cells and induce systemic anti-tumor immune responses. In this trial, the safety, immunogenicity, and clinical efficacy of G100 will be examined alone or with pembrolizumab. (NCT02501473)

Latest news:

• • On October 11, 2018, Immune Design announced program updates for its G100 intratumoral TLR4 agonist. The company has completed a portfolio review and determined that, given advances in G100 and its broad potential, and existing capital, it should focus on accelerating and expanding the development of G100.
• G100 has a unique mechanism of action that differs from current therapies in lymphoma. It triggers an immune-mediated anti-tumor effect with a favorable safety profile that could position G100 as a pillar of chemo-free regimens for the treatment of lymphomas and beyond.
• Immune Design’s first goal is to develop G100 in combination with pembrolizumab in follicular lymphoma patients who have received three prior lines of systemic therapy. These patients may represent an unmet medical need, which may allow for an accelerated approval path in this indication.
• The company will evaluate the clinical activity based on Objective Response Rate (ORR) in an open label setting.
• To accelerate enrollment, Immune Design plans to use both an open IND and submit a new IND for this specific unmet medical need population, as requested by the FDA. The data from both INDs would be combined in a potential BLA filing. Based on existing ORR data, approximately 100 patients may be required. The final sample size will be adapted depending on the ORR observed in the initial patients.
• Given its broad potential reach, Immune Design’s second goal is to evaluate G100 beyond late-stage follicular lymphoma. Immune Design intends to evaluate G100 in earlier-stage follicular lymphoma patients in combination with rituximab, the backbone treatment for lymphomas in multiple lines of therapy. The company also plans to explore G100 in combination with other agents in both indolent and aggressive lymphomas that are known to express TLR4. Finally, the company plans to evaluate the safety and efficacy of G100 in solid tumors, initially through supporting investigator-sponsored studies.
• • On March 12, 2018, Immune Design  announced updated data from trials evaluating its lead product candidates, G100. Immune Design initially presented data at the 2017 American Society of Hematology Annual Meeting (ASH 2017) from a randomized Phase 2 trial of 26 follicular lymphoma patients, pursuant to a collaboration with Merck&Co (see below). Patients were randomized evenly to one of two treatment arms: G100 with fractionated, low-dose radiation (XRT) or G100+XRT with pembrolizumab combination therapy. The data have matured as of the most recent data analysis, with observations as follows:
• • Additional responses have been observed in the combination arm (54% ORR, compared to a 15% ORR in the G100+XRT arm). This is an improvement from the ASH 2017 data, which showed an ORR of 39% in the combination arm.
• • The patient population with high TLR4 expression in the tumor continue to receive greater benefit, with an updated 75% ORR on the combination arm (6/8 patients), an increase from the 57% ORR reported at ASH 2017.
• These data compare favorably to pembrolizumab monotherapy presented at ASH 2017, which showed an 11% ORR in a separate follicular lymphoma study.
• • 77% of patients in the combination arm experienced abscopal tumor shrinkage in un-injected tumors, compared to 54% of patients in the G100+XRT arm.
• • Patients in the combination arm demonstrated a greater increase of CD8 T cells within the tumors, as compared to the G100+XRT arm.
• • The safety profile continues to appear favorable when compared to recently approved therapies for patients with relapsed/recurrent disease.
• • On December 10, 2017, Immune Design presented data from the randomized Phase 2 trial of its investigational intratumoral TLR4 agonist G100 plus low-dose radiation (G100 Monotherapy) with or without Keytruda® (pembrolizumab) in follicular non-Hodgkin's lymphoma (FL) patients at the 59th American Society of Hematology (ASH) Annual meeting. The G100 Monotherapy and pembrolizumab combination resulted in a 39% objective response rate (ORR), with a 57% ORR in those patients who expressed a potential predictive biomarker.
• The randomized Phase 2 trial was designed to examine intratumoral (IT) administration of G100 Monotherapy vs. G100 Monotherapy + pembrolizumab (G+P) in either treatment naïve or recurrent/refractory FL patients (13 patients/arm). Highlights from the study include:
• Clinical Benefit: Patients receiving G+P showed a 39% ORR, as compared to 15% in the G100 Monotherapy arm. Pembrolizumab monotherapy in a similar recurrent/refractory FL study showed 11% ORR (Ding, ASH 2017 abstract). Patients receiving G+P also had more frequent and deeper abscopal tumor shrinkage and a trend toward a better progression free survival (PFS).
• Safety: Adverse events considered possibly related to G100 were Grade 1 or 2, with no related serious adverse events. The safety experience in the G+P arm did not suggest any unexpected or worsening toxicity compared to what has been reported previously with pembrolizumab alone.
• Potential Predictive Biomarker: A strong association between baseline tumor TLR4 expression and objective clinical response was observed. Reported ORR in patients with a >50% TLR4 expression by IHC (TLR4high) receiving G+P increased to 57%, including patients with recurrent/refractory disease.
• Potential Further Development: Because clinical responses were observed in patients with recurrent/refractory disease, treatment failure <2 years after rituximab-containing chemotherapy, and high-risk patients based on GELF criteria, G+P may provide a therapeutic option in this unmet medical need population. Enrichment of patients more likely to respond may be attained by selecting for high expression of TLR4.
• • On June 5, 2017,  Immune Design has updated clinical and biomarker data for its lead immuno-oncology product candidate G100. The data have been presented at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting in Chicago. In a poster presentation , Christopher Flowers, M.D., Department of Hematology and Medical Oncology, Emory University School of Medicine, has presented results of 9 patients with follicular lymphoma treated with escalating doses of G100 monotherapy (with local radiation (XRT)).
• Patient characteristics: of the 9 FL patients enrolled, 45% were treatment-naïve and 56% were relapsed/refractory, and most had Stage III and IV disease (56% and 33%, respectively). Additionally, 55% of patients had received at least two prior therapies and 78% had progressive disease upon study entry.
• Disease control: • Objective responses were observed at all three dose levels tested.
• • 44% of the patients achieved a partial response (PR) based on WHO criteria (at least a 50% tumor reduction).
• • Some patients had tumor shrinkage over a prolonged period, e.g., continuing up to 8+ months, and a duration of response exceeding 4 months in some patients.
• • DCR of 100% of patients (44% PR, 56% SD).
• • 50% of evaluable patients experienced shrinkage of untreated distal (abscopal) lesion.
• Safety: G100 was well tolerated, with no related Grade 3/4 AEs in all three dose levels tested.
• Tumor microenvironment: G100 resulted in favorable tumor microenvironment changes • Tumor biopsies showed increased inflammatory responses and T cell infiltrates in abscopal, non-treated tumors.
• •  On April 20, 2016, Immune Design announced that a Phase 1b/2 study evaluating intratumoral G100 in patients with follicular non-Hodgkin's lymphoma is currently enrolling patients. The study is evaluating the intratumoral administration of G100 with intravenous administration of Keytruda® (pembrolizumab), in patients with follicular non-Hodgkin's lymphoma receiving local radiation, pursuant to a collaboration with Merck&Co. The study is designed to evaluate G100 plus local radiation and Keytruda® compared to G100 plus local radiation alone. In addition to an evaluation of the safety of the combination, the study will assess the response in both injected and non-injected lesions.

Is general: Yes