Aduro presented preliminary results from early clinical studies with the stimulator of interferon genes (STING) agonist ADU-S100 in heavily pre-treated patients with solid tumors and lymphomas at the Society for Immunotherapy of Cancer 33rd Annual Meeting (SITC 2018). The data showed encouraging initial clinical response both as a monotherapy and in combination with the ant-PD1 antibody Spartalizumab. Aduro and collaborator Novartis embarked on this first-in-human trial as an important first step in characterizing the safety profile and mechanism of ADU-S100 and its ability to activate the STING pathway.

Data Highlights from ADU-S100 Monotherapy Trial

The Phase 1 dose escalation and dose expansion clinical trial is designed to evaluate the safety, tolerability and clinical activity of ADU-S100 in patients with advanced, metastatic treatment-refractory solid tumors or lymphomas. In this multicenter, open-label trial, ADU-S100 is administered intratumorally on Days 1, 8 and 15 of a 28-day cycle.

The trial has enrolled 41 patients, with 40 patients evaluated for response. The median number of prior anti-cancer treatments was four (range 0-15). More than half of patients (53.7%) received prior therapy with a checkpoint inhibitor.

• More than 20 types of cancer have been treated in this trial, including Merkel cell, parotid gland, colorectal, endometrial, ER+ and triple-negative breast cancer, esophageal, collecting duct carcinoma, ovarian, Hodgkin’s disease, hemangioepithelioma and other cancers.
• Doses of 50-3200 mcg have been explored in this presentation; enrollment is ongoing for additional patient cohorts.
• No dose-limiting toxicities have been reported at these dose levels. The most common (≥10% of patients) treatment-related adverse events (TRAEs) were pyrexia, injection site pain and headache. Grade 3/4 TRAEs included increased lipase and elevated amylase, tumor pain, dyspnea, respiratory failure and injection site reaction.

Clinical and Biomarker Activity

• Importantly, increases in key systemic cytokines, including IL-6, MCP-1 and IFN-b, were observed after administration, indicating target engagement of ADU-S100 and activation of the STING pathway.
• Two of the 40 patients treated had a partial response (PR) – one patient with Merkel cell carcinoma and one patient with parotid gland cancer who had received prior anti-PD-1 therapy.
• 11 patients achieved stable disease (SD), including five patients who had received prior checkpoint inhibitor therapy.
• Three patients with SD remain on study and continue to receive treatment, including one patient with collecting duct carcinoma who has been on study for greater than one year.
• On-treatment tumor biopsies showed increases in CD8+ T cells in injected tumors in a subset of patients, including those with Merkel cell, collecting duct and esophageal carcinomas. Aduro and Novartis are continuing to evaluate additional pathology and other biomarkers to assess the pharmacological activity of ADU-S100 in these patients.

“We are encouraged by the data obtained from the dose escalation portion of this first-in-human trial of ADU-S100 in heavily pre-treated patients with a diverse set of advanced cancers,” commented Stephen T. Isaacs, chairman and chief executive officer of Aduro Biotech. “Based on the safety profile and interesting signals observed from the clinical approach to date, we expect to collect additional biomarker data and have begun to enrich monotherapy dose cohorts with additional patients of select tumor types. At the same time, we have expanded the breadth of our joint development program with our colleagues at Novartis to focus on combination with checkpoint inhibitors in melanoma and other homogeneous patient populations where we seek to deliver clinical benefit to patients in need.”

In September 2018, this trial was amended to include a study arm evaluating ADU-S100 in combination with ipilimumab at its approved dose and schedule. Following a short dose escalation, the expansion phase aims to enroll patients with cutaneously and viscerally accessible melanoma who have relapsed or are refractory to PD-1 inhibitors.

Ongoing Phase 1b Trial of ADU-S100 + Anti-PD-1 Monoclonal Antibody Spartalizumab

A Phase 1b dose escalation and dose expansion clinical trial is ongoing to evaluate the safety and preliminary efficacy of ADU-S100 in combination with spartalizumab (PDR001), Novartis’ investigational anti-PD-1 monoclonal antibody (see www.clinicaltrials.gov, identifier NCT03172936). The multicenter, open-label trial is currently enrolling patients with advanced, metastatic treatment-refractory solid tumors or lymphomas and is evaluating two treatment schedules of ADU-S100 in dose escalation with a fixed dose of spartalizumab. Patients in Group A receive a fixed dose of intravenous spartalizumab on day 1 and an intratumoral injection of ADU-S100 three times (day 1, 8, 15) in a 28-day cycle. Patients in Group B receive a fixed dose of intravenous spartalizumab on day 1 and an intratumoral injection of ADU-S100 on day 1 of every 28-day cycle.

• The dose escalation combination trial has enrolled 50 patients with multiple cancers and who received multiple lines of prior therapies including prior immunotherapy.
• Patients have been treated with full-dose PDR001 and increasing dosing of intratumoral ADU-S100 (50-400mcg); enrollment is ongoing for additional patient cohorts.
• No dose-limiting toxicities have been reported.

In the early dosing cohorts of the ongoing study of ADU-S100 in combination with spartalizumab, preliminary observations include: 1) clinical responses observed in several tumor types, including two patients who had previously demonstrated responses to checkpoint inhibitor therapy alone; 2) reduced tumor volume in injected and non-injected lesions in some patients; 3) several patients remained on study longer than 6 months; and 4) safety profile consistent with what has been observed in the ADU-S100 monotherapy study.

Isaacs continued, “While still early, the preliminary observations emerging from initial dose cohorts of ADU-S100 plus spartalizumab are promising. In particular, the observation of clinical benefit in patients who received prior PD-1 therapy may provide further evidence supporting the synergy between STING and checkpoint inhibitor therapy that was previously demonstrated by our preclinical results. Extensive biomarker analysis is ongoing to assess biological activity. We and Novartis are committed to further exploration of the potential of ADU-S100 as a combination agent with both spartalizumab and ipilimumab in dose escalation and expansion into homogeneous patient populations. We look forward to seeing how these data evolve over time and expect to report on the results of these studies at future medical meetings.”

Source: Aduro Biotech

Cristal Therapeutics, a clinical stage pharmaceutical company developing unique nanomedicines for the treatment of cancer and other diseases, announced that the first patient has been dosed in its Phase 2 clinical trial of lead nanomedicine candidate CPC634 for patients with platinum-resistant ovarian cancer.

CPC634 is a new drug modality. It combines CriPec® nanoparticles with docetaxel (Taxotere®), a clinically validated chemotherapy, as its therapeutic payload. This nanomedicine candidate has been designed to enable enhanced tumour accumulation and localised drug release at the target site, with the goal of boosting therapeutic efficacy. In addition, it is anticipated that CPC634 will overcome the shortfalls associated with current docetaxel products, including toxic systemic side effects.

Dr Joost Holthuis, Cristal Therapeutics’ CEO and co-founder said, “Results from our Phase 1 NAPOLY study demonstrated that CPC634 can be administered safely and was well tolerated by patients with advanced solid tumours. CPC634 also demonstrated encouraging signs of efficacy and reduction in systemic side effects commonly seen with docetaxel.”

Professor Jonathan Ledermann, BSc MD, FRCP, UCL Cancer Institute, London, and Principal Investigator added: “Treatment of platinum-resistant ovarian cancer is an area of high unmet medical need and this trial will give us the opportunity to assess both the therapeutic efficacy of CPC634 and its potential to reduce toxic systemic side-effects such as neutropenia and alopecia, seen with the current standard of care.”

The primary objective of the trial will be to determine the response rate as measured by RECIST, a standard unbiased method for assessing whether a tumour shrinks, stays the same, or gets bigger, with CPC634 monotherapy. The clinical study will be conducted in 10 centres across the UK, Belgium, Netherlands, and Spain.

Source: Cristal Therapeutics

Alexion and Dicerna have announced a collaboration to discover and develop RNA interference (RNAi) therapies for complement-mediated diseases. An RNAi-based approach to blocking the production of complement pathway factors offers the potential to inhibit the uncontrolled complement activation that leads to many diseases. The agreement provides Alexion with exclusive worldwide licenses as well as development and commercial rights for two of Dicerna’s preclinical, subcutaneously delivered GalXC™ RNAi molecules and an exclusive option for other preclinical GalXC RNAi molecules for two additional targets within the complement pathway.

“With Soliris, Alexion has demonstrated the transformative impact of complement inhibition on multiple serious and debilitating diseases,” said John Orloff, M.D., Executive Vice President and Head of Research & Development at Alexion. “This collaboration provides the opportunity to continue building on our more than two decades of complement expertise using Dicerna’s proprietary GalXC RNAi technology platform, which provides a potentially promising new way of inhibiting the uncontrolled complement activation that we know plays a significant role in many devastating diseases.”

“Dicerna’s proprietary GalXC technology is designed to silence the expression of disease-driving genes in a way that is highly specific, generally well tolerated, and allows for convenient, infrequent subcutaneous administration. Having recently demonstrated clinical proof-of-concept for DCR-PHXC, our lead program for the treatment of primary hyperoxaluria, we are eager to expand and advance our pipeline of innovative GalXC therapies, including both proprietary and partnered programs,” said Douglas M. Fambrough, Ph.D., President and Chief Executive Officer of Dicerna. “Our collaboration with Alexion provides access to the deep expertise and resources of an established leader in complement-mediated diseases. We look forward to working with Alexion to discover and develop promising new RNAi therapies.”

Under the terms of the agreement, Alexion and Dicerna will collaborate on the discovery and development of subcutaneously delivered GalXC RNAi molecules directed to two complement pathway targets for the treatment of complement-mediated diseases. In addition, Alexion will have the right to exercise options, for additional payment, for two additional GalXC RNAi molecules directed to complement pathway targets. Dicerna will lead the joint discovery and research efforts through the preclinical stage, and Alexion will lead development efforts beginning with Phase 1 studies. The agreement provides Alexion with exclusive worldwide licenses and commercial rights to the GalXC RNAi molecules developed in the collaboration. Dicerna will receive an immediate upfront payment of $22 million, with Alexion making a concurrent $15 million equity investment in Dicerna at a premium to market as of the collaboration effective date. The collaboration also provides for potential additional development and approval-related milestone payments of up to $105 million per target, plus sales milestones and mid-single to low-double digit royalties on future product sales.

Noodzaak en vermeende gevaren van vaccinatie tegen ziekten zijn volop in discussie. De Koninklijke Nederlandse Akademie van Wetenschappen (KNAW) hield er maandag in Amsterdam een symposium over.

Werden prikken in ons land vroeger vooral door wat kleinere groepen geweigerd uit geloofsovertuiging, nu is er vooral sprake van een groeiend aantal weigeraars onder jonge hoogopgeleiden, die bijvoorbeeld vinden dat de natuur zijn werk moet doen of ervan uitgaan dat het middel erger is dan de kwaal.

Zo zijn er mensen die denken dat je van een prik autistisch kunt worden. Intussen grijpt mazelen in Europa steeds forser om zich heen (al speelt dat nog amper in Nederland). Aan de andere kant was het vaccin tegen meningokokken in ons land weer niet aan te slepen na berichten over sterfgevallen.

Veel van de ‘wijsheden’ over prikken worden op eigen houtje van internet gehaald. Piek Vossen, hoogleraar aan de Vrije Universiteit in Amsterdam en een van de sprekers op het symposium, is met een klein aantal collega-wetenschappers bezig een systeem te ontwikkelen waarmee de internetter in één keer kan zien wie wat beweert over vaccinatie, wie wat gelooft of bestrijdt en hoe heftig, wat de bronnen zijn en hoe die zich weer onderling met elkaar verhouden.

Dergelijke software is natuurlijk voor alle onderwerpen handig, maar Vossen is met vaccinatie begonnen, wegens de overzichtelijkheid van het onderwerp. Ook is het eenvoudig effecten van zo’n toekomstige ‘perspectiefkaart’ te meten, gewoon door de kijken naar de vaccinatiegraad.

Hij hoopt binnen vijf jaar de software te hebben ,,waarmee je in een handomdraai een perspectiefkaart kan maken van de vaccinatiediscussie”, want de onzuiverheid van veel informatie is groot. ,,Veel berichten tegen vaccineren zijn terug te brengen op een enkele bron. Bovendien worden redenaties omgekeerd, zodat het de bronnen uitkomt. Zo gaat het verhaal dat er in Amerika nul mensen zijn gestorven aan mazelen en dat die gegevens afkomstig zijn van een belangrijk gezondheidsinstituut. Weggelaten is dat dat juist komt door de vaccinatie.”

Het symposium van maandag is bedoeld om uit te vinden hoe wetenschap en maatschappij concreet kunnen inhaken op een recent stuk van de Europese Commissie, dat pleit voor betere samenwerking tegen ziektes die met vaccinatie te voorkomen zijn. Wetenschappers op tal van terreinen werken mee aan de bijeenkomst.

Bron: Skipr