information: Treatment of the first patient
Announcement: update on patient enrollment
Company: Prima Biomed (Australia)
Product: IMP321 and pembrolizumab
mechanism: immunotherapy product/fusion protein/monoclonal antibody/immune checkpoint inhibitor. IMP321 is an antigen presenting cell (APC) activator. LAG-3, or Lymphocyte Activation Gene 3, is able to stimulate and in other cases inhibit an immune response, through involvement in a number of immune pathways. IMP321 is a soluble LAG-3Ig fusion protein which works by binding to MHC class II molecules on APCs such as dendritic cells to activate them. The APCs are important for showing cancer antigens to T cells and activating them to destroy cancer cells. IMP321 is a firstin-classAPC activator. The product has been developed by the french company Immutep which Prima Biomed acquired in December 2014.
Keytruda® (pembrolizumab - MK-3475) is a 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, pembrolizumab enables activation of the immune system’s T-cells that target cancer by essentially releasing a brake on the immune system.
The pre-clinical and clinical evidence to date has suggested that IMP321 can treat cancer by activating Antigen Presenting Cells (APC) to sustain an anti-cancer immune response. This is a markedly different mechanism of action from the checkpoint inhibitors and suggests that the two approaches can be used synergistically in combination.
area: Cancer - Oncology
details: ‘TACTI-mel’ (Two ACTive Immunotherapeutics in melanoma) is a multicentre, open label, Phase I study in which patients with unresectable or metastatic melanoma will be dosed with IMP321 in combination with an approved checkpoint inhibitor (pembrolizumab). The study will evaluate safety as the primary endpoint and anti-tumour activity and the immune response to the combination as secondary endpoints. TACTI-mel will recruit 24 patients with Stage III/IV metastatic melanoma being treated with an approved checkpoint inhibitor and add IMP321 to the dosing regimen. Patients will receive ascending subcutaneous doses of IMP321 up to 30 mg per injection fortnightly for 13 injections. (NCT02676869)
- • On April 20, 2017, Prima BioMed announced that approval has been granted for the third cohort of its Phase I clinical trial for IMP321 in combination with Keytruda® being conducted in Australia. The third cohort will recruit six patients with unresectable or metastatic melanoma. Interim data results from the first patient cohort released in December 2016 indicate IMP321 at the 1mg dose level is safe and well tolerated. Out of the six patients in the first cohort (all with suboptimal response to Keytruda® mono therapy) two patients had a partial or complete radiological tumour response according to immune related response criteria (irRC).
- The positive safety profile was also confirmed in the second cohort dosed with 6 mg of IMP321. None of the 6 patients treated with Keytruda® plus IMP321 at this higher dose level experienced any serious adverse reaction nor dose limiting toxicity. As a result, the independent Drug Safety Monitoring Board (DSMB) has granted approval for the third cohort, at the 30mg dose level, to commence with the first patient to be dosed in due course.
- • On January 12, 2017, Prima BioMed announced that the first patient has been dosed for the second cohort of its clinical trial program for IMP321 in combination with Keytruda® being conducted in Australia. The second cohort will recruit up to six patients with unresectable or metastatic melanoma that have had a suboptimal response to Keytruda®. Interim data from the first patient cohort released in December 2016 indicate IMP321 is safe and well tolerated. On the basis of this safety data, the Data Safety Monitoring Board (DSMB) gave approval for the second cohort to commence.
- • On December 29, 2016, Prima BioMed announced interim data for its TACTI-mel clinical trial program for IMP321 in unresectable or metastatic melanoma patients. The Database Safety Monitoring Board (DSMB) confirmed that IMP321 is safe and well tolerated at the first dose level when used in combination with the anti antibody pembrolizumab and dose escalation can continue as planned. No drug related serious adverse events have been reported and the DSMB approved the continuance of the dose escalation as planned. The trial will now proceed to the next dose level of 6 mg. Further data updates in terms of safety and activity could be expected throughout 2017.
- • On January 27, 2016, Prima BioMed announced the initiation of the first clinical trial site for TACTI-mel, a Phase I clinical study in melanoma using its lead compound IMP321, to be conducted in Australia. TACTI-mel’ (Two ACTive Immunotherapeutics in melanoma) is a multicentre, open label, Phase I study in which patients with unresectable or metastatic melanoma will be dosed with IMP321 in combination with an approved checkpoint inhibitor. The first clinical site, the Gallipoli Medical Research Foundation at the Greenslopes Private
Hospital in Queensland, has been approved by the Australian Therapeutic Goods Administration (TGA). Recruitment for the trial can now commence under the direction of Dr. Victoria Atkinson, Principal Investigator for the trial. The TACTI-mel study will recruit up to 24 patients across 6 sites in Australia, with the first patients expected to be dosed in the first quarter of 2016.
• On November 18, 2015, Prima BioMed unveiled a new clinical trial of IMP321, to be called ‘TACTI-mel’, short for ‘Two ACTive Immunotherapeutics in melanoma’. In this ground-breaking safety and dose finding study IMP321 will be combined with an approved checkpoint inhibitor in patients with metastatic melanoma.
The Human Research Ethics Committee at the Greenslopes Private Hospital in Greenslopes, Queensland has approved Prima’s Phase I clinical trial protocol, and it is expected that the first patient in the TACTI-mel study will be dosed in the first half of 2016. This will represent one of the first clinical occasions in which an Antigen Presenting Cell (APC) activator has been combined with a checkpoint inhibitor.
The pre-clinical and clinical evidence to date has suggested that IMP321 can treat cancer by activating APCs to sustain an anti-cancer immune response. This is a markedly different mechanism of action from the checkpoint inhibitors, and suggests that the two approaches can be used synergistically in combination. Prima advised the market in May 2015 that it had filed a provisional patent application over the use of IMP321 in combination with immune checkpoint inhibitors, thereby potentially providing patent exclusivity for the product to 2035 or beyond if granted. TACTI-mel now builds on the work that went into that patent filing by taking the concept into the clinic to evaluate its safety as well as the ideal dosing combination. TACTI-mel will be the second clinical study to be initiated for IMP321 since Prima BioMed acquired the compound in December 2014.