Clinical Trials

Date: 2017-01-20

Type of information: update on patient enrollment

phase: 2b

Announcement: update on patient enrollment

Company: Prima Biomed (Australia)

Product: IMP321

Action mechanism: immunotherapy product/fusion protein. IMP321 is an antigen presenting cell (APC) activator. LAG-3, or Lymphocyte Activation Gene 3, is an immune checkpoint receptor 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-class APC activator. The product has been developed by the french company Immutep which Prima Biomed  acquired  in December 2014.

Disease: metastatic breast cancer

Therapeutic area: Cancer - Oncology

Country: Belgium, France, Hungary, The Netherlands, UK

Trial details: AIPAC (Active Immunotherapy PAClitaxel) AIPAC is the acronym for Prima’s planned multicenter, Phase IIb, randomized, double blinded, placebo-controlled clinical trial in HER-2 negative metastatic breast cancer patients receiving IMP321 or placebo as adjunctive to the standard-of-care chemotherapy drug paclitaxel. In a Phase IIa trial, IMP321 was able to increase the response rate (as per the RECIST criteria) at six months in these patients from the 25% expected of paclitaxel2 to 50% for IMP321 plus paclitaxel. The primary purpose of the AIPAC trial is to determine the clinical benefit of IMP321 in terms of Progression-Free Survival in this patient population (power 80%). The design of the study has been examined by the EMA’s Scientific Advice expert panel in the view of using these data for Marketing Authorization in the EU in tested setting. The protocol that arose from Prima’s interaction with the EMA will see women recruited into AIPAC with metastatic breast cacer where the tumour is HER-2-negative but hormone receptor positive. These patients will be receiving paclitaxel as first line chemotherapy after having failed on hormone therapy. They will represent a large patient population (hormone receptor-positive breast cancer is accounting for app. 75 percent of all cases) for which there are few viable treatment options, as indicated by the fact that PFS in such patients can be as low as six months. In the AIPAC study, patients will be administered subcutaneous doses of IMP321 on days 2 and 16 of a weekly regimen of paclitaxel, the day after their paclitaxel infusion. AIPAC will aim to initially recruit 15 patients for a smaller safety run-in in three different countries. This section of the trial will test in combination with paclitaxel the safety of IMP321 in doses up to 30 mg per dose, which has previously been shown to be safe when tested as a monotherapy and is significantly higher than the maximum 6.25 mg dose from the Phase I in metastatic breast cancer.  After the safety run-in the AIPAC investigators will proceed to recruit 196 patients, randomising them 1:1 to either standard-of-care paclitaxel plus placebo or paclitaxel plus IMP321 for six months as per the Phase I dosing regimen, after which the responding or stable patients will be maintained for another year with monthly IMP321 injections. The study has been powered to show a four-month PFS advantage for the treatment group. Allowing time for patient recruitment and follow-up, AIPAC’s expected duration is around three years. Prima envisages setting up at least 30 study sites for AIPAC in six European countries – starting with Belgium, France and the Netherland.(NCT02614833)

Latest news:

• • On January 20, 2017, Prima BioMed announced the first patient has been dosed as part of the enlarged randomised phase of its AIPAC Phase IIb clinical trial for IMP321 in metastatic breast cancer. The randomised phase of AIPAC (Active Immunotherapy PAClitaxel) will see half of the 226 patients receiving paclitaxel plus a placebo and half receiving paclitaxel in conjunction with IMP321. This follows the Dose Escalation Committee approval of the 30 mg dosage level for IMP321 and commencement of the randomised study on December 30, 2016.
• • On December 22, 2016, Prima BioMed announced interim data from the AIPAC Phase IIb clinical trial for IMP321 in metastatic breast cancer (Active Immunotherapy PAClitaxel). The initial data confirms previous trial results showing IMP321 is safe and well tolerated. In this Phase IIb study of IMP321 plus paclitaxel chemotherapy in patients with hormone receptor-positive metastatic breast cancer, data from all 15 patients in the safety run-in phase demonstrated that IMP321 is safe and well tolerated at both the 6mg and 30mg dosage levels. Immune monitoring data has also confirmed that IMP321, as an Antigen Presenting Cell (APC) activator, is working to generate the desired immune responses. The data demonstrated activation and an increased level of blood monocytes, dendritic cells and CD8 T-cells. Subject to the confirmation of the dose escalation committee on the 30th December, Prima will now commence the randomised phase of the trial in January 2017. Patients will receive paclitaxel treatment plus placebo or paclitaxel in conjunction with IMP321.
• • On December 20, 2016, Prima BioMed announced that it has received approval from the Competent Authority and Ethics Committee in the UK for its Phase IIb, AIPAC clinical trial of IMP321. Following conclusion of the safety run in phase, expected in late December, and subject to the dose escalation committee meeting, screening for the larger, randomised phase of the trial is expected to commence in January 2017. The safety run-in phase of the first cohort of 15 patients is being conducted across 11 clinical sites in Belgium, The Netherlands and Hungary. Recruitment of the last two patients in this cohort was completed in October. The first safety and pharmacokinetic data from these 15 patients is expected in late December 2016. As previously announced, AIPAC’s expected duration based on forecast recruitment times and patient follow up is approximately three years. Prima also confirms that interim data from the first cohort of patients in its Phase I, TACTI-mel clinical trial of IMP321 together with pembrolizumab for metastatic melanoma patients is also expected in late December 2016. • On June 22, 2016, Prima BioMed announce initial safety data from the first cohort of patients in its Phase IIb AIPAC chemo-immunotherapy clinical study of IMP321. The trial is currently being conducted out of Belgium, The Netherlands and now also Hungary, with further European sites to be initiated in the future. The first six patients have received 6 mg doses of IMP321 in combination with paclitaxel. This dose has proved to be safe and well tolerated with no drug related serious adverse events. The data also demonstrated activation of blood monocytes/dendritic cells and CD8 T cells. Prima BioMed will now start enrolling nine additional patients in the second cohort with 30 mg of IMP321, with the results of both cohorts to be presented and compared in the fourth quarter of 2016. Then the randomisation phase with the recommended phase IIb dose will begin enrolling approximately 196 patients.
• • On March 2, 2016, WuXi Biologics , a wholly owned subsidiary of WuXi AppTec, and Prima BioMed , an Australian immuno-oncology company, announced that through theirstrategic supply partnership, Prima’s first-in-class immuno-oncology product candidate IMP321 (LAG-3 Ig fusion protein), manufactured at WuXi’s state-of-the-art cGMP facility in China, has now been dosed in a Phase IIb clinical trial in Belgium. This event represents two significant milestones. It is the first time a biologic manufactured in China has been released for use in a clinical trial within countries in the EU. It also marks the first patient being dosed in AIPAC (Active Immunotherapy PAClitaxel), Prima’s Phase IIb clinical trial in metastatic breast cancer. WuXi is supplying IMP321 to Prima’s AIPAC trial, which is being conducted in Europe, as well as to its TACTI-Mel Phase I melanoma trial currently recruiting in Australia.
• • On December 22, 2015, Prima BioMed announced the initiation of the first trial site for AIPAC. In October, Belgium had become the first jurisdiction to clear the AIPAC clinical trial application by the competent regulatory authority. Now, four sites within Belgium and three sites within the Netherlands have been approved by their Institutional Review Boards. The University Hospital Saint-Luc in Brussels will be the first AIPAC trial site ready for patient enrolment. The first patient is expected to be dosed in early 2016. AIPAC is expected to recruit patients across 30 sites in 6 European countries once all approvals have been obtained. Work with the relevant pharmaceutical regulators and site administrators will continue for the remainder of 2015 and into 2016 to progress the study to its full recruitment capacity. As advised in July 2015, AIPAC’s expected duration based on forecast recruitment times and patient follow up, is around three years. • On October 27, 2015, Prima BioMed announced its first regulatory approval facilitating commencement of thelandmark Phase IIb clinical study of IMP321. The AIPAC (Active Immunotherapy PAClitaxel) clinical trial application has been cleared by Belgium’s Federal Agency for Medicines and Health Products (FAMHP). Prima continues work to obtain ethics approval by the Institutional Review Boards (IRB) at the chosen study sites in Belgium. IRB approval is the final approval required before trial initiation.
• • On July 7, 2015, Prima BioMed announced that it has received positive Scientific Advice from the European Medicines Agency (EMA) on the development path for its lead product, IMP321 in metastatic breast cancer. After dialogue between Prima and the EMA, the Agency has now confirmed in writing its endorsement of the  development program of IMP321 in metastatic breast cancer.
• Encouragingly, the planned Phase IIb study, to be called AIPAC (Active Immunotherapy PAClitaxel) is considered well designed by the Agency. AIPAC is now expected to initiate in Europe during the 4th quarter of 2015. While the EMA never endorses any statement on the likelihood of future regulatory decisions, the Agency’s communication has suggested that the achievement of certain clinical endpoints may lead to Marketing Authorization in the EU based on this one pivotal study. After a smaller safety run-in phase that will extend into 2016 and will yield valuable safety, pharmacokinetic and pharmacodynamic data, AIPAC will proceed to recruit around 200 patients with HER-2 negative metastatic breast cancer, randomising them 1:1 to either standard-of-care paclitaxel plus placebo or paclitaxel plus IMP321.The trial will have Progression-Free Survival as its Primary Endpoint, with response rates according to the RECIST criteria and Overall Survival among the secondary endpoints. The study has been powered to show a four-month PFS  advantage for the treatment group. Allowing time for patient recruitment and follow-up, AIPAC’s expected duration is around three years.

Is general: Yes