Welcome to this first blog, which I will use to expand on the details of our upcoming clinical study. It’s a somewhat unusual design, so worth a moment or two to look at in some detail.
The first thing to comment on is why we are conducting the study in Eastern Europe and not Australia. Georgia has been selected mainly because of access to patients and speed of recruitment. We could have conducted the study in Australia, but it would have taken considerably longer to start and to fully recruit. The saying ‘time is money’ is no more important than in drug development, particularly with the clock ticking away on patent life. Every 12 months you can shave off a drug’s development represents 5% of that drug’s ultimate value.
Other factors we took into consideration were the availability of experienced investigators, a good infrastructure for clinical research, and a good general standard of health care. The FDA recently conducted an audit of clinical data coming out of Georgia and gave it the tick of approval.
https://clinicalaccelerator.com/2014/10/07/fda-inspections-produce-solid-evidence-of-high-quality-clinical-trial-data-originating-in-central-and-eastern-europe/
Just a quick note about the patients. They will have solid cancers (not leukaemias) and will have failed to respond to standard treatment options, including standard cytotoxic drugs such as carboplatin, cisplatin and paclitaxel. On the whole, these will be patients who would not normally be expected to show any meaningful response to further treatment with cytotoxic chemotherapy such as carboplatin.
The ‘time is money’ mantra also has driven the design of the clinical study, with 3 phases (1a, 1b, 2a) compressed into the one study using the adaptive design approach. Adaptive design essentially means that you build into the design upfront the ability to change the study in response to clinical observations. Then instead of having to stop the study and submit a design for a new study to the approving authorities, the original study can be amended/expanded according to pre-agreed principles.
The Phase 1a study simply is looking at safety of idronoxil on its own. Idronoxil has been used in enough patients (> 400) for us to know that it is very well tolerated. In fact the only notable toxicity reported is fatigue, and that was at high dosages. This high safety profile is unremarkable, fitting in with the target of idronoxil being restricted to cancer cells. Despite this, we nevertheless have to go back and re-evaluate its safety because we now are using it in a way that we believe is going to deliver considerably higher levels of active drug in the body than ever was achieved in the past. We won’t be giving any more drug than has been used before; it is just being given in a way that we expect to lead to much more drug being available to work, and that means needing formally to re-check its tolerability.
As part of testing for safety, we are using 3 different dosages of idronoxil (400, 800 and 1200 mg per day). There will be 5 patients in each dosage cohort and each patient is treated daily for 14 days. If these dosages are well tolerated, as we expect, then patients progress (following a week’s rest) onto the Phase 1b arm, retaining their dosage of idronoxil.
The Phase 1b arm introduces carboplatin into the treatment regime. The carboplatin is administered intravenously once per month for 6 months. Idronoxil is administered daily for 7 days, starting the day before the carboplatin injection.
Patients receive a low dose of carboplatin (AUC=4) for the first 3 months and then that increases to a standard dose of AUC=6 for the final 3 months.
The aims of the Phase 1b arm are (a) to look for any unexpected toxicity with the idronoxil + carboplatin combination, (b) to observe any clinical responses (as determined by CT scan each 3 months), and (c) to determine whether idronoxil can provide meaningful clinical response with a sub-standard, but well tolerated, dosage of carboplatin.
Where a clinical signal is observed, that will serve to trigger the Phase 2a arm. This arm will be conducted in patients with selective cancer types, with a maximum of 2 cancer types to be studied. Simply by way of example, if we saw meaningful clinical responses (partial or complete remission) in at least 1 patient with lung cancer and in another patient with breast cancer, then another 10 patients would be recruited with lung cancer at the same stage of disease as the original responder, and similarly another 10 patients with breast cancer.
The 3 arms – Phase 1a, Phase 1b and Phase 2a – will be reported on separately as each concludes over the course of the anticipated 15-18 months of the study.
The study is based on 2 hypotheses:
a) The first is that idronoxil can abrogate multi-drug resistance mechanisms and restore sensitivity to carboplatin in late-stage cancers, resulting in meaningful and durable clinical response;
b) The second is that we will see sufficient evidence of clinical benefit when idronoxil is matched with a dose of carboplatin generally considered to be too low to provide any anti-cancer effect.
The next level of study then is expected to build on either or both scenarios.
In my next Blog I will discuss the technology behind NOX66.