SanFran,

Look back at slide 17 of the Q2 update slides. That slide detailed the "3 + 3 Dose Escalation Design" of the trial. Here's a little explanation from a journal article I pulled up that explains this trial design. Just something to keep in mind.

They started dosing June 15, 2016 and each dose escalation step happens every 28 days. So my understanding is that the 28 day cycles will end July 13 (cycle 1), August 10 (cycle 2), September 7 (cycle 3), October 5 (cycle 4), November 2 (cycle 5), November 30 (cycle 6), December 28 (cycle 7). It may take a few cycles to start getting into the therapeutic dose range, since they are likely starting at a sub-therpeutic dose. Additionally, the optimal therapeutic dose and maximally tolerated doses may not be for 1-3 cycles after that. This means we will likely still be in Q4 2016 before the pharmacokinetic and safety portion is far enough along to conclude the the optimal dose/maximally tolerated dose and dosing schedule. If my understanding is correct, with each subsequent cycle they only add 3 patients each time they go to the next highest dose. So there will be "few patients actually receiv[ing] doses at or near the recommended dose for phase II trials."

Oncoethix and their first generation OTX-015 pan BET-inhibitor started at 10 mg dose, went up to 120 mg for lymphoma/multiple myeloma, or 160 mg dose for acute leukemia, and decided on 80 mg dose for phase 2. This was their 4th dose.

In my opinion, the most important things for value creation is efficacy without side effects and ability to perform daily dosing without an on drug/off drug cycle needed for some of these earlier first generation pan BET-inhibitors. Efficacy is important, but safety and daily dosing would really set Zenith apart from other pan BET inhibitors.

"Traditional 3+3 Design

The traditional 3+3 design remains the prevailing method for conducting phase I cancer clinical trials (7). It requires no modeling of the dose–toxicity curve beyond the classical assumption for cytotoxic drugs that toxicity increases with dose. This rule-based design proceeds with cohorts of three patients; the first cohort is treated at a starting dose that is considered to be safe based on extrapolation from animal toxicological data, and the subsequent cohorts are treated at increasing dose levels that have been fixed in advance (Figure 2, B). Historically, dose escalation has followed a modified Fibonacci sequence in which the dose increments become smaller as the dose increases (eg, the dose first increases by 100% of the preceding dose, and thereafter by 67%, 50%, 40%, and 30%–35% of the preceding doses). In most cases, the prespecified dose levels do not fit the exact Fibonacci sequence as described in the 12th century (5). If none of the three patients in a cohort experiences a dose-limiting toxicity, another three patients will be treated at the next higher dose level. However, if one of the first three patients experiences a dose-limiting toxicity, three more patients will be treated at the same dose level. The dose escalation continues until at least two patients among a cohort of three to six patients experience dose-limiting toxicities (ie, ≥33% of patients with a dose-limiting toxicity at that dose level). The recommended dose for phase II trials is conventionally defined as the dose level just below this toxic dose level.

The main advantages of the traditional 3+3 design are that it is simple to implement and safe (Table 2). In addition, the accrual of three patients per dose level provides additional information about pharmacokinetic interpatient variability. However, a disadvantage of this design is that it involves an excessive number of escalation steps, which results in a large proportion of patients who are treated at low (ie, potentially subtherapeutic) doses while few patients actually receive doses at or near the recommended dose for phase II trials. This latter point is illustrated in Table 3, which presents the dose escalation method used as well as the number of dose levels in recent first-in-human single-agent phase I trials for anticancer agents that were eventually (1992–2008) approved by the US Food and Drug Administration (FDA) for the treatment of solid tumors. Among 21 trials that used the traditional 3+3 design, more than half involved six or more dose levels."