- The Phase 1 portion of our Phase 1/2 clinical trial of AP26113 is ongoing, and we expect to transition into the four Phase 2 expansion cohorts [crizotinib-naive ALK+ NSCLC, crizotinib-resistant ALK+ NSCLC, EGFR-mutant NSCLC resistant to at least one EGFR inhibitor, and other ALK+ or ROS fusion tumors] in the second quarter of 2013.
- A fifth Phase 2 cohort in ALK-positive NSCLC patients with brain metastases is also being planned [big problem - over 50% of NSCLC failures, including crizotinib failures. No comment on whether these patients will have had crizotinib already...Excited about CNS activity that has been seen with '113. Best way to characterize activity was to study separately in phase 2...not to say these patients won't be part of broader ALK registrational strategy...no comment on entry criteria for pivotal trial until it starts...no comment on if they are seeing brain met responses in the dose escalation phase].
- We will advance a dose and schedule for AP26113 in the Phase 2 cohorts that are appropriate based on safety, tolerability, and pharmacokinetics (i.e., circulating trough plasma levels of AP26113) [to provide best opportunity for clinical success in each of the patient groups being studied - want to get to IC90 for target mutant EGFR oncogene...have a large margin for inhibition of ALK...determining this dose/schedule is the hurdle to move into phase 2...also see my follow-up exchange with IR below].
- In parallel to the Phase 2 expansion cohorts, we plan to begin enrollment in a pivotal trial of AP26113 in ALK-positive NSCLC patients who are resistant to crizotinib in the third quarter of 2013 [no hurdle from phase 1/2 in terms of efficacy - we had enough efficacy data at ESMO last year to go forward with pivotal trial...we will enroll the phase 2 cohorts in the meantime, but they are not any prerequisite for the phase 3 trial].
- We will present clinical updates on AP26113 at the 2013 annual meetings of theAmerican Society of Clinical Oncology in June [will include all available data from phase 1 dose escalation, including more on activity in activity in patients with brain mets] and the European Society of Medical Oncology in September [expect to include additional phase 1 follow-up and initial phase 2 expansion cohort data, will make data cutoff as late as possible, sometime in September...amount of data will depend on how soon we transition to phase 2...but should have a couple months to enroll and follow patients].
- We will also apply for Breakthrough Designation status for AP26113 with the U.S. Food and Drug Administration. This designation is not required in advance of the start of the pivotal trial of AP26113 [as part of overall regulatory strategy...we asked the question directly and FDA's policy is that there can be multiple drugs for same indication can receive BT...not shut out because Novartis's LDK378 was first...jury is out on what difference it makes vs. priority review, accelerated approval, fast track...look at ICLUSIG, how could it be any faster?].
Analyst question: How will phase 2 patient population differ from the phase 1 dose escalation population? Phase 2 subjects will be more homogeneous, better defined/characterized, "more strict boundaries about being EGFR mutant". Want to be sure and verify from new tissue sample that they have mutant EGFR and tumor is dependent on the oncogene at the time of failure of previous EGFR inhibitor (ie, erlotinib). A goal for phase 2 is to define the timing between failure of the prior EGFR inhibitor and initiation of AP26113 (2-4 weeks or maybe even shorter). Phase 1 patients may have had history of EGFR mutation, but may not be reproducible. Also, of a given 10 erlotinib failures, only five or so would be expected to have T790M mutation and be responsive to a better EGFR inhibitor...others would have different mechanisms of resistance.
I also followed up with Ariad IR rep Kendra Adams via email after the conference call:
Could you clarify as to whether you would consider different doses/schedules for the different phase 2 expansion cohorts?
Our plan has always been to have one dose for both the ALK and EGFR opportunity for AP26113. Having said that, we plan to have the optimal dose and schedule for each of these opportunities. We will have more of an update to provide when we move to the phase 2 cohorts.