Molecularly Tailored Therapy to Standard of Care as Second-Line Therapy in Metastatic Pancreatic Cancer

This is an open label, randomized Phase II trial for patients with metastatic pancreatic cancer. The trial is designed to compare the outcomes (primary endpoint will be progression-free survival (PFS)) for patients who receive molecularly-tailored therapy (MTT) to those who receive physician discretion standard of care (SOC). To successfully allow for this assessment, and minimize confounding variables, we will need to ensure that:

• There is enough tissue for the molecular profiling to occur. Thus, only patients with adequate tumor tissue will be allowed to enroll.
• There is enough time for the molecular profiling to be completed; for the medical review panel (MRP) to render a determination on the optimal molecularly-guided therapy; and for the treating physician to obtain access to therapies, particularly if the MRP-determined therapy includes an off-label treatment OR a clinical trial. We anticipate this process will take a minimum of 4 weeks.

These factors will inevitably lead to a selection bias towards patients with a better prognosis. However, the randomization design should mitigate this selection bias.

Patients with metastatic pancreatic cancer who are actively on (or about to initiate) first-line therapy, who meet the inclusion and exclusion criteria as detailed in Section 3 will be enrolled. For all enrolled patients, at the time of enrollment, the treating physician will be asked to submit the planned second line SOC treatment he/she would recommend.

In an effort to streamline accrual, and based on data that demonstrate that the tumor genetic profile does not change significantly overtime in patients with pancreatic cancer, archived tumor tissue may be used for determination of MTT. The archived tissue may be, for example, core needle biopsies obtained at the time of establishing the diagnosis of metastatic disease; or for example, a surgical specimen obtained prior to the identification of metastatic disease. Archived tissue may be used as long as there is sufficient tissue for full molecular testing. Of note, even if sufficient archived tissue is available for testing, patients will still be required to undergo a new biopsy to obtain fresh tissue for ex vivo analysis, prior to initiation of second line therapy.

Patients will then undergo tumor testing, as detailed next. If a patient undergoes tumor testing but his/her disease progresses on first-line therapy prior to an MRP-determined therapeutic plan, then the patient will be considered a screen failure, and will be replaced.

Then, for all patients for whom adequate tissue is available for profiling, an MRP-determined therapeutic plan will be developed. This process of determining the MRP-determined therapeutic plan will be kept blinded to the treating physician (i.e. each treating physician will NOT be involved in the determination of MTT for his/her patient) - but once the plan is available, the patients will be randomized to either MTT or SOC (See Figure 4):

Patients will be monitored closely while on first-line therapy. For patients who are randomized to MTT, the MRP-determined therapeutic plan will be unblinded to the treating physician, and preparation for MTT can begin, including acquiring access to off label therapy, if required. Patients who are randomized to SOC therapy will receive the SOC treatment initially recommended by the treating physician

Once a patient experiences disease progression on first-line therapy, they will receive MTT vs. SOC as second-line therapy, according to their randomization. Patients in both groups will receive second-line therapy until disease progression or therapy intolerance (with dose and schedule modifications as needed). Response assessment will occur approximately every 8 weeks (based on the calendar) as determined from the time of the initiation of therapy. All patients will have the option to undergo a repeat tumor biopsy upon disease progression.

Once patients on SOC therapy experience progressive disease on second-line therapy, the MRP-determined therapeutic plan will unblinded to the treating physician, and MTT therapy can be administered as third-line therapy (crossover to MTT). Third-line therapy can also incorporate correlative analyses on the patient tumor samples tested ex vivo (detailed below) if these results are available at the time that third line therapy is required. As this may impact the overall survival assessment, the primary endpoint is disease progression at 4 months (PFS4mos), and the primary objective is to compare the PFS4mos for MTT treated vs. SOC treated patients. We hypothesize that MTT will improve the PFS4mos from 50% for SOC (based on historical data), to ≥75%. We anticipate having 80% power to detect an improvement in the PFS4mos from 50% to ≥75% (hazard ratio (HR) = 0.5), assuming a 1-sided significance level of 0.05 and an accrual rate of 4 patients per month (see statistics below).

Of note, the treating physician may opt to incorporate the molecular data to select third-line therapy for patients whose disease progresses on second-line MTT therapy. The results of ongoing analyses and testing of the patient tumor samples, ex vivo including the CRCs, organoids, and the zebrafish avatars may be available at the time that the patient requires third-line therapy. If so, the treating physician may incorporate the results of these analyses into the decision plan for third-line therapy. These patients will continue to be followed longitudinally for survival, but there will be no formal comparison of third line therapy outcomes with the "crossover" group.