Molecularly Tailored Therapy to Standard of Care as Second-Line Therapy in Metastatic Pancreatic Cancer
Molecularly Tailored Therapy to Standard of Care as Second-Line Therapy in Metastatic Pancreatic Cancer
The purpose of this study is to determine whether molecularly tailored therapy can improve
 the efficacy of treatment when compared to standard chemotherapy combinations for patients
 with metastatic pancreatic cancer receiving their second line of therapy for metastatic
 disease.
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.
Inclusion Criteria:

 1. Histologically confirmed metastatic adenocarcinoma of the pancreas (at enrollment)

 2. Actively on (or about to initiate) first line therapy for metastatic pancreatic cancer
 (at enrollment)

 -  Patients may have had neo-adjuvant and/or chemotherapy that must have been
 completed >3 months prior to starting first line therapy

 -  Patients may be actively on "maintenance" therapy, such as maintenance
 capecitabine up to starting first line therapy for metastatic disease

 3. Radiographically measurable disease (prior to initiation of second-line therapy)

 4. Tumor deposits that are clearly accessible for serial tumor biopsies - A patient's
 biopsied lesion must be at least 1cm in diameter (in at least one dimension) (prior to
 initiation of second-line therapy)

 5. Age ≥ 18 years (at enrollment)

 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Table 6, Appendix
 D) (at enrollment)

 7. Adequate hepatic, bone marrow, and renal function at the time of enrollment AND at
 initiation of second line therapy:

 -  Bone Marrow: Absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 75,000/mm3;
 Hemoglobin ≥ 9.0 g/dL

 -  Patients may have a transfusion of red blood cells to meet the hemoglobin
 requirement

 -  Renal function: Serum creatinine ≤ 1.5 X upper normal limit of institution's
 normal range OR creatinine clearance ≥ 50 mL/min/1.73 m2 for subjects with
 creatinine levels above institutional normal

 -  Hepatic function: Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 3
 X the upper normal limit of institution's normal range; bilirubin ≤ 1.5 X the
 upper limit of normal. For patients with known hepatic metastases, AST and ALT ≤
 5 X the upper normal limit of institution's normal range

 -  Prothrombin Time and Partial Thromboplastin Time (PTT) must be ≤ 2 X the upper
 limit of the institution's normal range and International Normalized Ratio (INR)
 < 2. Subjects on anticoagulation (such as coumadin) will be permitted to enroll
 as long as the INR is in the acceptable therapeutic range as determined by the
 investigator

 8. Patients must have fully recovered from all effects of surgery (prior to initiation of
 second-line therapy). Patients must have had at least two weeks after minor surgery
 and four weeks after major surgery before starting therapy. Minor procedures requiring
 "Twilight" sedation such as endoscopies or mediport placement may only require a
 24-hour waiting period, but this must be discussed with an investigator.

 9. Women of childbearing potential must have a negative serum pregnancy test within 14
 days prior to initiation of treatment and/or postmenopausal women must be amenorrheic
 for at least 12 months to be considered of non-childbearing potential (at enrollment).

 10. Subject is capable of understanding and complying with parameters as outlined in the
 protocol and able to sign and date the informed consent, approved by the Institutional
 Review Board (IRB), prior to the initiation of any screening or study-specific
 procedures (at enrollment).

 Exclusion Criteria:

 1. Known or suspected brain or central nervous system metastases, irrespective of prior
 treatment

 2. The subject has had another active malignancy within the past three years except for
 cervical cancer in situ, in situ carcinoma of the bladder or non-melanoma carcinoma of
 the skin. Questions regarding the inclusion of individual subjects should be directed
 to the Study Chair.

 3. Clinically significant peripheral neuropathy at the time of enrollment (defined in the
 NCI Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE v4.0] as grade 2
 or greater neurosensory or neuromotor toxicity)

 4. Patients receiving any other investigational agents.

 5. Active severe infection, or known chronic infection with HIV or hepatitis B virus

 -Patients with chronic Hepatitis C virus may be enrolled if there is no
 clinical/laboratory evidence of cirrhosis AND the patient's liver function tests fall
 within the parameters set in Section 3.2.7.3, Inclusion Criteria, Hepatic function

 6. Cardiovascular disease problems including unstable angina, therapy for
 life-threatening ventricular arrhythmia, or myocardial infarction, stroke within the
 last 3 months, or a diagnosis of congestive heart failure

 7. Life-threatening visceral disease or other severe concurrent disease

 8. Women who are pregnant or breastfeeding

 9. Anticipated patient survival under 2 months