This randomized phase II trial studies how well selumetinib and Akt inhibitor MK2206 work compared to modified fluorouracil, leucovorin calcium, and oxaliplatin (mFOLFOX) therapy in treating patients with metastatic pancreatic cancer previously treated with chemotherapy. Selumetinib and Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as oxaliplatin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet know whether selumetinib and Akt inhibitor MK2206 are more effective than oxaliplatin and fluorouracil in treating patients with metastatic pancreatic cancer.

PRIMARY OBJECTIVES:

I. To assess overall survival in patients with metastatic pancreatic cancer treated with the combination of AZD6244 hydrogen sulfate (selumetinib) and MK-2206 (Akt inhibitor MK2206) compared to those treated with mFOLFOX.

SECONDARY OBJECTIVES:

I. To assess the frequency and severity of toxicity associated with the combination of AZD6244 hydrogen sulfate and MK-2206 compared to those with mFOLFOX in this patient population.

TERTIARY OBJECTIVES:

I. To assess progression free survival (PFS) in patients with metastatic pancreatic cancer treated with the combination of AZD6244 hydrogen sulfate and MK-2206 compared to those treated with mFOLFOX.

II. To assess objective tumor response in the subset of patients with measurable disease (confirmed and unconfirmed complete and partial response) in patients with metastatic pancreatic cancer treated with the combination of AZD6244 hydrogen sulfate and MK-2206 compared to those treated with mFOLFOX.

III. To bank tissue and blood for future translational medicine studies.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours on days 1 and 15 and fluorouracil IV over 46-48 hours on days 1-2 and 15-16 (mFOLFOX).

ARM II: Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, 15, and 22, and selumetinib PO daily on days 1-28.

In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 3 years.

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma; patients with endocrine or neuroendocrine tumors, lymphoma of the pancreas, or ampullary cancer are not eligible

• Patients must have distant metastatic disease; patients with macroscopic residual disease post-resection as the only site of disease are not eligible; patient must not have clinically significant ascites (defined as requiring paracentesis) or have brain metastases

• Patients must have received one line, and no more than one line, of prior gemcitabine-based chemotherapy for advanced/metastatic pancreatic cancer and must have documentation of metastatic disease progression while on this treatment; documented disease progression must occur within 42 days of the last treatment; OR

  • For patients who received one line of gemcitabine-based chemotherapy for treatment in the adjuvant setting, recurrence to a metastatic site must be documented by imaging studies within 6 months of completing chemotherapy; chemoradiation as part of adjuvant treatment is acceptable; if the patient received one line of adjuvant gemcitabine-based treatment and had disease recurrence after 6 months of completing chemotherapy, patients will only be eligible after failing one additional line of gemcitabine-based chemotherapy used to treat the metastatic disease

• Patients must have measurable and/or non-measurable disease; x-rays, scans. or physical examinations for assessment of measurable disease must have been completed within 28 days prior to registration; x-rays, scans, or other tests for assessment of non-measurable disease must have been completed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form

• Patients must have completed systemic therapy at least 14 days prior to registration, any surgical procedure must have been performed at least 14 days prior to registration, and radiation therapy must be completed at least 7 days prior to registration; patients must have recovered to =< grade 1 from any of the effects of prior therapies or procedures

• Patients must not plan to receive concurrent chemotherapy, radiotherapy, agents known to prolong corrected QT (QTc) interval, or agents known to be strong inducers or inhibitors of cytochrome P450 3A4/5 (CYP3A4/5) or cytochrome P450 1A2 (CYP1A2)

• Patient must not have received prior treatment with fluorouracil, irinotecan, leucovorin calcium, and oxaliplatin (FOLFIRINOX), FOLFOX, oxaliplatin-based chemotherapy, mitogen-activated protein kinase (MEK) inhibitors, phosphoinositide-3-kinase (PI3K) inhibitors, or protein kinase B (AKT) inhibitors

• Zubrod performance status of 0-1

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count (ANC) >= 1,500/mcL

• Platelets >= 100,000/mcL

• Hemoglobin >= 9.0 g/dL

• Patients must have adequate kidney function as evidenced by at least ONE of the following:

  • Serum creatinine =< 1.5 mg/dL within 14 days prior to registration
  • Calculated creatinine clearance >= 60 mL/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to registration

• Total bilirubin =< 1.5 times institutional upper limit of normal(IULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 2.5 times IULN

• Patients must have an albumin level >= 3.0 g/dL within 14 days prior to registration

• Patients must have an International Normalized Ratio (INR) =< 1.5 times IULN within 14 days prior to registration

• Patients must have an electrocardiogram (ECG) within 14 days prior to registration; patients must have QTcF (by Fridericia's calculation) =< 450 msec (male) or =< 470 msec (female)

• Patients with baseline neuropathy must be =< grade 1 according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.0

• Patients must not have uncontrolled diarrhea or active infection requiring antibiotics and be fully recovered from any previous serious infections within 7 days prior to registration

• Patients must be able to swallow tablets and capsules

• Patients with diabetes must be well controlled with fasting glucose =< grade 1 according to CTCAE v 4.0 within 14 days prior to registration

• Patients with history of congestive heart failure must have an ejection fraction >= 55% within 14 days prior to registration

• Patients must not have any of the following: uncontrolled hypertension, acute coronary syndrome within 6 months prior to registration, poorly controlled angina, New York Heart Association class II-IV heart failure, prior or current cardiomyopathy, atrial fibrillation, or severe valvular heart disease

• Patients must not have a current or past history of central serous retinopathy, retinal vein occlusion, retinal detachment, or have uncontrolled glaucoma (irrespective of intraocular pressure [IOP])

• No prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for five years

• Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method during the study plus at least 16 weeks after last dose; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures

• Prestudy history and physical must be obtained within 28 days prior to registration

• Sites must seek additional patient consent for the future use of specimens

• All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

• As part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered into the system