Paclitaxel Albumin-Stabilized Nanoparticle Formulation and Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Previously Untreated Pancreatic Cancer That Is Metastatic or Cannot Be Removed by Surgery
Paclitaxel Albumin-Stabilized Nanoparticle Formulation and Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Previously Untreated Pancreatic Cancer That Is Metastatic or Cannot Be Removed by Surgery
This partially randomized phase I/II trial studies the side effects and best dose of WEE1
 inhibitor MK-1775 when given together with paclitaxel albumin-stabilized nanoparticle
 formulation and gemcitabine hydrochloride and how well they work in treating patients with
 previously untreated pancreatic cancer that has spread to another place in the body or cannot
 be removed by surgery. Drugs used in chemotherapy, such as paclitaxel albumin-stabilized
 nanoparticle formulation and gemcitabine hydrochloride, work in different ways to stop the
 growth of tumor cells, either by killing the cells, by stopping them from dividing, or by
 stopping them from spreading. WEE1 inhibitor MK-1775 may stop the growth of tumor cells by
 blocking some of the enzymes needed for cell growth. It is not yet known whether paclitaxel
 albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride are more effective
 with or without WEE1 inhibitor MK-1775 in treating patients with pancreatic cancer.
PRIMARY OBJECTIVES:

 I. To evaluate the toxicity of combination therapy with nab-paclitaxel (paclitaxel
 albumin-stabilized nanoparticle formulation), gemcitabine (gemcitabine hydrochloride) and
 AZD1775 (WEE1 inhibitor MK-1775) in patients with treatment-naive metastatic adenocarcinoma
 of the pancreas or locally-advanced adenocarcinoma of the pancreas which is not surgically
 resectable. (Phase I) II. To determine the dose of AZD1775 to be used in combination with
 nab-paclitaxel and gemcitabine chemotherapy in the phase II portion of the trial. (Phase I)
 III. To determine the pharmacokinetics of AZD1775 in combination with nab-paclitaxel and
 gemcitabine. (Phase I) IV. To evaluate progression-free survival (PFS) associated with
 nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with
 metastatic adenocarcinoma of the pancreas. (Phase II)

 SECONDARY OBJECTIVES:

 I. To evaluate overall survival (OS) associated with nab-paclitaxel/gemcitabine/placebo or
 nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the
 pancreas. (Phase II) II. To evaluate response rate (complete response [CR] + partial response
 [PR]) associated with nab-paclitaxel/gemcitabine/placebo or
 nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the
 pancreas. (Phase II) III. To evaluate disease control rate (CR + PR + stable disease [SD])
 associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in
 patients with metastatic adenocarcinoma of the pancreas. (Phase II)

 TERTIARY OBJECTIVES:

 I. To evaluate the ability of AZD1775 to inhibit Wee1 and increase deoxyribonucleic acid
 (DNA) damage and tumor cell death when combined with nab-paclitaxel/gemcitabine compared to
 nab-paclitaxel/gemcitabine/placebo. (Phase II) II. To evaluate if biomarker changes in tumor
 tissue associated with Wee1 inhibition may also be present in hair follicles. (Phase II) III.
 To evaluate the change in tumor fludeoxyglucose (FDG) uptake (maximum standardized uptake
 value [SUVmax]) between baseline FDG-positron emission tomography (PET) and week 4 FDG-PET as
 a predictor of response using Response Evaluation Criteria in Solid Tumors (RECIST) as the
 reference standard for response. (Phase II) IV. To evaluate the change in tumor FDG uptake
 (SUVmax) between baseline FDG-PET and week 4 FDG-PET as a predictor of progression-free
 survival. (Phase II) V. To compare the change in tumor FDG uptake (SUVmax) between baseline
 FDG-PET and week 4 FDG-PET between the patients from treatment arms C and D. (Phase II) VI.
 To evaluate if an early increase in tumor fluorothymidine (FLT) uptake (FLT-flare) is
 observed within 24 hours after initiation of treatment with
 nab-paclitaxel/gemcitabine/placebo. (Phase II) VII. To evaluate if an early (within 24 hours
 [h]) increase in tumor FLT uptake (FLT-flare) is abrogated after initiation of treatment with
 nab-paclitaxel/gemcitabine/AZD1775. (Phase II) VIII. To compare the change in tumor FLT
 uptake (SUVmax) from baseline to 24 hours after initiation of treatment between the patients
 from treatment arms C and D. (Phase II)

 OUTLINE: This is a phase I, dose escalation study of WEE1 inhibitor MK-1775 followed by a
 randomized phase II study. Patients in phase I are assigned to arm A or B and patients in
 phase II are randomized to arm C or D.

 ARM A (PHASE I, DOSE LEVEL 1): Patients receive paclitaxel albumin-stabilized nanoparticle
 formulation intravenously (IV) over 30 minutes and gemcitabine hydrochloride IV over 30
 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor MK-1775 orally (PO) daily
 on days 1, 2, 8, 9, 15, and 16.

 ARM B (PHASE I, DOSE LEVEL 2): Patients receive paclitaxel albumin-stabilized nanoparticle
 formulation, gemcitabine hydrochloride, and WEE1 inhibitor MK-1775 as in Arm A.

 ARM C (PHASE II, PLACEBO): Patients receive paclitaxel albumin-stabilized nanoparticle
 formulation and gemcitabine hydrochloride as in Arm A. Patients also receive placebo PO daily
 on days 1, 2, 8, 9, 15, and 16.

 ARM D (PHASE II, WEE1 INHIBITOR MK-1775): Patients receive paclitaxel albumin-stabilized
 nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor MK-1775 as in Arm A.

 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 3 months for 2 years.
Inclusion Criteria:

 -  PHASE I STUDY -- ARM A (DOSE LEVEL 1) AND ARM B (DOSE LEVEL 2)

 -  Patients must have histologically or cytologically confirmed metastatic or
 unresectable locally advanced adenocarcinoma of the pancreas with no prior systemic
 therapy for metastatic or locally advanced disease

 -  Previous neo-adjuvant or adjuvant treatment is allowed provided that it was given >= 6
 months prior to registration

 -  Patients must NOT be receiving any other investigational agents concurrently and must
 not have received any other investigational agents =< 4 weeks prior to registration

 -  Patients must not have a pre-existing > grade 1 motor or sensory neuropathy

 -  Patients must NOT have history of allergic reactions attributed to compounds of
 similar chemical or biologic composition to nab-paclitaxel, gemcitabine or AZD1775

 -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0
 or 1

 -  Patients must have a life expectancy of >= 12 weeks

 -  Patients may have had prior radiotherapy for metastatic disease as long as it was > 4
 weeks prior to registration and the patient has recovered from adverse events
 associated with the radiotherapy

 -  Patients must NOT be taking current medications or substances that are inhibitors or
 inducers of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4)

 -  Patients must NOT have uncontrolled serious medical illness including, but not limited
 to, ongoing or active infection, cardiac arrhythmia, or psychiatric illness that would
 limit compliance with study requirements

 -  Patients with known human immunodeficiency virus (HIV) are not eligible if cluster of
 differentiation (CD)4 count is =< 200 cell/mm^3 or if receiving antiretroviral therapy

 -  Patients must be able to swallow capsules whole

 -  Patients must NOT have previous or concurrent malignancy; exceptions are made for
 patients who meet any of the following conditions:

 -  Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or
 superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ)

 -  Prior malignancy completely excised or removed and patient has been continuously
 disease free for > 5 years

 -  Patients must be able to tolerate computed tomography (CT), magnetic resonance imaging
 (MRI) or PET imaging including contrast agents

 -  Women must not be pregnant or breast-feeding

 -  Females of childbearing potential must have a blood test or urine study within 5
 days prior to registration to rule out pregnancy; a female of childbearing
 potential is any woman, regardless of sexual orientation or whether they have
 undergone tubal ligation, who meets the following criteria: 1) has not undergone
 a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
 postmenopausal for at least 24 consecutive months (i.e., has had menses at any
 time in the preceding 24 consecutive months)

 -  Women of child-bearing potential and men must agree to use adequate contraception
 (hormonal and barrier method of birth control; two barrier methods of birth control;
 abstinence) for the duration of study treatment and for 3 months after the last dose
 of study treatment; should a woman become pregnant or suspect she is pregnant while
 participating in this study, she should inform her treating physician immediately;
 should a man impregnate or suspect that he has impregnated a woman while participating
 in this study, he should inform his treating physician immediately

 -  Leukocytes >= 3,000/mcL

 -  Absolute neutrophil count >= 1,500/mcL

 -  Hemoglobin >= 9 g/dL

 -  Platelets >= 100,000/mcL

 -  Total bilirubin =< 1.5 institutional upper limit of normal (ULN)

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 =< 3 X institutional upper limit of normal (ULN) or =< 5 X ULN if the patient has
 liver metastases

 -  Creatinine =< 1.5 mg/dL or creatinine clearance (Cockcroft-Gault) >= 60 mL/min for
 patients with creatinine levels above institutional upper limit of normal (ULN)

 -  RANDOMIZED PHASE II STUDY -- ARMS C AND D

 -  PHASE II: Patients must have histologically or cytologically confirmed metastatic
 adenocarcinoma of the pancreas with no prior systemic therapy for metastatic disease

 -  PHASE II: Patients must NOT have locally advanced disease

 -  PHASE II: Patients must have measurable disease outside of the primary tumor
 (pancreas) by RECIST 1.1 criteria; baseline measurements and evaluations of all sites
 of disease must be obtained =< 4 weeks prior to randomization

 -  PHASE II: Previous neo-adjuvant or adjuvant treatment is allowed provided that there
 was no evidence of recurrent disease for at least 6 months after completion of
 neo-adjuvant/adjuvant treatment

 -  PHASE II: Patients may have had prior radiotherapy for metastatic disease as long as
 it was > 4 weeks prior to randomization and the patient has recovered from adverse
 events associated with the radiotherapy

 -  PHASE II: Patients must NOT be taking current medications or substances that are
 inhibitors or inducers of CYP3A4

 -  PHASE II: Patients must NOT have received prior Wee1 inhibitors or AZD1775

 -  PHASE II: Patients must NOT have received gemcitabine or nab-paclitaxel in a
 metastatic setting

 -  PHASE II: Patients must NOT be receiving any other investigational agents concurrently
 and must not have received any other investigational agents =< 4 weeks prior to
 randomization

 -  PHASE II: Patients must not have a pre-existing > grade 1 motor or sensory neuropathy

 -  PHASE II: Patients must NOT have history of allergic reactions attributed to compounds
 of similar chemical or biologic composition to nab-paclitaxel, gemcitabine or AZD1775

 -  PHASE II: Patients must have ECOG performance status of 0 or 1

 -  PHASE II: Patients must have a life expectancy of >= 12 weeks

 -  PHASE II: Patients must NOT have uncontrolled serious medical illness including, but
 not limited to, ongoing or active infection, cardiac arrhythmia, or psychiatric
 illness that would limit compliance with study requirements

 -  PHASE II: Patients must be able to swallow capsules whole

 -  PHASE II: Patients with biliary stents are allowed

 -  PHASE II: Patients must NOT have previous or concurrent malignancy; exceptions are
 made for patients who meet any of the following conditions:

 -  Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or
 superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ)
 • Prior malignancy completely excised or removed and patient has been
 continuously disease free for > 5 years

 -  PHASE II: Patients must be able to tolerate CT, MRI or PET imaging including contrast
 agents

 -  PHASE II: Women must not be pregnant or breast-feeding

 -  Females of childbearing potential must have a blood test or urine study within 5
 days prior to randomization to rule out pregnancy; a female of childbearing
 potential is any woman, regardless of sexual orientation or whether they have
 undergone tubal ligation, who meets the following criteria: 1) has not undergone
 a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
 postmenopausal for at least 24 consecutive months (i.e., has had menses at any
 time in the preceding 24 consecutive months)

 -  PHASE II: Women of child-bearing potential and men must agree to use adequate
 contraception (hormonal and barrier method of birth control; two barrier methods of
 birth control; abstinence) for the duration of study treatment and for 3 months after
 the last dose of study treatment; should a woman become pregnant or suspect she is
 pregnant while participating in this study, she should inform her treating physician
 immediately; should a man impregnate or suspect that he has impregnated a woman while
 participating in this study, he should inform his treating physician immediately

 -  PHASE II: Leukocytes >= 3,000/mcL

 -  PHASE II: Absolute neutrophil count >= 1,500/mcL

 -  PHASE II: Hemoglobin >= 9 g/dL

 -  PHASE II: Platelets >= 100,000/mcL

 -  PHASE II: Total bilirubin =< 1.5 institutional upper limit of normal (ULN)

 -  PHASE II: AST (SGOT)/ALT (SGPT) =< 3 X institutional upper limit of normal (ULN) or =<
 5 X ULN if the patient has liver metastases

 -  PHASE II: Creatinine =< 1.5 mg/dL or creatinine clearance (Cockcroft-Gault) >= 60
 mL/min for patients with creatinine levels above institutional upper limit of normal
 (ULN)

 -  PHASE II: For participation in the imaging research studies, patients must meet the
 additional following criteria:

 -  PHASE II: The patient is participating in the trial at an institutional which has
 agreed to perform the imaging research studies, completed the American College of
 Radiation Imaging Network (ACRIN) defined scanner qualification procedures and
 received ACRIN approval

 -  PHASE II: The patient has consented in writing to participate in one of the imaging
 research studies

 -  PHASE II: The patient meets the criteria required for the imaging study in which the
 site is participating:

 -  NOTE: Eligibility for participating in either imaging sub-study will depend on
 the availability of the imaging sub-study at a particular institution

 -  For participation in the FDG-PET sub-study:

 -  Patients must NOT have poorly controlled diabetes (defined as fasting
 glucose level >= 200 mg/dL) despite efforts to improve glucose control by
 fasting duration and adjustment of medications

 -  Patient must NOT weigh more than the maximum weight limit for the PET table

 -  Patients must have an evaluable lesion of > 20 mm in size on standard
 practice imaging study as assessed by site (either primary pancreas mass or
 metastasis)

 -  For participation in the FLT-PET sub-study:

 -  Patients must be able to lie still for a 1.5 hour PET scan.

 -  Patient must NOT have a history of allergic reaction attributable to
 compounds of similar chemical or biologic composition to 18F-fluorothymidine

 -  Patient must NOT weigh more than the maximum weight limit for the PET table

 -  Patients must have an evaluable lesion in the pancreas > 20 mm in size on
 standard practice imaging study as assessed by site (lesion must be likely
 primary adenocarcinoma of the pancreas that is not primarily fibrotic or
 mucinous in nature)