| Eligibility |
Inclusion Criteria:
- Ability to understand and the willingness to sign a written informed consent document
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Clinically-confirmed diagnosis of resectable, borderline resectable, locally-advanced
or metastatic adenocarcinoma of the pancreas.
- Patients with disease that is eligible for curative surgery may not be eligible
for all study arms.
- Participants may be treatment naïve or have received prior therapy for the
treatment of their pancreatic ductal adenocarcinoma (PDAC). A minimum washout
period of 10-days after completing the most recent line of therapy is required
before a participant can initiate treatment with study agent(s)
- Based on available imaging, participant must have at least one disease lesion that can
be biopsied in accordance with institutional standards
- Hemoglobin >= 9.0 g/dL with no blood transfusion within 28 days of starting treatment
(within 4 weeks prior to initiating window treatment). Note: laboratory tests
performed after initial screening (but still within the screening window) will be
evaluated by the investigator; should any of these values fall outside eligibility
parameters, the patient may still be eligible per investigator discretion
- White blood cells (WBC) > 3 x 10^9/L (within 4 weeks prior to initiating window
treatment). Note: laboratory tests performed after initial screening (but still within
the screening window) will be evaluated by the investigator; should any of these
values fall outside eligibility parameters, the patient may still be eligible per
investigator discretion
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (> 1500 per mm^3) (within 4 weeks
prior to initiating window treatment). Note: laboratory tests performed after initial
screening (but still within the screening window) will be evaluated by the
investigator; should any of these values fall outside eligibility parameters, the
patient may still be eligible per investigator discretion.
- May be waived on a case-by-case basis for patient populations recognized to have
normal baseline values below this level
- Platelet count >= 100 x 10^9/L (> 100,000 per mm^3) (within 4 weeks prior to
initiating window treatment). Note: laboratory tests performed after initial screening
(but still within the screening window) will be evaluated by the investigator; should
any of these values fall outside eligibility parameters, the patient may still be
eligible per investigator discretion
- Creatinine =< 1.5 x upper limit of normal (ULN), OR measured or calculated creatinine
clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or
creatinine clearance [CrCl]) >= 60 mL/min/1.73m^2 for participants with creatinine
levels > 1.5 x institutional ULN (within 4 weeks prior to initiating window
treatment). Note: laboratory tests performed after initial screening (but still within
the screening window) will be evaluated by the investigator; should any of these
values fall outside eligibility parameters, the patient may still be eligible per
investigator discretion.
- Creatinine clearance should be calculated per institutional standard. For
participants with a baseline calculated creatinine clearance below normal
institutional laboratory values, a measured baseline creatinine clearance should
be determined. Individuals with higher values felt to be consistent with inborn
errors of metabolism will be considered on a case-by-case basis
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 4 weeks
prior to initiating window treatment). Note: laboratory tests performed after initial
screening (but still within the screening window) will be evaluated by the
investigator; should any of these values fall outside eligibility parameters, the
patient may still be eligible per investigator discretion
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN (within 4 weeks prior to initiating window treatment). Note: laboratory tests
performed after initial screening (but still within the screening window) will be
evaluated by the investigator; should any of these values fall outside eligibility
parameters, the patient may still be eligible per investigator discretion
- Participants must be willing to undergo mandatory on-study tumor biopsies
- Participant is willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations including
follow up
- Participant must be able to swallow tablets or capsules. A participant with any
gastrointestinal disease that would impair ability to swallow, retain, or absorb drug
is not eligible
- Participants of childbearing potential must have a negative urine or serum pregnancy
test within 72 hours prior to receiving the first dose of study medication. If the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required
- Participants must agree to use an adequate method of contraception starting with the
first dose of study therapy and for the required length of time ascribed to the
assigned study drug assignment
- No other prior invasive malignancy is allowed except for the following: adequately
treated basal (or squamous cell) skin cancer, in situ breast or cervical cancer, any
malignancy treated with a curative intent without evidence of disease recurrence for
at least 6 months
- Individuals must not have known active hepatitis B virus (HBV). Those who have
completed curative therapy for hepatitis C virus (HCV) are eligible. HCV infection
permitted but patient must be Child's Pugh A. Patients with known human
immunodeficiency virus (HIV) infection are eligible if they meet all of the following
3 criteria:
- CD4 counts >= 350 mm^3
- Serum HIV viral load of < 25,000 IU/ml and
- Treated on a stable antiretroviral regimen
- Note: HIV testing is not required at screening, unless if required by local
regulations, where the testing will be done by local laboratory
- OLAPARIB SPECIFIC CRITERIA (SUB-PROTOCOL WOO-1): Participants must agree to use an
adequate method of contraception as follows:
- Participants of childbearing potential must agree to use adequate methods of
contraception starting with the first dose of study therapy through at least 6
months after the last dose of study therapy
- Sperm-producing participants must use a condom during treatment and for 3 months
after the last dose of olaparib when having sexual intercourse with an individual
that is pregnant or of childbearing potential. Individuals that are partners of
sperm-producing participants should also use a highly effective form of
contraception if they are of childbearing potential
- COBIMETINIB SPECIFIC CRITERIA SUB-PROTOCOL WOO-2: Participants must agree to use an
adequate method of contraception as follows:
- Participants of childbearing potential must agree to use adequate methods of
contraception starting with the first dose of study therapy through at least 2
weeks after the last dose of study therapy
- ONVANSERTIB SPECIFIC CRITERIA (SUB-PROTOCOL WOO-4): Prior treatment with an
investigational PLK1 inhibitor
- ONVANSERTIB SPECIFIC CRITERIA (SUB-PROTOCOL WOO-4): Use of strong CYP3A4 or UGT1A1
inhibitors or strong CYP3A4 inducers. Individuals currently receiving these agents who
are able to switch to alternate therapy are not excluded.
- CYP3A4 or UGT1A1 inhibitors should be stopped at least one week prior to the
first dose of onvansertib
- CYP3A4 inducers should be stopped at least two weeks prior to the first dose of
onvansertib
- ONVANSERTIB SPECIFIC CRITERIA (SUB-PROTOCOL WOO-4): Participants must agree to use an
adequate method of contraception as follows:
- Participants of childbearing potential agree to use adequate methods of
contraception for the duration of study participation
- Sperm-producing participants must agree to refrain from sperm donation during the
study and for 30 days after the last dose of study drug
Exclusion Criteria:
- Tumor not accessible for core biopsy
- Medical co-morbidities that are deemed to make risk of surgery unacceptably high as
determined by institutional standards
- Recent major surgery within 4 weeks prior to starting study treatment. Minor surgery
within 2 weeks of starting study treatment. Patients must be recovered from effects of
surgery
- Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) or
moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil)
- Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.,
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil)
- Concomitant use of other anti-cancer therapy (chemotherapy, immunotherapy, hormonal
therapy (hormone replacement therapy is acceptable), radiotherapy (except for
palliative), biological therapy or other novel agent) or live virus and live bacterial
vaccines while the patient is receiving study medication. Strong or moderate CYP3A
inhibitors and inducers should not be taken with study treatment; however, if no other
suitable alternative concomitant medication is available, dose reductions may be
allowed under careful monitoring
- Known severe hypersensitivity to the study agent(s) (or equivalent agents,
respectively), or any excipient of these medicinal products, or history of allergic
reactions attributed to compounds of similar chemical or biologic composition to the
study agent(s)
- Clinically significant cardiac disease or impaired cardiac function, including any of
the following:
- Clinically significant and/or uncontrolled heart disease such as congestive heart
failure (New York Heart Association grade >= 2) uncontrolled hypertension, or
clinically significant arrhythmia currently requiring medical treatment
- Corrected QT using Fridericia's formula (QTcF) > 470 msec for females, or > 450
msec for males, on screening electrocardiogram (ECG) or congenital long QT
syndrome
- Acute myocardial infarction or unstable angina pectoris < 6 months prior to
screening
- Clinically significant cardiac disease or impaired cardiac function
- Female participant who is pregnant or lactating
- Participant is known to have dysphagia, short-gut syndrome, gastroparesis, or other
conditions that limit the ingestion or gastrointestinal absorption of drugs
administered orally
- Participant has active uncontrolled systemic fungal, bacterial, or viral infection
(defined as ongoing signs/symptoms related to the infection without improvement
despite appropriate antibiotics, antiviral therapy, and/or other treatment)
- Psychiatric illness/social situations that would limit compliance with study
requirements
- Participants with a history of hypersensitivity reactions to study agents or their
excipients
- Participant is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the trial, starting with the screening visit through
at least 120 days after the last dose of trial treatment
- COBIMETINIB SPECIFIC CRITERIA (SUB-PROTOCOL WOO-2): Participants are not eligible to
receive cobimetinib if (any of the following):
- Participant has significant active cardiac disease within 6 months prior to the
start of study treatment, including New York Heart Association (NYHA) class III
or IV congestive heart failure; acute coronary syndrome (ACS); and/or stroke; or
left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or
multi-gated acquisition (MUGA) scan obtained within 28 days prior to the start of
study treatment
- Known risk factors for ocular toxicity, consisting of any of the following:
- History of serous retinopathy
- History of retinal vein occlusion (RVO)
- Evidence of ongoing serous retinopathy or RVO at screening
- ONVANSERTIB SPECIFIC CRITERIA (SUB-PROTOCOL WOO-4): Use of concomitant medications
known to increase QTc or risk of Torsades. These drugs should only be used if there
are no other alternatives and only with appropriate monitoring (i.e., ECGs).
- AZENOSERTIB SPECIFIC CRITERIA (SUB-PROTOCOL WOO-5):
- Prior treatment with a WEE1 inhibitor are not eligible
- History or current evidence of congenital or family history of long QT syndrome
or Torsade de Pointes.
- Patients are not eligible in cases of unresolved toxicity of Grade > 1 attributed
to any prior therapies (excluding Grade 2 neuropathy, alopecia or skin
pigmentation).
- Patients are not eligible if there is known hypersensitivity to any drugs similar
to ZN-c3 in class.
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