PRIMARY OBJECTIVE:
I. Assess the feasibility of detecting a measurable change in tumor biology at post-treatment
from baseline (i.e., before the 10-day treatment window) for all feasibility-evaluable
participants.
SECONDARY OBJECTIVES:
I. Assess preliminary safety and tolerability of the proposed study agent(s) in each study
arm.
II. Assess the feasibility of detecting a measurable change in tumor biology at
post-treatment from baseline (i.e., before the 10-day treatment window) among participants in
an assigned study arm.
EXPLORATORY OBJECTIVES:
I. Identify predictive biomarkers of sensitivity to assigned study agent(s). II. Identify
emerging mechanism(s) of resistance to assigned study agent(s). III. Determine cellular and
molecular changes in pancreatic tumor cells exposed to assigned study agent(s).
IV. Identify tumor markers suggestive of combinatorial therapy that could overcome resistance
to therapy.
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I: Patients receive cobimetinib orally (PO) once daily (QD) on days 1-10 in the absence
of disease progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy
or surgery as clinically appropriate per institutional standards for management of patient's
disease.
ARM II: Patients receive olaparib PO twice daily (BID) on days 1-10 in the absence of disease
progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy or surgery
as clinically appropriate per institutional standards for management of patient's disease.
After completion of study treatment, patients are followed up for 30 days.
Inclusion Criteria:
- Ability to understand and the willingness to sign a written informed consent document
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Clinically-confirmed diagnosis of adenocarcinoma of the pancreas (resectable,
borderline resectable, locally advanced, or metastatic disease at presentation) are
eligible
- Participants may be treatment naive 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
- Based on available imaging, participant must have at least one disease lesion that can
be biopsied in accordance with institutional standards
- Hemoglobin >= 10.0 g/dL with no blood transfusion within 28 days of starting treatment
(within 4 weeks prior to initiating window treatment)
- White blood cells (WBC) > 3 x 10^9/L (within 4 weeks prior to initiating window
treatment)
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (> 1500 per mm^3) (within 4 weeks
prior to initiating window treatment)
- 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)
- 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)
- 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)
- 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)
- Participants must be willing to undergo one mandatory on-study tumor biopsies prior to
initiating window treatment with assigned study agent(s)
- 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 through at least 14 after the last dose of study therapy.
Longer use of contraception may be required depending on 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 each 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
- HIV testing is not required
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
- 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
120 days after the last dose of trial treatment
