| Eligibility |
Inclusion Criteria:
- Participants must have a histologically confirmed advanced pancreatic adenocarcinoma
that is not curable with standard approaches based on the judgement of the treating
investigator. Patients with metastatic pancreatic cancer and unresectable pancreatic
cancer are eligible.
- Patients must have progressed on a platinum-based regimen prior to enrolling on the
trial.
- Patients must have received no more than 1 prior lines of platinum-based chemotherapy
in the metastatic setting. Therapy given in the adjuvant or neoadjuvant setting is
counted as a prior therapy if it occurred less than 6 months before cancer recurrence
or progression.
- Age = 18 years. As no dosing or adverse event data are currently available in
participants < 18 years of age, children and adolescents are excluded from this study.
- ECOG performance status of 0 or 1 (see Appendix A).
- Participants must have adequate organ and marrow function as defined below:
- Absolute neutrophil count = 1,500/mm3
- Platelets = 100,000/mm3
- Hemoglobin = 9 g/dL
- Total bilirubin = 1.5 × institutional upper limit of normal (ULN); or total
bilirubin =3.0 x ULN with direct bilirubin WNL in patients with documented
Gilbert's Syndrome.
- Alanine aminotransferase (ALT) and = 3 × institutional ULN; or = 5 ×
institutional aspartate aminotransferase (AST) ULN if known hepatic metastases
- Albumin = 2.7 g/dL
- Serum creatinine = 1.5 × institutional ULN -OR-
- Creatinine clearance measured creatinine clearance (CrCl) =50 mL/min as
calculated by either the Cockcroft-Gault method, a 24-hour urine test or another
validated test as per local practice (confirmation of creatinine clearance is
only required when creatinine is >1.5 x institutional ULN)
Cockcroft-Gault equation for estimated CrCL:
CrCl (glomerular filtration rate [GFR]) = (140-age) x (weight/kg) x Fa (72 x serum
creatinine mg/dL)
1. where F= 0.85 for females and F=1 for males - Participants must have measurable
disease by RECIST v. 1.1 criteria and be willing to undergo a pre-treatment and
on-treatment tumor biopsy. The biopsy requirement can be waived only with approval
from the sponsor-investigator.
- For participants with evidence of chronic hepatitis B virus (HBV) infection, the
HBV viral load must be undetectable on suppressive therapy, if indicated.
- Patient has read and understands the informed consent form (ICF) and has been
given written ICF prior to any study procedures which includes compliance with
the requirements and restrictions listed in the ICF and in this protocol.
- Female patients who are not of child-bearing potential* and women of childbearing
potential who agree to use adequate contraceptive measures from 2 weeks prior to
the study and 5x half-lives of adavosertib + 6 months after study treatment
discontinuation, who are not breastfeeding, and who have a negative serum or
urine pregnancy test within 7 days prior to the start of study treatment.
* Evidence of non-childbearing status, defined as below:
-- Women who are surgically sterile (i.e., have undergone bilateral
salpingectomy, bilateral oophorectomy, or complete hysterectomy).
-- Age =50 years with any one or more of the conditions below:
- Amenorrheic for 12 months or more following cessation of all hormonal
replacement therapy
- Had radiation-induced menopause with last menses >1 year ago
- Had chemotherapy-induced menopause with last menses >1 year ago
- Age <50 if amenorrhoeic for 12 months or more following cessation of all
hormonal replacement therapy and if luteinizing hormone and
follicle-stimulating hormone levels are in the post-menopausal range per
institutional standards of practice.
- Male patients should be willing to abstain or use barrier contraception (i.e.,
condoms) for the duration of the study drug exposure and for 5x half-lives of
adavosertib + 3 months after study treatment discontinuation.
- Participants with a history of hepatitis C virus (HCV) infection must have been
treated and cured. For participants with HCV infection who are currently on
treatment, they are eligible if they have an undetectable HCV viral load.
Exclusion Criteria:
- Patients who have previously received adavosertib are not eligible.
- Use of an anti-cancer treatment drug = 21 days or 5 half-lives (whichever is
shorter) prior to the first dose of adavosertib (AZD1775).
- Any prior palliative radiation must have been completed at least 7 days prior to the
first dose of adavosertib, and patient must have recovered from any acute adverse
effects, that the treating investigator thinks could impair the tolerance of the study
drugs, prior to the start of study treatment.
- Participants who have undergone major surgical procedures = 28 days, or minor
surgical procedures = 7 days, of the first dose of adavosertib. No waiting period is
required following port-a-cath or other central venous access placement.
- Presence of CTCAE v5.0 Grade >1 toxicity from prior therapy (except alopecia,
anorexia or CTCAE grade 2 peripheral neuropathy).
- Patient is unable to swallow oral medications. Note: Patient may not have a
percutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteral
nutrition (TPN).
- Participants with known malignant central nervous system (CNS) disease other than
neurologically stable, treated brain metastases - defined as metastasis having no
evidence of progression or hemorrhage for at least 2 weeks after the completion of
treatment (including brain radiotherapy). Must be off any systemic corticosteroids for
the treatment of brain metastases for at least 14 days prior to enrollment.
- Participants receiving any medications or substances that are known to be moderate
to strong inhibitors or inducers of CYP3A4 and which cannot be discontinued at least 2
weeks prior to the first dose of adavosertib are ineligible. Because the lists of
these agents are constantly changing, it is important to regularly consult a
frequently-updated medical reference. As part of the enrollment/informed consent
procedures, the participant will be counseled on the risk of interactions with other
agents, and what to do if new medications need to be prescribed or if the participant
is considering a new over-the-counter medicine or herbal product. Refer to Protocol
Section 5 for information on prohibited concomitant medications.
- Use of herbal medications or supplements within 7 days prior to the first dose of
adavosertib.
- History of hypersensitivity to compounds of similar chemical or biologic composition
to gemcitabine or adavosertib.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, uncontrolled major seizure disorder, unstable spinal cord compression,
superior vena cava syndrome, or psychiatric illness/social situations that would limit
compliance with study requirements.
- Known HIV-positive participants are ineligible because these participants are at
increased risk of lethal infections when treated with marrow-suppressive therapy.
- Participants with a clinically significant gastrointestinal disorder that in the
opinion of the treating investigator could impact the absorption of the study drugs,
including but not limited to refractory nausea and vomiting, chronic gastrointestinal
disease, inability to swallow the formulated product, or previous significant bowel
resection that would preclude adequate absorption, distribution, metabolism, or
excretion of adavosertib.
- Participants with a history of a clinically relevant second primary malignancy
within the past 2 years. Exceptions include: resected basal and squamous cell
carcinomas of the skin and completely resected carcinoma in situ of any type.
- Pregnant or lactating women are excluded from this study because
gemcitabine/adavosertib are anti-cancer agents with the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with
gemcitabine/adavosertib, breastfeeding should be discontinued if the mother is treated
with gemcitabine/adavosertib.
- Any of the following cardiac diseases currently or within 6 months of the first
dose of adavosertib:
-- Unstable angina pectoris
-- Acute myocardial infarction
-- Congestive heart failure = Class 2 (as defined by New York Heart Association
(NYHA))
-- Conduction abnormality not controlled with pacemaker or medication
- Significant ventricular or supraventricular arrhythmias (patients with
chronic rate-controlled atrial fibrillation in the absence of other cardiac
abnormalities are eligible)
- History of Torsades de pointes unless all risk factors that contributed to
Torsades have been corrected.
- Participants ECG must not meet the following criteria:
- Resting corrected QTc interval using the Fridericia formula (QTcF) >480 msec
(as calculated per institutional standards) (Note: if one ECG performed as
screening demonstrates a QTcF > 480 msec, then a mean QTcF of = 480 msec
obtained from 3 ECGs 2-5 minutes apart, is required at study entry for the
participant to be considered eligible)
- congenital long QT syndrome
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