This research study is studying a combination of targeted therapies as a possible treatment
for Advanced Solid Tumors.
The study interventions involved in this study are:
- LY2606368
- Olaparib
This research study is a Phase I clinical trial, which tests the safety of an investigational
intervention and also tries to define the appropriate dose of the investigational
intervention to use for further studies. "Investigational" means that the intervention is
being studied.
The FDA (the U.S. Food and Drug Administration) has not approved LY2606368 as a treatment for
any disease.
The FDA (the U.S. Food and Drug Administration) has approved Olaparib for ovarian cancer but
it has not been approved for other uses.
LY2606368 is a checkpoint kinase 1 (CHK1) inhibitor that is being developed as a treatment
for patients with advanced cancer. CHK1 inhibitors work by preventing the cancer cells from
being able to repair damaged DNA (one of the building blocks of a cell) which then leads to
cell death.
Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor. PARP is a protein in the body
that repairs damage to DNA. In cells that are rapidly growing such as cancer cells, blocking
repair of DNA may be of benefit, since it will cause the cell to die.
In this research study, the investigators are combining LY2606368 with Olaparib in the hopes
that it will be a safe combination and that the LY2606368 will enhance how the cancer will
respond to Olaparib. In previous laboratory studies performed by treating cancer cells with a
CHK1 inhibitor and a PARP inhibitor, it was found that the CHK1 inhibitor was successful in
increasing efficacy.
Inclusion Criteria:
- Written informed consent obtained prior to any study-specific procedures not
considered part of routine medical care.
- For enrollment to expansion cohort 2, patients must have high-grade serous ovarian or
fallopian tube cancer and documentation of BRCA1 or BRCA2 mutation by a CLIA certified
lab.
- Patients must have measurable disease by RECIST version 1.1. Measurable disease is
defined as at least one dimension (longest diameter to be recorded for non-nodal
lesions and short axis for nodal lesions) as ≥ 20mm (≥ 2cm) with conventional
techniques or as ≥ 10mm (≥ 1cm) with spiral computed tomography (CT) scan, MRI, or
calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
- There are no limits on prior lines of therapy; however, patients must have recovered
to eligibility levels from prior toxicity or adverse events as a result of previous
treatment prior to entering the study (except alopecia).
- Age ≥18 years, as no dosing or adverse event data are currently available on the use
of prexasertib in combination with olaparib in patients < 18 years of age, children
are excluded from this study.
- ECOG performance status 0-1. PERFORMANCE STATUS CRITERIA.
- Patients must have normal organ and marrow function as defined below:
- absolute neutrophil count ≥ 1,500/microliters
- platelets ≥ 100,000/microliters
- white blood cells (WBC) ≥ 3 x 109/L
- hemoglobin ≥ 10 g/dL
- total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
- AST(SGOT)/ALT(SGPT) ≤2.5 x institutional ULN or ≤ 5 x institutional ULN in the
setting of liver mets
- creatinine ≤ 1.5X institutional ULN OR
- creatinine clearance ≥60 mL/min by Cockcroft-Gault equation for participants with
creatinine levels above institutional normal.
- The effects of prexasertib and olaparib on the developing human fetus are unknown. For
this reason, women of childbearing potential and male patients with partners of
childbearing potential must agree to use two highly effective forms of contraception
(see Section 5.5.2) prior to study entry, for the duration of study participation, and
for 3 months after completion of study. Men treated or enrolled on this protocol must
also agree to use adequate contraception prior to the study, for the duration of study
participation, and for 3 months after completion of prexasertib and olaparib
administration. Should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this study, she should inform her treating physician
immediately.
- Women of childbearing potential enrolling on study must have a negative serum
pregnancy test prior to registration.
- Childbearing potential is defined as women who are not postmenopausal (defined as
amenorrheic for ≥ 12 months following cessation of any exogenous hormonal treatments;
LH and FSH levels in the postmenopausal range for women under 50; radiation-induced
oophorectomy with last menses > 12 months prior; or chemotherapy-induced menopause
with last menses > 12 months prior) or surgically sterile (bilateral oophorectomy or
hysterectomy).
- Ability to understand and the willingness to sign a written informed consent document.
Patients must be willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations.
- Patients must be able to tolerate oral medications and not have gastrointestinal
processes that would preclude absorption of olaparib.
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study. Patients who have received
prior PARP inhibitor will not be excluded. Patients who have received prior CHK1
inhibitor will be excluded.
- Participants who have undergone major surgery within 14 days of starting the study
treatment, or participants who have not recovered to baseline status from the effects
of surgery received more than 14 days prior.
- Patients who are receiving any other investigational agents.
- Patients with known brain metastases or carcinomatous meningitis are excluded from
this clinical trial, with the exception of patients with brain metastatic disease that
has previously been treated and remained stable on MRI ≥ 2 months prior to enrollment,
without steroids or anti-epileptic medications. These patients may be enrolled at the
discretion of the Principal Investigator.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to prexasertib or olaparib.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, uncontrolled seizures, myocardial infarction within the past 3 months,
superior vena cava syndrome, unstable spinal cord compression (untreated and unstable
for at least 28 days prior to study entry), or psychiatric illness/social situations
that would limit compliance with study requirements. Additionally, patients with other
co-morbid disease or metabolic dysfunction that would render the subject at high risk
for treatment complications may be excluded at the discretion of the Principal
Investigator in the interest of patient safety.
- The effects of prexasertib and olaparib on the developing human fetus are unknown. For
this reason, pregnant women are excluded from this study. Because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of the
mother with prexasertib and olaparib, breastfeeding women are also excluded.
- Known HIV-positive participants on combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions with prexasertib and
olaparib. In addition, these participants are at increased risk of lethal infections
when treated with marrow-suppressive therapy.
- Participants with known active Hepatitis B or C.
- Participants who have received a previous allogeneic bone marrow transplant.
- Consistent QTc > 470 msec on more than one screening ECGs. Patients with a history of
long QTc syndrome or personal or family history of ventricular arrhythmias will be
excluded.
- Participants with involvement in the planning and/or conduct of the study (applies to
both AstraZeneca staff and/or staff at the study site).
- Participants receiving any medications or substances that are strong or moderate
inhibitors or inducers of CYP3A4 are ineligible. Please see Section 5.5.1 for further
detail and required washout periods. Because the lists of these agents are constantly
changing, it is important to regularly consult a frequently updated list such as
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as
the Physicians' Desk Reference may also provide this information. As part of the
enrollment/informed consent procedures, the patient 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 patient is considering a new over-the-counter medicine or herbal
product.
- Participants with a history of myelodysplastic syndrome or acute myeloid leukemia.
- Participants with evidence of pneumonitis on scans at screening will be excluded due
to pulmonary toxicities associated with olaparib
