The investigators propose an open label, one-arm study to assess the safety and efficacy of
olaparib and pembrolizumab in patients with cholangiocarcinoma who have progressed on or
cannot tolerate gemcitabine-based therapy.
The primary objective of the study is to assess the ORR of patients with advanced
cholangiocarcinoma receiving a combination of pembrolizumab and olaparib. It is hypothesized
that the addition of olaparib will improve the response rate of second line systemic therapy
from 17.5% to 35% in patients with advanced cholangiocarcinoma.
The study is designed to enroll 33 subjects (for 85% power) with advanced stage
cholangiocarcinoma to test the hypothesis that the combination of olaparib and pembrolizumab
will increase the ORR in comparison with the ORR from second line systemic chemotherapy
(historical control) in this patient population. As the primary study endpoint, which is also
being used to determine the sample size of the study, the investigators propose that the
combination of olaparib and pembrolizumab will increase the ORR to 35% from 17.5% (achieved
with systemic cytotoxic chemotherapy including mFOLFOX-historical control). To allow a 10%
patient drop off rate, the investigators expect to enroll a total of 36 subjects into this
study. In addition, as secondary study endpoints the investigators expect to see an increase
in the PFS and OS of patients receiving combination therapy compared to cytotoxic
In this study, the investigators propose the collection of three biopsies-one at baseline
prior to the start of treatment, one at the beginning of week 4, three weeks after the
administration of combination olaparib and pembrolizumab, and one at the time of cancer
progression-for the elucidation of exploratory study endpoints. Patients will have a CT or
MRI scan at the beginning of treatment and then every 6 weeks thereafter for the first six
months of study treatment administration, then every 9 weeks for up to 12 months after the
start of treatment, followed by every 12 weeks up to 24 months on study. All patients will
continue to receive olaparib and pembrolizumab combination treatment as tolerated unless
unacceptable toxicities or cancer progression occur, at which time therapy will cease. In the
absence of any problems, the planned study duration is 20-36 months.
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be ≥ 18 years of age on day of signing informed consent.
3. Patients must have received 1 line of prior systemic therapy for metastatic or
resectable disease (i.e. patients may have received adjuvant gemcitabine and then
later platin-based therapy for recurrent metastatic disease)
4. Histological confirmation of cholangiocarcinoma manifesting as either intrahepatic,
extrahepatic or gallbladder cancer. Patients with ampullary cancer are excluded.
5. Have measurable disease based on RECIST 1.1.
6. Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion. Newly obtained is defined as a specimen obtained up to 6 weeks (42 days)
prior to initiation of treatment on Day 1. Subjects for whom newly obtained samples
cannot be provided (e.g. inaccessible or subject safety concern) may submit an
archived specimen only upon agreement from the sponsor-investigator. Subjects from
whom a biopsy is not medically possible or safe may be enrolled on the study upon
agreement from the principal investigator.
7. Have a performance status of 0 or 1 on the ECOG Performance Scale.
8. Demonstrate adequate organ function as defined in Table 1. All screening labs will be
performed within 28 days of registration.
Table 1: Adequate Organ Function Laboratory Values System Laboratory Value
Hematological Absolute neutrophil count (ANC) ≥ 1,500 /μL Platelets ≥ 100,000 / μL
Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or EPO dependency (within 7
days of assessment) Renal Serum creatinine OR Measured or calculateda creatinine
clearance (GFR can also be used in place of creatinine or CrCl) ≤ 1.5 X upper limit of
normal (ULN) OR
≥ 50 mL/min for subject with creatinine levels > 1.5 x institutional ULN Hepatic Serum
total bilirubin ≤ 2.0 X ULN AST (SGOT) and ALT (SGPT) ≤ 3.0 X ULN OR
≤ 5 X ULN for subjects with liver metastases Albumin > 2.5 mg/dL Coagulation
International Normalized Ratio (INR) or Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is
within therapeutic range of intended use of anticoagulants aCreatinine clearance
should be calculated per institutional standard.
9. Female subject of childbearing potential should have a negative urine or serum
pregnancy 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.
10. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication (Reference
Section in Appendix 3). Subjects of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > 1 year.
11. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy.
1. A history of anaphylaxis to olaparib
2. Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.
3. A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test
within 72 hours prior to 1st dose of treatment (see Appendix 3). If the urine test is
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
4. Has a known history of active TB (Bacillus Tuberculosis).
5. Has known hypersensitivity to pembrolizumab or any of its excipients.
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier.
7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent.
NOTE: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may
qualify for the study.
NOTE: If subject received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy.
8. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.
9. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis, which is excluded regardless of clinical stability.
10. Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
11. Has known history of, or any evidence of active, non-infectious pneumonitis.
12. Has an active infection requiring systemic therapy.
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the site investigator.
14. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
17. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.
18. Has known active Hepatitis B without HBV treatment (HBV infection with ongoing HBV
treatment is allowed); chronic Hepatitis C infection is allowed. Any patient receiving
treatment for HCV should wait at least 14 days after completion of HCV treatment
before beginning study treatment. No patient should receive HCV treatment while
receiving study treatment. Note: no testing for Hepatitis B and Hepatitis C is
required unless mandated by local health authority.
19. Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.