Pembrolizumab and Olaparib for the Treatment of Metastatic Bile Duct Cancer
This phase II trial investigates how well pembrolizumab and olaparib work in treating patients with cholangiocarcinoma (cancer of the bile duct) that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. The purpose of this study is to determine the effects (good and bad) of pembrolizumab and olaparib in patients with cancer of the bile duct.
Inclusion Criteria
- Be willing and able to provide written informed consent/assent for the trial
- 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)
- Histological confirmation of cholangiocarcinoma manifesting as either intrahepatic, extrahepatic or gallbladder cancer. Patients with ampullary cancer are excluded
- Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- 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
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
- Absolute neutrophil count (ANC) >= 1,500/uL (within 28 days of registration)
- Platelets >= 100,000/uL (within 28 days of registration)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment (within 28 days of registration)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 50 mL/min for subject with creatinine levels (Glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) > 1.5 x institutional ULN (within 28 days of registration) * Creatinine clearance should be calculated per institutional standard
- Serum total bilirubin =< 2.0 x ULN (within 28 days of registration)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x ULN OR =< 5 x ULN for subjects with liver metastases (within 28 days of registration)
- Albumin >= 2.5 mg/dL (within 28 days of registration)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 28 days of registration)
- 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 of anticoagulants (within 28 days of registration)
- 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
- 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. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
- 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
Exclusion Criteria
- A history of anaphylaxis to olaparib
- 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
- A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test within 72 hours prior to 1st dose of treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Has a known history of active TB (Bacillus tuberculosis)
- Has known hypersensitivity to pembrolizumab or any of its excipients
- 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
- 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
- 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
- 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
- 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
- Has known history of, or any evidence of active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy
- 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
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- 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
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- 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
- Has known active hepatitis B without hepatitis B virus (HBV) treatment (HBV infection with ongoing HBV treatment is allowed); chronic hepatitis C infection is allowed. Any patient receiving treatment for hepatitis C virus (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
- 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-Guerin (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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04306367.
PRIMARY OBJECTIVE:
I. Assess the objective response rate (ORR) of patients receiving pembrolizumab and olaparib combination therapy.
SECONDARY OBJECTIVES:
I. Assess the duration of response (DOR) of patient receiving pembrolizumab and olaparib, taking best overall response to progression.
II. Assess progression free survival (PFS) of patients receiving pembrolizumab and olaparib taking best overall response to progression or death from any cause, whichever occurs first.
III. Assess overall survival (OS) of patients receiving pembrolizumab and olaparib from baseline to date of death or last follow up.
IV. Assess the safety and tolerability of combined pembrolizumab and olaparib therapy.
EXPLORATORY OBJECTIVES:
I. To correlate in tumor samples the baseline density of CD3 and CD8 in the tumor interior and invasive margin, the expression of PD-L1, and the clonality of the T-cell repertoire with ORR, DOR, PFS, and OS.
II. To assess in tumor samples the baseline density of CD3 and CD8 in the tumor interior and invasive margin, the expression of PD-L1, and the clonality of the T-cell repertoire at baseline and after three weeks of treatment, and then correlate these assessments with ORR, DOR, PFS, and OS.
III. To compare in tumor samples the density of CD3 and CD8 in the tumor interior and invasive margin, the expression of PD-L1, and the clonality of the T-cell repertoire at three time points: at the time of disease progression, after three weeks of treatment, and at baseline.
IV. To correlate in the cholangiocarcinoma tissue the baseline expression of ERCC (DRCC +/-) or the baseline mutation status of IDH1 or 2 (mutant or non-mutant) with ORR, DOR, PFS, and OS.
OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and olaparib orally (PO) twice daily (BID) on days 1-21. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients who stop treatment with stable disease (SD) or better receive an additional 17 cycles (1 year) of pembrolizumab in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days (visit 1), 6 weeks after visit 1 (visit 2), then every 12 weeks thereafter.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMedStar Georgetown University Hospital
Principal InvestigatorJohn Lindsay Marshall
- Primary IDSTUDY00000908
- Secondary IDsNCI-2020-05323
- ClinicalTrials.gov IDNCT04306367