Testing the Addition of Pembrolizumab, an Immunotherapy Cancer Drug to Olaparib Alone as Therapy for Patients With Pancreatic Cancer That Has Spread With Inherited BRCA Mutations
Purpose
This phase II trial studies whether adding pembrolizumab to olaparib (standard of care) works better than olaparib alone in treating patients with pancreatic cancer with germline BRCA1 or BRCA2 mutations that has spread to other places in the body (metastatic). BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged deoxyribonucleic acid (DNA) and, therefore, play a role in ensuring the stability of each cell's genetic material. When either of these genes is mutated, or altered, such that its protein product is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to some types of cancer, including pancreatic cancer. 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. Olaparib is an inhibitor of PARP, a protein that helps repair damaged DNA. Blocking PARP may help keep tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. The addition of pembrolizumab to the usual treatment of olaparib may help to shrink tumors in patients with metastatic pancreatic cancer with BRCA1 or BRCA2 mutations.
Conditions
- Metastatic Pancreatic Adenocarcinoma
- Pancreatic Adenocarcinoma
- Stage IV Pancreatic Cancer AJCC v8
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- Patients must have a histologic or cytologic diagnosis of pancreatic adenocarcinoma.
Patients with neuroendocrine tumors, acinar cell and adenosquamous carcinomas are
excluded. All disease must be assessed and documented on the Baseline Tumor
Assessment Form
- Patients must have one of the following mutations: germline mutation in BRCA 1 or 2
that was tested in a Clinical Laboratory Improvement Act (CLIA) certified lab
defined as positive and/or deleterious (that is, pathogenic or likely pathogenic
variant). (NOTE: Patients with tumor somatic mutations are not eligible)
- Patients must have metastatic disease and received first line platinum-based
chemotherapy (i.e. fluorouracil, irinotecan, leucovorin and oxaliplatin
[FOLFIRINOX], leucovorin calcium, 5-fluorouracil, and oxaliplatin [FOLFOX],
gemcitabine + nab-paclitaxel + cisplatin or gemcitabine + cisplatin)
- Patients must have had a CT or MRI showing stable or responding disease on first
line platinum-based chemotherapy within 30 days prior to registration
- Patients with known human immunodeficiency virus (HIV)-infection are eligible
providing they are on effective anti-retroviral therapy and have undetectable viral
load at their most recent viral load test and within 6 months prior to registration
- Patients with history of chronic hepatitis B virus (HBV) infection must have
undetectable HBV viral load within 30 days prior to registration
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment must have
an undetectable HCV viral load within 30 days prior to registration
- Patients must have received at least 16 weeks of first line platinum-based
chemotherapy for metastatic disease. Patients may have also received one cycle of
treatment (no more than 4 weeks) with gemcitabine + nab-paclitaxel while waiting for
germline test results, prior to platinum-based therapy
- Patients' last chemotherapy treatment must be within 30 days prior to registration
- Patients must have resolved or stable =< grade 1 toxicity from prior administration
of another investigational drug and/or prior anti-cancer treatment, excluding
neuropathy and alopecia
- Patients must not have a known hypersensitivity to olaparib or any of the excipients
of the product
- Patients must not be planning to receive strong or moderate CYP3A inhibitors or
inducers while on olaparib treatment. Patients receiving strong or moderate CYP3A
inhibitors must discontinue use at least 2 weeks prior to receiving olaparib.
Patients receiving strong or moderate CYP3A inducers must discontinue use at least 5
weeks prior to receiving olaparib. Medications should be checked using a frequently
updated medical reference for a list of drugs to avoid
- Patients must not have received live vaccines within 42 days prior to randomization
and must not be planning to receive live virus or live bacterial vaccines while
receiving study treatment and during the 30 day follow up period. Examples of live
vaccines include, but are not limited to, the following: measles, mumps, rubella,
chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally
killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,
Flu-Mist) are live attenuated vaccines, and are not allowed. Coronavirus disease
2019 (COVID-19) messenger ribonucleic acid (mRNA) vaccine is allowed
- Patients must not have had prior therapy with an anti-PD-1, anti-PD-L1, or
anti-PD-L2 agent, or any other immune checkpoint inhibitors
- Patients must not have had prior therapy with PARP inhibitors
- Patients must not have had a prior diagnosis of immunodeficiency or receiving
systemic steroid therapy (defined as >= 10 mg prednisone or equivalent) or any other
form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment
- Zubrod performance status of 0-1
- Patients must be >= 18 years old
- Patients must have a complete medical history and physical exam within 28 days prior
to registration
- Absolute neutrophil count >= 1.5 x 10^3/uL (within 14 days of registration)
- Platelets >= 100 x 10^3/uL (within 14 days of registration)
- Total bilirubin =< 1.5 institutional upper limit of normal (ULN) (within 14 days of
registration)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x institutional
ULN (within 14 days of registration)
- Albumin >= 3.0 g/dL (within 14 days of registration)
- Hemoglobin >= 9.0 g/dL (within 14 days of registration)
- Creatinine clearance (Cockcroft _Gault) > 50 mg/dL (within 14 days of registration)
- Participants must have a serum creatinine =< the institutional (I)ULN OR measured OR
calculated creatinine clearance >= 50 mL/min using the following Cockcroft-Gault
Formula. This specimen must have been drawn and processed within 14 days prior to
registration
- Patients must have CA19-9 obtained within 42 days prior to registration
- Patients must be able to swallow and retain oral medications and have no known
gastrointestinal disorders likely to interfere with absorption of the study
medication
- Participants with a prior or concurrent malignancy whose natural history or
treatment (in the opinion of the treating physician) does not have the potential to
interfere with the safety or efficacy assessment of the investigational regimen are
eligible for this trial provided it does not require concurrent therapy
- Participants must not be pregnant or nursing due to the possibility of harm to the
fetus or nursing infant from this treatment regimen. Women of childbearing potential
must have a negative urine or serum pregnancy test within 28 days prior to
registration. Women/men of reproductive potential must have agreed to use an
effective contraceptive method for the course of the study through 6 months after
the last dose of study medication. A woman is considered to be of "reproductive
potential" if she has had menses at any time in the preceding 12 consecutive months.
In addition to routine contraceptive methods, "effective contraception" also
includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a
side-effect of pregnancy prevention) defined as a hysterectomy, bilateral
oophorectomy or bilateral tubal ligation. However, if at any point a previously
celibate participant chooses to become heterosexually active during the time period
for use of contraceptive measures, he/she is responsible for beginning contraceptive
measures. 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
- Patients must not have a history of (non-infectious) pneumonitis that required
steroids or current pneumonitis
- Patients must not have an active infection requiring systemic therapy
- Patients must not have active autoimmune disease that has required systemic
treatment in 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
- Patients must be offered the opportunity to participate in specimen banking of
formalin-fixed paraffin-embedded (FFPE) tissue and whole blood. If a patient is
unable to submit archival tissue, should the patient need to undergo a standard of
care biopsy per National Comprehensive Cancer Network (NCCN) guidelines, patients
must then be offered the opportunity to submit the fresh tumor tissue from that
biopsy. With participant consent, specimens must be collected and submitted via the
Southwest Oncology Group (SWOG) Specimen Tracking System
- Patients must be informed of the investigational nature of this study and must sign
and give informed consent in accordance with institutional and federal guidelines.
For participants with impaired decision making capabilities, legally authorized
representatives may sign and give informed consent on behalf of study participants
in accordance with applicable federal, local, and Canada Industrial Relations Board
(CIRB) regulations
- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has
been entered in the system
Study Design
- Phase
- Phase 2
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Arm A (olaparib, pembrolizumab) |
Patients receive olaparib PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 19, patients receive olaparib PO BID on days 1-42 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study. |
|
|
Active Comparator Arm B (olaparib) |
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study. |
|
Recruiting Locations
Nashville, Tennessee 37232
Site Public Contact
800-811-8480
More Details
- Status
- Recruiting
- Sponsor
- National Cancer Institute (NCI)
Study Contact
Detailed Description
PRIMARY OBJECTIVE: I. To evaluate the progression free survival (PFS) of advanced pancreatic cancer patients with germline BRCA1 or BRCA2 mutations treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability associated with the combination of olaparib + pembrolizumab versus (vs.) olaparib alone as maintenance therapy. II. To evaluate the overall survival (OS) of patients treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. III. To evaluate the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, including confirmed and unconfirmed, complete and partial response, of patients treated with olaparib + pembrolizumab compared to olaparib alone, in the subset of patients with measurable disease. IV. To evaluate the duration of response (DoR) by RECIST 1.1 in patients treated with olaparib + pembrolizumab compared to olaparib alone. BANKING OBJECTIVE: I. To bank tissue and blood specimens for future correlative studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive olaparib orally (PO) twice daily (BID) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 19, patients receive olaparib PO BID on days 1-42 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan or magnetic resonance imaging (MRI), tumor biopsy and blood sample collection throughout the study. After completion of study treatment, patients are followed for 30 days and every 6 months for 3 years from the date of randomization.