Description:
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.
Title
- Brief Title: 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
- Official Title: Randomized Phase II Clinical Trial of Olaparib + Pembrolizumab vs. Olaparib Alone as Maintenance Therapy in Metastatic Pancreatic Cancer Patients With Germline BRCA1 or BRCA2 Mutations
Clinical Trial IDs
- ORG STUDY ID:
NCI-2020-06838
- SECONDARY ID:
NCI-2020-06838
- SECONDARY ID:
S2001
- SECONDARY ID:
S2001
- SECONDARY ID:
U10CA180888
- NCT ID:
NCT04548752
Conditions
- Metastatic Pancreatic Adenocarcinoma
- Stage IV Pancreatic Cancer AJCC v8
Interventions
Drug | Synonyms | Arms |
---|
Olaparib | AZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281 | Arm A (olaparib, pembrolizumab) |
Pembrolizumab | Keytruda, Lambrolizumab, MK-3475, SCH 900475 | Arm A (olaparib, pembrolizumab) |
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.
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 overall response rate (ORR) by immune RECIST, 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.
V. 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. 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.
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. Cycles repeat every 21 days in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed for 30 days and every 6 months for
3 years from the date of randomization.
Trial Arms
Name | Type | Description | Interventions |
---|
Arm A (olaparib, pembrolizumab) | Experimental | Patients receive olaparib PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1. 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. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. | |
Arm B (olaparib) | Active Comparator | Patients receive olaparib PO BID on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. | |
Eligibility Criteria
Inclusion Criteria:
- Patient 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)
- Patient 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], or gemcitabine +
cisplatin)
- Patients must have had a computed tomography (CT) or magnetic resonance imaging (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 but no more than 24 weeks of first line
platinum-based therapy for metastatic disease
- 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
- Zubrod performance status of 0-1
- Patients must have a complete medical history and physical exam within 28 days prior
to registration
- Absolute neutrophil count >= 1,500/mcL (within 14 days of registration)
- Platelets >= 100,000/mcL (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)
- Creatinine =< 1.5 mg/dl (within 14 days of registration)
- Albumin >= 3.0 (within 14 days of registration)
- Hemoglobin >= 9.0 g/dL
- 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
- 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
Exclusion Criteria:
- 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
- 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
- Participants must not be pregnant or nursing due to the possibility of harm to the
fetus or nursing infant from this treatment regimen. 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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Progression-free survival (PFS) |
Time Frame: | Up to 3 years |
Safety Issue: | |
Description: | Primary analysis of PFS will be conducted in all eligible patients according to the intent-to-treat principle using a log rank test stratified by first line chemotherapy, performance status and disease status after first line platinum-based treatment. Distributions of PFS by treatment arm will be estimated using the method of Kaplan-Meier. |
Secondary Outcome Measures
Measure: | Incidence of adverse events |
Time Frame: | Up to 3 years |
Safety Issue: | |
Description: | Will utilize the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 for toxicity and serious adverse event reporting. |
Measure: | Overall survival |
Time Frame: | Up to 3 years |
Safety Issue: | |
Description: | Distributions of overall survival in each arm will be estimated using the method of Kaplan-Meier and compared using the stratified log-rank test. |
Measure: | Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) |
Time Frame: | Up to 3 years |
Safety Issue: | |
Description: | Measured per RECIST 1.1. ORR will be estimated in the subset of patients with measurable disease. Assuming 90% of patients (n=35 per arm) will present with measurable disease, ORR can be estimated to within 18% (95% confidence interval) and will be compared by treatment arm using logistic regression. |
Measure: | ORR per Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST) |
Time Frame: | Up to 3 years |
Safety Issue: | |
Description: | Measured per iRECIST. ORR will be estimated in the subset of patients with measurable disease. Assuming 90% of patients (n=35 per arm) will present with measurable disease, ORR can be estimated to within 18% (95% confidence interval) and will be compared by treatment arm using logistic regression. |
Measure: | Duration of response (DoR) |
Time Frame: | Up to 3 years |
Safety Issue: | |
Description: | Distributions of DoR in each arm will be estimated using the method of Kaplan-Meier and compared using the stratified log-rank test. |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Last Updated
August 31, 2021