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Trial record 3 of 3 for:    s2001
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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

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ClinicalTrials.gov Identifier: NCT04548752
Recruitment Status : Recruiting
First Posted : September 16, 2020
Last Update Posted : March 23, 2023
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Metastatic Pancreatic Adenocarcinoma Stage IV Pancreatic Cancer AJCC v8 Drug: Olaparib Biological: Pembrolizumab Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 88 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 4, 2020
Estimated Primary Completion Date : March 31, 2025
Estimated Study Completion Date : March 31, 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm A (olaparib, pembrolizumab)
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.
 Drug: Olaparib
Given PO
Other Names:
  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475
Active Comparator: Arm B (olaparib)
Patients receive olaparib PO BID on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
 Drug: Olaparib
Given PO
Other Names:
  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281


Outcome Measures
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Primary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: Up to 3 years ]
    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 :
  1. Incidence of adverse events [ Time Frame: Up to 3 years ]
    Will utilize the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 for toxicity and serious adverse event reporting.

  2. Overall survival [ Time Frame: Up to 3 years ]
    Distributions of overall survival in each arm will be estimated using the method of Kaplan-Meier and compared using the stratified log-rank test.

  3. Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 3 years ]
    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.

  4. ORR per Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST) [ Time Frame: Up to 3 years ]
    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.

  5. Duration of response (DoR) [ Time Frame: Up to 3 years ]
    Distributions of DoR in each arm will be estimated using the method of Kaplan-Meier and compared using the stratified log-rank test.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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], gemcitabine + nab-paclitaxel + cisplatin 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 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
  • 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)
  • 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
  • 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. 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
  • 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04548752


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Vincent Chung Southwest Oncology Group
More Information
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04548752    
Other Study ID Numbers: NCI-2020-06838
NCI-2020-06838 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S2001 ( Other Identifier: SWOG )
S2001 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
First Posted: September 16, 2020    Key Record Dates
Last Update Posted: March 23, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
 Pembrolizumab
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Antineoplastic Agents, Immunological
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action