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Trial record 1 of 1 for:    GY016
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Pembrolizumab and Epacadostat in Treating Patients With Recurrent, Persistent, or Progressive Ovarian Clear Cell Carcinoma

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ClinicalTrials.gov Identifier: NCT03602586
Recruitment Status : Suspended (Scheduled Interim Monitoring)
First Posted : July 27, 2018
Last Update Posted : April 30, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well pembrolizumab and epacadostat work in treating patients with ovarian clear cell carcinoma that has come back, remains despite treatment, or is growing, spreading, or getting worse. 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. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and epacadostat may work better in treating patients with ovarian clear cell carcinoma.

Condition or disease Intervention/treatment Phase
Malignant Ovarian Clear Cell Tumor Recurrent Ovarian Carcinoma Drug: Epacadostat Biological: Pembrolizumab Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the objective tumor response (proportion of objective response by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria) of the combination of pembrolizumab (MK-3475 [pembrolizumab]) and epacadostat in patients with recurrent or persistent clear cell carcinoma of the ovary.

SECONDARY OBJECTIVES:

I. To determine the nature and degree of toxicity of MK-3475 (pembrolizumab) + epacadostat as assessed by Common Terminology Criteria for Adverse Events (CTCAE) in patients with recurrent or persistent clear cell carcinoma of the ovary.

II. To estimate the progression-free survival (PFS) and overall survival (OS) in patients treated with combination of MK-3475 (pembrolizumab) and epacadostat.

EXPLORATORY TRANSLATIONAL OBJECTIVES:

I. Determine whether the ratio of plasma tryptophan to kynurenine (T:K) correlates with response to MK-3475 (pembrolizumab) + epacadostat, by evaluating plasma T:K pre-treatment, during treatment, and at disease progression.

II. Determine whether the presence of PD-L1, IDO-1, tumor-infiltrating regulatory T cells (Tregs), CD8 tumor-infiltrating lymphocytes (TILs), and human leukocyte antigen (HLA) class I in the tumor microenvironment at baseline correlates with objective response to MK-3475 (pembrolizumab) + epacadostat.

III. Determine whether soluble PD-L1 (sPD-L1) levels in plasma are correlated with response to MK-3475 (pembrolizumab) + epacadostat, by evaluating sPD-L1 concentrations pre-treatment, during treatment, and at disease progression.

OUTLINE:

Patients receive epacadostat orally (PO) twice daily (BID) and pembrolizumab intravenously (IV) over 30 minutes once every 3 weeks (Q3W). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years, and annually thereafter.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 23 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of MK-3475 (Pembrolizumab) (NSC #776864) + Epacadostat (NSC #766086) in Recurrent Clear Cell Carcinoma of the Ovary
Actual Study Start Date : September 28, 2018
Estimated Primary Completion Date : April 30, 2021
Estimated Study Completion Date : April 30, 2021


Arm Intervention/treatment
Experimental: Treatment (epacadostat, pembrolizumab)
Patients receive epacadostat PO BID and pembrolizumab IV over 30 minutes Q3W. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Epacadostat
Given PO
Other Names:
  • INCB 024360
  • INCB024360

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Complete or partial objective tumor response [ Time Frame: Within 7 months of study entry ]
    Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v.) 1.1 criteria. Exact 95% confidence limits, accounting for interim analysis, will be provided in the final report.


Secondary Outcome Measures :
  1. Nature and degree of adverse events [ Time Frame: Up to 5 years ]
    Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5. Descriptive statistics, including frequencies, of maximum grade of adverse events by term and category will be reported. Adverse events categorized as Grade 5 will be individually reported.

  2. Progression-free survival (PFS) [ Time Frame: From the start of study treatment to time of progression or death, whichever occurs first, assessed up to 5 years ]
    Disease progression will be defined using RECIST v. 1.1 criteria. The distributions of PFS will be estimated and graphed using the Kaplan-Meier product limit method.

  3. Overall survival (OS) [ Time Frame: From the start of study treatment to time of death or the date of last contact, assessed up to 5 years ]
    The distributions of OS will be estimated and graphed using the Kaplan-Meier product limit method.


Other Outcome Measures:
  1. Ratio of plasma tryptophan to kynurenine (T:K) [ Time Frame: Up to 5 years ]
    Will determine whether the ratio of plasma T:K correlates with response to MK-3475 (pembrolizumab) and epacadostat, by evaluating plasma T:K pre-treatment, during treatment, and at disease progression. Pre-treatment levels of T:K ratio in plasma will be assessed for association with radiographic response to MK-3475 (pembrolizumab) and epacadostat. Changes between pre-treatment and post-cycle 1 and changes between post-cycle 1 and disease progression for T:K ratio will be evaluated with paired Student's T tests.

  2. Presence of PD-L1, IDO-1, tumor-infiltrating regulatory T cells (Tregs), CD8 tumor-infiltrating lymphocytes (TILs), and human leukocyte antigen (HLA) class I in the tumor microenvironment [ Time Frame: Up to 5 years ]
    Will determine whether the presence of PD-L1, IDO-1, Tregs, CD8 TILs, and HLA class I in the tumor microenvironment at baseline correlates with objective response to MK-3475 (pembrolizumab) + epacadostat. Baseline presence of PD-L1, IDO-1, Tregs, TILs, and HLA class I in the tumor microenvironment will also be assessed for correlation with radiographic response to MK-3475 (pembrolizumab) and epacadostat. Will consider logistic regression models for these analyses of continuous biomarkers, if appropriate given the number of responses and if exact tests of response for categorized levels of the biomarkers.

  3. Soluble PD-L1 (sPD-L1) levels in plasma [ Time Frame: Up to 5 years ]
    Will determine whether sPD-L1 levels in plasma are correlated with response to MK-3475 (pembrolizumab) + epacadostat, by evaluating sPD-L1 concentrations pre-treatment, during treatment, and at disease progression. Pre-treatment levels of sPD-L1 in plasma will be assessed for association with radiographic response to MK-3475 (pembrolizumab) and epacadostat. Changes between pre-treatment and post-cycle 1 and changes between post-cycle 1 and disease progression for sPD-L1 will be evaluated with paired Student's T tests.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Primary tumors must be at least 50% clear cell histomorphology in order to be eligible or have a histologically documented recurrence with at least 50% clear cell histomorphology. Recurrence should be biopsy proven as per standard of care unless the tumor is located in an area deemed unsafe to biopsy. Histologic confirmation of the original primary tumor is required via the pathology report. The percentage of clear cell histomorphology must be documented in the pathology report or in an addendum to the original report. If slides of the primary tumor are not available for review due to disposal of slides by the histology laboratory (typically 10 years after diagnosis), a biopsy of the recurrent or persistent tumor is required to confirm at least 50% clear cell histomorphology, as long as tumor is located in an area deemed safe to biopsy. The percentage of clear cell involvement must be documented in the pathology report or in an addendum to the original report
  • All patents must have measurable disease, and at least one "target lesion" to be used to assess response as defined by RECIST 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray. Lymph nodes must be >= 15 mm in short axis when measured by CT or MRI
  • Appropriate stage for study entry based on the following diagnostic workup:

    • History/physical examination within 28 days prior to registration
    • Imaging of target lesions within 28 days prior to registration
    • Further protocol-specific assessments

      • Recovery from adverse effects of recent surgery, radiotherapy or chemotherapy
      • Any other prior therapy directed at the malignant tumor including chemotherapy, and biologic/targeted agents must be discontinued at least 4 weeks prior to registration. Any hormonal therapy directed at the malignant tumor must be discontinued at least 2 weeks prior to registration
      • Any prior radiation therapy must be completed at least 4 weeks prior to registration, and progression must be outside the radiation field
      • At least 4 weeks must have elapsed since any major surgery prior to registration
  • The trial is open only to women with recurrent or progressive clear cell carcinoma of the ovary
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 28 days prior to registration
  • Patients must have had one prior platinum-based chemotherapy for management of primary disease. Patients are allowed to receive, but are not required to receive, up to two additional cytotoxic regimens for management of recurrent or persistent disease
  • Absolute neutrophil count (ANC) >= 1,500/ul (within 14 days prior to registration)
  • Platelets >= 100,000/ul (within 14 days prior to registration)
  • Hemoglobin (Hgb) >= 8.0 g/dL within 14 days prior to registration (Note: the use of transfusion of other intervention to achieve a Hgb >= 8.0 g/dL is acceptable)
  • Creatinine =< 1.5 x institutional upper limit of normal (ULN) or creatinine clearance (CrCl) >= 60 mL/min using Cockcroft-Gault formula (within 14 days prior to registration)
  • Bilirubin =< 2.5 x ULN (within 14 days prior to registration)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (within 14 days prior to registration)
  • Normal thyroid function testing (thyroid-stimulating hormone [TSH]) (within 14 days prior to registration)
  • Negative pregnancy test in women of childbearing potential
  • Women of childbearing potential who are sexually active should be willing and able to use medically acceptable forms of contraception for the course of the study through 120 days after the last dose of MK-3475 (pembrolizumab). Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile, who have had a hysterectomy and/or bilateral oophorectomy) do not require contraception
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry

Exclusion Criteria:

  • Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years
  • Patients who have had prior therapy with MK-3475 (pembrolizumab) or epacadostat or with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune check point pathways
  • History of severe hypersensitivity reaction to any monoclonal antibody
  • Patients with active auto-immune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease, Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease. Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
  • Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure and unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures which are not controlled with non-enzyme inducing anticonvulsants, and/or epidural disease, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months prior to the first date of study treatment. Those with brain metastases are permitted as long as they have been treated with brain radiation therapy and have been documented stability 4 weeks following completion of brain radiation therapy
  • In order for patients with human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) to be eligible, they must be on a stable highly active antiretroviral therapy (HAART) regimen with no drug-drug interaction with UGT1A9, have CD4+ counts > 350, with no detectable viral load on quantitative polymerase chain reaction (PCR), and no opportunistic infection
  • Patients with treated hepatitis viral infections (hepatitis B and C) are eligible if they have completed definitive treatment at least 6 months prior, have no detectable viral load on quantitative PCR, and liver function tests (LFTs) meet eligibility requirements
  • Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration
  • Therapy with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitor (SSRIs) within the last 4 weeks or history of serotonin syndrome. Concomitant use of monoamine oxidase inhibitors with epacadostat (INCB024360) is prohibited
  • Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, abdominal/pelvic fistula, gastrointestinal perforation, gastrointestinal (GI) obstruction and/or who require parenteral hydration and/or nutrition
  • Epacadostat (INCB024360) is a substrate of CYP3A4, CYP1A2, CYP2C19, UGT1A9, P-gp, and BCRP. Use caution when administered with strong inhibitors/inducers of these isoenzymes and transporter proteins. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference
  • History or presence of an abnormal electrocardiography (ECG) that, in the investigator's opinion, is clinically meaningful. Screening QTc interval > 480 milliseconds is excluded (corrected by Fridericia). In the event that a single QTc is > 480 milliseconds, the subject may enroll if the average QTc for the 3 ECGs is < 480 milliseconds. For subjects with an intraventricular conduction delay (QRS interval > 120 msec), the JTc interval may be used in place of the QTc with sponsor approval. The JTc must be < 340 milliseconds if JTc is used in place of QTc. Subjects with left bundle branch block are excluded
  • Patients who are pregnant or nursing

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): NCT03602586


  Show 364 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Lilian T Gien NRG Oncology

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03602586     History of Changes
Other Study ID Numbers: NCI-2018-01561
NCI-2018-01561 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GY016 ( Other Identifier: NRG Oncology )
NRG-GY016 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: July 27, 2018    Key Record Dates
Last Update Posted: April 30, 2019
Last Verified: April 2019

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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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Carcinoma
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Adenomyoepithelioma
Adenocarcinoma, Clear Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Neoplasms, Complex and Mixed
Adenocarcinoma
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents