Clinical Trials /

Testing Whether the Combination of Two Immunotherapy Drugs Have Activity in Recurrent or Persistent Clear Cell Ovarian Cancer

NCT03602586

Description:

This phase II trial studies how well pembrolizumab and epacadostat work in treating patients with ovarian clear cell carcinoma that has come back (recurrent), remains despite treatment (persistent), or is growing, spreading, or getting worse (progressive). 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 compared to usual treatment (surgery, radiation, or cytotoxic chemotherapy) in treating patients with ovarian clear cell carcinoma.

Related Conditions:
  • Ovarian Clear Cell Adenocarcinoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing Whether the Combination of Two Immunotherapy Drugs Have Activity in Recurrent or Persistent Clear Cell Ovarian Cancer
  • Official Title: A Phase II Study of MK-3475 (Pembrolizumab) (NSC #776864) + Epacadostat (NSC #766086) in Recurrent Clear Cell Carcinoma of the Ovary

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-01561
  • SECONDARY ID: NCI-2018-01561
  • SECONDARY ID: NRG-GY016
  • SECONDARY ID: NRG-GY016
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT03602586

Conditions

  • Malignant Ovarian Clear Cell Tumor
  • Recurrent Ovarian Carcinoma

Interventions

DrugSynonymsArms
EpacadostatINCB 024360, INCB024360Treatment (epacadostat, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (epacadostat, pembrolizumab)

Purpose

This phase II trial studies how well pembrolizumab and epacadostat work in treating patients with ovarian clear cell carcinoma that has come back (recurrent), remains despite treatment (persistent), or is growing, spreading, or getting worse (progressive). 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 compared to usual treatment (surgery, radiation, or cytotoxic chemotherapy) in treating patients with ovarian clear cell carcinoma.

Detailed Description

      PRIMARY OBJECTIVE:

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (epacadostat, pembrolizumab)ExperimentalPatients 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.
  • Epacadostat
  • Pembrolizumab

Eligibility 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 (residual grade 1 toxicity is considered recovered)

                    -  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 or SSRIs 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete or partial objective tumor response
Time Frame:Within 7 months of study entry
Safety Issue:
Description: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

Measure:Nature and degree of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:The distributions of OS will be estimated and graphed using the Kaplan-Meier product limit method.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Suspended
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

October 14, 2020