Clinical Trials /

Immune Checkpoint Inhibitor Nivolumab in People With Recurrent Select Rare CNS Cancers

NCT03173950

Description:

Background: More than 130 primary tumors of the central nervous system (CNS) have been identified. Most affect less than 1,000 people in the United States each year. Because these tumors are so rare, there are few proven therapies. This study will test whether the immunotherapy drug nivolumab is an effective treatment for people with rare CNS tumors. Objectives: To learn if stimulating the immune system using the drug nivolumab can shrink tumors in people with rare CNS (brain or spine) tumors or increase the time it takes for these tumors to grow or spread. Eligibility: Adults whose rare CNS tumor has returned. Design: Participants will be screened: - Heart and blood tests - Physical and neurological exam - Hepatitis tests - Pregnancy test - MRI. They will lay in a machine that takes pictures. - Tumor tissue sample. This can be from a previous procedure. At the start of the study, participants will have blood tests. They will answer questions about their symptoms and their quality of life. Participants will get nivolumab in a vein every 2 weeks for up to 64 weeks. Participants will have monthly blood tests. Every other month they will have an MRI and a neurologic function test. They will also answer questions about their quality of life. Genetic tests will be done on participants' tumor tissue. Participants will be contacted if any clinically important results are found. After treatment ends, participants will be monitored for up to 5 years. They will have a series of MRIs and neurological function tests. They will be asked to report any symptoms they experience....

Related Conditions:
  • Anaplastic Pleomorphic Xanthoastrocytoma
  • Atypical Meningioma
  • Atypical Teratoid/Rhabdoid Tumor
  • Central Nervous System Embryonal Neoplasm
  • Central Nervous System Sarcoma
  • Choroid Plexus Neoplasm
  • Diffuse Midline Glioma, H3 K27M-Mutant
  • Embryonal Tumor with Multilayered Rosettes, C19MC-Altered
  • Embryonal Tumor with Multilayered Rosettes, Not Otherwise Specified
  • Ependymoma
  • Glioma
  • Gliomatosis Cerebri
  • Gliosarcoma
  • Medulloblastoma
  • Pineal Region Neoplasm
  • Pineoblastoma
  • Pineocytoma
  • Pleomorphic Xanthoastrocytoma
  • Primitive Neuroectodermal Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Immune Checkpoint Inhibitor Nivolumab in People With Select Rare CNS Cancers
  • Official Title: Phase II Trial of the Immune Checkpoint Inhibitor Nivolumab in Patients With Select Rare CNS Cancers

Clinical Trial IDs

  • ORG STUDY ID: 170102
  • SECONDARY ID: 17-C-0102
  • NCT ID: NCT03173950

Conditions

  • Medulloblastoma
  • Ependymoma
  • Pineal RegionTumors
  • Choroid Plexus Tumors
  • Atypical/Malignant Meningioma

Interventions

DrugSynonymsArms
Nivolumab1/Experimental Therapy

Purpose

Background: More than 130 primary tumors of the central nervous system (CNS) have been identified. Most affect less than 1,000 people in the United States each year. Because these tumors are so rare, there are few proven therapies. This study will test whether the immunotherapy drug nivolumab is an effective treatment for people with rare CNS tumors. Objectives: To learn if stimulating the immune system using the drug nivolumab can shrink tumors in people with rare CNS (brain or spine) tumors or increase the time it takes for these tumors to grow or spread. Eligibility: Adults whose rare CNS tumor has returned. Design: Participants will be screened: - Heart and blood tests - Physical and neurological exam - Hepatitis tests - Pregnancy test - MRI. They will lay in a machine that takes pictures. - Tumor tissue sample. This can be from a previous procedure. At the start of the study, participants will have blood tests. They will answer questions about their symptoms and their quality of life. Participants will get nivolumab in a vein every 2 weeks for up to 64 weeks. Participants will have monthly blood tests. Every other month they will have an MRI and a neurologic function test. They will also answer questions about their quality of life. Genetic tests will be done on participants' tumor tissue. Participants will be contacted if any clinically important results are found. After treatment ends, participants will be monitored for up to 5 years. They will have a series of MRIs and neurological function tests. They will be asked to report any symptoms they experience....

Detailed Description

      Background:

        -  There are more than 130 identified primary tumors of the central nervous system (CNS).
           Most have an annual incidence of less than 1000 in the United States.

        -  Given the rarity of each of the tumors listed above, there is a paucity of proven
           therapies. Most of these neoplasms are treated with maximum surgical resection followed
           by treatment with external beam radiotherapy. With few exceptions (medulloblastoma,
           adult ependymoma), there are no effective systemic regimens and even in chemotherapy
           sensitive disease, most patients with recurrence eventually have no remaining salvage
           treatments available.

        -  In the setting of this unmet need, we propose to create a basket protocol that will
           evaluate the efficacy of the PD-1 inhibitor, nivolumab, in patients with refractory rare
           central nervous system neoplasms.

        -  This study seeks to establish effective therapies at recurrence in patients with rare
           CNS tumors. We hypothesize that this therapy will improve progression free survival
           and/or objective responses.

        -  It will be important to determine whether any determined survival benefit is associated
           with improvements in symptoms or does a worsening of symptoms offset the increase in
           survival. Precedence exists for measuring non-therapeutic endpoints in oncology
           research, and specifically in studies evaluating therapeutic benefit in patients with
           CNS tumors. There have been efforts in neuro-oncology to evaluate secondary endpoints
           using validated instruments as an additional indicator of benefit. The M.D. Anderson
           Symptom Inventory-Brain Tumor Module (MDASI-BT) and Spine Tumor Module (MDASI-SP) allow
           for the self-reporting of symptom severity and interference with daily activities for
           patients with either brain or spinal cord tumors. The availability of validated
           instruments provides an opportunity to prospectively assess the impact of treatment,
           both positive and negative, on patients.

      Objective:

      Determine the efficacy of nivolumab in a variety of recurrent, refractory primary central
      nervous system tumors as measured by disease control rate (confirmed CR/PR or durable SD for
      at least 6 months).

      Eligibility:

        -  Documented recurrent or progressive disease that corresponds to one of the tumors
           eligible for testing.

        -  Age greater than or equal to 18 years of age.

        -  Karnofsky Performance greater than or equal to 70%.

        -  Tumor tissue available for review to confirm morphologic diagnosis

        -  Tumor tissue or slides available for molecular and immune profiling

      Design:

        -  This is an open label phase II clinical trial. Patients will be treated with the immune
           checkpoint inhibitor, nivolumab, at a standard dose of 240 mg intravenously every 2
           weeks (+/- 3 days) for cycles 1 through 2, then doses of 480 mg every 4 weeks for a
           total of 14 additional doses (cycles). A maximum of 18 treatments will be given (64
           weeks).

        -  A cycle will be defined as 4 weeks and patients will undergo efficacy assessments using
           MR imaging every 2 cycles. Toxicity assessments will occur before the initiation of each
           cycle and patient outcomes measures (PROs) will be completed at the time of each

      imaging study (every 2 cycles) but prior to the patient being informed of the imaging
      results.

      -After completion of the planned treatment course or if treatment was stopped because of
      toxicity, patients will undergo imaging evaluations and PRO measurements every 8 weeks (or 2
      months) for one year, then every 3 months for the next year, then every 4

      months for the next year and then every 6 months while the patient remains on the protocol.
      Patients off treatment because of disease progression will not undergo future imaging or PRO
      assessments on this protocol.

        -  Bayesian Optimal Phase 2 design (BOP2), will be used to conduct this phase II trial in
           patients with a variety of recurrent, refractory primary central nervous system tumors.

        -  The study will be comprised of 2 disease cohorts: heavily pretreated (defined as having
           received 3 or more prior therapies due to relapse) and non-heavily pretreated (defined
           as having received up to 2 prior therapies due to relapse). Each cohort will be
           evaluated

      independently for efficacy.
    

Trial Arms

NameTypeDescriptionInterventions
1/Experimental TherapyExperimentalParticipants will receive nivolumab at standard dose of240mg IV every 2 weeks for cycles 1 through 2, thendoses of 480mg every 4 weeks for a total of 14 additional doses
  • Nivolumab

Eligibility Criteria

        -  INCLUSION CRITERIA:

               1. Histopathologically proven diagnosis of Ependymoma, Medulloblastoma, Parenchymal
                  Pineal Region Tumors (Pineoblastoma, Pineocytoma, Pineal Tumor of Intermediate
                  Differentiation, Papillary Tumor of the Pineal Region), Choroid Plexus Tumors
                  (Carcinoma, Papilloma, Atypical Papilloma), Histone Mutated Gliomas, Gliomatosis
                  Cerebri, ATRT, Malignant/Atypical Meningioma, Gliosarcoma or Primary CNS Sarcoma,
                  Pleomorphic Xanthoastrocytoma (PXA) and Anaplastic Pleomorphic Xanthoastrocytoma
                  (APXA), and tumors formerly known as Primitive Neuro-Ectodermal Tumors (Embryonal
                  Tumor with Multilayered Rosettes, Medulloepithelioma, CNS Neuroblastoma, CNS
                  Ganglioneuroblastoma, CNSEmbryonal Tumor NOS) prior to registration as confirmed
                  by NCI Laboratory of Pathology.

               2. The tumor tissue (e.g. block or 15 unstained slides) must be available to be sent
                  for immunophenotyping.

               3. Patients must have progressive tumor growth after having received established
                  standard of care treatment for their disease. Patients will be enrolled into 2
                  different cohorts (cohort 1 or heavily pretreated; cohort 2 or not heavily
                  pretreated)

               4. Age greater than or equal to 18;

               5. Karnofsky performance status greater than or equal to 70 within 14 days prior to
                  Step 2 registration;

               6. Adequate hematologic function based on CBC/differential within 14 days prior to
                  Step 2 registration defined as follows:

                    -  Absolute neutrophil count greater than or equal to 1,500 cells/mm3;

                    -  Platelet count greater than or equal to 100,000 cells/mm3

                    -  Hemoglobin > 9.0 g/dl (may be transfused to achieve this level)

               7. Adequate renal function within 14 days prior to Step 2 registration defined as
                  follows:

                    -  BUN less than or equal to 30 mg/dl and

                    -  Serum creatinine less than or equal to 1.7 mg/dl

               8. Adequate hepatic function within 14 days prior to Step 2 registration defined as
                  follows:

                    -  Total bilirubin (except patients with Gilbert s Syndrome, who are eligible
                       for the study but exempt from the total bilirubin eligibility criterion)
                       less than or equal to 2.0 mg/dl and

                    -  ALT and AST less than or equal to 2.5x ULN

                    -  No active or chronic hepatitis infection. HCV antibody (for Hepatitis C) and
                       Hepatitis B Surface antigen and Hepatitis B core antibody must be negative.
                       This has been routinely incorporated into immunotherapy trials with
                       checkpoint inhibitors because of concerns that the risk of treatment-induced
                       hepatic injury is increased in the setting of active viral hepatitis.

               9. The patient must not be on a corticosteroid dose greater than physiologic
                  replacement dosing defined as 30 mg of cortisone per day or its equivalent.

              10. The patient must provide study-specific informed consent prior to study entry. No
                  Durable Power of Attorney or Next of Kin can provide initial consent.

              11. The effects of nivolumab on the developing human fetus are unknown. For this
                  reason, women of childbearing potential (WOCBP) must use appropriate method(s) of
                  contraception. WOCBP should use an adequate method to avoid pregnancy for 5
                  months (30 days plus the time required for nivolumab to undergo five half-lives)
                  after the last dose of investigational drug.

        Men who are sexually active with WOCBP must use any contraceptive method with a failure
        rate of less than 1% per year. Men receiving nivolumab and who are sexually active with
        WOCBP will be instructed to adhere to contraception for a period of 7 months after the last
        dose of investigational product. Women who are not of childbearing potential (i.e., who are
        postmenopausal or surgically sterile as well as azoospermic men do not require
        contraception.

        EXCLUSION CRITERIA:

          1. Patients who are receiving any other investigational agents.

          2. Use of an immunotherapy such as a vaccine therapy, dendritic cell vaccine or
             intracavitary or convectional enhanced delivery of therapy

          3. Prior or concurrent malignancy unless its natural history or treatment does not have
             the potential to interfere with the safety or efficacy assessment of the
             investigational regimen

          4. Severe, active co-morbidity defined as follows:

               -  Unstable angina within the last 6 months prior to Step 2 registration

               -  Transmural myocardial infarction within the last 6 months prior to Step 2
                  registration

               -  Evidence of recent myocardial infarction or ischemia by the findings of S-T
                  elevations of greater than or equal to 2 mm using the analysis of an EKG
                  performed within 14 days prior to Step 2 registration

               -  New York Heart Association grade II or greater congestive heart failure requiring
                  hospitalization within 12 months prior to Step 2 registration

               -  History of stroke, cerebral vascular accident (CVA) or transient ischemic attack
                  within 6 months prior to Step 2 registration

               -  Serious and inadequately controlled cardiac arrhythmia

               -  Significant vascular disease (e.g., aortic aneurysm, history of aortic
                  dissection) or clinically significant peripheral vascular disease

               -  Evidence of bleeding diathesis or coagulopathy

               -  Serious or non-healing wound, ulcer, or bone fracture or history of abdominal
                  fistula, gastrointestinal perforation, intra-abdominal abscess major surgical
                  procedure, open biopsy, or significant traumatic injury within 28 days prior to
                  Step 2 registration, with the exception of the craniotomy for tumor resection.

               -  Acute bacterial or fungal infection requiring intravenous antibiotics at the time
                  of registration

               -  Chronic obstructive pulmonary disease exacerbation or other respiratory illness
                  requiring hospitalization or precluding study therapy at the time of registration

               -  Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;

               -  Known acquired immune deficiency syndrome (AIDS) based upon current CDC
                  definition; note, however, that HIV testing is not required for entry into this
                  protocol. The need to exclude patients with AIDS is based on the lack of
                  information regarding the safety of nivolumab in patients with active HIV
                  infection.

               -  Active connective tissue disorders, such as lupus or scleroderma, which in the
                  opinion of the treating physician may put the patient at high risk for
                  immunologic toxicity.

          5. Patients with active autoimmune 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 or CIDP,
             myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue
             diseases, scleroderma, inflammatory bowel disease (IBD), 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.

             --Of note, patients with vitiligo, endocrine deficiencies including thyroiditis
             managed with replacement hormones including physiologic corticosteroids are eligible.
             Patients with rheumatoid arthritis and other arthropathies, Sj(SqrRoot)(Delta)gren 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. However, patients with vitiligo, diabetes
             mellitus, and Hashimoto thyroiditis on appropriate replacement therapy may be
             enrolled.

          6. Any other major medical illnesses or psychiatric impairments that in the
             investigator's opinion will prevent administration or completion of protocol therapy.

          7. Allergies and Adverse Drug Reaction: History of allergy to study drug components

          8. Pregnancy or lactating females due to possible adverse effects on the developing fetus
             or infant due to study drug. Women of childbearing potential must have a negative
             serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
             24 hours prior to Step 2 registration.

          9. History of severe hypersensitivity reaction to any monoclonal antibody.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:objective response
Time Frame:end of treatment
Safety Issue:
Description:Rate of achieving a confirmed Complete Response/Partial Response (confirmed by imaging one month later)

Details

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

Trial Keywords

  • Immunotherapy
  • Anti-PD-1 Antibody
  • Brain Tumors
  • MDASI-BT
  • Spinal Cord Tumors

Last Updated

April 20, 2020