Clinical Trials /

Avelumab With Radiotherapy in Patients With Leptomeningeal Disease



This study is to find a safe dose of the combination of Avelumab and Whole Brain Radiotherapy (WBRT) in patients with Leptomeningeal Disease.

Related Conditions:
  • Cancer
Recruiting Status:



Phase 1

Trial Eligibility



  • Brief Title: Avelumab With Radiotherapy in Patients With Leptomeningeal Disease
  • Official Title: Phase IB Study of Avelumab With Radiotherapy in Patients With Leptomeningeal Disease

Clinical Trial IDs

  • ORG STUDY ID: MCC-19648
  • SECONDARY ID: W1239387
  • NCT ID: NCT03719768


  • Leptomeningeal Metastases
  • Leptomeningeal Disease


AvelumabBavencioAvelumab and Whole Brain Radiotherapy


This study is to find a safe dose of the combination of Avelumab and Whole Brain Radiotherapy (WBRT) in patients with Leptomeningeal Disease.

Trial Arms

Avelumab and Whole Brain RadiotherapyExperimentalAvelumab 800 mg intravenously (IV) and 3000 centriGray units (cGy) Whole Brain Radiotherapy once every 2 weeks
  • Avelumab

Eligibility Criteria

        Inclusion Criteria:

          -  1. Histologically or cytologically confirmed diagnosis of any cancer except leukemia

          -  2. Patients must have the presence of malignant cells in the CSF (CSF+) OR at least 2
             of the 3 following features: 1) clinical signs and symptoms of LMDz 2) characteristic
             radiographic abnormalities , and 3) "suspicious" CSF (Chamberlain 2017)

          -  3. Patients must have an Eastern Cooperative Oncology Group performance scale of < 3
             OR Karnofsky Performance Status of >50.

          -  4. An interval of at least 2 weeks after the end of prior radiation therapy to the
             brain (e.g., stereotactic radiosurgery or other-WBRT is excluded)

          -  5. An interval of at least 4 weeks following any surgical resection of brain lesions
             prior to treatment

          -  6. Be > 18 years of age on the day of signing consent

          -  7. Demonstrate adequate organ function as defined in Table 2. All screening labs
             should be performed with 14 days of treatment initiation

          -  8. Resting baseline O2 saturation by pulse oximetry of > 92% at rest

          -  9. Patients must have recovered from the toxic effects of prior therapies (< Grade 1)

          -  10. Provision of signed and dated informed consent form

          -  11. Life expectancy of > 8 weeks

          -  12. Pregnancy test: negative serum or urine pregnancy test at screening for women of
             childbearing potential.

          -  13. Contraception: Highly effective contraception for both male and female subjects
             throughout the study and for at least 30 days after last Avelumab treatment
             administration, if the risk of conception exists.

          -  14. If the disease has progressed on current treatment in the CNS prior to consent,
             patients may continue Her 2 directed antibody treatment (trastuzumab and pertuzumab),
             aromatase inhibitor or tamoxifen while on the study; patients with triple negative
             breast cancer may continue capecitabine, eribulin or paclitaxel while on the study per
             PI discretion.

          -  15. Adequate Organ Function as defined per protocol

        Exclusion Criteria:

          -  1. Receiving other treatments specifically administered to treat LMDz or antibody
             based therapies within the last 4 weeks. However, patients receiving concomitant
             non-cytotoxic therapy (hormonal or cytostatic therapy) to control systemic disease or
             bulk CNS disease will be eligible, provided the therapy is not a phase I agent, an
             agent which significantly penetrates the CSF (e.g., high-dose methotrexate, thiotepa,
             or high-dose ara-C), or an agent known to have serious unpredictable CNS side effects
             Except as listed in Inclusion Criteria #15 (above). Careful documentation of
             concurrently administered systemic drugs is required

          -  2. Patients with a ventriculoperitoneal or ventriculoatrial shunt must have an on/off
             device in their shunt systems to be eligible for the study. Patients must be able to
             tolerate shunt closure for ~4 hours without development of clinical signs of increased
             intracranial pressure. Patients unable to tolerate shunt closure for ~4 hours will not
             be eligible for the study

          -  3. Unable or unwilling to have a contrast-enhanced brain MRI

          -  4. Currently participating in or having participated in a study of an investigational
             agent or device < 4 weeks prior to the first dose of study treatment

          -  5. Patients on steroid therapy unless < 2 mg/day dexamethasone equivalents

          -  6. Prior chemotherapy or targeted small molecule therapy except as listed in Inclusion
             Criteria #15 and Exclusion #1(above) within 4 weeks prior to study Day 1 or
             nonrecovery (i.e., < Grade 1 or at baseline) from adverse events (AEs) due to agents
             administered > 4 weeks earlier

          -  7. Known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy

          -  8. Has an active autoimmune disease requiring systemic treatment within the past 3
             months (i.e. with use of disease modifying agents, corticosteroids or
             immunosuppressive agents) or has a diagnosis of immunodeficiency. Subjects with
             vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
             Subjects that require intermittent use of bronchodilators or local steroid injections
             would not be excluded from the study. Subjects with hypothyroidism stable on hormone
             replacement or Sjorgen's syndrome will not be excluded from the study. Replacement
             therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy
             for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic

          -  9. Has evidence of active, non-infectious pneumonitis

          -  10. Has an active infection requiring systemic therapy

          -  11. Had major surgical procedure, open biopsy, or significant traumatic injury within
             28 days prior to day 1 of treatment on study. Ommaya placement is allowed

          -  12. Requires escalating or chronic supraphysiologic doses of corticosteroids (> 10
             mg/day prednisone equivalents)

          -  13. Has a history of current evidence of any condition, therapy, or laboratory
             abnormality that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

          -  14. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  15. Is pregnant or breastfeeding, or expecting to conceive or father children within
             the projected duration of the trial, starting with the pre-screening or screening
             visit through 90 days after the last dose of trial treatment

          -  16. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137,
             or anti- Cytotoxic T-lymphocyte-associated antigen-4 (cTLA-4) antibody (including
             ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
             or checkpoint pathways) within 6 months before the beginning of study treatment

          -  17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1, 2 antibodies)

          -  18. Any test for hepatitis B (HBV) or hepatitis C virus (HCV) indicating acute or
             chronic infection

          -  19. Has received a live vaccine within 30 days prior to the first dose of trial

          -  20. Prior administration of WBRT

          -  21. Known symptomatic brain metastases requiring steroids. Patients with previously
             diagnosed brain metastases are eligible if they have completed their treatment and
             have recovered from the acute effects of radiation therapy or surgery prior to study
             treatment, have discontinued corticosteroid treatment for these metastases for at
             least 4 weeks and are neurologically stable. Short courses of corticosteroids are
             permitted if these were started for leptomeningeal disease and can be tapered down to
             < 2 mg/day of dexamethasone equivalents and patients remain stable for 3 days prior to
             study treatment

          -  22. Known severe hypersensitivity reactions to monoclonal antibodies (Grade > 3) or
             any known history of anaphylaxis

          -  23. ORGAN TRANSPLANTATION: Prior organ transplantation including allogenic stem-cell

          -  24. CARDIOVASCULAR DISEASE: Clinically significant (i.e., active) cardiovascular
             disease: cerebral vascular accident/stroke (< 6 months prior to enrollment),
             myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive
             heart failure (> New York Heart Association Classification Class II), or serious
             cardiac arrhythmia requiring medication

          -  25. OTHER PERSISTING TOXICITIES: "Persisting toxicity related to prior therapy (NCI
             CTCAE v.5.0 Grade > 1); however, alopecia, sensory neuropathy Grade < 2, or other
             Grade < 2 not constituting a safety risk based on investigator's judgment are

          -  26. Other severe acute or chronic medical conditions, including immune colitis,
             inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric
             conditions including recent (within the past year) or active suicidal ideation or
             behavior; or laboratory abnormalities that may increase the risk associated with study
             participation or study treatment administration or may interfere with the
             interpretation of study results and, in the judgment of the investigator, would make
             the patient inappropriate for entry into this study
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and Dose Limiting Toxicity (DLT) measured by number of subjects with adverse events (AEs)
Time Frame:End of treatment (3 months)
Safety Issue:
Description:Adverse events will only include those that are determined to be related to study drug. A DLT will be defined as any one of the following adverse events occurring within 28 days from first dose of Avelumab. Central Nervous System (CNS) toxicities: Any grade 3 or higher central nervous adverse events, including but not limited to cerebral hemorrhage and new-onset neurologic deficit. Non-CNS toxicities: Any grade 3 or higher nonhematologic AE with the exception of alopecia and fatigue - Grade > 3 nausea, vomiting, or diarrhea despite maximal medical therapy - Grade > 3 laboratory value if 1)medical intervention is required to treat the patient or 2) the abnormality leads to hospitalization • Any grade 3 or 4 event that does not improve within 6 weeks

Secondary Outcome Measures

Measure:Number of T Cells
Time Frame:Up to 11 months
Safety Issue:
Description:The number of T cells in the cerebrospinal fluid (CSF) and the CSF cytokine activation profile in the CSF (relative to serum) measured before and after Avelumab administration.
Measure:Activation Status of T Cells
Time Frame:Up to 11 months
Safety Issue:
Description:The activation status of T cells in the cerebrospinal fluid (CSF) and the CSF cytokine activation profile in the CSF (relative to serum) measured before and after Avelumab administration.
Measure:Leptomeningeal Disease (LMDz)/CNS Response Rate and Systemic Response Rate
Time Frame:Up to 11 months
Safety Issue:
Description:Any solid brain metastases associated with LMDz will be assessed with Response Assessment in Neuro-Oncology (RANO)-Brain Metastases (BM) criteria. Responses in the rest of the body will be measured using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.


Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:H. Lee Moffitt Cancer Center and Research Institute

Trial Keywords

  • Whole Brain Radiotherapy
  • meningeal
  • LMDz
  • brain metastases
  • Immunotherapy

Last Updated

June 14, 2021