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Clinical Trial 19648

Cancer Type: Neurologic Oncology
Study Type: Treatment
NCT#: NCT03719768

Phase: Phase I
Principal Investigator: Forsyth, Peter

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Study Title

Phase IB Study of 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.


Objectives: Primary Objectives: To establish the safety of combination of Avelumab and WBRT in patients with LMDz and perform exploratory analysis of the patient survival rate. Secondary Objectives: To gather preliminary data regarding clinical outcomes of the study therapy Endpoints: Primary Endpoints: 1) Safety and dose limiting toxicities. 2) The proportion of patients surviving at least 15 weeks after the first dose of Avelumab. Secondary Endpoints: 1) The number and activation status of T cells and the CSF cytokine activation profile in the CSF (relative to serum and relative to collection time), measured before and after Avelumab administration; 2) LMDz/central nervous system response rate and systemic (i.e., non-central nervous system) response rates; 3) the association between serum/CSF levels of Avelumab/activated T-cell responses and clinical toxicities and responses; 4) overall survival and progression-free survival; 5) the association between enumerated CSF circulating tumor cells, conventional CSF cytology, and response rates; 6) evolution of clinical status associated with the cardinal CSF biomarkers; and 7) levels of Avelumab in the serum and CSF.



Immunotherapy; Radiotherapy


Avelumab (); MSB00100718C (Avelumab)

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 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 (>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 i.e. Except as listed in Inclusion Criteria #14 (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 > 5. Patients on steroid therapy unless > 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., 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 Sjorgens 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 treatment.
  • 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 subjects 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
  • Other Exclusions will apply

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