A Trial of Pembrolizumab for Refractory Atypical and Anaplastic Meningioma

A Phase II, Open-label, Single Arm Trial of Pembrolizumab for Refractory Atypical and Anaplastic Meningioma

A Phase II, Open-label, Single Arm Trial of Pembrolizumab for Refractory Atypical and Anaplastic Meningioma

Study Overview

• Status: Unknown
• Conditions: Hemangiopericytoma; Atypical Meningioma; Anaplastic Meningioma
• Intervention / Treatment: Drug: Pembrolizumab

Detailed Description

This is a multicenter, prospective, single arm, open label, interventional study. The goal of this study, is to evaluate feasibility and efficacy of pembrolizumab for the treatment of recurrent or progressive meningioma (WHO grades II-III) or hemangiopericytoma (HPC). All patients will receive IV pembrolizumab, at a dose of 200mg, every 3 weeks. Patients will be treated until disease progression or intolerable toxicity. Treatment can be stopped after one year of treatment in case of stable disease or completer response, with re-initiation of treatment upon progression. Expression of PD1 and PD-L1 will be tested, on tumor cells, using IHC staining on biopsy material obtained from previous surgeries.

All patients will have a baseline neurologic and clinical exam, MRI scan, a brain dedicated CT-PET scan, a baseline cognitive exam and QOL assessment with a dedicated questionnaire. Patients will have a clinical and neurological exam every treatment cycle. MRI scan will be repeated after 2 months from the beginning of the trial drug administration and then every 2-3 months. There are no designated and specific criteria for response assessment in the treatment of meningioma. Therefore, response evaluation will be made using the RECIST 1.1 criteria, as used for solid tumors. The trial will allow the continuation of pembrolizumab in case of stable or improved clinical response, when pseudo-progression is suspected in the MRI. In addition, response assessment will also be made according to the RANO criteria, as used for high grade glioma. This will be compared to the RECIST evaluation, but will not be used for treatment decision making.

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Dror Limon, Dr; Phone Number: 972-54-3009451; Email: drorlim@tlvmc.gov.il
• Study Contact Backup: Name: Shlomit Yust-Katz, Dr; Phone Number: 972-58-7454567; Email: shlomit2@clalit.org.il

Study Locations

• Israel
  • Petach Tikva, Israel
    • Recruiting
    • Rabin Medical Center
    • Principal Investigator: Shlomit Yust-Katz, MD
  • Tel Aviv, Israel
    • Not yet recruiting
    • Tel Aviv Medical Center
    • Contact: Dror Limon, MD
    • Principal Investigator: Dror Limon, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Be willing and able to provide written informed consent/assent for the trial.
2. Be 18 years of age on day of signing informed consent.
3. Have measurable disease based on RECIST 1.1.
4. Histologically, previously proven, grade II or III meningioma, HPC or classic radiographic features of a recurrent surgically inaccessible atypical or anaplastic meningioma.
5. All patients would have to have recurrence despite radiotherapy, unless radiotherapy is contraindicated.
6. No limit on the number of prior surgeries, radiation or radiosurgery treatments.
7. No limit on prior systemic therapies - chemotherapy or biological agents.
8. Patients who received stereotactic radiosurgery (SRS) are eligible without histologic documentation of recurrence if at least 6 months have passed from previous SRS treatment, and preferably, but not necessarily a 2-fluoro-2-deoxy-D-glucose PET imaging demonstrated hypermetabolism.
9. KPS≥50%
10. At least 4 weeks since any prior therapy.
11. Life expectancy of at least 4 months.
12. Dexamethasone use will be allowed up to a dose of 2mg per day. Steroids dose should be reduced or stopped 7 days prior to treatment with study drug.

13. Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 10 days of treatment initiation.

    Table 1 Adequate Organ Function Laboratory Values

    Hematological Absolute neutrophil count (ANC)≥1,500 /mcL Platelets≥100,000 / mcL Hemoglobin≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment) Renal Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl)≤1.5 X upper limit of normal (ULN) OR

    ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR

    ≤ 5 X ULN for subjects with liver metastases Albumin >2.5 mg/dL Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT)

    Activated Partial Thromboplastin Time (aPTT)≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

    ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants a Creatinine clearance should be calculated per institutional standard.

14. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

15. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication.

    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

16. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
3. Patients who are steroid dependent and cannot reduce the dexamethasone dose to a maximal dose of 2mg per day.
4. Has a known history of active TB (Bacillus Tuberculosis)
5. Hypersensitivity to pembrolizumab or any of its excipients.
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

   • Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
   • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
8. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
9. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
11. Has known history of, or any evidence of active, non-infectious pneumonitis.
12. Has an active infection requiring systemic therapy.
13. Has a history or 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 120 days after the last dose of trial treatment.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
19. Has received a live vaccine within 30 days of planned start of study therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; IV Pembrolizumab 200mg, given every 3 weeks until disease progression or intolerable toxicity	Drug: Pembrolizumab; anti PD-L1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
progression free survival (PFS)	To determine the 6 months progression free survival (PFS) rate for patients with recurrent or progressive meningioma on pembrolizumab therapy, using the RECIST 1.1 criteria.	6 months
progression free survival (PFS)	To determine the 12 months progression free survival (PFS) rate for patients with recurrent or progressive meningioma on pembrolizumab therapy, using the RECIST 1.1 criteria.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	To determine OS of patients with recurrent or progressive meningioma treated with pembrolizumab.	4 years

Collaborators and Investigators

• Sponsor: Rabin Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2018
• Primary Completion (Anticipated): February 1, 2020
• Study Completion (Anticipated): February 1, 2022

Study Registration Dates

• First Submitted: December 22, 2016
• First Submitted That Met QC Criteria: January 9, 2017
• First Posted (Estimate): January 10, 2017

Study Record Updates

• Last Update Posted (Actual): April 18, 2019
• Last Update Submitted That Met QC Criteria: April 16, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms, Connective Tissue; Neoplasms, Vascular Tissue; Meningeal Neoplasms; Neoplasms, Fibrous Tissue; Meningioma; Hemangiopericytoma; Solitary Fibrous Tumors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: MK-3475-415

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No