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ASP8374 + Cemiplimab in Recurrent Glioma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04826393
Recruitment Status : Not yet recruiting
First Posted : April 1, 2021
Last Update Posted : April 1, 2021
Sponsor:
Collaborators:
Regeneron Pharmaceuticals
Astellas Pharma Inc
ImaginAb, Inc.
Information provided by (Responsible Party):
David Reardon, MD, Dana-Farber Cancer Institute

Brief Summary:

This study is looking at the safety and efficacy of the drug combination of ASP8374 with cemiplimab in people with recurrent malignant glioma.

The study will be conducted in two parts, the first portion of the study will be to establish the highest dose of ASP8374 that can be given safely with cemiplimab and will be used as the recommended dose of ASP8374 in combination with cemiplimab for the second portion of the study. The second portion of the study will be to compare the effect of having ASP8374 in combination with cemiplimab prior to surgery.

The names of the study drugs involved in this study are:

  • ASP8374
  • Cemiplimab
  • 89Zr-Df-IAB22M2C (Administered as part of scan procedure)

Condition or disease Intervention/treatment Phase
Glioblastoma Recurrent Glioblastoma Drug: ASP8374 Drug: cemiplimab Drug: 89Zr-Df-IAB22M2C Phase 1

Detailed Description:

This is a multicenter, randomized, open-label, phase Ib trial of ASP8374 plus cemiplimab among recurrent malignant glioma participants.

Initially, eligible participants will enroll to Cohort 1 which will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of ASP8374 when combined with cemiplimab among recurrent malignant glioma participants using a 3+3 design.

Upon determination of the MTD/RP2D of ASP8374 plus cemiplimab in Cohort 1, a dose expansion will be performed in which eligible participants who are candidates for surgical resection will enroll to Cohort 2 and will be randomized into one of four treatment groups (2A-2D).

Group 2A: IV ASP8374 within 14± 5 days prior to surgery.

Group 2B: IV Cemiplimab within 14± 5 days prior to surgery.

Group 2C: IV ASP8374 plus cemiplimab within 14± 5 days prior to surgery at the MTD/RP2D established in Cohort 1.

Group 2D: No immune checkpoint therapy prior to surgery.

The U.S. Food and Drug Administration (FDA) has not approved ASP8374 as a treatment for any disease. The U.S. Food and Drug Administration (FDA) has not approved cemiplimab for recurrent malignant glioma but it has been approved for other uses. The U.S. Food and Drug Administration (FDA) has not approved 89Zr-Df- IAB22M2C as a treatment for any disease.

The research study procedures include: screening for eligibility, then study treatment including evaluations and follow up visits. Participants will receive study treatment for up to two years and will be followed for their tumor's response, whether or not their disease gets worse, and for side effects.

It is expected that about 65 people will take part in this research study. At least 6 in cohort 1 and 55 in cohort 2.

Pharmaceutical company Astellas is supporting this research study by providing study funding and study drug, ASP8374, Regeneron is supporting this research by providing study drug cemiplimab, and ImaginAb is supporting this research by providing study drug 89Zr-Df-IAB22M2C.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 65 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib Trial of ASP8374 and Cemiplimab in Recurrent Malignant Glioma Patients
Estimated Study Start Date : September 2021
Estimated Primary Completion Date : June 1, 2022
Estimated Study Completion Date : December 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ASP8374 and Cemiplimab-Cohort 1

A 3+3 dose escalation design will be used to determine maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of ASP8374 when combined with cemiplimab.

Participants will receive ASP8374 and Cemiplimab every 3 weeks for up to 2 years.

Drug: ASP8374
every 3 weeks by intravenous infusion

Drug: cemiplimab
intravenous infusion
Other Name: Libtayo

Experimental: ASP8374 and Cemiplimab-Cohort 2

Upon determination of the MTD/RP2D of ASP8374 plus cemiplimab in Cohort 1, a dose expansion will be performed in which eligible participants who are candidates for surgical resection will enroll to Cohort 2 and will be randomized into one of four treatment groups (2A-2D).

Group 2A: IV ASP8374 within 14± 5 days prior to surgery.

Group 2B: IV Cemiplimab within 14± 5 days prior to surgery.

Group 2C: IV ASP8374 plus cemiplimab within 14± 5 days prior to surgery at the MTD/RP2D established in Cohort 1.

Group 2D: No immune checkpoint therapy prior to surgery.

Post-operatively, all Cohort 2 participants will receive ASP8374 plus cemiplimab every 3 weeks administered at the MTD/RP2D established by Cohort 1

Per determination of treating clinician, participants will have 89Zr-Df-IAB22M2C administered prior to PET scans.

Drug: ASP8374
every 3 weeks by intravenous infusion

Drug: cemiplimab
intravenous infusion
Other Name: Libtayo

Drug: 89Zr-Df-IAB22M2C
intravenous infusion prior to PET Imaging




Primary Outcome Measures :
  1. Maxium Tolerated Dose-MTD/ Phase 2 Recommend Dose-RP2D - Cohort 1 [ Time Frame: Enrollment up to 2 years ]
    primary endpoint for Cohort 1 will be determination of the MTD/RP2D of ASP8374 when administered with cemiplimab among recurrent malignant glioma participants.

  2. CD8+ TIL Tumor Density-Cohort 2 [ Time Frame: Enrollment up to 2 years ]
    CD8+ TIL density from tumors obtained from participants randomized to each neoadjuvant study arm (2A, 2B and 2C) will be compared to tumor CD8+ TIL density obtained from control participants enrolled on Arm 2D who do not receive neoadjuvant therapy.


Secondary Outcome Measures :
  1. Rate of Adverse Events [ Time Frame: Enrollment up to 2 years ]
    Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

  2. progression-free survival (PFS) [ Time Frame: 6 months ]
    Assessed by Response Assessment in Neuro-Oncology (RANO)1 and Immunotherapy RANO (iRANO) guidelines.

  3. overall survival (OS). [ Time Frame: 12 months ]
    Assessed by Response Assessment in Neuro-Oncology (RANO)1 and Immunotherapy RANO (iRANO) guidelines.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have histologically confirmed WHO grade IV GBM or its variants. Participants will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of GBM is made. Participants with WHO grade III recurrent malignant glioma will be allowed to enroll to Cohort 1 only.
  • Be willing and able to provide written informed consent/assent for the trial.
  • Be ≥ 18 years of age on day of signing informed consent.
  • Have a Karnofsky performance status (KPS) ≥ 70 (Appendix A).
  • Previous first line therapy with at least radiotherapy.
  • Be at first or second relapse. Note: Relapse is defined as progression following initial therapy (i.e., radiation ± chemotherapy). For participants who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse.
  • Participants must have shown unequivocal evidence for tumor progression by MRI or CT scan.
  • Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 14 days of registration.

    • Table 1: Adequate Organ Function Laboratory Values

      • System Laboratory Value

        • 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 a creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 X institutional upper limit of normal (ULN) OR

          ≥60 mL/min for participant with creatinine levels > 1.5 X institutional ULN a Creatinine clearance should be calculated per institutional standard.

        • Hepatic Serum total bilirubin ≤ 1.5 X institutional ULN OR Direct bilirubin ≤ institutional ULN for participants with total bilirubin levels > 1.5 institutional ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X institutional ULN OR

          ≤ 5 X institutional ULN for participants with Gilberts syndrome Albumin >2.5 mg/dL

        • Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤1.5 X institutional ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants ≤1.5 X institutional ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Contrast enhanced CT or MRI within 14 days prior to start of study therapy.
  • An interval of at least 3 weeks (to registration) between prior surgical resection or one week for stereotactic biopsy.
  • An interval of at least 12 weeks from the completion of radiation therapy to registration unless there is unequivocal histologic confirmation of tumor progression or radiographic progression outside of the prior radiation field.
  • Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy (exceptions include but not limited to alopecia, laboratory values not listed per inclusion criteria, and lymphopenia which is common after therapy with temozolomide).
  • From start of study therapy, the following time periods must have elapsed:

    • 5 half-lives from any small molecule investigational agent
    • 4 weeks from cytotoxic therapy (except 23 days for temozolomide, 6 weeks from nitrosoureas, and 7 days from daily administered agents)
    • 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies
    • No wash-out period required for prior TTF or vaccine therapies
  • Participants must be planned to undergo surgery that is clinically indicated as determined by their care providers (Cohort 2 only).
  • Female participant of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment she considered not of child bearing potential.
  • Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during study treatment and for 120 days after study discontinuation. Highly effective contraception is defined as either:

    • i. True Abstinence: When this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    • ii. Sterilization: Surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment (as described in item 12 above).
    • iii. Male Partner Sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female participants on the study, the vasectomized male partner should be the sole partner for that participant.
    • Use of a combination of any two of the following:

      1. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
      2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
      3. Appropriate hormonal contraceptives (including any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent - including oral, subcutaneous, intrauterine, or intramuscular agents)
  • Male participants should agree to use adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of therapy.

Exclusion Criteria:

  • Current or planned participation in a study of an investigational agent or using an investigational device.
  • Has a diagnosis of immunodeficiency.
  • Has tumor primarily localized to the brainstem or spinal cord.
  • Has presence of diffuse leptomeningeal disease or extracranial disease.
  • Has received systemic immunosuppressive treatments, aside from systemic corticosteroids as described in Section 3.2.7, (such as methotrexate, chloroquine, azathioprine, etc.) within six months of registration.
  • Has received anti-VEGF or anti-VEGFR targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc.).
  • Requires treatment with moderate or high dose systemic corticosteroids defined as dexamethasone > 2 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of registration.
  • Has received prior interstitial brachytherapy or stereotactic radiosurgery (Cohort 2 only).
  • Has history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of registration.
  • Has a known history of active TB (Bacillus Tuberculosis).
  • Has gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3 within 6 months of registration.
  • Has a known additional malignancy that is progressing or requires active treatment within 2 years of registration. Exceptions include malignancies treated with surgery alone including but not limited to basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
  • 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. See Section 5.4.3 for additional information on allowed corticosteroid dosing.
  • Has confirmed history or any evidence of active non-infectious pneumonitis.
  • Has an active infection requiring systemic therapy.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. Examples include but are not limited to symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Is pregnant or breastfeeding or expecting to conceive within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment. It is unknown whether ASP8374 and/or cemiplimab is excreted in human milk or may have adverse effects on a fetus in utero. Since many drugs are excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant or fetus, these participants are not eligible for enrollment.
  • Has received prior therapy with an anti-TIGIT, anti-PD-1, anti-PD-L1, 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.
  • Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  • Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Has received a live vaccine within 30 days prior to registration.
  • Has a known hypersensitivity to any of the study therapy products.
  • Has been previously treated with the PI3K inhibitor idelalisib.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04826393


Contacts
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Contact: David A Reardon, MD 617-632-4750 david_reardon@dfci.harvard.edu

Locations
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United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Contact: David A Reardon, MD    617-632-4750    david_reardon@dfci.harvard.edu   
Principal Investigator: David A Reardon, MD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
Regeneron Pharmaceuticals
Astellas Pharma Inc
ImaginAb, Inc.
Investigators
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Principal Investigator: David A Reardon, MD Dana-Farber Cancer Institute
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Responsible Party: David Reardon, MD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT04826393    
Other Study ID Numbers: 21-054
First Posted: April 1, 2021    Key Record Dates
Last Update Posted: April 1, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data can be shared no earlier than 1 year following the date of publication
Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by David Reardon, MD, Dana-Farber Cancer Institute:
Glioblastoma
Recurrent Glioblastoma
Glioma, Grade 3
Additional relevant MeSH terms:
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Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Cemiplimab
Antineoplastic Agents, Immunological
Antineoplastic Agents