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CD24Fc for the Treatment of Immune Related Adverse Events in Patients With Advanced Solid Tumors, TIRAEC Study

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ClinicalTrials.gov Identifier: NCT04552704
Recruitment Status : Recruiting
First Posted : September 17, 2020
Last Update Posted : November 12, 2020
Sponsor:
Collaborators:
National Cancer Institute (NCI)
OncoImmune, Inc.
Information provided by (Responsible Party):
Tianhong Li, University of California, Davis

Tracking Information
First Submitted Date  ICMJE September 10, 2020
First Posted Date  ICMJE September 17, 2020
Last Update Posted Date November 12, 2020
Actual Study Start Date  ICMJE October 30, 2020
Estimated Primary Completion Date October 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 10, 2020)
  • Incidence of new adverse event (AE) of >= grade 3 (Phase I) [ Time Frame: At day 60 ]
    Will assess event of new AE of >= grade 3 that are outside the spectrum of immune related adverse events (irAEs) when CD24 extracellular domain-IgG1 Fc domain recombinant fusion protein CD24Fc (CD24Fc) is given in cancer patients who developed grade 2-3 irAEs. Toxicity is evaluated by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. The type, grade, frequency and proportion of toxicities noted during the treatment period will be reported, along with associated 95% confidence interval of proportion. All adverse events noted by the investigator will be tabulated according to the affected body system.
  • Recovery rate (Phase II) [ Time Frame: At day 42 ]
    Defined by reduction of irAE by one grade. Kaplan-Meier plots and confidence intervals will be used to summarize outcomes. Medians and associated 95% confidence intervals will be calculated, and comparisons between groups will be performed by log-rank tests. Cox proportional hazard models will be used to explore association between covariates and outcomes.
  • Time to recovery from grade 2 or 3 irAE (Phase II) [ Time Frame: Up to 1 year ]
    Will assess time to recovery from grade 2 or 3 irAE (as defined by reduction of at least 1 grade in irAE severity) from the initiation of CD24Fc treatment. Patients who have not been documented to have event (reduction of at least 1 grade) will be censored at the date of the latest clinical assessment that documented as being free of event.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 10, 2020)
  • Time to irAE reduction by at least 1 grade from the initiation of CD24Fc treatment (Phase I) [ Time Frame: Up to 1 year ]
    Kaplan-Meier plots and confidence intervals will be used to summarize outcomes. Medians and associated 95% confidence intervals will be calculated, and comparisons between groups will be performed by log-rank tests. Cox proportional hazard models will be used to explore association between covariates and outcomes.
  • Time to all irAEs reduced to =< 1 from the initiation of CD24Fc treatment (Phase I) [ Time Frame: Up to 1 year ]
    Assessed by NCI CTCAE v5.0. Kaplan-Meier plots and confidence intervals will be used to summarize outcomes. Medians and associated 95% confidence intervals will be calculated, and comparisons between groups will be performed by log-rank tests. Cox proportional hazard models will be used to explore association between covariates and outcomes.
  • Time to resume immune check point inhibitor (ICI) treatment from the initiation of CD24Fc treatment (Phase I) [ Time Frame: Up to 1 year ]
    Kaplan-Meier plots and confidence intervals will be used to summarize outcomes. Medians and associated 95% confidence intervals will be calculated, and comparisons between groups will be performed by log-rank tests. Cox proportional hazard models will be used to explore association between covariates and outcomes.
  • Recovery rate (reduction of irAE by one grade) (Phase I) [ Time Frame: At day 42 ]
    The fraction of patients who experience a partial response (PR) or complete response (CR) will be determined by dividing the number of responders by the total evaluable patients. The fraction will be reported along with 95% two-sided confidence intervals. Comparisons between groups will be performed by Fisher's Exact tests. Will also characterize the proportion who remain that either respond or have stable disease, compared to those who progress.
  • Time to all irAEs reduced to =< 1 from the initiation of CD24Fc treatment (Phase II) [ Time Frame: Up to 1 year ]
    Assessed by NCI CTCAE v5.0. Kaplan-Meier plots and confidence intervals will be used to summarize outcomes. Medians and associated 95% confidence intervals will be calculated, and comparisons between groups will be performed by log-rank tests. Cox proportional hazard models will be used to explore association between covariates and outcomes.
  • Use of steroids and other drugs (drug, dose, duration) (Phase II) [ Time Frame: Up to 1 year ]
    Descriptive statistics will be used to summarize use of steroids (drug, dose, duration) and other treatment for irAE.
  • Overall response rate after retreatment with ICI with or without CD24Fc after resolution of irAE (Phase II) [ Time Frame: Up to 1 year ]
    The fraction of patients who experience a PR or CR will be determined by dividing the number of responders by the total evaluable patients. The fraction will be reported along with 95% two-sided confidence intervals. Comparisons between groups will be performed by Fisher's Exact tests. Will also characterize the proportion who remain that either respond or have stable disease, compared to those who progress.
  • Progression free survival (PFS) (Phase II) [ Time Frame: From initiation of ICI to first documented evidence of disease progression or death, whichever comes first, assessed up to 1 year ]
    Kaplan-Meier plots and confidence intervals will be used to summarize PFS; medians and associated 95% confidence intervals will be calculated, and comparisons between groups will be performed by log-rank tests. Cox PH models will be used to explore association between outcomes and covariates.
  • Overall survival (OS) (Phase II) [ Time Frame: From diagnosis to death, assessed up to 1 year ]
    Kaplan-Meier plots and confidence intervals will be used to summarize OS; medians and associated 95% confidence intervals will be calculated, and comparisons between groups will be performed by log-rank tests. Cox PH models will be used to explore association between outcomes and covariates.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE CD24Fc for the Treatment of Immune Related Adverse Events in Patients With Advanced Solid Tumors, TIRAEC Study
Official Title  ICMJE Treatment of Immune Related Adverse Events With CD24Fc (TIRAEC)
Brief Summary This phase I/II trial investigates the side effects and how well CD24Fc works in treating immune related adverse events in patients with solid tumors that have spread to other places in the body (advanced). CD24Fc may prevent autoimmune reactions due to the tissue damage induced by cancer treatment. CD24Fc binds to injured cell components and prevents inflammatory responses. CD24Fc also acts to turn off the immune system after it has been activated ("immune checkpoint"). Adding CD24Fc to standard treatment may shorten the recovery time and reduce the severity of side effects from immunotherapy.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of CD24 extracellular domain-IgG1 Fc domain recombinant fusion protein CD24Fc (CD24Fc) in patients with advanced solid tumors who developed debilitating immune-related adverse events (irAEs) from immune check point inhibitors (ICIs). (Phase I) II. To determine if CD24Fc shortens the recovery time of irAE and increases the recovery rate of irAE in cancer patients with grade (G)2 or 3 irAEs. (Randomized phase II)

SECONDARY OBJECTIVES:

I. Time to irAE reduction by at least 1 grade. (Phase I) II. Time to all irAEs reduced to grade =< 1. (Phase I) III. Time to resume ICI treatment. (Phase I) IV. Recovery rate (as defined by reduction of irAE by one grade) at day (D)42. (Phase I) V. To estimate the time to all irAEs reduced to =< 1. (Randomized phase II) VI. To record the use of steroids (drug, dose, duration) and other treatment for irAE. (Randomized phase II) VII. To record the time to resume ICI treatment. (Randomized phase II) VIII. To estimate the preliminary overall response rate (ORR), progression free survival (PFS), and 1-year overall survival (OS) after treatment with or without CD24Fc. (Randomized phase II) IX. To determine if CD24Fc treatment changes the levels of inflammatory markers in the plasma. (Randomized phase II)

OUTLINE:

PHASE I: Patients receive CD24Fc intravenously (IV) over 60 minutes on days 1, 14, and 28 with standard of care (i.e., steroids per treating physician and best supportive care) in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive CD24Fc IV over 60 minutes on days 1, 14, and 28 in addition to standard of care treatment for irAE in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo IV over 60 minutes on days 1, 14, and 28 in addition to standard of care treatment for irAE in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at days 42 and 60 and then every 3 months for up to 1 year.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Advanced Malignant Solid Neoplasm
Intervention  ICMJE
  • Biological: CD24 Extracellular Domain-IgG1 Fc Domain Recombinant Fusion Protein CD24Fc
    Given IV
    Other Names:
    • CD24Fc
    • CD24Fc CD24IgG
  • Drug: Placebo Administration
    Given IV
Study Arms  ICMJE
  • Experimental: Phase I (CD24Fc)
    Patients receive CD24Fc IV over 60 minutes on days 1, 14, and 28 with standard of care (i.e., steroids per treating physician and best supportive care) in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: CD24 Extracellular Domain-IgG1 Fc Domain Recombinant Fusion Protein CD24Fc
  • Experimental: Phase II, Arm I (CD24Fc)
    Patients receive CD24Fc IV over 60 minutes on days 1, 14, and 28 in addition to standard of care treatment for irAE in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: CD24 Extracellular Domain-IgG1 Fc Domain Recombinant Fusion Protein CD24Fc
  • Placebo Comparator: Phase II, Arm II (placebo)
    Patients receive placebo IV over 60 minutes on days 1, 14, and 28 in addition to standard of care treatment for irAE in the absence of disease progression or unacceptable toxicity.
    Intervention: Drug: Placebo Administration
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 10, 2020)
78
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2023
Estimated Primary Completion Date October 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Ability to understand and willingness to sign an informed consent form
  • Histologically confirmed advanced solid tumors
  • Patients must have grade 2 or 3 irAEs from at least one ICI-containing regimen. Both newly emerging and persistent irAEs are allowed. Systemic steroid therapy or any other form of immunosuppressive therapy for irAEs is allowed. The specific irAEs are

    • Grade 2-3 diarrhea/colitis: Patients with >= 4 stools per day or moderate-severe increase in ostomy output compared to baseline but not life-threatening diarrhea
    • Grade 2-3 pneumonitis: Mild to moderate (grade 2) or severe (grade 3) symptoms (including hypoxia, shortness of breath, requiring oxygen) but not life-threatening respiratory compromise requiring urgent intervention (e.g., tracheostomy or intubation)
    • Grade 2-3 renal irAE: Creatine increased between 1.6-6.0 x upper limit of normal (ULN) or =< 3.0 x baseline if baseline was abnormal, estimated glomerular filtration rate (eGFR) or creatinine clearance >= 15 ml/min/1.73m^2 but not life-threatening consequences or requiring dialysis
    • Grade 2-3 hepatic irAE: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/alkaline phosphatase (ALP) levels 3-20 x ULN if baseline was normal or 2-20 x baseline if baseline was abnormal, T bilirubin increased =< 10.0 x ULN if baseline was normal or =< 10 x baseline if baseline was abnormal
    • Grade 2-3 skin rash: moderate (10-30% body surface area, BSA) to severe (> 30% BSA) but not life-threatening skin lesions or Stevens-Johnson syndrome
  • Eastern Cooperative Oncology Group (ECOG) performance status < 2
  • Life expectancy of >= 3 months at the time of enrollment
  • Pretreatment absolute neutrophil count (ANC) >= 1,000/uL obtained within 14 days prior to 1st dose of treatment
  • Pretreatment hemoglobin >= 8 gm/dL obtained within 14 days prior to 1st dose of treatment
  • Pretreatment platelet count of >= 75,000/uL obtained within 14 days prior to 1st dose of treatment
  • Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for >= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Or, female subjects of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the first study drug administration
  • Male and female subjects who agree to use highly effective method of birth control (e.g., implants, injectables, birth control pills with two hormones, intrauterine devices [IUDs], complete abstinence or sterilized partner, and female sterilization) and a barrier method (e.g., condoms, vaginal ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug

Exclusion Criteria:

  • Prior CD24Fc therapy
  • Any known active hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, including patients who have an active infection requiring systemic therapy. History of COVID-19 or known asymptomatic carrier of SARS-CoV-2 virus is allowed
  • Pregnant or lactating women
  • Any medical condition including additional laboratory abnormalities, or psychiatric illness that would, in the opinion of the investigator, prevent the subject from participating and adhering to study related procedures
  • Any known severe bacterial, fungal, or viral infection that in the opinion of the investigator would interfere with patient safety or compliance on trial within 2 weeks prior to enrollment
  • Patients with concomitant proarrhythmic medications
  • Patients with heart failure in New York (NY) Heart Association stage IV
  • Any grade 4 irAE symptoms and Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 grade 4 toxicity
  • AST, ALT, gamma glutamyl transpeptidase (GGT), or ALP > 20.0 x ULN regardless of baseline
  • Blood bilirubin > 10.0 x ULN regardless of baseline
  • Creatinine > 6.0 x ULN
  • Urine: Anuria < 140 ml in 24 hours
  • Electrolytes hyponatremia, sodium < 120 mmol/L
  • Hypokalemia, potassium < 2.5 mmol/L
  • Creatine kinase (CPK) > 10.0 ULN
  • Electrocardiogram (ECG): Prolonged QT interval >= 480 mS, corrected by Fridericia's formula. Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrythmia
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04552704
Other Study ID Numbers  ICMJE 1626396
NCI-2020-05955 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
UCDCC#292 ( Other Identifier: University of California Davis Comprehensive Cancer Center )
P30CA093373 ( U.S. NIH Grant/Contract )
CD24Fc-006 ( Other Grant/Funding Number: OncoImmune, Inc. )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Tianhong Li, University of California, Davis
Study Sponsor  ICMJE Tianhong Li
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • OncoImmune, Inc.
Investigators  ICMJE
Principal Investigator: Tianhong Li University of California, Davis
PRS Account University of California, Davis
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP