CD22 CAR-T-Zellen zur Verlängerung der Remission nach kommerziellen CD19 CAR-T-Zellen bei Kindern, Jugendlichen und Erwachsenen mit rezidivierter/refraktärer B-Zell akuter lymphoblastischer Leukämie
Eine Phase-II-Studie zur Untersuchung der Auswirkung von CD22-CAR-T-Zellen auf die Verlängerung der Remissionsdauer nach kommerziellen CD19-CAR-T-Zellen bei Kindern, Jugendlichen und Erwachsenen mit rezidivierter/refraktärer B-Zell-akuter lymphoblastischer Leukämie
Background:
Acute lymphoblastic leukemia (ALL) is a type of blood cancer. Chimeric antigen receptor (CAR) therapy involves taking immune cells (T cells) from a person and modifying them to better target cancer cells. CAR T-cell therapy that targets a marker called CD19 has been show to can cure ALL in many children and adults. But in about 50% of patients, the ALL comes back within a year. Researchers want to find out if a second treatment with CAR T-cell therapy that targets a different marker, CD22, can keep the cancer away longer.
Objective:
To see if CD22 CAR T-cell therapy can keep ALL away longer.
Eligibility:
People aged 3 to 65 years who have no signs of cancer after CD19 CAR T-cell treatment for ALL.
Design:
Participants will be screened. They will have imaging scans and tests of their heart function. A sample of tissue (biopsy) will be collected from their bone marrow. They will have a fluid sample collected from the area around their spinal cord.
Participants will undergo collection of their white blood cells (T cells) during a procedure called leukapheresis. Blood will be taken from their body through a vein. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different vein. The cells will be altered in a lab to create CD22 CAR T-cell therapy.
Participants will take drugs over 4 consecutive days to prepare their body for the CAR T-cell therapy; then they will receive their modified T cells through a tube inserted into a vein. Some people may need to stay in the hospital during treatment.
Participants will have follow-up visits for 2 years.
Studienübersicht
Status
Status
Bedingungen
Bedingungen
Intervention / Behandlung
Intervention / Behandlung
Detaillierte Beschreibung
Background:
- Despite impressive cure rates in children and young adults with B-cell acute lymphoblastic leukemia (B-ALL) generally, patients with relapsed/refractory disease have historically suffered from limited treatment options. CD19 and CD22 chimeric antigen receptor (CAR) T-cells are effective at inducing remission in the majority of children and young adults with relapsed/refractory B-ALL.
- However, remissions are often not durable, and many patients will relapse in the absence of a consolidative hematopoietic stem cell transplant (HSCT), which is associated with high morbidity and mortality.
- Leukemic antigen escape has led to the interest in multi-antigen targeting approaches, targeting both CD19 and CD22 to enhance the long-term effectiveness of CAR T-cells. We have previously treated patients on phase 1/2 clinical trials using a bivalent CD19/22 CAR T-cell as well as a bicistronic CD19xCD22 CAR T-cell as combinatorial strategies.
- Some of the best long-term results in the literature have been seen with co-infusion of CD19 and CD22 CAR T-cells. Three FDA-approved CD19 CAR T-cell products are available commercially, and our phase 1/2 trial of CD22 CAR T-cells has demonstrated efficacy and safety.
- The use of CD22 CAR T-cells as consolidation of CD19 CAR T-cell-induced remission offers the potential to extend the durability of remission while limiting the toxicity associated with HSCT.
Objective:
-To determine the 1-year relapse-free survival (RFS) from the time of CD22 CAR T-cell infusion.
Eligibility:
-Participants aged 3-65 years who have relapsed/refractory B-ALL with a history of demonstrated expression of CD19 and CD22 and have achieved an MRD-negative remission after receiving an FDA-approved CD19 CAR T-cell product.
Design:
- Single-arm study with 4 days lymphodepleting preparative regimen, including fludarabine and cyclophosphamide, followed by CD22 CAR T-cells administration.
- Participants will be evaluated for toxicity, antitumor effects, CAR expansion and persistence, and other biological correlatives for 2 years after cell infusion.
- The trial will accrue 16 evaluable participants. The accrual ceiling for the trial is 20 participants to account for inevaluable participant and screen failures.
Studientyp
Studientyp
Einschreibung (Geschätzt)
Einschreibung
Phase
Phase
- Phase 2
Kontakte und Standorte
Studienkontakt
Studienkontakt
- Name: NCI Ped LeukemiaLymph Cell Tx Tm
- Telefonnummer: (240) 760-6970
- E-Mail: ncilltct@mail.nih.gov
Studieren Sie die Kontaktsicherung
- Name: Sara K Silbert, M.D.
- Telefonnummer: (240) 760-6970
- E-Mail: sara.silbert@nih.gov
Studienorte
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Maryland
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Bethesda, Maryland, Vereinigte Staaten, 20892
- Rekrutierung
- National Institutes of Health Clinical Center
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Kontakt:
- National Cancer Institute Referral Office
- Telefonnummer: 888-624-1937
- E-Mail: ncimo_referrals@mail.nih.gov
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Teilnahmekriterien
Zulassungskriterien
Zulassungskriterien
Studienberechtigtes Alter
Akzeptiert gesunde Freiwillige
Studienberechtigte Geschlechter
Beschreibung
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INCLUSION CRITERIA:
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Participants must have documentation of pathologic confirmation of a diagnosis of relapsed/refractory B cell acute lymphoblastic leukemia (ALL).
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History of CD19 and CD22 expression on malignant cells at diagnosis or relapse.
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Age between >= 3 years and <= 65 years
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Participants must have received an FDA-approved CD19 CAR T-cell construct for treatment of B cell ALL within the time period of >= 2 months and <= 7 months prior to apheresis or lymphodepleting (LD) (if apheresis is not done on this protocol).
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Must be in an MRD-negative remission as demonstrated by flow cytometry at screening.
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Must be ineligible for or unwilling to undergo allogeneic stem cell transplant (SCT).
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Clinical performance status (PS): Karnofsky >= 50% (participants >= 16 years of age), or Lansky scale >= 50% (participants < 16 years of age). Participants who are unable to walk because of paralysis, but who are upright in a wheelchair may be considered eligible.
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Must have no ongoing signs of CRS from prior CAR T cell infusion and/or ICANs at screening.
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Participants must have adequate organ function as defined below:
- Total bilirubin <= 2 x institutional upper limit of normal (ULN)
- Aspartate Aminotransferase (AST) <= 10 x ULN
- Alanine Aminotransferase (ALT) <= 10 x ULN
- creatinine <= the maximum for age listed below OR measured creatinine clearance >= 60 mL/min/1.73 m^2 for participants with
creatinine levels above the max
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Age: <=5, Maximum Serum, Creatinine <= .8 mg/dL
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Age: >5 to <=10, Maximum Serum, Creatinine <= 1.0mg/dL
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Age: >10, Maximum Serum, Creatinine <= 1.2mg/dL
- A participant may have continued to expect CAR T cell-associated cytopenias of any grade.
- Cardiac function: left ventricular ejection fraction>= 45% or fractional shortening >= 28%.
- Pulmonary function: baseline oxygen saturation >= 92% on room air; participants with respiratory symptoms (e.g., dyspnea, hypoxia <92%) must have a diffusing capacity of the lungs for carbon monoxide (DLCO)/adjusted > 45%.
- Women of childbearing potential (WOCBP) must agree to use highly effective contraception (hormonal, intrauterine device (IUD), abstinence, surgical sterilization) at the study entry and up to 12 months after the last dose of combined chemotherapy.
Note: WOCBP is defined as any individual who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.
Men able to father a child must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 7 months after the last dose of study drugs. We also will recommend men ask their partners to be on highly effective birth control (hormonal, IUD, surgical sterilization). Individuals able to father a child must not freeze or donate sperm within the same period.
- Nursing participants must be willing to discontinue nursing from study treatment initiation through 6 months after the last dose of the study drug(s).
- Participants must be enrolled on protocol 15-C-0028, Follow-Up Evaluation for Gene- Therapy Related Delayed Adverse Events after Participation in Pediatric Oncology Branch Clinical Trials.
- Ability of participant or /Legally Authorized Representative (LAR) to understand and be willing to sign a written informed consent document.
EXCLUSION CRITERIA:
- Any central nervous system (CNS) involvement or signs of non-CNS extramedullary disease.
- Any active graft versus host disease (GVHD) in participants who are post-HSCT.
- Participants with disease recurrence requiring therapy post CD19 CAR. Note: Maintenance therapy post CD19 CAR (e.g., vincristine or tyrosine kinase inhibitor) for remission maintenance is allowed and will require a 1-week washout prior to apheresis or LD (if apheresis is not done on this protocol).
- Any investigational agent within 1 week before apheresis or LD (if apheresis is not done on this protocol).
- Pregnancy confirmed with beta-human chorionic gonadotropin (beta-HCG) serum or urine test performed at screening.
- Human immunodeficiency virus (HIV) infection, as measured by seropositivity for (HIV) antibody.
- Hepatitis B virus (HBV) infection, as measured by positivity for hepatitis B surface antigen (HBsAg).
- Hepatitis C virus (HCV) infection, as measured by seropositivity for hepatitis C.
- History of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biological composition to any agent used in the study or in the manufacturing of cells.
- Uncontrolled, symptomatic intercurrent illness evaluated by medical history, physical exam, and/or laboratory testing, or social situation that would limit compliance with study requirements or would pose an unacceptable risk to the participant.
Studienplan
Wie ist die Studie aufgebaut?
Designdetails
- Hauptzweck: Behandlung
- Zuteilung: N / A
- Interventionsmodell: Einzelgruppenzuweisung
- Maskierung: Keine (Offenes Etikett)
Anzahl der Arme
Waffen und Interventionen
Teilnehmergruppe / ArmTeilnehmergruppe / Arm |
Intervention / BehandlungIntervention / Behandlung |
|---|---|
|
Experimental: 1
Lymphodepleting chemotherapy followed by CD22 CAR T-cells |
Cyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the patient s body weight, at 500 mg/m^2/dose after fludarabine infusion on days -3 and -2. Fludarabine is administered as an IV infusion in an appropriate solution over 30 minutes on days -5 through -2. To prevent undue toxicity the dose will be based on BSA (30 mg/m^2/dose). CD22-CAR-transduced T cells on D0 after lymphodepleting preparative regimen |
Was misst die Studie?
Primäre Ergebnismessungen
Primäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
|---|---|---|
|
1-year RFS (recurrence free survival)
Zeitfenster: 1 year post cell infusion
|
RFS of participants will be assessed by a Kaplan-Meier curve. The RFS probability and the median RFS will be reported along with 95% confidence intervals. |
1 year post cell infusion
|
Sekundäre Ergebnismessungen
Sekundäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
|---|---|---|
|
2-year RFS
Zeitfenster: 2 years post cell infusion
|
RFS probability will be reported along with 95% confidence intervals. |
2 years post cell infusion
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1-year and 2-year OS (overall survival)
Zeitfenster: 2 years post cell infusion
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OS of participants will be assessed by Kaplan-Meier curves along with 95% confidence intervals. OS will be described for participants with HSCT and without HSCT, for descriptive purposes, along with 95% confidence intervals. |
2 years post cell infusion
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Short-term safety
Zeitfenster: 28 days post cell infusion
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Short-term safety of CD22 CAR T-cell infusion for participants in remission after CD19 CAR T-cell infusion will be evaluated by describing: CRS incidence and severity per ASTCT; ICANS incidence and severity per ASTCT; EC-HS incidence and severity; ICAHT incidence and severity; and incidence of grade >= 3 serious adverse events per CTCAE v.5.0. |
28 days post cell infusion
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Long-term safety
Zeitfenster: up to 2 years post cell infusion
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Long-term safety of CD22 CAR T-cell infusion for participants in remission after CD19 CAR T-cell infusion will be evaluated by describing: incidence of severe adverse events related to CD22 CAR T-cells |
up to 2 years post cell infusion
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|
RFS from the time of additional CD22 CAR T-cell infusions
Zeitfenster: up to 2 years post-cell infusion
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RFS probability will be reported along with 95% confidence intervals. |
up to 2 years post-cell infusion
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Mitarbeiter und Ermittler
Sponsor
Sponsor
Ermittler
Ermittler
- Hauptermittler: Sara K Silbert, M.D., National Cancer Institute (NCI)
Publikationen und hilfreiche Links
Nützliche Links
Studienaufzeichnungsdaten
Haupttermine studieren
Studienbeginn (Tatsächlich)
Studienbeginn
Primärer Abschluss (Geschätzt)
Primärer Abschluss
Studienabschluss (Geschätzt)
Studienabschluss
Studienanmeldedaten
Zuerst eingereicht
Zuerst eingereicht
Zuerst eingereicht, das die QC-Kriterien erfüllt hat
Zuerst eingereicht, das die QC-Kriterien erfüllt hat
Zuerst gepostet (Tatsächlich)
Zuerst gepostet
Studienaufzeichnungsaktualisierungen
Letztes Update gepostet (Tatsächlich)
Letztes Update gepostet
Letztes eingereichtes Update, das die QC-Kriterien erfüllt
Letztes eingereichtes Update, das die QC-Kriterien erfüllt
Zuletzt verifiziert
Zuletzt verifiziert
Mehr Informationen
Begriffe im Zusammenhang mit dieser Studie
Schlüsselwörter
Zusätzliche relevante MeSH-Bedingungen
- Neubildungen
- Erkrankungen des Immunsystems
- Neubildungen nach histologischem Typ
- Hämatologische Erkrankungen
- Lymphatische Erkrankungen
- Lymphoproliferative Erkrankungen
- Immunproliferative Erkrankungen
- Leukämie, lymphatisch
- Leukämie
- Hämische und lymphatische Krankheiten
- Vorläuferzelle lymphoblastische Leukämie-Lymphom
- Organische Chemikalien
- Kohlenwasserstoffe
- Phosphoramid -Senf
- Stickstoffsenfverbindungen
- Senfverbindungen
- Kohlenwasserstoffe, halogeniert
- Phosphoramide
- Organophosphorverbindungen
- Cyclophosphamid
- Fludarabine
Andere Studien-ID-Nummern
Andere Studien-ID-Nummern
- 10001986
- 001986-C
Plan für individuelle Teilnehmerdaten (IPD)
Planen Sie, individuelle Teilnehmerdaten (IPD) zu teilen?
Beschreibung des IPD-Plans
This study will comply with the NIH Data Management and Sharing (DMS) Policy, which applies to all new and ongoing NIH-funded research in the IRP, as of January 25, 2023, that is associated with a ZIA, with a clinical protocol that undergoes scientific review and/or will involve genomic data sharing.
IPD-Sharing-Zeitrahmen
Data will be made available as soon as possible or at the time of associated publication. Data not published in a manuscript will be shared via public source once the data set completes QC.
IPD-Sharing-Zugriffskriterien
Clinical data will be made available upon request and with the permission of the study PI. Genomic data are made available via dbGAP through requests to the data custodians.
Art der unterstützenden IPD-Freigabeinformationen
- STUDIENPROTOKOLL
- SAFT
- ICF
Arzneimittel- und Geräteinformationen, Studienunterlagen
Studiert ein von der US-amerikanischen FDA reguliertes Arzneimittelprodukt
Studiert ein von der US-amerikanischen FDA reguliertes Geräteprodukt
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