B細胞リンパ腫に対するCAR20(NAP)-T療法（CARMA-01研究） (CARMA-01)
再発/難治性B細胞リンパ腫患者におけるCAR20(NAP)-Tの安全性と有効性を評価する第I/IIa相多施設共同研究（CARMA-01研究）
The purpose is to study the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of CAR20(NAP)-T for patients with B-cell malignancies.
調査の概要
詳細な説明
A cancer patient's T cells can be isolated and engineered to express a chimeric antigen receptor (CAR), which re-directs the T cells to recognize and kill tumor cells expressing that particular antigen. CD19-targeted CAR-T cell therapy has shown good effects for B cell malignancies, even cure, in otherwise therapy refractory patients.
Antigen escape, i.e., the downregulation of the antigen targeted by the CAR due to the selective pressure caused by the CAR-T cell therapy is a challenge. For patients treated with CD19 CAR-T cell therapy, about 30% of the patients are resistant to treatment and about 20% of patients relapse after an initial response.
CAR20(NAP)-T cells target CD20 and upon target recognition secrete a bacterial-derived pluripotent immune-stimulating factor named NAP (Helicobacter pylori Neutrophil-activating protein). Secretion of NAP in the tumor microenvironment can induce an endogenous bystander immune response, that counteracts antigen escape and thereby improves the therapeutic outcome.
CAR20(NAP)-T is an investigational agent not yet approved by authorities.
Design:
The study is designed as 3+3 dose escalation phase I, and a dose expansion Phase IIa. The safety, tolerability, PK/PD, and efficacy will be evaluated.Dose escalation is to be based on the incidence of dose-limiting toxicity (DLTs). The investigator or sub-investigator will decide if the AE is related to IMP-treatment on a case-by-case basis depending on the character of the DLT symptoms. Investigator or sub-investigator has a possibility to classify various toxicity observed in patient as DLT.The Recommended phase II dose (RP2D) is decided based on safety, PK/PD data as well as preliminary clinical activity data from the Phase I dose escalation. After setting the RP2D, additional patients will be treated at RP2D to make sure at least 6 patients will be treated at RP2D dose level already at the phase I part.
Protocol treatment:
The enrolled patient will undergo a leukapheresis procedure to harvest enough T cells for IMP production. During CAR20(NAP)-T manufacturing, the patient may receive bridging therapy to control tumor burden. All patients will receive pre-conditioning chemotherapy (cyclophosphamide and fludarabine) followed by one dose of CAR20(NAP)-T cell infusion intravenously. The patient will then be followed by doctor/study nurse for evaluation of the health status and side effects. At follow-up visits, blood samples will be obtained and CT imaging will be performed. Patient will actively participate in the study for about 24 months when the final follow-up visit will be scheduled.
研究の種類
入学 (推定)
段階
- フェーズ2
- フェーズ 1
連絡先と場所
研究連絡先
- 名前：Di Yu, PhD
- 電話番号：+46707204196
- メール：di.yu@igp.uu.se
研究連絡先のバックアップ
- 名前：Gunilla Enblad, MD/PhD
- 電話番号：+46186110000
- メール：gunilla.enblad@igp.uu.se
研究場所
-
-
-
Stockholm、スウェーデン
- 募集
- Karolinska University Hospital
-
コンタクト：
- Stephan Mielke
-
主任研究者：
- Stephan Mielke, MD, PhD
-
Uppsala、スウェーデン
- 募集
- Uppsala University Hospital
-
コンタクト：
- Gunilla Enblad
-
主任研究者：
- Gunilla Enblad, MD/PhD
-
-
参加基準
適格基準
就学可能な年齢
- 子
- 大人
- 高齢者
健康ボランティアの受け入れ
受講資格のある性別
説明
Key Inclusion Criteria:
-
Signed informed consent.
-
Relapsed or refractory CD20+ large B-cell lymphoma (DLBCL, NOS or high-grade malignant B-cell lymphoma), mantle cell lymphoma or indolent lymphoma.
-
The patient should have been treated with at least one line of therapy and have no curative treatment option, assessed by the Investigator and documented in the source data prior to enrolment, specifically:
- Relapsed or refractory CD20+ B-cell lymphoma that are not suitable to receive clinically approved CD19-directed CAR T cell treatment
- Relapsed or refractory CD20+ B-cell lymphoma who are considered CD19 neg-ative
- Relapsed or refractory B-cell lymphoma who relapse after CD19-directed CAR T cell treatment
- Not suitable for autologous stem cell transplant
- Relapsed after allogeneic transplantation
-
In phase I age >18 years, in phase II all ages.
-
Measurable disease per Lugano classification.
-
Performance status ECOG 0-2.
-
Bone marrow function, if impairment is not caused by lymphoma infiltration, as evidenced by:
- Absolute neutrophil count (ANC) ≥ 1x109/L
- Platelet ≥ 50x 109/L
- Absolute lymphocyte count ≥ 0.1x109/L
-
Adequate renal, hepatic, cardiac, and pulmonary function as evidenced by:
- Creatinine clearance (Cockcroft Gault) ≥ 30 mL/min
- Serum Alanine aminotransferase/Aspartate aminotransferase (ALT/AST) ≤ 2.5 Upper limit of normal (ULN) and S-Bilirubin <1.5x UNL
- Cardiac ejection fraction ≥ 40%
-
Functional venous access for administration of IMP.
-
Fertile individuals must consent to use contraceptives during participation in the trial.
Exclusion Criteria:
- Other CD20-positive lymphomas e.g Burkitt lymphoma, primary CNS lymphoma, plasmablastic lymphoma or CLL transformed to DLBCL/HGBL (Richter transformation)
- Any significant medical or psychiatric illness that would prevent the subject from giving informed consent or from following the study procedures.
- Known human immunodeficiency virus (HIV) infection.
- Impending organ-compromising disease.
- Rapidly progressing disease
- Active and/or severe infection (e.g., tuberculosis, sepsis and opportunistic infections, active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.
- Other serious underlying medical conditions, which, in the Investigator's judgment, could impair the ability of the subject to tolerate the treatment.
- Treatment with an investigational product within 30 days prior to enrolment
- Potential sign of hypersensitivity reaction to tocilizumab or any of the agents used in this study
- Systemic corticosteroid treatment (>10mg/day) <5 days prior to IMP treatment or <7 days prior leukapheresis.
- Pregnancy
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：なし
- 介入モデル：単一グループの割り当て
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
実験的：Treatment
CAR20(NAP)-T treatment |
Autologous CAR-T cells targeting CD20 and upon target recognition express and secrete NAP
他の名前：
pre-conditioning chemotherapy pre-conditioning chemotherapy |
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Incidence of dose limiting toxicity
時間枠：First infusion up to 30 days
|
The incidence of dose limiting toxicity (DLT). Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs) |
First infusion up to 30 days
|
|
Adverse events
時間枠：24 months
|
The nature, frequency, severity, and tolerability of adverse events (AEs) including clinically significant laboratory data, and their relation to dosage. |
24 months
|
|
Pharmacodynamic (PD) and pharmacokinetic (PK)
時間枠：Either 24 month or 15 years during long-term follow up if clinically indicated
|
PD is assessed by determine circulating B cell level; PK is assessed by determine circulating CAR20(NAP)-T cells. |
Either 24 month or 15 years during long-term follow up if clinically indicated
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Objective response rate [ORR]
時間枠：24 months
|
ORR is defined as the incidence of a complete response or a partial response by the revised Lugano classification as determined by the study investigators. All patients that do not meet the criteria for an objective response by the analysis cutoff date will be considered non-responders. |
24 months
|
|
Progression free survival [PFS]
時間枠：24 months
|
PFS is defined as the time from the IMP treatment date to the date of disease progression per the revised Lugano classification or death from any cause. |
24 months
|
|
Best Objective Response
時間枠：24 months
|
the incidence of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or unevaluable (UE) as best response to treatment. |
24 months
|
|
Duration of Response (DOR)
時間枠：24 months
|
DOR is defined as the date of their first objective response (which is subsequently confirmed) to disease progression per the revised Lugano classification or death regardless of cause. Patients not meeting the criteria for progression or death by the analysis data cutoff date will be censored at their last evaluable disease assessment date and their response will be noted as ongoing. |
24 months
|
|
Overall Survival (OS)
時間枠：either 24 months or 15 years during long-term follow up if clinically indicated
|
defined as the time from IMP treatment to the date of death. Patients alive by the analysis data cutoff date will be censored at their last contact date. The overall survival rate will be reported at different cut-off time points. |
either 24 months or 15 years during long-term follow up if clinically indicated
|
その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Anti-NAP response
時間枠：either 24 months or 15 years during long-term follow up if clinically indicated
|
Determine anti-NAP immune response |
either 24 months or 15 years during long-term follow up if clinically indicated
|
|
Bystander immunity activation
時間枠：either 24 months or 15 years during long-term follow up if clinically indicated
|
Assess induced tumor specific endogenous T-cell immune response |
either 24 months or 15 years during long-term follow up if clinically indicated
|
協力者と研究者
スポンサー
捜査官
- スタディディレクター：Di Yu, PhD、Uppsala University
出版物と役立つリンク
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- ELC301-CARMA-01
- 2022-004157-31 (EudraCT番号)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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