DK-CLIC-1901 CAR T-cells for treatment of patients with relapsed/refractory CD19 positive hematological malignancies (DAN-CART 1901)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rigshospitalet

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Neoplasms [C04]

Trial duration

3 Oct 2022 → ongoing

Decision date (initial)

2024-08-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Børnecancerfonden · Region Hovedstadens Apotek · Regionernes Medicinpulje

External identifiers

EU CT number

2024-515174-27-00

EudraCT number

2021-006556-14

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Therapy, Efficacy

To test safety and feasibility of treatment with CLIC-1901 CAR T-cell in relapsed or refractory CD19-expressing hematological malignancies.

Secondary objectives 1

1. To test efficacy of treatment with CLIC-1901 CAR T-cells and analyse factors contributing to to non-efficacy

Conditions and MedDRA coding

Acute Lymphoblastic Leukemia and B-cell Non Hodgkin Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. Relapsed/refractory hematologic disease (in peripheral blood, bone marrow or lymph node biopsy by flow cytometry) defined as one of the following: a. CD19 expressing B-cell acute lymphoblastic leukemia (B-ALL) with one of the following: • First VHR relapse (very early relapse (<18 months from initial diagnosis of ALL or very high risk genetic features ((KMT2A-AFF1, E2A/TCF3-PBX1 rearrangements, hypodiploidy, TP53 alterations) • NCI HR and MRD ≥0.01% at end of consolidation according to the ALLTogether protocol • Second or greater bone marrow (BM) relapse. • Any relapse after allogeneic haematopoietic stem cell transplantation (HSCT). • Primary refractory, defined as not achieving complete remission (CR) after 2 cycles of standard chemotherapy regimen, or chemo refractory, defined as not achieving CR after 1 cycle of standard chemotherapy for relapsed leukemia. • Philadelphia chromosome-positive ALL intolerant of or with 2 failed lines of tyrosine kinase inhibitor (TKI) therapy or if TKI therapy is contraindicated. • Ineligible for allogeneic HSCT due to comorbidity, contraindications to conditioning regimen, lack of a suitable donor, prior HSCT, or declined allogeneic HSCT after documented detailed discussion of this treatment option with the given patient. b. Histologically confirmed B-cell non-Hodgkin’s lymphoma including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, High-grade B cell lymphoma with or without double hit, precursor B-cell lymphoblastic lymphoma (B-LBL), primary mediastinal large B-cell lymphoma, mantle cell lymphoma, Richter-transformed chronic lymphocytic lymphoma (CLL) or transformed follicular lymphoma with one of the following: • Second or greater relapse. • Relapse after autologous or allogeneic haematopoietic stem cell transplantation (HSCT). • Primary refractory, defined as not achieving at least partiel remission (PR) at time of end of treatment scanning or as defined in frontline protocol. b. Follicular lymphoma (FL) with both of the following: • ≥2 prior lines of therapy that included both an anti-CD20 antibody and an alkylating agent. • Histologically confirmed by a pathology review to have FL (grade 1, 2 or 3A), and no evidence of histologic transformation or FL grade 3B. c. Chronic lymphocytic lymphoma (CLL) and small lymphocytic lymphoma (SLL) with both of the following: • ≥2 prior lines of therapy that included Bruton tyrosine kinase inhibitors • No evidence of active CNS involvement.
2. 2. Age of 1-75 years
3. 3. Life expectancy ≥ 12 weeks after enrollment
4. 4. Adequate organ function defined as: a. Lansky (<16 years) or Karnofsky (>16 years) score > 50% b. FEV1 or DLCOc ≥ 40 % of expected and oxygen saturation > 90% without oxygen supply c. LVEF > 45% and no symptoms of ischemic heart disease d. Bilirubin < 2 x upper normal limit for age (except for patient diagnosed with Gilbert syndrome) e. ALT < 5 x upper normal limit for age f. EDTA clearance >40mL/min (adults) or >30% of normal limit for age (children)
5. 5. Signed statement of consent after receiving oral and written study information
6. 6. Agreement to utilize highly effective contraception methods from time of leukapheresis until a minimum of 12 months after CAR-T infusion for all female patients of childbearing potential and all male patients with a female partner of childbearing potential. Highly effective contraception is defined as: total abstinence, female sterilization (oophorectomy, total hysterectomy or tubal ligation), male sterilization or use of oral, injected or implanted hormonal methods of contraception or placement or an intrauterine system/device.

Exclusion criteria 13

1. Prior malignancy (except for non-melanoma skin cancer) with on-going evidence of active disease or expected 5-year survival below 50% (as best estimation by treating oncologist)
2. Patients with concomitant genetic syndrome, such as Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known familial bone marrow failure syndrome
3. Prior treatment with any gene therapy product
4. Treatment with any investigational agent within 30 days prior to enrollment
5. Treatment with allogeneic haematopoietic stem cell transplantation within 6 months or donor lymphocyte infusion within 6 weeks from CAR-T infusion
6. Acute or chronic graft-versus-host disease with the need for systemic corticosteroid treatment within 4 weeks prior to enrollment
7. Acute or chronic infections with HIV
8. Active infection with, hepatitis B or hepatitis C
9. Active severe bacterial, viral or fungal infection
10. Active Central Nervous System (CNS) involvement by malignancy, defined by CNS-3 per NCCN guidelines for ALL, or any evidence of lymphoma on lumbar puncture or brain imaging (if performed).
11. Pre-existing significant central neurological disorder defined as CTCAE grade 3-4 (other than CNS involvement of underlying hematological malignancy)
12. History of anaphylaxis to gentamicin or its derivates
13. Pregnant or breastfeeding women

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. CRS: registration according to international grading system[31]. Endpoints include proportion of patients experiencing CRS of all grades and CRS grade 3-4
2. ICANS: registration according to international grading system[31]. Endpoints include proportion of patients experiencing ICANS of all grades and ICANS grade 3-4.
3. Treatment with tocilizumab and/or glucocorticoids for CRS/ICANS.
4. Cytopenia, including ICAHT grade ≥3 at day +28 and time to reach acceptable levels of neutrophils (≥1,.0 in three consecutive days), thrombocytes (≥100 in three consecutive days) and hemoglobin after CAR T-cell infusion.
5. Episodes of neutropenic fever (temperature >38.5 °C and neutrophils <0.5)
6. Admission at the intensive care unit (ICU) or pediatric intensive care unit (PICU)
7. Death from any cause

Secondary endpoints 2

1. Response rates defined as complete response, partial response, stable response or progressive disease
2. Overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM) and treatment with allogeneic hematopoietic stem cell transplantation (HSCT)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rigshospitalet

Sponsor organisation

Rigshospitalet

Address

Blegdamsvej 9

City

Copenhagen Oe

Postcode

2100

Country

Denmark

Scientific contact point

Organisation

Rigshospitalet

Contact name

Marianne Ifversen

Public contact point

Organisation

Rigshospitalet

Contact name

Marianne Ifversen

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications