Clinical trial NCT01864902: Treatment of Relapsed and/or Chemotherapy Refractory CD33 Positive Acute Myeloid Leukemia by CART-33
Official title: Clinical Study of Chimeric CD(Cluster of Differentiation)33 Antigen Receptor-modified T Cells in Relapsed and/or Chemotherapy Refractory Acute Myeloid Leukemias
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Relapsed Adult Myeloid Leukemia
Chemotherapy Refractory Adult Myeloid Leukemia
Keywords: CD33 positive acute myeloid leukemia (AML)
Lead sponsor: Chinese PLA General Hospital
Sponsor class: OTHER
First posted: 2013-05-30
Enrollment: 10
Sex: ALL
Minimum age (years): 5
Maximum age (years): 90
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Placing a tumor antigen chimeric receptor that has been created in the laboratory into patient autologous or donor-derived T cells may make the body build immune response to kill cancer cells.

PURPOSE: This clinical trial is to study genetically engineered lymphocyte therapy in treating patients with CD33 positive acute myeloid leukemias that is relapsed (after stem cell transplantation or intensive chemotherapy) or refractory to further chemotherapy.

Detailed description: PRIMARY OBJECTIVES:

I. Determine the safety and feasibility of the chimeric antigen receptor T cells transduced with the anti-CD33 vector (referred to as CART-33 cells).

II. Determine duration of in vivo survival of CART-33 cells. RT-PCR (reverse transcription polymerase chain reaction) analysis of whole blood will be used to detect and quantify survival of CART-33 TCR zeta:CD137 and TCR (T-cell receptor) zeta cells over time.

SECONDARY OBJECTIVES:

I. For patients with detectable disease, measure anti-leukemia response due to CART-33 cell infusions.

II. To determine if the CD137 transgene is superior to the TCR zeta only transgene as measured by the relative engraftment levels of CART-33 TCR zeta:CD137 and TCR zeta cells over time.

III. Estimate relative trafficking of CART-33 cells in bone marrow.

IV. For patients with stored or accessible leukemia blasts, determine leukemia cell killing by CART-33 cells in vitro.

V. Determine if cellular or humoral host immunity develops against the murine anti-CD33, and assess correlation with loss of detectable CART-33 (loss of engraftment).

VI. Determine the relative subsets of CART-33 T cells (Tcm, Tem, and Treg).

OUTLINE: Patients are assigned to 1 group according to order of enrollment.

Patients receive anti-CD33-CAR (coupled with CD137 and CD3 zeta signalling domains)vector-transduced autologous T cells on days 0,1, and 2 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed intensively for 6 months, every 3 months for 2 years, and annually thereafter for 13 years.

Eligibility criteria: Inclusion Criteria:

* Male and female subjects with CD33+ acute myeloid leukemia in patients with no available curative treatment options (such as autologous or allogeneic SCT) who have limited prognosis (several months to \< 2 year survival) with currently available therapies will be enrolled

  * CD33+ acute myeloid leukemia CR can not be achieved after at least 2 prior combination chemotherapy regimens.

AML in CR(complete remission)2 or CR3 and not eligible for allogeneic SCT because of age, comorbid disease, or lack of available family member or unrelated donor.

Less than 1 year between last chemotherapy and progression (i.e. most recent progression free interval \< 1 year).

Relapsed after prior autologous or allogenic SCT. AML patients with relapsed or residual disease after at least 1 prior therapy and not eligible for allogeneic SCT.

Residual disease after primary therapy and not eligible for autologous SCT

* Expected survival \> 12 weeks
* Creatinine \< 2.5 mg/dl
* ALT(alanine aminotransferase)/AST (aspartate aminotransferase)\< 3x normal
* Bilirubin \< 2.0 mg/dl
* Any relapse after prior SCT will make patient eligible regardless of other prior therapy
* Adequate venous access for apheresis, and no other contraindications for leukapheresis
* Voluntary informed consent is given

Exclusion Criteria:

* Pregnant or lactating women

  * The safety of this therapy on unborn children is not known
  * Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion
  * Uncontrolled active infection
  * Active hepatitis B or hepatitis C infection
  * Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary
  * Previously treatment with any gene therapy products
  * Feasibility assessment during screening demonstrates \< 30% transduction of target lymphocytes, or insufficient expansion (\< 5-fold) in response to CD3/CD137 costimulation
  * Any uncontrolled active medical disorder that would preclude participation as outlined
  * HIV infection

Primary outcomes:
measure: Occurrence of study related adverse events
timeFrame: Until week 24
Secondary outcomes:
measure: Anti-leukemia responses to CART-33 cell infusions
timeFrame: up to 24 weeks
Other outcomes:
measure: in vivo existence of CART33
timeFrame: 1 year
Locations:
city: Beijing
country: China
facility: Biotherapeutic Department and Pediatrics Department of Chinese PLA General Hospital, Hematological Department, Affiliated Hospital of Changzhi Medical College
state: Beijing
Study officials:
References:
citation: Wang QS, Wang Y, Lv HY, Han QW, Fan H, Guo B, Wang LL, Han WD. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther. 2015 Jan;23(1):184-91. doi: 10.1038/mt.2014.164. Epub 2014 Sep 1.