Flotetuzumab for the Treatment of Relapsed or Refractory Advanced CD123-Positive Hematological Malignancies

  • End date
    Nov 15, 2023
  • participants needed
  • sponsor
    City of Hope Medical Center
Updated on 14 November 2021


This phase I trial studies the best dose and side effects of flotetuzumab for the treatment of patients with blood cancers (hematological malignancies) that have spread to other places in the body (advanced) and have come back after a period of improvement (relapsed) or does not respond to treatment (refractory). Flotetuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread.



I. To determine the maximum tolerated dose (recommended phase 2 dose, RP2D) of flotetuzumab, when given as a single agent.

II. Evaluate the safety and tolerability of flotetuzumab in CD123-positive advanced acute lymphoblastic leukemia (ALL) (Cohort A) and other hematological malignancies (Cohort B), by evaluation of toxicities including: type, frequency, severity, attribution, and duration of the toxicity.


I. Obtain preliminary estimates of remission; (complete remission [CR], complete remission with incomplete count recovery [CRi], complete remission with partial hematological recovery [CRh] or morphologic leukemia free state [MLFS] in Cohort A or CR/molecular response [MR] in Cohort B) rate and duration.

II. Estimate 1-year overall survival. III. Evaluate minimal residual disease (MRD) status in responders in the ALL cohort.

IV. Evaluate the percentage of patients who receive subsequent allogeneic transplantation.


I. Examine immune profile pre- and post-treatment with flotetuzumab. II. Assess the association between CD123 expression and tumor response. III. Assess the association between alterations in tumor genetic or microenvironment with response.

IV. Assess cytokine levels during therapy.

OUTLINE: This is a dose-escalation study.

INDUCTION THERAPY: Patients receive flotetuzumab via continuous intravenous (IV) infusion on days 1-28. Patients who achieve stable disease (SD)/partial remission (PR) (Cohort A) or PR/clinical improvement (CI) (Cohort B), receive an additional induction cycle. Patients who achieve PR (Cohort A) or PR/CI/major molecular response (MMR) (Cohort B) after cycle 2 re-induction, may continue induction therapy for up to 4 more cycles.

CONSOLIDATION THERAPY: Patients who achieve CR/CRi/CRh/MLFS (Cohort A) or CR/MR (Cohort B) after cycle 1 or cycle 2 of induction therapy, receive flotetuzumab via continuous IV infusion on days 1-28 for up to 5 and 6 cycles, respectively, in the absence of disease progression or unacceptable toxicity. Patients with PR (Cohort A) or PR/CI/MMR (Cohort B) who have received up to 6 cycles of induction therapy may receive up to 2 cycles of consolidation therapy in the absence of disease progression or unacceptable toxicity.

SUPPORTIVE CARE: Patients also receive acetaminophen orally (PO) or ibuprofen PO every 8 hours for 48 hours, diphenhydramine or equivalent IV or PO every 8 hours for 48 hours, ranitidine or equivalent IV every 8 hours for 48 hours, and dexamethasone IV up to 30 minutes prior to dosing and then at 12 hours after dosing on week 1 days 1 and 7.

After completion of study treatment, patients are followed up at 30 days, then every 3 months for 1 year.

Condition Refractory B Acute Lymphoblastic Leukemia, Recurrent Hodgkin Lymphoma, Refractory Hodgkin Lymphoma, Refractory Acute Leukemia, Recurrent Acute Leukemia, Recurrent T Acute Lymphoblastic Leukemia, Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Recurrent Hematologic Malignancy, Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Systemic mastocytosis, Refractory Blastic Plasmacytoid Dendritic Cell Neoplasm, Refractory Hematologic Malignancy, Refractory T Acute Lymphoblastic Leukemia, Refractory Hairy Cell Leukemia, Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm, Recurrent Hairy Cell Leukemia, Recurrent B Acute Lymphoblastic Leukemia
Treatment Dexamethasone, ibuprofen, Acetaminophen, Diphenhydramine, Ranitidine, Flotetuzumab
Clinical Study IdentifierNCT04681105
SponsorCity of Hope Medical Center
Last Modified on14 November 2021


Yes No Not Sure

Inclusion Criteria

Documented informed consent of the participant and/or legally authorized representative
Assent, when appropriate, will be obtained per institutional guidelines
Agreement to allow the use of archival tissue from diagnostic tumor biopsies
If unavailable, exceptions may be granted with study principal investigator (PI) approval
Eastern Cooperative Oncology Group (ECOG) =< 2
Histologically confirmed diagnosis of
Cohort A. Acute lymphoblastic leukemia
B-cell phenotype: patients with relapsed or refractory ALL who have received at least 2 prior regimens and failed or are ineligible for CD19-based targeted therapy
T-cell phenotype: patients with relapsed or refractory who have received at least 1 prior regimen
Cohort B. Other CD123+ hematological malignancies that failed standard regimens, excluding acute myeloid leukemia and myelodysplastic syndrome
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) patients who have failed or relapsed after initial therapy
Chronic myelocytic leukemia (CML) patients who have failed or relapsed or ineligible for third generation tyrosine kinase inhibitor (ponatinib)
Hairy cell leukemia patients who have failed or progressed shortly after purine analogs or failed 2 cycles of purine analog
Systemic mastocytosis patients who have failed or progressed on midostaurin
Hodgkin lymphoma patients who have failed or relapsed after PD-1/PD-L1- inhibitors and brentuximab vedotin
Advanced acute leukemia patients with ambiguous lineage or biphenotypic leukemia that failed 2 lines of prior regimens
Patients with any other advanced CD123+ hematological malignancy who have failed standard therapy per the treating physician's judgement
Relapsed or refractory disease as defined above
Tumor expressing CD123 either by flow cytometry or immunohistochemistry staining
Measurable disease of at least 1.5 cm on computed tomography (CT)/magnetic resonance imaging (MRI) for cases without bone marrow involvement
Peripheral blast count < 20,000/ul at the time of initiation of infusion on Cycle 1 Day 1
Life expectancy of at least 4 weeks
Fully recovered from the acute toxic effects (except alopecia) to =< grade 1 to prior anti-cancer therapy
Absolute neutrophil count (ANC) >= 1000/ul (without bone marrow involvement, performed within 14 days prior to day 1 of protocol therapy)
Platelets >= 75,000/ul (without bone marrow involvement, performed within 14 days prior to day 1 of protocol therapy)
Lumbar puncture to assess presence of central nervous system (CNS) disease if there are symptoms and signs concerning for CNS involvement (performed within 14 days prior to day 1 of protocol therapy)
Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease) (performed within 14 days prior to day 1 of protocol therapy)
Aspartate aminotransferase (AST) =< 2.5 x ULN (performed within 14 days prior to day 1 of protocol therapy)
Alanine aminotransferase (ALT) =< 2.5 x ULN (performed within 14 days prior to day 1 of protocol therapy)
Left ventricular ejection fraction (LVEF) >= 50%. Note: To be performed within 28 days prior to day 1 of protocol therapy
Corrected QT (QTc) =< 480 ms. Note: To be performed within 28 days prior to day 1 of protocol therapy
If able to perform pulmonary function tests: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and DLCO (diffusion capacity) >= 50% of predicted (corrected for hemoglobin). If unable to perform pulmonary function tests: oxygen (O2) saturation > 90% on room air. Note To be performed within 28 days prior to day 1 of protocol therapy
Calculated or measured creatinine clearance of > 50 ml/min (performed within 14 days prior to Day 1 of protocol therapy)
Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (performed within 14 days prior to day 1 of protocol therapy)
Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy
Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria

Autologous or allogeneic hematopoietic cell transplant performed within 100 days prior to study drug administration in Day 1 of Cycle 1 of protocol therapy
However, patients who received allogeneic hematopoietic cell transplantation (HCT) more than 100 days are allowed if no active graft versus host disease (GVHD) > grade 1, not actively on systemic immunosuppressive therapy and off calcineurin inhibitors for at least 4 weeks prior to start therapy
Chemotherapy, radiation therapy, biological therapy, within 14 days prior to Day 1 of protocol therapy. Maintenance-type ALL chemotherapies, including vincristine and mercaptopurine are allowed up to 7 days before starting therapy. High dose steroids are allowed up to 3 days before starting therapy. Cytoreduction with hydroxyurea is allowed to control leukocytosis until to the day of starting therapy. Hydroxyurea can be given during cycle 1 of flotetuzumab administration to control leukocytosis but need to be discussed with the study PI
Previous treatment with immunotherapeutic agents (for example chimeric antigen receptor [CAR] T cells, long acting bispecific antibodies, etc) in the 28 days period prior to study drug administration on Day 1 Cycle 1, with the exception of short-half bispecific antibodies (blinatumomab) where the washout period is only 14 days
Requirement, at the time of study entry, for concurrent steroid > 10 mg/day of oral prednisone or the equivalent, except steroid inhaler, nasal spray or ophthalmic solution
Use of immunosuppressant medications (other than steroid as noted above) in the 2 weeks prior to study drug administration (Cycle 1 Day 1)
Known central nervous system involvement. Patients with suspected CNS involvement must be evaluated by lumbar puncture and be free of CNS disease prior to study entry. Previously treated CNS involvement is allowed provided adequate treatment has been provided and the patient is free of CNS disease
History of allergic reactions attributed to compounds of similar chemical or biologic composition to flotetuzumab
Any active untreated autoimmune disorders (with the exception of vitiligo)
Dementia or altered mental status that would preclude sufficient understanding to provide informed consent
Second primary malignancy that requires active therapy. Adjuvant hormonal therapy is allowed
Active uncontrolled infection
Significant pulmonary compromise
Unstable angina or clinically significant heart disease (left ventricular ejection fraction < 50%)
Major trauma or surgery within 4 weeks before enrollment
Clinically significant uncontrolled illness
Females only: Pregnant or breastfeeding
Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
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