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Trial to Evaluate the Safety and Efficacy of MB-102 in Patients With BPDCN, AML, and hrMDS.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04109482
Recruitment Status : Not yet recruiting
First Posted : September 30, 2019
Last Update Posted : October 1, 2019
Sponsor:
Information provided by (Responsible Party):
Mustang Bio

Brief Summary:
A phase 1/2 study to assess the safety and efficacy of MB-102 in patients with relapsed or refractory BPDCN, AML or high-risk MDS.

Condition or disease Intervention/treatment Phase
Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Acute Myeloid Leukemia Relapsed or Refractory HRMDS Biological: MB-102 Drug: Decitabine Drug: Fludarabine Drug: Cyclophosphamide Phase 1 Phase 2

Detailed Description:

The Phase 1 portion of the study will determine the maximum tolerated dose of MB-102.

The Phase 2 portion of the trial is divided into three arms to evaluate the efficacy of MB-102 in relapsed or refractory BPDCN (Arm 1), relapsed or refractory AML (Arm 2) and demethylation resistant high-risk MDS (Arm 3).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 126 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2, Open Label, Multicenter Trial to Assess the Safety and Efficacy of MB-102 in Patients With Relapsed or Refractory Blastic Plasmacytoid Dendritic Cell Neoplasm, Acute Myeloid Leukemia, and High Risk Myelodysplastic Syndrome
Estimated Study Start Date : October 16, 2019
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : April 2026


Arm Intervention/treatment
Experimental: Relapsed or Refractory BPDCN
Treatment with MB-102.
Biological: MB-102

The study drug, MB-102 consists of adoptively transferred T cells that are genetically modified using a self-inactivating (SIN) lentiviral vector to express a CD123-specific, CD28-costimulatory chimeric antigen receptor (CAR) as well as a truncated human epidermal growth factor receptor (EGFRt) (CD123.CD28.CD3ζ.EGFRt+T cells) derived from autologous leukapheresis which is administered after a lymphodepletion regimen.

Single dose of MB-102 up to 600 x 10 6 CART-T+ cells (Day 0) as defined by Phase 1.

Other Name: CD123 CAR-T

Drug: Decitabine
Decitabine will be administered at Visit 4 (Day -7) through Visit 8 (Day -3) at 20mg/m2 per day.
Other Name: Dacogen

Drug: Fludarabine

Fludarabine 30 mg/m2/day IV (3 days) on days -5, -4, and -3

  • A 20% dose reduction (24 mg/m2/day IV (3 days) on days -5, -4, and -3) is required for patients with moderately impaired renal function (creatine clearance ≤ 70 mL/min).
Other Name: Fludara

Drug: Cyclophosphamide
Cyclophosphamide 300 - 500 mg/m2/day IV (3 days) on days -5, -4, and -3
Other Name: Cytoxan

Experimental: Relapsed or Refractory AML
Treatment with MB-102.
Biological: MB-102

The study drug, MB-102 consists of adoptively transferred T cells that are genetically modified using a self-inactivating (SIN) lentiviral vector to express a CD123-specific, CD28-costimulatory chimeric antigen receptor (CAR) as well as a truncated human epidermal growth factor receptor (EGFRt) (CD123.CD28.CD3ζ.EGFRt+T cells) derived from autologous leukapheresis which is administered after a lymphodepletion regimen.

Single dose of MB-102 up to 600 x 10 6 CART-T+ cells (Day 0) as defined by Phase 1.

Other Name: CD123 CAR-T

Drug: Decitabine
Decitabine will be administered at Visit 4 (Day -7) through Visit 8 (Day -3) at 20mg/m2 per day.
Other Name: Dacogen

Drug: Fludarabine

Fludarabine 30 mg/m2/day IV (3 days) on days -5, -4, and -3

  • A 20% dose reduction (24 mg/m2/day IV (3 days) on days -5, -4, and -3) is required for patients with moderately impaired renal function (creatine clearance ≤ 70 mL/min).
Other Name: Fludara

Drug: Cyclophosphamide
Cyclophosphamide 300 - 500 mg/m2/day IV (3 days) on days -5, -4, and -3
Other Name: Cytoxan

Experimental: Demethylation resistant high risk MDS
Treatment with MB-102.
Biological: MB-102

The study drug, MB-102 consists of adoptively transferred T cells that are genetically modified using a self-inactivating (SIN) lentiviral vector to express a CD123-specific, CD28-costimulatory chimeric antigen receptor (CAR) as well as a truncated human epidermal growth factor receptor (EGFRt) (CD123.CD28.CD3ζ.EGFRt+T cells) derived from autologous leukapheresis which is administered after a lymphodepletion regimen.

Single dose of MB-102 up to 600 x 10 6 CART-T+ cells (Day 0) as defined by Phase 1.

Other Name: CD123 CAR-T

Drug: Decitabine
Decitabine will be administered at Visit 4 (Day -7) through Visit 8 (Day -3) at 20mg/m2 per day.
Other Name: Dacogen

Drug: Fludarabine

Fludarabine 30 mg/m2/day IV (3 days) on days -5, -4, and -3

  • A 20% dose reduction (24 mg/m2/day IV (3 days) on days -5, -4, and -3) is required for patients with moderately impaired renal function (creatine clearance ≤ 70 mL/min).
Other Name: Fludara

Drug: Cyclophosphamide
Cyclophosphamide 300 - 500 mg/m2/day IV (3 days) on days -5, -4, and -3
Other Name: Cytoxan




Primary Outcome Measures :
  1. Safety and Tolerability as measured by the number of patients with treatment related adverse events [ Time Frame: 28 Days ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 in Phase 1

  2. Maximum Tolerated Dose (MTD) and recommended Phase 2 dose [ Time Frame: 28 Days ]
    To determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose of MB-102

  3. Response Rate of patients with BPDCN [ Time Frame: 28 days ]
    Relapsed or refractory Blastic Plasmacytoid Dendritic Cell Neoplasm is measured by a response rate which consists of Complete Response and clinical Complete Response and Complete Response with incomplete hematologic recovery (CR + CRc + CRi) at day 28 post infusion

  4. Response Rate of patients with AML [ Time Frame: 28 Days ]
    Relapsed or refractory Acute Myeloid Leukemia is measured by response rate which consist of Complete Response and Complete Response with incomplete hematologic recovery (CR + CRi) at day 28 post infusion.

  5. Response Rate of patients with high risk MDS [ Time Frame: 28 days ]
    Demethylation resistant High Risk Myelodysplastic Syndrome is measured by response rate which consists of Complete Remission, Partial Remission and marrow Complete Remission (CR + PR + mCR) at day 28 post infusion


Secondary Outcome Measures :
  1. BPDCN - DOR [ Time Frame: up to 3 years ]
    Duration of Response

  2. BPDCN - PFS [ Time Frame: up to 3 years ]
    Progression-Free Survival

  3. BPDCN - OS [ Time Frame: up to 3 years ]
    overall survival

  4. BPDCN - MRD [ Time Frame: up to 3 years ]
    CR MRD- Response Rate for patients with CR and CRi

  5. AML - DOR [ Time Frame: up to 3 years ]
    Duration of Response

  6. AML - EFS [ Time Frame: up to 3 years ]
    Event-Free Survival

  7. AML - RFS [ Time Frame: up to 3 years ]
    Relapse-Free Survival

  8. AML - OS [ Time Frame: up to 3 years ]
    Overall Survival

  9. AML - MRD [ Time Frame: up to 3 years ]
    CR MRD- Response Rate for patients with CR and CRi

  10. high risk MDS - Rate of patients with Hematologic Improvement [ Time Frame: up to 3 years ]
    Rate of patients achieving Hematologic Improvement in either erythroid, neutrophil or platelet responses.

  11. high risk MDS - Clinical Benefit Rate [ Time Frame: up to 3 years ]
    Clinical benefit rate (CR + PR + HI+ marrow CR)

  12. high risk MDS - Rate of cytogenetic CR [ Time Frame: up to 3 years ]
    Rate of cytogenetic CR

  13. high risk MDS - DOR [ Time Frame: up to 3 years ]
    Duration of Response

  14. high risk MDS - TI [ Time Frame: up to 3 years ]
    Transfusion independence

  15. high risk MDS - Rate of Leukemic Trasformation [ Time Frame: up to 3 years ]
    Rate of leukemic transformation

  16. high risk MDS - EFS [ Time Frame: up to 3 years ]
    Event-Free Survival

  17. high risk MDS - RFS [ Time Frame: up to 3 years ]
    Relapse-Free Survival

  18. high risk MDS - OS [ Time Frame: up to 3 years ]
    overall survival

  19. high risk MDS - PFS [ Time Frame: up to 3 years ]
    Progression-Free Survival

  20. high risk MDS - MRD [ Time Frame: up to 3 years ]
    CR MRD- Response Rate for patients with CR or mCR

  21. Phase 2 - Adverse events [ Time Frame: up to 3 years ]
    Incidence of treatment-emergent AEs (TEAEs), including SAEs, therapy-related AEs or death.

  22. Phase 2 -Change from Baseline in the European Organization for Research and Treatment (EORTC) QLQ-C 30 Version 3.0. [ Time Frame: up to 3 years ]

    The European Organization for Research and Treatment (EORTC) QLQ-C 30 Version 3.0 is an integrated, modular approach for evaluating the quality of life of patients participating in international clinical trials. The questionnaire is designed to measure cancer patients' physical, psychological and social functions. The questionnaire is composed of 5 multi-item scales (physical, role, social, emotional and cognitive functioning) and 9 single items (pain, fatigue, financial impact, appetite loss, nausea/vomiting, diarrhea, constipation, sleep disturbance and quality of life).

    It utilizes a four-point scales for the first 28 questions which are coded with response categories as "Not at all", "A little", "Quite a bit" and "Very much.". the final two question consist of an overall physical condition questions which have employed a 7-point response scale where the higher number indicates a better overall health.


  23. Phase 2 - Change from Baseline in the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Version 4.0. [ Time Frame: up to 3 years ]

    The Functional Assessment of Cancer treatment for cancer, and a transplant-specific module, bone marrow transplant (BMT) concerns, that addresses disease and treatment-related questions specific to BMT.

    It utilizes a 5 point scale assessing physical, social, emotional, functional and other well-being concerns. Response categories are coded as "Not at all", "A little bit", "Somewhat", "Quite a bit" and "Very much.".


  24. Phase 2 - Change from Baseline in the The Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) Version 4.0 [ Time Frame: up to 3 years ]

    The Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) Version 4.0 is a modular approach to assess patient HQL and leukemia-specific symptoms using a core set of questions as well as a cancer site-specific leukemia subscale.

    It utilizes a 5 point scale assessing physical, social, emotional, functional and other well-being concerns. Response categories are coded as "Not at all", "A little bit", "Somewhat", "Quite a bit" and "Very much.".


  25. Phase 2 - Number of patients showing evidence of replication competent lentivirus [ Time Frame: up to 1 year ]
    To confirm the absence of replication competent lentivirus



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Blastic Plasmacytoid Dendritic Cell Neoplasm

  1. Patients with a diagnosis of BPDCN according to WHO classification (Arber et al., 2016) confirmed by hematopathology and histological/cytological evidence of BPDCN in the peripheral blood, bone marrow, spleen, lymph nodes, skin and/or other sites who have failed one prior therapy.

    Acute Myeloid Leukemia

  2. Must have pathologically confirmed diagnosis of relapsed or refractory AML with early relapse (less than 6 months after initial therapy).

    High Risk Myelodysplastic Syndrome

  3. Patients with a diagnosis of high or very high-risk MDS (herein called hrMDS) according to IPSS-R classification (Greenberg et al., 2012) who are resistant or refractory to at least one course of therapy including demethylating agents (decitabine or 5-azacitidine).

    General Inclusion Criteria

  4. Male and female patients ≥ 18 years of age at the time of consent.
  5. Written informed consent in accordance with federal, local, and institutional guidelines.
  6. Must be able to adhere to the study visit schedule and other protocol requirements.
  7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  8. Meet the following laboratory criteria:

    • Absolute lymphocyte count (ALC) > 100/mm3
    • ALT/SGPT and AST/SGOT < 2.5x the upper limit of normal (ULN) unless due to underlying disease state
    • Calculated creatinine clearance ≥ 45.0 mL/min as estimated by Cockcroft Gault and dialysis independent
    • Total bilirubin ≤ 3.0 mg/dL

      • Patients with Gilbert's Syndrome must have a total bilirubin < 5.0 mg/dL.
  9. Cardiac ejection fraction ≥ 45%, with no evidence of pericardial effusion as determined by an echocardiogram (ECHO) or if not available, a multigated acquisition scan (MUGA).
  10. Females participants of childbearing potential must have a negative serum test.
  11. Patients must agree to use a highly effective method of contraception if procreative potential exists from the start of the study until one year after the completion of lymphodepletion for females and 4 months after completion of lymphodepletion for males.
  12. Patients with a previously treated malignancy if treatment of that malignancy was completed greater than 2 years before screening and the patient has no evidence of disease at the time of screening.
  13. Patients who have previously undergone allogenic or autologous bone marrow transplants are allowed.
  14. Confirmed CD-123 positivity on the bone marrow.

Exclusion Criteria:

  1. Patients with a corticosteroid dependence on doses greater than physiological replacement i.e., prednisone no more than 7.5 mg/day or hydrocortisone less than 12mg/m2/day.
  2. Contraindication or hypersensitivity to decitabine, fludarabine, cyclophosphamide.
  3. Hypersensitivity or known history of allergic reactions attributed to Cetuximab or other anti-EGFR -monoclonal antibodies.
  4. Immunotherapy treatments within 28 days prior to screening.
  5. Previous treatment with anti-CD123 CAR-T treatment.

    • Previous treatment with non-CAR-T anti-CD123 agents is allowed e.g. SL-401.
  6. Previous treatment with any other antileukemic or investigational agent within 14 days of leukapheresis.

    • Hydroxyurea is allowed up to 3 days prior to leukapheresis.
  7. Patients with history or active seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease or any autoimmune disease with CNS involvement.
  8. Patients with known CNS leukemic involvement that are refractory to intrathecal chemotherapy and/or cranio-spinal radiation that have NOT been effectively treated to complete remission (defined as < 5 WBC/mm3 and no blasts in CSF).
  9. Patients with active Graft versus Host Disease (GVHD).
  10. Acute active infection requiring systemic treatment within 14 days prior to leukapheresis.

    • Patients being administered prophylactic antibiotics, antivirals, or antifungals are permitted.
  11. Patients who have any form of primary immunodeficiency, such as severe combined immunodeficiency disease, human immunodeficiency virus (HIV), or acquired immune deficiency syndrome (AIDS).
  12. History or active infection with hepatitis B or C.
  13. Patients requiring supplemental oxygen or mechanical ventilation or oxygen saturation < 92% on room air.

    • Patients with an oxygen saturation < 92%, a pulmonary function test with a result of Diffusing capacity of the lungs for carbon monoxide (DLCO) and a forced expiratory volume in one second (FEV1) > 45% predicted will be accepted.
  14. Patients with hepatic cirrhosis.
  15. Pregnant or lactating females.
  16. Any other clinically significant medical disease or condition that, in the investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent.
  17. Patients diagnosed with Acute Promyelocytic Leukemia

    • Patients who are relapsed or refractory and have previously been treated with anthracycline and/or arsenic trioxide may be allowed to enter the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04109482


Contacts
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Contact: Mark Awadalla 781-693-9087 mawadalla@mustangbio.com

Locations
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United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
Contact: Lihua E Budde, MD    626-218-1133    ebudde@coh.org   
Sponsors and Collaborators
Mustang Bio
Investigators
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Principal Investigator: Lihua E Budde, MD City of Hope Medical Center

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Responsible Party: Mustang Bio
ClinicalTrials.gov Identifier: NCT04109482    
Other Study ID Numbers: MB102-CD123-001
First Posted: September 30, 2019    Key Record Dates
Last Update Posted: October 1, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Mustang Bio:
CD123 CAR-T
AML
BPDCN
high risk MDS
blastic plasmacytoid dendridic cell neoplasm
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Neoplasms by Histologic Type
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Decitabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Enzyme Inhibitors