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Venetoclax, Azacitidine, and Lintuzumab-Ac225 in AML Patients

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ClinicalTrials.gov Identifier: NCT03932318
Recruitment Status : Not yet recruiting
First Posted : April 30, 2019
Last Update Posted : April 30, 2019
Sponsor:
Information provided by (Responsible Party):
Actinium Pharmaceuticals

Brief Summary:

The study is a multicenter, open label Phase I/II trial.

  1. To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 when given in combination with venetoclax and azacitidine for patients with CD33 positive AML. (Phase I portion)
  2. To assess the percentage of patients with CR, CRh, CRi, MLFS or Overall Response (CR + CRh + CRi + MLFS), up to 6 months after the start of treatment without receiving other AML therapies.. (Phase 2 portion)

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Relapsed Adult AML Biological: Lintuzumab-Ac225 Drug: Venetoclax Drug: Azacitidine Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Venetoclax and Azacitidine and Lintuzumab-Ac225 in Patients With Refractory or Relapsed AML
Estimated Study Start Date : July 2019
Estimated Primary Completion Date : January 2021
Estimated Study Completion Date : January 2023


Arm Intervention/treatment
Experimental: Phase I and Phase II

Lintuzumab-Ac225 will be administered on Day 8 of each cycle for four cycles (unless in the 0.5 μCi/kg or 0.25 μCi/kg cohorts, where there is a potential for an additional four cycles, pending PI and Medical Monitor review).

Venetoclax will be taken on Days 1-21 of each cycle for up to 12 cycles.

Azacitidine will be administered on Days 1-7 of each cycle for up to 12 cycles.

Each cycle is 28 days, with a potential to expand to 42 days to allow for full hematologic recovery.

Biological: Lintuzumab-Ac225
In the Phase I, patients will be enrolled into the following dose escalation cohorts: 0.50 μCi/kg, 1.0 μCi/kg, and 1.5 μCi/kg. If the 0.50 μCi/kg dose is determined to exceed the MTD, a 0.25 μCi/kg dose will be explored.
Other Name: Actimab

Drug: Venetoclax
400 mg daily will be taken orally on Days 1-21 of a 28-day cycle. There will be a ramp up of venetoclax dosing in the first cycle, with 100 mg administered on Day 1, 200 mg on Day 2, and 400 mg on Day 3 and Day 4 and later. Patients on antifungal azoles should receive one-half these doses, up to a maximum of 200 mg of venetoclax.
Other Name: Venclexta

Drug: Azacitidine
75 mg/m2 will be administered on days 1-7 of a 28-day cycle.
Other Name: Vidaza




Primary Outcome Measures :
  1. Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225 [ Time Frame: Cycle 1, up to 48 days ]
    To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 when given in combination with venetoclax and azacitidine for patients with CD33 positive AML

  2. Phase II: Overall Response (CR + CRh + CRi + MLFS) [ Time Frame: Up to 6 months ]
    To assess the percentage of patients achieving CR, CRh, CRi, morphologic leukemia-free state (MLFS), or Overall Response (CR + CRh + CRi + MLFS), up to 6 months after the start of treatment without receiving other AML therapies


Secondary Outcome Measures :
  1. Phase I: Overall Response [ Time Frame: Up to 6 months ]
    Number of patients who's overall response is CR or CRh or CRi or MLFS

  2. Phase I: OS [ Time Frame: Phase I: End of 6 months, 12 months, 24 months. ]
    Number of patients who died

  3. Phase II: OS [ Time Frame: Phase II: End of 6 months, 12 months, 24 months ]
    Number of patients who died

  4. Phase I and II: DFS [ Time Frame: Through study completion, up to 2 years ]
    Disease-free survival

  5. Phase I and II: Evaluate incidence of AEs and SAEs [ Time Frame: Through study completion, up to 2 years ]
    Rate of AEs and SAEs, including infusion-related reactions

  6. Phase I and II: Lab abnormalities (other than hematologic indices) [ Time Frame: Through study completion, up to 2 years ]
    Summary of rate of Grade 3/4 lab abnormalities

  7. Phase I and II: Evaluate BH3 priming assay results [ Time Frame: Completion of Cycle 1, estimated 1 month ]
    Summary of assay results

  8. Phase I and II: MRD status [ Time Frame: From date of first dose until the date of first documented response, first assessment at 6 months ]
    Number of patients who are MRD negative



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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:

  1. Histologically confirmed acute myeloid leukemia
  2. Refractory or relapsed AML which will include:

    1. Refractory disease will be defined as at least 1 prior treatment with no remission.
    2. Relapsed disease will be defined as 5% or more blasts in bone marrow seen after remission.
    3. Patients with AML arising from myelodysplastic syndromes (including CMML) or myeloproliferative neoplasms (secondary AML, ts-AML) are also eligible.
  3. White blood cell (WBC) count < 10 x 109/L;

    a. Use of hydroxyurea, prior to Cycle 1 and during Cycles 1 and 2, is permitted to lower the WBC count in the peripheral blood.

  4. Age > 18 years.
  5. Estimated creatinine clearance ≥ 50 mL/min calculated by the Cockroft-Gault formula.
  6. AST and ALT ≤ 3.0 x ULN (unless considered to be due to leukemic organ involvement).
  7. Bilirubin ≤ 3.0 x ULN (unless considered to be due to leukemic organ involvement).
  8. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.

Exclusion Criteria:

  1. Have acute promyelocytic leukemia (APL).
  2. Active CNS leukemia. Patients with symptoms of CNS involvement, particularly those with M4 or M5 subtypes, should undergo lumbar puncture prior to treatment on study to exclude CNS disease. Symptoms include cranial neuropathies, other neurologic deficits, and headache.
  3. Have received prior radiation to maximally tolerated levels to any critical normal organ.
  4. Participant has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment.
  5. Clinically significant cardiac disease.
  6. Active, uncontrolled serious infection.
  7. Have other non-myeloid malignancy within 2 years of entry (with exceptions).
  8. Psychiatric disorder that would preclude study participation
  9. Previous solid organ transplant (prior treatment with SCT is allowed but not if patient as GVHD or is still receiving immunosuppression/GVHD therapy).

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): NCT03932318


Contacts
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Contact: Actinium Pharmaceuticals, Inc. +1-646-677-3878 actimab@actiniumpharma.com

Sponsors and Collaborators
Actinium Pharmaceuticals

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Responsible Party: Actinium Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03932318     History of Changes
Other Study ID Numbers: LIN-AC225-AML03
First Posted: April 30, 2019    Key Record Dates
Last Update Posted: April 30, 2019
Last Verified: April 2019

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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 Actinium Pharmaceuticals:
Lintuzumab-Ac225
Venetoclax
Azacitidine
Lintuzumab
Refractory AML

Additional relevant MeSH terms:
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Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Neoplasms
Azacitidine
Venetoclax
Lintuzumab
Antibodies, Monoclonal
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Antineoplastic Agents, Immunological
Immunologic Factors
Physiological Effects of Drugs