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Talazoparib and Gemtuzumab Ozogamicin for the Treatment of CD33 Positive Relapsed or Refractory Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT04207190
Recruitment Status : Not yet recruiting
First Posted : December 20, 2019
Last Update Posted : March 13, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:
This phase I/Ib trial studies the side effects and best dose of talazoparib given together with gemtuzumab ozogamicin and to see how well they work in treating patients with CD33 positive acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). Talazoparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Gemtuzumab ozogamicin is a protein (antibody) combined with a chemotherapy drug which specifically targets acute myeloid leukemia cells expressing a marker (CD33). Adding talazoparib to the gemtuzumab ozogamicin therapy may lead to an increased effectiveness in treatment.

Condition or disease Intervention/treatment Phase
Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Gemtuzumab Ozogamicin Other: Quality-of-Life Assessment Other: Questionnaire Administration Drug: Talazoparib Drug: Talazoparib Tosylate Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of talazoparib given in combination with gemtuzumab ozogamicin therapy in adult patients with relapsed and/or refractory acute myeloid leukemia (AML).

II. Determine the overall response rate (ORR consisting of complete remission [CR] or complete remission with incomplete hematologic recovery [CRi]) of combination therapy with talazoparib and gemtuzumab ozogamicin in patients with relapsed and/or refractory AML.

SECONDARY OBJECTIVE:

I. Evaluate the preliminary anti-leukemic efficacy of talazoparib given in combination with gemtuzumab ozogamicin as determined by complete remission (CR) rate, best response rate (CRi + partial remission [PR]), duration of remission, leukemia-free survival (LFS), transfusion independence (TI), and overall survival (OS) in patients treated with this combination therapy.

EXPLORATORY OBJECTIVES:

I. Evaluate the efficacy of talazoparib given in combination with gemtuzumab ozogamicin on minimal residual disease (MRD) in treated patients.

II. Evaluate mechanistic biomarkers including levels of PARP inhibition and deoxyribonucleic acid (DNA) damage effects in peripheral blood and marrow samples from patients treated with combination therapy.

III. Evaluate quality of life (QOL) of patients with relapsed/refractory AML treated with talazoparib and gemtuzumab ozogamicin.

IV. Evaluate the number of patients able to proceed onto subsequent hematopoietic stem cell transplantation (HSCT) following combination therapy.

OUTLINE: This is a dose-escalation study of talazoparib.

Patients receive talazoparib orally (PO) daily on days 1-28 and gemtuzumab ozogamicin intravenously (IV) over 2 hours on days 1, 4, and 7 or day 1 for patients who CR/CRi after cycles 1 or 2. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 3 months for up to 12 months.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/1b Trial of Talazoparib and Gemtuzumab Ozogamicin in Adult Patients With Relapsed and/or Refractory Acute Myeloid Leukemia
Estimated Study Start Date : April 1, 2020
Estimated Primary Completion Date : February 1, 2022
Estimated Study Completion Date : February 1, 2023


Arm Intervention/treatment
Experimental: Treatment (talazoparib, gemtuzumab ozogamicin)
Patients receive talazoparib PO daily on days 1-28 and gemtuzumab ozogamicin IV over 2 hours on days 1, 4, and 7 or day 1 for patients who CR/CRi after cycles 1 or 2. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Gemtuzumab Ozogamicin
Given IV
Other Names:
  • Calicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody
  • CDP-771
  • CMA-676
  • gemtuzumab
  • hP67.6-Calicheamicin
  • Mylotarg
  • WAY-CMA-676

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Drug: Talazoparib
Given PO
Other Names:
  • BMN 673
  • BMN-673

Drug: Talazoparib Tosylate
Given PO
Other Name: Talzenna




Primary Outcome Measures :
  1. Maximum tolerated dose [ Time Frame: Up to 28 days ]
    Will identify the maximum tolerated dose of talazoparib in combination with gemtuzumab ozogamicin. The maximum dose level where 1 or fewer dose limiting toxicities (DLTs) are observed in 6 patients will be defined as the recommended phase 2 dose.

  2. Overall response rate (ORR) [ Time Frame: Up to 12 months post treatment ]
    ORR will consist of complete remission (CR), complete remission with incomplete hematologic recovery (CRi) of combination therapy with talazoparib and gemtuzumab ozogamicin. Will be estimated by a 90% confidence interval obtained by Jeffrey's prior method.


Secondary Outcome Measures :
  1. Complete remission rate [ Time Frame: Up to 12 months post treatment ]
    The complete remission will be estimated with 90% confidence intervals obtained by Jeffrey's prior method.

  2. Best response rate [ Time Frame: Up to 12 months post treatment ]
    Best response rate will consist of CRi and partial remission (PR).

  3. Duration of remission [ Time Frame: Up to 12 months post treatment ]
    Duration of response will be estimated using standard Kaplan-Meier methods, where estimates of the median will be obtained with 90% confidence intervals.

  4. Leukemia-free survival (LFS) [ Time Frame: Up to 12 months post treatment ]
    LFS will be estimated using standard Kaplan-Meier methods, where estimates of the median will be obtained with 90% confidence intervals.

  5. Transfusion independence rate [ Time Frame: Up to 12 months post treatment ]
    Transfusion independence rate will be estimated with 90% confidence intervals obtained by Jeffrey's prior method.

  6. Hematopoietic stem cell transplantation (HSCT) rates [ Time Frame: Up to 12 months post treatment ]
    HSCT will be estimated with 90% confidence intervals obtained by Jeffrey's prior method.

  7. Overall survival (OS) [ Time Frame: Up to 12 months post treatment ]
    OS will be estimated using standard Kaplan-Meier methods, where estimates of the median will be obtained with 90% confidence intervals.

  8. Incidence of adverse events (AEs) [ Time Frame: Up to 30 days post treatment ]
    The observed AEs, serious AEs (SAEs), DLTs, and toxicities will be summarized by dose level and grade using frequencies and relative frequencies. AEs, SAEs, DLTs, and toxicity rates will be estimated with 90% confidence intervals obtained using Jeffrey's prior method.



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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:

  • Eastern Cooperative Oncology Group performance status between 0-2
  • Creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine clearance (Cockcroft and Gault ) > 30 mL/min (performed on plasma unless otherwise indicated)
  • Alanine aminotransferase (ALT) =< 2.5 x ULN (performed on plasma unless otherwise indicated)
  • Direct bilirubin < 1.5 mg/dL (performed on plasma unless otherwise indicated)
  • Left ventricular ejection fraction (LVEF) >= 40% as assessed by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan performed within 28 days of enrollment
  • Diagnosis of CD33+ acute myeloid leukemia (AML) with evidence of >= 5% myeloblasts in the bone marrow, peripheral blood, or in an extramedullary site by pathology. Any CD33 receptor expression level > 0.01% by institute flow cytometric analysis will suffice
  • Relapsed or refractory disease, defined as:

    • Any bone marrow relapse after allogeneic HSCT: subjects must be at least 1 month from HSCT at the time of screening and off immunosuppressive medication for at least 2 weeks at time of initial treatment (with the exception of low-dose steroids =< 20 mg prednisone equivalent) and have no active graft versus (vs.) host disease (GVHD)
    • AML with no prior CR/CRi after at least 1 prior cycle of remission induction chemotherapy (i.e. cytarabine or hypomethylating based regimen(s) allowed)
    • AML recurring after prior CR/CRi, which was achieved following at least one prior chemotherapy cycle (i.e. cytarabine or hypomethylating based regimen(s) allowed)
  • Participants of childbearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

  • Acute promyelocytic leukemia (APL, FAB M3) with t(15-17) and/or evidence of promyelocytic leukemia/retinoic acid receptor alpha (PML-RAR alpha)
  • Blast phase of prior chronic phase chronic myeloid leukemia with t(9;22)
  • Receipt of chemotherapy, radiotherapy, or investigational drug therapy within 2 weeks prior to treatment on study or those who have not recovered from adverse events due to agents administered > 2 weeks earlier
  • Known active central nervous system involvement; patients who have a history of central nervous system (CNS) disease which has been effectively treated as defined by at least one negative cerebrospinal sample prior to screening are eligible
  • Active uncontrolled malignancy requiring ongoing chemotherapy and/or radiation. Examples of eligible patients include individuals with a prior history of malignancy treated with curative intent with no current evidence of active disease such as:

    • Subjects with stage I breast cancer that has been completely and successfully treated, requiring no therapy or only anti-hormonal therapy
    • Subjects with T1N0M0 or T2N0M0 colorectal cancer who have been completely and successfully resected and who are disease-free for > 2 years prior to screening
    • Subjects with indolent prostate cancer, defined as clinical stage T1 or T2a, Gleason score =< 6, and prostate specific antigen (PSA) < 10 ng/mL, requiring no therapy or only anti-hormonal therapy
    • Subjects with a history of basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix, fully resected, and with no evidence of active disease
    • Other prior or concurrent malignancies will be considered on a case-by-case basis after discussion with the principal investigator (PI)
  • Uncontrolled current medical illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction, cardiac arrhythmia, torsades de pointes, cerebrovascular accident, transient ischemic attack, or psychiatric illness/social situations that in the opinion of the investigator would limit compliance with study requirements
  • Known malabsorption syndrome or other condition that may impair the absorption of the study drug and/or inability and/or unwillingness to swallow tablets
  • Uncontrolled active systemic fungal, bacterial, viral, or other infection with patient still exhibiting ongoing signs and symptoms due to infection despite appropriate anti-infective therapy at time of screening
  • Pregnant or breastfeeding female participants
  • Known active hepatitis B, active hepatitis C, or any human immunodeficiency virus (HIV) infection at the time of screening which requires therapy
  • Presence of grade II-IV acute or extensive chronic GVHD at time of screening
  • Unwilling or unable to follow protocol requirements
  • Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug including, but not limited to, medical, psychological, familial, social or geographical considerations

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): NCT04207190


Locations
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United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Contact: Eunice S. Wang    716-845-3544    Eunice.wang@roswellpark.org   
Principal Investigator: Eunice S. Wang         
Sponsors and Collaborators
Roswell Park Cancer Institute
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Eunice S Wang Roswell Park Cancer Institute

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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT04207190    
Other Study ID Numbers: I 435819
NCI-2019-07826 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 435819 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
First Posted: December 20, 2019    Key Record Dates
Last Update Posted: March 13, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Gemtuzumab
Talazoparib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action