Clinical Trials /

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

NCT04207190

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Talazoparib and Gemtuzumab Ozogamicin for the Treatment of CD33 Positive Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: Phase 1/1b Trial of Talazoparib and Gemtuzumab Ozogamicin in Adult Patients With Relapsed and/or Refractory Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: I 435819
  • SECONDARY ID: NCI-2019-07826
  • SECONDARY ID: I 435819
  • SECONDARY ID: P30CA016056
  • NCT ID: NCT04207190

Conditions

  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Gemtuzumab OzogamicinCalicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody, CDP-771, CMA-676, gemtuzumab, hP67.6-Calicheamicin, Mylotarg, WAY-CMA-676Treatment (talazoparib, gemtuzumab ozogamicin)
TalazoparibBMN 673, BMN-673Treatment (talazoparib, gemtuzumab ozogamicin)
Talazoparib TosylateTalzennaTreatment (talazoparib, gemtuzumab ozogamicin)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (talazoparib, gemtuzumab ozogamicin)ExperimentalPatients 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.
  • Gemtuzumab Ozogamicin
  • Talazoparib
  • Talazoparib Tosylate

Eligibility 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) =< 5 x ULN (performed on plasma unless otherwise
             indicated)

          -  Direct bilirubin < 2.0 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose
Time Frame:Up to 28 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Complete remission rate
Time Frame:Up to 12 months post treatment
Safety Issue:
Description:The complete remission will be estimated with 90% confidence intervals obtained by Jeffrey's prior method.
Measure:Best response rate
Time Frame:Up to 12 months post treatment
Safety Issue:
Description:Best response rate will consist of CRi and partial remission (PR).
Measure:Duration of remission
Time Frame:Up to 12 months post treatment
Safety Issue:
Description:Duration of response will be estimated using standard Kaplan-Meier methods, where estimates of the median will be obtained with 90% confidence intervals.
Measure:Leukemia-free survival (LFS)
Time Frame:Up to 12 months post treatment
Safety Issue:
Description:LFS will be estimated using standard Kaplan-Meier methods, where estimates of the median will be obtained with 90% confidence intervals.
Measure:Transfusion independence rate
Time Frame:Up to 12 months post treatment
Safety Issue:
Description:Transfusion independence rate will be estimated with 90% confidence intervals obtained by Jeffrey's prior method.
Measure:Hematopoietic stem cell transplantation (HSCT) rates
Time Frame:Up to 12 months post treatment
Safety Issue:
Description:HSCT will be estimated with 90% confidence intervals obtained by Jeffrey's prior method.
Measure:Overall survival (OS)
Time Frame:Up to 12 months post treatment
Safety Issue:
Description:OS will be estimated using standard Kaplan-Meier methods, where estimates of the median will be obtained with 90% confidence intervals.
Measure:Incidence of adverse events (AEs)
Time Frame:Up to 30 days post treatment
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Roswell Park Cancer Institute

Last Updated

December 18, 2019