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Study of the Safety and Efficacy of Gemtuzumab Ozogamicin (GO) and Venetoclax in Patients With Relapsed or Refractory CD33+ Acute Myeloid Leukemia:Big Ten Cancer Research Consortium BTCRC-AML17-113

NCT04070768

Description:

This is a Phase Ib Study to determine the Maximum Tolerated Dose (MTD) of Venetoclax in combination with Gemtuzumab Ozogamicin(GO) in subjects with relapsed/refractory acute myeloid leukemia. Using a standard 3+3 design, subjects will receive once cycle of combination therapy. After one cycle of combination therapy, subjects showing response will continue on to one cycle of consolidation therapy with GO\Veneoclax. Subjects who respond to combination therapy will continue on maintenance Venetoclax until progression or unacceptable toxicity. Dose-limiting toxicity, defined as an adverse event related (possible, probably, or definite) to Venetoclax and/or Gemtuzumab fulfilling one of the following criteria: - Hematologic toxicity: treatment-related grade 4 or worse bone marrow hypocellularity present at the end of cycle one (day 28); specifically grade 4 cytopenias (anemia, neutropenia and/or thrombocytopenia) with the bone marrow documented to be free of leukemic infiltration. Note: patients who enter the study with grade 3 or worse cytopenias will not be evaluable for hematologic dose-limiting toxicities. - Non-hematologic toxicity: any grade 3 or worse treatment-related toxicity (excluding grade 4 infections during cycle one). The study will also evaluate the Overall Response Rate, Anti-leukemic activity, Relapse-free Survival (RFS), event-free survival (EFS) , and overall survival (OS). The study will evaluate quality of life using the European Organization for the Research and Treatment of Cancer 30 item questionnaire (EORTC QLQ-C30).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of the Safety and Efficacy of Gemtuzumab Ozogamicin (GO) and Venetoclax in Patients With Relapsed or Refractory CD33+ Acute Myeloid Leukemia:Big Ten Cancer Research Consortium BTCRC-AML17-113
  • Official Title: Phase Ib Study of the Safety and Efficacy of Gemtuzumab Ozogamicin (GO) and Venetoclax in Patients With Relapsed or Refractory CD33+ Acute Myeloid Leukemia:Big Ten Cancer Research Consortium BTCRC-AML17-113

Clinical Trial IDs

  • ORG STUDY ID: BTCRC-AML17-113
  • NCT ID: NCT04070768

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Gemtuzumab OzogamicinGOGemtuzumab Ozogamicin(GO) + Venetoclax
VenetoclaxGemtuzumab Ozogamicin(GO) + Venetoclax

Purpose

This is a Phase Ib Study to determine the Maximum Tolerated Dose (MTD) of Venetoclax in combination with Gemtuzumab Ozogamicin(GO) in subjects with relapsed/refractory acute myeloid leukemia. Using a standard 3+3 design, subjects will receive once cycle of combination therapy. After one cycle of combination therapy, subjects showing response will continue on to one cycle of consolidation therapy with GO\Veneoclax. Subjects who respond to combination therapy will continue on maintenance Venetoclax until progression or unacceptable toxicity. Dose-limiting toxicity, defined as an adverse event related (possible, probably, or definite) to Venetoclax and/or Gemtuzumab fulfilling one of the following criteria: - Hematologic toxicity: treatment-related grade 4 or worse bone marrow hypocellularity present at the end of cycle one (day 28); specifically grade 4 cytopenias (anemia, neutropenia and/or thrombocytopenia) with the bone marrow documented to be free of leukemic infiltration. Note: patients who enter the study with grade 3 or worse cytopenias will not be evaluable for hematologic dose-limiting toxicities. - Non-hematologic toxicity: any grade 3 or worse treatment-related toxicity (excluding grade 4 infections during cycle one). The study will also evaluate the Overall Response Rate, Anti-leukemic activity, Relapse-free Survival (RFS), event-free survival (EFS) , and overall survival (OS). The study will evaluate quality of life using the European Organization for the Research and Treatment of Cancer 30 item questionnaire (EORTC QLQ-C30).

Trial Arms

NameTypeDescriptionInterventions
Gemtuzumab Ozogamicin(GO) + VenetoclaxExperimentalGemtuzumab Ozogamicin(GO) + Venetoclax
  • Gemtuzumab Ozogamicin
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent and HIPAA authorization for release of personal health
             information. NOTE: HIPAA authorization may be included in the informed consent or
             obtained separately.

          -  Ages 18 to 75 years at the time of consent.

          -  ECOG Performance Status of 0-2 within 7 days prior to registration.

          -  Patients must have AML, as defined,28 that is relapsed or refractory. Prior therapy
             including chemotherapy, immunotherapy, biological or targeted therapy (e.g. FMS-like
             tyrosine kinase-3 (FLT3) inhibitors, other kinase inhibitors, azacitidine, ATRA) is
             allowed.

          -  CD33 expression by flow cytometry, assessed as CD33 expression in at least 20% of the
             leukemia blasts per local pathologist.29

          -  Prior cancer treatment must be completed at least 21 days prior to registration and
             the subject must have recovered from all reversible acute toxic effects of the regimen
             (other than alopecia) to ≤Grade 1 or baseline.

          -  Demonstrate adequate organ function as defined in the protocol.

          -  Females of childbearing potential must have a negative serum pregnancy test within 7
             days prior to registration. NOTE: Females are considered of child bearing potential
             unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal
             ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least
             12 consecutive months

          -  Females of childbearing potential and males must be willing to use effective
             contraception during treatment and for at least 30 days after the last dose of
             Venetoclax. Females will be advised to use effective contraception for at least 6
             months after the last dose of Gemtuzumab and males for at least 3 months after the
             last dose of Gemtuzumab.

          -  As determined by the enrolling physician or protocol designee, ability of the subject
             to understand and comply with study procedures for the entire length of the study

        Exclusion Criteria:

          -  Patients with history of prior use of GO or Venetoclax

          -  History of myeloproliferative neoplasm [MPN] including myelofibrosis, essential
             thrombocythemia, polycythemia vera, CML with or without BCR-ABL1 translocation, and
             AML with BCR-ABL1 translocation.

          -  More than two lines of prior therapy.

          -  WBC >25 × 109/L. Cytoreduction is required (hydroxyurea as per local standard of
             care).

          -  Acute promyelocytic leukemia.

          -  Unresolved ≥grade 2 clinically significant nonhematologic toxicities from prior
             anticancer therapy or unresolved disseminated intravascular coagulation ≥ grade 2 per
             CTCAE v5 criteria.

          -  History of other malignancies within 1 year prior to study entry, with the exception
             of: adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
             breast; basal cell carcinoma of the skin or localized squamous cell carcinoma of the
             skin; previous malignancy confined and surgically resected (or treated with other
             modalities), with curative intent.

          -  Investigational drug within 4 weeks of study entry.

          -  History of CHF requiring treatment, left ventricular ejection fraction ≤ 50%, cardiac
             insufficiency grade III or IV per New York Heart Association classification (NYHA), or
             chronic stable angina.

          -  Patients who are HIV positive.

          -  Known CNS involvement with AML.

          -  Previous hematopoietic stem cell transplant within 2 months.

          -  Previous history of veno-occlusive disease/sinusoidal obstruction syndrome.

          -  Patients who are positive for hepatitis B or C infection with the exception of those
             with an undetectable viral load within 3 months. Subjects with serologic evidence of
             prior vaccination to HBV [i.e., HBs Ag-, and anti-HBs+] may participate.

          -  Active uncontrolled infection or severe systemic infection. Enrollment is possible
             after control of infection, at discretion of the treating physician.

          -  Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
             mother is being treated on study).

          -  Patients who have received strong and/or moderate CYP3A inducers or inhibitors within
             7 days prior to the initiation of study treatment. (See Appendix III)

          -  Patients who have consumed grapefruit, grapefruit products, Seville oranges (including
             marmalade containing Seville oranges) or Starfruit within 3 days prior to the
             initiation of study treatment.

          -  Malabsorption syndrome or other condition that precludes enteral route of
             administration.

          -  Psychological, familial, sociological, or geographical condition that would preclude
             study compliance and follow-up.

          -  Unable or unwilling to undergo a screening bone marrow study.

          -  Other severe acute or chronic medical or psychiatric condition, or laboratory
             abnormality that may increase the risk associated with study participation or
             investigational product administration or may interfere with the interpretation of
             study results and, in the judgment of the investigator, would make the patient
             inappropriate for enrollment in this study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of Venetoclax when administered with GO
Time Frame:42 days
Safety Issue:
Description:Assess the maximum tolerated dose (MTD) of Venetoclax when administered with GO in patients with AML. Dose-limiting toxicity, defined as an adverse event related (possible, probably, or definite) to Venetoclax and/or Gemtuzumab fulfilling one of the following criteria: Hematologic toxicity: treatment-related grade 4 or worse bone marrow hypocellularity present at the end of cycle one (day 28); specifically grade 4 cytopenias (anemia, neutropenia and/or thrombocytopenia) with the bone marrow documented to be free of leukemic infiltration. Note: patients who enter the study with grade 3 or worse cytopenias will not be evaluable for hematologic dose-limiting toxicities. Non-hematologic toxicity: any grade 3 or worse treatment-related toxicity (excluding grade 4 infections during cycle one.

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:7 months
Safety Issue:
Description:Overall response rate (CR/CRi), as defined by the revised IWG criteria
Measure:Rate of Anti-leukemic activity
Time Frame:7 months
Safety Issue:
Description:Anti-leukemic activity (CR/Cri/PR), as defined by the revised IWG criteria
Measure:Relapse-free survival
Time Frame:7 months
Safety Issue:
Description:patients achieving CR or CRi; measured from the date of achievement of a remission until the date of relapse or death from any cause; patients not known to have relapsed or died at last follow-up are censored on the date they were last examined
Measure:Event-free Survival
Time Frame:7 months
Safety Issue:
Description:Event-free Survival will be measured from the date of entry to the date of treatment failure, disease relapse, or death from any cause; patients not known to have any of these events are censored on the date they were last examined
Measure:overall survival
Time Frame:7 months
Safety Issue:
Description:Overall survival will be measured from the date of entry to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Big Ten Cancer Research Consortium

Trial Keywords

  • relapsed
  • refractory
  • CD33+

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