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GTB-3550 Tri-Specific Killer Engager (TriKE®) for High Risk Hematological Malignancies

Primary Purpose

High-risk Myelodysplastic Syndromes, Acute Myelogenous Leukemia, Systemic Mastocytosis

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
GTB-3550 TriKE® Phase I
GTB-3550 TriKE® Phase II
Sponsored by
GT Biopharma, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for High-risk Myelodysplastic Syndromes focused on measuring Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Eligible Diseases

  • Diagnosis of one of the following CD33-expressing myeloid malignancies with greater than or equal to 50% CD33+ target cells with no good standard of care treatment options including:
  • High Risk Myelodysplastic Syndromes (MDS) progressive on two or more prior regimens and requiring treatment that meets at least one of the following:

    • Revised International Prognostic Scoring System (IPSS-R) High or Very High Risks
    • World Health Organization (WHO) Classification: Refractory anemia with excess blasts-1 (RAEB-1) or RAEB-2
    • Poor and very-poor risk cytogenetic abnormality as defined by the IPSS-R cytogenetic classifications
    • WHO Based Prognostic Scoring System (WPSS): High or Very High Risk
  • Therapy related MDS and not a candidate for induction chemotherapy or had an inadequate treatment response after induction chemotherapy.
  • Refractory or Relapsed Acute Myelogenous Leukemia (AML) meeting at least one of the following:

    • Refractory AML defined as failure to achieve remission after at least 3 induction attempts

      ** Elderly AML not fit for induction therapy can be enrolled after 2 failed inductions

    • Relapsed AML

      • Not a candidate for hematopoietic stem cell transplant (HSCT), at least one re-induction attempt required
      • Prior HSCT relapse beyond 3 months may be included only if off immunosuppression for a minimum of 4 weeks and do not have graft-versus-host disease (GVHD)
  • Advanced systemic mastocytosis (defined as mast cell leukemia, aggressive systemic mastocytosis, and systemic mastocytosis associated with hematologic neoplasm) may enroll without any prior treatment, given there is no standard established therapy.

Inclusion Criteria: Age, Performance Status, Organ Function, Contraception Use

  • At least 18 years of age
  • Karnofsky score ≥ 70%
  • Adequate organ function within 14 days (30 days for cardiac and pulmonary) of study enrollment defined as:

    • Renal: an estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2
    • Hepatic: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and total bilirubin within normal range
    • Pulmonary function: Diffusing capacity for carbon monoxide (DLCO) corrected (ml/min/mm Hg) defined as no more than 5 units below lower limit of normal (Common Terminology Criteria for Adverse Events [CTCAE] v5 Grade 1 carbon monoxide diffusing capacity decreased) based on patient's height, weight, and gender as reported by the institutional pulmonary function lab.
    • Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia; left ventricular ejection fraction ≥ 45% by echocardiogram, multigated acquisition (MUGA) scan or cardiac MRI.
  • Absolute lymphocyte count (ALC) ≥ 200 cells/mm³ OR absolute circulating CD56+/CD3- NK cell count >25 cells/μl within the 14 days prior to start of therapy
  • Sexually active females of childbearing potential and males with partners of child-bearing potential must agree to use adequate birth control during study treatment
  • Participant provides voluntary written consent signed before performance of any study-related procedure not part of normal medical care

Exclusion Criteria

  • New or progressive pulmonary infiltrates on screening chest x-ray or chest computerized tomography (CT) scan unless cleared for study by Pulmonary. Infiltrates attributed to infection must be stable/improving with associated clinical improvement after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections).
  • Uncontrolled bacterial, fungal or viral infections, known history of HIV
  • Active Hepatitis B or Hepatitis C (virus detectable by polymerase chain reaction [PCR]) - chronic asymptomatic viral hepatitis is allowed
  • Other concurrent active cancer within the last year (excluding non-melanoma skin cancers)
  • Severely clinically obese patients, BMI >38
  • Currently taking any over-the-counter (OTC), vitamin, mineral, or dietary supplement within 14 days prior to study drug administration on Day 1 and during study conduct that may confound study safety goals (e.g., St. John's wort). Questions should be discussed with GT Biopharma.
  • Pregnant or breast feeding. The effect of GTB-3550 TriKE on the fetus is unknown. Females of childbearing potential must have a blood test within 7 days prior to enrollment to rule out pregnancy - must be repeated if not within 7 days of treatment initiation
  • History of central nervous system (CNS) malignancy or symptoms of active CNS disease
  • A family history of long QT syndrome or with a corrected QT (QTc) interval > 480 msec at screening
  • Currently taking medications known to prolong QT/QTc interval as the potential risk of QT/QTc prolongation is unknown in humans.
  • A candidate for potentially curative therapy, including hematopoietic cell transplant
  • Unwilling to remain within a 90 minute drive of the study center through at least Day 29

Sites / Locations

  • Masonic Cancer Center, University of Minnesota
  • University of Wisconsin Clinical Science Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

GTB-3550 TriKE® (Phase I: Dose Finding Component)

GTB-3550 TriKE® Only (Phase II: Extended Component)

Arm Description

Patients receive a single course of GTB-3550 TriKE® at their assigned dose as 3 weekly treatment blocks. Each block consists of four consecutive 24 hour continuous infusions (over approximately 96 hours) of GTB-3550 TriKE® followed by a 72 hour break after Block #1 and #2. All treatment is given as an inpatient. The assigned dose will be calculated on a weight obtained within 5 days prior to or on day of the 1st dose. The dose is not be recalculated for subsequent treatment blocks.

The treatment schedule is identical to the dose finding component. The extended component uses a Simon's MiniMax two-stage design for continued enrollment using the maximum tolerated dose (MTD) established during Phase I with monitoring guidelines to stop the study early for excessive toxicity.

Outcomes

Primary Outcome Measures

GTB-3550 Dosing Summary
The study was terminated prior to reaching the maximal tolerated dose. This outcome measure presents information regarding the number of participants receiving each dose of GTB-3550.
GTB-3550 Extent of Treatment (Summary)
This outcome measure summarizes the number of GTB-3550 treatment blocks participants received during the first cycle of treatment.

Secondary Outcome Measures

Number of GTB-3550 TriKE® Treatment-Emergent Adverse Events (TEAEs) [Safety and Tolerability]
The number of unexpected events in relation to GTB-3550 TriKE®. TEAEs were measured up to Day 28 relative to GTB-3550 therapy.
Overall Survival (OS)
Number of patients surviving at 6 months post-treatment on this study.
Number of Participants Experiencing a Reduction in Blast Count Post-GTB-3550 Therapy
Blast count was measured at the time of standard of care disease assessment after GTB-3550 therapy. Blast percent was assessed by morphology and/or flow cytometry.

Full Information

First Posted
July 7, 2017
Last Updated
October 14, 2022
Sponsor
GT Biopharma, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03214666
Brief Title
GTB-3550 Tri-Specific Killer Engager (TriKE®) for High Risk Hematological Malignancies
Official Title
GTB-3550 (CD16/IL-15/CD33)Tri-Specific Killer Engager (TriKE®) for the Treatment of High Risk Myelodysplastic Syndromes, Refractory/Relapsed Acute Myeloid Leukemia and Advanced Systemic Mastocytosis
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Terminated
Why Stopped
Development of GTB-3550 halted due to development of the second generation camelid nanobody TriKE drug product, GTB-3650.
Study Start Date
January 1, 2020 (Actual)
Primary Completion Date
August 2, 2021 (Actual)
Study Completion Date
September 29, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GT Biopharma, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a multi-center Phase I/II clinical trial of GTB-3550 (CD16/IL-15/CD33) tri-specific killer cell engager (TriKE®) for the treatment of CD33-expressing high risk myelodysplastic syndromes, refractory/relapsed acute myeloid leukemia or advanced systemic mastocytosis. The hypothesis is that GTB-3550 TriKE® will induce natural killer cell function by targeting malignant cells as well as CD33+ myeloid derived suppressor cells (MDSC) which contribute to tumor induced immunosuppression. Because CD16 is the most potent activating receptor on natural killer (NK) cells, this single agent may induce a targeted anti-CD33+ tumor response.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
High-risk Myelodysplastic Syndromes, Acute Myelogenous Leukemia, Systemic Mastocytosis, Mast Cell Leukemia
Keywords
Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
GTB-3550 TriKE® (Phase I: Dose Finding Component)
Arm Type
Experimental
Arm Description
Patients receive a single course of GTB-3550 TriKE® at their assigned dose as 3 weekly treatment blocks. Each block consists of four consecutive 24 hour continuous infusions (over approximately 96 hours) of GTB-3550 TriKE® followed by a 72 hour break after Block #1 and #2. All treatment is given as an inpatient. The assigned dose will be calculated on a weight obtained within 5 days prior to or on day of the 1st dose. The dose is not be recalculated for subsequent treatment blocks.
Arm Title
GTB-3550 TriKE® Only (Phase II: Extended Component)
Arm Type
Experimental
Arm Description
The treatment schedule is identical to the dose finding component. The extended component uses a Simon's MiniMax two-stage design for continued enrollment using the maximum tolerated dose (MTD) established during Phase I with monitoring guidelines to stop the study early for excessive toxicity.
Intervention Type
Drug
Intervention Name(s)
GTB-3550 TriKE® Phase I
Other Intervention Name(s)
CD16/IL-15/CD33
Intervention Description
The 1st two patients will be assigned Dose Level 1. The study statistician will assign each new cohort of 2 patients to the most appropriate dose level based on updated toxicity probabilities. Dose Level 1 - 5 μg/kg/day Dose Level 2 - 10 μg/kg/day Dose Level 3 - 25 μg/kg/day Dose Level 4 - 50 μg/kg/day Dose Level 5 - 100 μg/kg/day Dose Level 6 - 150 μg/kg/day Dose Level 7 - 200 μg/kg/day
Intervention Type
Drug
Intervention Name(s)
GTB-3550 TriKE® Phase II
Other Intervention Name(s)
CD16/IL-15/CD33
Intervention Description
Patients will receive the maximum tolerated dose (MTD) established during Phase I with monitoring guidelines to stop the study early for excessive toxicity.
Primary Outcome Measure Information:
Title
GTB-3550 Dosing Summary
Description
The study was terminated prior to reaching the maximal tolerated dose. This outcome measure presents information regarding the number of participants receiving each dose of GTB-3550.
Time Frame
Day 1 (start of GTB-3550 therapy)
Title
GTB-3550 Extent of Treatment (Summary)
Description
This outcome measure summarizes the number of GTB-3550 treatment blocks participants received during the first cycle of treatment.
Time Frame
Day 28 relative to the start of GTB-3550 therapy
Secondary Outcome Measure Information:
Title
Number of GTB-3550 TriKE® Treatment-Emergent Adverse Events (TEAEs) [Safety and Tolerability]
Description
The number of unexpected events in relation to GTB-3550 TriKE®. TEAEs were measured up to Day 28 relative to GTB-3550 therapy.
Time Frame
Day 28 relative to the start of GTB-3550 therapy
Title
Overall Survival (OS)
Description
Number of patients surviving at 6 months post-treatment on this study.
Time Frame
6 Months
Title
Number of Participants Experiencing a Reduction in Blast Count Post-GTB-3550 Therapy
Description
Blast count was measured at the time of standard of care disease assessment after GTB-3550 therapy. Blast percent was assessed by morphology and/or flow cytometry.
Time Frame
After Day 28 Relative to GTB-3550 Therapy

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Eligible Diseases Diagnosis of one of the following CD33-expressing myeloid malignancies with greater than or equal to 50% CD33+ target cells with no good standard of care treatment options including: High Risk Myelodysplastic Syndromes (MDS) progressive on two or more prior regimens and requiring treatment that meets at least one of the following: Revised International Prognostic Scoring System (IPSS-R) High or Very High Risks World Health Organization (WHO) Classification: Refractory anemia with excess blasts-1 (RAEB-1) or RAEB-2 Poor and very-poor risk cytogenetic abnormality as defined by the IPSS-R cytogenetic classifications WHO Based Prognostic Scoring System (WPSS): High or Very High Risk Therapy related MDS and not a candidate for induction chemotherapy or had an inadequate treatment response after induction chemotherapy. Refractory or Relapsed Acute Myelogenous Leukemia (AML) meeting at least one of the following: Refractory AML defined as failure to achieve remission after at least 3 induction attempts ** Elderly AML not fit for induction therapy can be enrolled after 2 failed inductions Relapsed AML Not a candidate for hematopoietic stem cell transplant (HSCT), at least one re-induction attempt required Prior HSCT relapse beyond 3 months may be included only if off immunosuppression for a minimum of 4 weeks and do not have graft-versus-host disease (GVHD) Advanced systemic mastocytosis (defined as mast cell leukemia, aggressive systemic mastocytosis, and systemic mastocytosis associated with hematologic neoplasm) may enroll without any prior treatment, given there is no standard established therapy. Inclusion Criteria: Age, Performance Status, Organ Function, Contraception Use At least 18 years of age Karnofsky score ≥ 70% Adequate organ function within 14 days (30 days for cardiac and pulmonary) of study enrollment defined as: Renal: an estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 Hepatic: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and total bilirubin within normal range Pulmonary function: Diffusing capacity for carbon monoxide (DLCO) corrected (ml/min/mm Hg) defined as no more than 5 units below lower limit of normal (Common Terminology Criteria for Adverse Events [CTCAE] v5 Grade 1 carbon monoxide diffusing capacity decreased) based on patient's height, weight, and gender as reported by the institutional pulmonary function lab. Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia; left ventricular ejection fraction ≥ 45% by echocardiogram, multigated acquisition (MUGA) scan or cardiac MRI. Absolute lymphocyte count (ALC) ≥ 200 cells/mm³ OR absolute circulating CD56+/CD3- NK cell count >25 cells/μl within the 14 days prior to start of therapy Sexually active females of childbearing potential and males with partners of child-bearing potential must agree to use adequate birth control during study treatment Participant provides voluntary written consent signed before performance of any study-related procedure not part of normal medical care Exclusion Criteria New or progressive pulmonary infiltrates on screening chest x-ray or chest computerized tomography (CT) scan unless cleared for study by Pulmonary. Infiltrates attributed to infection must be stable/improving with associated clinical improvement after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections). Uncontrolled bacterial, fungal or viral infections, known history of HIV Active Hepatitis B or Hepatitis C (virus detectable by polymerase chain reaction [PCR]) - chronic asymptomatic viral hepatitis is allowed Other concurrent active cancer within the last year (excluding non-melanoma skin cancers) Severely clinically obese patients, BMI >38 Currently taking any over-the-counter (OTC), vitamin, mineral, or dietary supplement within 14 days prior to study drug administration on Day 1 and during study conduct that may confound study safety goals (e.g., St. John's wort). Questions should be discussed with GT Biopharma. Pregnant or breast feeding. The effect of GTB-3550 TriKE on the fetus is unknown. Females of childbearing potential must have a blood test within 7 days prior to enrollment to rule out pregnancy - must be repeated if not within 7 days of treatment initiation History of central nervous system (CNS) malignancy or symptoms of active CNS disease A family history of long QT syndrome or with a corrected QT (QTc) interval > 480 msec at screening Currently taking medications known to prolong QT/QTc interval as the potential risk of QT/QTc prolongation is unknown in humans. A candidate for potentially curative therapy, including hematopoietic cell transplant Unwilling to remain within a 90 minute drive of the study center through at least Day 29
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark B Juckett, MD
Organizational Affiliation
Masonic Cancer Center, University of Minnesota
Official's Role
Principal Investigator
Facility Information:
Facility Name
Masonic Cancer Center, University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
University of Wisconsin Clinical Science Center
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States

12. IPD Sharing Statement

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GTB-3550 Tri-Specific Killer Engager (TriKE®) for High Risk Hematological Malignancies

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