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

Sponsor

GT Biopharma, Inc. (Industry)

Overall Status

Terminated

CT.gov ID

NCT03214666

Collaborator

(none)

Enrollment

Locations

Arms

20.9

Actual Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

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 NK cells, this single agent may induce a targeted anti-CD33+ tumor response.

Condition or Disease	Intervention/Treatment	Phase
High-risk Myelodysplastic Syndromes Acute Myelogenous Leukemia Systemic Mastocytosis Mast Cell Leukemia	Drug: GTB-3550 TriKE® Phase I Drug: GTB-3550 TriKE® Phase II	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

12 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jan 1, 2020

Actual Primary Completion Date :

Aug 2, 2021

Actual Study Completion Date :

Sep 29, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GTB-3550 TriKE® (Phase I: Dose Finding Component) 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.	Drug: GTB-3550 TriKE® Phase I 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 Other Names: CD16/IL-15/CD33
Experimental: GTB-3550 TriKE® Only (Phase II: Extended Component) 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.	Drug: GTB-3550 TriKE® Phase II Patients will receive the maximum tolerated dose (MTD) established during Phase I with monitoring guidelines to stop the study early for excessive toxicity. Other Names: CD16/IL-15/CD33

Arm

Intervention/Treatment

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

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.

Drug: GTB-3550 TriKE® Phase I

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

Other Names:

CD16/IL-15/CD33

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

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.

Drug: GTB-3550 TriKE® Phase II

Patients will receive the maximum tolerated dose (MTD) established during Phase I with monitoring guidelines to stop the study early for excessive toxicity.

Other Names:

CD16/IL-15/CD33

Outcome Measures

Primary Outcome Measures

Phase I Maximum Tolerated Dose (MTD) of GTB-3550 TriKE® Finding [Day 28]
To identify the maximum tolerated dose (MTD) of GTB-3550 TriKE® defined as the dose level that most closely corresponds to a dose limiting toxicity rate (DLT) of 20%
Phase II Incidence of complete and partial remission due to GTB-3550 TriKE® treatment [Day 42]
The incidence of clinical response by Day 42 after the start of the 1st infusion.

Secondary Outcome Measures

Incidence of GTB-3550 TriKE® Treatment-Emergent Adverse Events [Safety and Tolerability] [Day 28]
The incidence of unexpected events in relation to GTB-3550 TriKE®
Overall Survival (OS) [6 Months]
Incidence of survival of patients treated on this study

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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:
IPSS-R High or Very High Risks
WHO Classification: 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 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: AST, ALT, alkaline phosphatase and total bilirubin within normal range
Pulmonary function: DLCO corrected (ml/min/mm Hg) defined as no more than 5 units below lower limit of normal (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, MUGA 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 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 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 malignancy or symptoms of active CNS disease
A family history of long QT syndrome or with a 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota	United States	55455
2	University of Wisconsin Clinical Science Center	Madison	Wisconsin	United States	53792