Flotetuzumab in Primary Induction Failure (PIF) or Early Relapse (ER) Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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Open-label, multi-dose, single-arm, multi-center, Phase 1/2 study conducted in three segments: the Single Patient Dose Escalation Segment (complete), followed by the Multi-Patient Dose Escalation Segment (complete) and the Maximum Tolerated Dose and Schedule (MTDS) Expansion Cohort Segment (closed). Having characterized safety and determined the maximum tolerated dose and schedule, the primary objective of this study now is to assess the anti-neoplastic activity of flotetuzumab in patients with PIF/ER AML, as determined by the proportion of patients who achieve CR or CRh. Starting with Cycle 2, patients who are benefiting from flotetuzumab may receive up to a maximum of 8 cycles of treatment. Patients will receive daily increasing doses of flotetuzumab for the first week of Cycle 1 (Lead-In Dosing) followed by 3 weeks of continuous intravenous infusion at a specifiedthe assigned dose. Subsequent cycles are each 4 weeks of continuous infusion at the assigned dose. Dosing may continue for up to 8 cycles. Follow up visits may continue for 6 months after treatment is discontinued.

Official Title
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A Phase 1/2, First in Human, Dose Escalation Study of MGD006, a CD123 x CD3 DART® Bi-Specific Antibody Based Molecule, in Patients With Relapsed or Refractory AML or Intermediate-2/High Risk Myelodysplastic Syndrome (MDS)

Conditions
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AML

Intervention / Treatment
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* Biological: Flotetuzumab dose escalation
* Biological: Flotetuzumab dose expansion
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of primary or secondary AML [any subtype except acute promyelocytic leukemia (APL)] according to World Health Organization (WHO) classification Patients with AML must meet one of the following criteria, a or b: Primary Induction Failure (PIF) AML, defined as disease refractory to either, i or ii: i. An intensive induction attempt, per institution. Induction attempts include high-dose and/or standard-dose cytarabine ± an anthracyclines/anthracenedione ± an anti-metabolite, with or without growth factor or targeted therapy containing regimens. Examples include but are not limited to: 1 cycle of high dose cytarabine (HiDAC) containing regimen, 1 cycle of liposomal cytarabine and daunorubicin, 2 cycles of standard dose cytarabine containing regimen ii. For adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy; PIF is defined as AML refractory to one of the following less intensive regimens: i ≥ 2 but ≤ 4 cycles of Bcl-2 inhibitors in combination with azacitidine, decitabine, or low dose cytarabine, or ii ≥ 2 but ≤ 4 cycles of gemtuzumab ozogamicin monotherapy Early relapse (ER) AML, defined as AML in first relapse with initial CR1 duration < 6 months Limit of 3 prior lines of therapy (excluding focal radiation therapy for palliative purposes): up to 2 induction (induction, re-induction) or 1 induction plus/minus 1 consolidation attempt, followed by a maximum of 1 salvage/re-induction attempt. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 Life expectancy of at least 4 weeks Peripheral blast count </= 20,000/mm3 at the time of first dose Acceptable laboratory parameters and adequate organ reserve Exclusion Criteria: History of allogeneic stem cell transplantation Prior treatment with an anti-CD123-directed agent Need for concurrent other cytoreductive chemotherapy Any active untreated autoimmune disorders (with the exception of vitiligo, resolved childhood atopic dermatitis, prior Grave's disease now euthyroid clinically and with stable supplementation) Second primary malignancy that requires active therapy. Adjuvant hormonal therapy is allowed. Antitumor therapy or investigational agent within 14 days or 5 half-lives of Cycle 1 Day 1. Requirement, at the time of study entry, for concurrent steroids > 10 mg/day of oral prednisone or the equivalent, except steroid inhaler, otic preparations, nasal spray or ophthalmic solution Use of immunosuppressant medications in the 2 weeks of Cycle 1 Day 1 Use of granulocyte colony stimulating or granulocyte-macrophage colony stimulating factor in the 2 weeks of Cycle 1 Day 1 Known central nervous system (CNS) leukemia Active uncontrolled infection (including, but not limited to viral, bacterial, fungal, or mycobacterial infection), Known human immunodeficiency virus infection, unless all of the following criteria are met: CD4+ count ≥ 350 cells/μL, undetectable viral load, and receiving highly active antiretroviral therapy. Known, active, history of or current acute or chronic hepatitis B or C virus (HBV) infection (as evidenced by detectable HBV surface antigen and HBV DNA ≥ 500 IU/mL), History of hepatitis C virus (HCV) infection, unless the infection has been treated and cured, Active SARS-CoV-2 infection. While SARS-CoV-2 testing is not mandatory for study entry, testing for ongoing infection should follow local clinical practice guidelines/standards. Participants with a positive test result for ongoing SARS-CoV-2 infection, known asymptomatic infection, or suspected infection are excluded unless or until asymptomatic and with subsequent negative SARS-CoV-2 laboratory test.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Flotetuzumab dose escalation:<br>Participants will be assigned sequentially to escalating doses of flotetuzumab, up to the maximum tolerated dose (MTD). | Biological: Flotetuzumab dose escalation<br>* Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART® molecule.<br>* Other names: MGD006;|
| Experimental: Flotetuzumab dose expansion<br>Participants will receive flotetuzumab at the recommended phase 2 dose (RP2D) and schedule identified during dose escalation. | Biological: Flotetuzumab dose expansion<br>* Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART® molecule.<br>* Other names: MGD006;|
| Experimental: Flotetuzumab and ruxolitinib<br>Participants will receive flotetuzumab at the recommended phase 2 dose (RP2D) and schedule identified during dose escalation in combination with one of two escalating doses of ruxolitinib. | Biological: Flotetuzumab dose expansion<br>* Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART® molecule.<br>* Other names: MGD006;Drug: Ruxolitinib<br>* Ruxolitinib will be administered at the assigned dose.<br>* Other names: Jakafi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy based on CR or CRh rate | Proportion of patients achieving a best response of CR (morphologic CR [mCR], cytogenetic CR [CRc], molecular CR [CRm], or CRh per Interworking Group AML response criteria. | up to 14 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall complete response rate | Rate of CR + CRh + CRi (CR with incomplete blood cell recovery [CR with incomplete neutrophil {CRn}or platelet recovery {CRp}]) + MLFS (morphologic leukemia-free state) | up to 14 months | 
| CR rate | Proportion of patients achieving a best response of CR (morphologic CR [mCR], cytogenetic CR [CRc], or molecular CR [CRm] per Interworking Group AML response criteria. | up to 14 months | 
| CRh rate | Proportion of patients achieving a best response of CRh per Interworking Group AML response criteria. | up to 14 months | 
| Overall response rate | Proportion of patients achieving a best response of CR, CRh, CRi, MLFS or partial response per Interworking Group AML response criteria. | up to 14 months | 
| Duration of response of patients with CR or CRh | Time of initial documentation of response to the time of disease relapse or death due to any cause, whichever occurs first. | Up to 2 years | 
| Post-baseline transfusion independence rate | The number of patients who were transfusion-dependent at baseline and did not receive transfusions during any consecutive 56-day period will be calculated. The number of patients who are transfusion independent at baseline and remain independent during any 56-day post-baseline period will also be calculated. | 56 days | 
| Overall survival | Time from first dose to death from any cause | Up to 2 years | 
| HSCT rate | Rate of successful hematopoietic stem cell transplantation (HSCT) after the start flotetuzumab treatment and before subsequent therapy. | up to 8 months | 
| Incidence rate of hospitalization for patients in the Expansion Cohort | Incidence rate of hospitalization will be calculated | up to 8 months | 
| Duration of hospitalization for patients in the Expansion Cohort | Duration of hospitalization will be characterized | up to 8 months | 
| Event-free survival | Time from the first dose of study drug until date of evidence of progression, relapse, or death from any cause, whichever occurs first. | Up to 2 years | 
| Time to response | Time from first dose of study drug to first CR, CRh, CRi, or MLFS | up to 14 months | 
| Mortality rate | rate of death from any cause within 30, 60, 90, or 180 days of first dose of study drug | Up to 180 days | 
| 6-month survival rate | Probability of survival at 6 months from first dose of study drug | 6 months | 
| One-year survival rate | Probability of survival at 1 year from first dose of study drug | 1 year | 
| Number of patients with infusion related reaction (IRR)/cytokine release syndrome (CRS) management | Determine safety and efficacy of tocilizumab in the treatment of IRR/CRS as measured by incidence of IRR/CRS | During study drug administration (up to 8 months) | 
| Occurrence of dose limiting toxicity | Maximum Tolerated Dose/Schedule: the MTDS is defined as the highest dose/schedule administered during any Cohort in the study at which the incidence of DLT is < 33% during the first cycle of MGD006 treatment. | Cycle 1 of a 28 day cycle. | 
| Occurrence of adverse events (AEs) and serious adverse events (SAEs) | Cycle 1 through end of treatment | up to 9 months | 
| Serum concentration of flotetuzumab | Measure the pharmacokinetics (PK) of flotetuzumab | Study day 1, then every 28 days and 28 days after the last dose (up to 8 months) | 
| ADA | Occurrence of anti-drug antibody | Study Day 1, then every 28 days through 28-days after the last dose (up to 8 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, leukemia, myelogenous, myeloid, refractory