A Phase II Multicenter Study to Assess the Feasibility and Efficacy of the Addition of an Interphase Cycle With Flotetuzumab Prior to Start Conditioning for an Allogeneic HCT in AML With MRD After 2 Cycles of Intensive Chemotherapy
Overview
- Phase
- Phase 2
- Intervention
- Flotetuzumab
- Conditions
- AML
- Sponsor
- Stichting Hemato-Oncologie voor Volwassenen Nederland
- Locations
- 4
- Primary Endpoint
- Rate of CR/CRi without MRD defined as MRD < 0.1% by flowcytometry or undetectable mutant NPM1 by qPCR after 1 cycle of flotetuzumab
- Status
- Withdrawn
- Last Updated
- 4 years ago
Overview
Brief Summary
Patients who have measurable residual disease (MRDpos, defined as MRD > 0.1% by flowcytometry or detectable mutant Nucleophosmin 1 (NPM1) by quantitative polymerase chain reaction (qPCR) after two cycles of intensive chemotherapy) prior to start conditioning for an allogeneic Hematopoietic Cell Transplantation (HCT) have a very high risk of relapse after transplantation. Important questions in the field are whether patients with MRD after intensive chemotherapy can be converted to MRD negativity (i.e. undetectable MRD, MRDneg) and whether this conversion impacts on the relapse rate after transplantation. This trial aims to develop effective "interphase" treatment for patients in morphological complete remission (CR) with MRD after at least 2 cycles of intensive chemotherapy and prior to start conditioning for an allogeneic HCT. Flotetuzumab, a bispecific antibody-based molecule against CD3 and CD123 in a dual-affinity re-targeting antibody (DART®) format is a new treatment modality based on immunomodulation. The rationale to use flotetuzumab in this study is: 1) its antileukemic activity reported in R/R AML; 2) its limited extra-medullary (i.e. tissue) toxicity; and 3) its short halflife.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age ≥18 years.
- •Diagnosis of ELN AML other than acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants of these according to the 2016 WHO classification.
- •In first CR/CRi/CRh after at at least 2 cycles of intensive chemotherapy with MRD by l MFC-based MRD assay or qPCR mutant NPM1 assessed by central lab. Three cycles of intensive treatment is allowed if 2 cycles of treatment were needed to reach morphological remission.
- •Should be off any active systemic therapy for AML for at least 14 days or 5 half-lives (whichever is longer) prior to study registration
- •All Grade 2-4 non-hematologic toxicities should have resolved.
- •Planned to undergo myeloablative or reduced intensity conditioning prior to alloHCT with a likely source for donor cells identified.
- •Eastern Cooperative Oncology Group (ECOG)/ WHO performance status 0-
- •Adequate hepatic and renal function
- •Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (less or equal then) 2.5 times the institutional upper limit of normal (ULN).
- •Total bilirubin level (less or equal then) 1.5 times the ULN (unless the patient has a history of Gilbert's Syndrome, in which case, total bilirubin must be (less or equal then) 2.5 times the ULN).
Exclusion Criteria
- •Prior history of allogeneic HCT.
- •Prior treatment with an anti-CD123-directed agent.
- •Favorable risk AML other than AML with NPM1 mutation (according to 2017 ELN)
- •Myeloid blast crisis of chronic myeloid leukemia (CML).
- •Concomitant illness associated with an estimated survival of \<1 year.
- •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. Patients with the following history/concurrent conditions are allowed:
- •Basal or squamous cell carcinoma of the skin
- •Carcinoma in situ of the cervix
- •Carcinoma in situ of the breast
Arms & Interventions
Single arm - Flotetuzumab
1 - 3 cycles of Flotetuzumab. Flotetuzumab will be administered intravenously via continuous (pump) administration. At least for the first 7 days of cycle 1, the drug will be administered in an inpatient hospital setting, but afterwards may be administered in an outpatient setting using an ambulatory pump configuration. Flotetuzumab will be dosed using multi-step increments in dosing over the first week as follows: 30, 60, 100, 200, 300, and 400 ng/kg/day each for 24 hours. On day 7, the dose will be increased to 500 ng/kg/day and administered as a continuous infusion for the remainder of cycle 1. After 1 cycle of flotetuzumab patients will proceed with alloHCT. However if there is a delay in access to transplantation, patients are allowed to receive up to 2 additional cycles flotetuzumab provided all non-hematologic toxicities have resolved to Grade \<2.
Intervention: Flotetuzumab
Outcomes
Primary Outcomes
Rate of CR/CRi without MRD defined as MRD < 0.1% by flowcytometry or undetectable mutant NPM1 by qPCR after 1 cycle of flotetuzumab
Time Frame: 1 year after inclusion last patient
The primary objective of this study is to assess the rate of MRDneg remission after treatment with one cycle of flotetuzumab. The rate of MRDneg remission after one treatment cycle will be tabulated and exact 95% confidence intervals will be calculated.