Phase 1 Clinical Investigation of Human Myeloid Progenitor Cells (CLT-008) As a Supportive Care Measure during Chemotherapy for Acute Myeloid Leukemia (AML)
Authors: Wieduwilt Matthew J. , Cerny Jan , Akard Luke , Ustun Celalettin , Ravandi Farhad , Rossetti James M. , Hill Brian T. , Brown Janice (Wes) , Kellerman Lois , Van Syoc Rod , Reed William , Andreadis Charalambos 
Published: October 2019

Abstract
Background: Current management of chemotherapy and radiation-induced neutropenia is unsatisfactory with frequent infection-related deaths. A novel allogeneic human myeloid progenitor cell product, CLT-008, that is culture-derived from G-CSF mobilized HSCs, can be cryopreserved and infused without HLA matching. Cells are intended to engraft transiently and produce mature myeloid effector cells that migrate to tissues and may mitigate the risk of bacterial or fungal infection for weeks, as has been demonstrated in murine models.
Methods: To evaluate the safety of CLT-008, a phase 1 dose escalation study was conducted in subjects with AML, MDS or ALL during consolidation (n=18) or with AML or tAML during first or subsequent induction (n=31). Eligible subjects were age 18 or older and treated with a high-dose or standard-dose cytarabine-based regimen. All 18 consolidation subjects and 23 induction subjects received CLT-008. Subjects received CLT-008 on study day 6 (consolidation 106 or 107cells/kg) or on study day 9 (induction 107 or 3x107 cells/kg). G-CSF was given at 5 µg/kg daily from the day of CLT-008 until the ANC was 500/µL. During induction, 8 non-randomly selected controls received G-CSF without CLT-008. Dose limiting toxicities (DLT) were defined as any grade 3-5 infusion reaction, grade 4-5 organ toxicity (not due to the primary malignancy, infection, pre-existing condition, or initiation of new chemotherapy), any Grade III to IV GVHD, or failure of autologous neutrophil recovery at Day 42 not clearly attributable to another cause. All subjects were followed for 49 days and status was assessed at 6 months.
Results: Among 41 currently evaluable subjects, 1 experienced a DLT of grade 3 allergic infusion-related reaction which resolved promptly with steroids and antihistamine. There were no other DLTs and no GVHD of any grade. Treatment-emergent adverse events occurring in 3 or more subjects included febrile neutropenia, infection, mucosal inflammation, fatigue, diarrhea, tachycardia and nausea but were not judged related to the product. Among the 23 induction subjects receiving CLT-008 with G-CSF, there was a reduction in mucositis (WHO grade 2 or greater) and in duration of febrile episodes when compared to the 8 control subjects. CLT-008-derived cells were detectable in the peripheral blood for 6 of 23 induction subjects at 2-10% of nucleated cells using STR-PCR; there was no clear effect on ANC from this chimerism. To date, 8 of 23 induction subjects went on to subsequent HSC transplant. Seven engrafted while one died on post-transplant day 10 from an unrelated cause.
Conclusions: CLT-008 was safe and well tolerated in this phase 1 study. Only 1 DLT occurred and the pattern of AEs was as expected for this population. Among the induction subjects treated at 3x107 cells/kg, efficacy signals with respect to mucositis and duration of fever were found in the absence of high-level peripheral blood CLT-008 chimerism. These observations suggest that CLT-008-derived myeloid effector cells preferentially migrate to chemotherapy-damaged mucosal tissues where they could function to mitigate infection risk. Further clinical development is planned in a randomized phase 2 study using an enhanced potency iteration of CLT-008, assessment of tissue-level chimerism, and specific ascertainment of outcomes related to infection and chemotherapy sequellae.
Figure 1 Figure 1.

Disclosures
Wieduwilt: Cellerant Therapeutics: Honoraria, Research Funding. Cerny:Cellerant Therapeutics: Honoraria, Research Funding. Akard:Cellerant Therapeutics: Research Funding. Ustun:Cellerant Therapeutics: Honoraria, Research Funding. Ravandi:Cellerant Therapeutics: Research Funding. Rossetti:Cellerant Therapeutics: Research Funding. Hill:Cellerant Therapeutics: Honoraria, Research Funding. Brown:Cellerant Therapeutics: Consultancy, Equity Ownership, Patents & Royalties. Kellerman:Cellerant Therapeutics: Employment, Equity Ownership. Van Syoc:Cellerant Therapeutics: Employment, Equity Ownership. Reed:Cellerant Therapeutics: Employment, Equity Ownership. Andreadis:Cellerant Therapeutics: Research Funding.