A Phase I Study of CHR-2797, an Orally Active Aminopeptidase Inhibitor in Elderly and/or Treatment Refractory Patients with Acute Myeloid Leukemia or Multiple Myeloma.

Abstract Background. CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn++-dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, NOXA. CHR-79888 is an active metabolite of CHR-2797. Methods. This was an open label, single agent, dose escalating phase I salvage study to assess tolerance, MTD/DLT, activity, and pharmacokinetics of CHR-2797 in patients with hematological malignancies. Elderly patients and/or relapsed patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM) were eligible. Patients were treated with escalating once daily doses (60–180 mg) for up to 84 days or until progressive disease (PD). Clinical responses were assessed by monthly bone marrow aspirates in AML/MDS patients and by M-protein levels in MM patients. Results. Sixteen adults (4 women, 12 men) of median age 70 yrs, (range 45–84 yrs) were accrued between May 2006 and Jan 2007: 13 patients with AML, 1 with MDS, and 2 with MM. Thirteen patients finished the dose finding phase of 28 days and 6 patients continued for at least 84 days. CHR-2797 was well tolerated and, except for one patient with grade III ALT elevation, no grade III/IV drug related non-hematological toxicity was observed during the first 28 days of treatment. Two patients on 180 mg developed DLT that was considered drug related: >75 percent reduction in platelet count. CHR-2797 had no influence on hemoglobin or neutrophils in this trial. Overall the most frequently reported adverse events were thrombocytopenia (6.7%), diarrhea (4.5%), dizziness (3.9%), and fatigue (3.9%). Five AML patients died in the first 3 months of the trial or within 4 weeks of discontinuing CHR-2797: 3 due to disease progression and 2 following a MI (not related to drug). Bone marrow studies revealed complete responses (< 5% blasts in bone marrow) in 3/12 AML patients after 1–3 months of therapy (60 and 130mg), one of which was also a cytogenetic response. One of the 2 responding patients on 130 mg was evaluated as a CRp at 3 months; this patient was in remission for 3 months following platelet recovery after the drug was stopped. One further AML patient (60 mg) became completely transfusion independent and remained so for 6 weeks. Good exposure to CHR-2797, including levels of the active metabolite CHR-79888 has been observed on days 1 and 28 with a terminal half life (for 79888) of 8– 11 hours. Conclusions. Oral once daily CHR-2797 in AML/MDS/MM patients with adverse prognostic risk was well tolerated. MTD for maintenance therapy was reached at 180 mg. Single agent CHR-2797 therapy showed encouraging clinical activity (incl. 3/12 CRs) in these elderly and poor risk AML patients who were able to continue therapy for at least 28 days. Because of the favorable results a phase II study with CHR-2797 in advanced AML is currently in progress.

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A Phase I Study of Tipifarnib Combined with Conventional Induction and Consolidation Therapy for Previously Untreated Patients with Acute Myeloid Leukemia Age 60 and Over.

Blood ◽

10.1182/blood.v110.11.899.899 ◽

2007 ◽

Vol 110 (11) ◽

pp. 899-899 ◽

Cited By ~ 2

Author(s):

Joseph M. Brandwein ◽

Brian F. Leber ◽

Kang Howson-Jan ◽

Aaron D. Schimmer ◽

Andre C. Schuh ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Phase I ◽

Dose Level ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Phase I Study ◽

Single Agent ◽

Hematologic Toxicity ◽

Grade Iii ◽

Acute Myeloid

Standard induction therapy for patients over age 60 with acute myeloid leukemia (AML) has produced complete response (CR) rates of around 55%, but most patients eventually relapse. Tipifarnib (R115777, ZarnestraR) has shown activity as a single agent in AML, and is well tolerated in older patients at doses up to 600 mg BID. This agent also has additive/synergistic effects on AML cell lines when combined with daunorubicin (DNR). From 2005–2007, patients age 60 and over with previously untreated AML (de novo or secondary) were enrolled in a Phase I study combining tipifarnib with standard induction therapy. The regimen consisted of cytarabine 100 mg/m2/day continuous IV infusion on days 1–7, DNR 60 mg/m2/day IV push x 3 on days 6–8 and tipifarnib orally twice daily on days 6–15. Tipifarnib was escalated over four doses levels in successive patient cohorts (200, 300, 400 and 600 mg). Patients achieving CR were eligible to received one consolidation using the same regimen. Dose-limiting toxicity (DLT) was defined as Grade III–IV non–hematologic toxicity or hematologic recovery times > 40 days unless due to persistent leukemia. Up to 2/6 DLTs were permitted at each dose level. The following DLT’s were identified during induction: Dose level I: 2/6 (grade III hyperbilirubinemia, grade IV transient respiratory arrest), dose level II: 0/3, dose level III: 0/3 and dose level IV: 2/6 (grade III typhlitis, grade III supraventricular tachycardia). Four additional patients were enrolled at dose level IV, with one DLT (grade III diarrhea). There were no DLTs during consolidation. There were no cases of delayed hematologic recovery. Of 22 evaluable patients, there were 9 CR, 3 MLFS, 2 PR and 8 non-responders. Of 7 patients with adverse risk cytogenetics, there were 3 CR, 1 MLFS and 1 PR. In summary, this regimen was well tolerated and the DLT was not reached, although somewhat more GI toxicity was seen at dose level IV. Because of the inherent toxicity of the underlying regimen and the elderly population, it was decided not to escalate further, and tipifarnib 600 mg BID has been chosen as the recommended dose for further study using this regimen.

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Phase I Study of Lenalidomide in Acute Leukemia: Remissions in Post-Allogeneic Relapse of Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v114.22.841.841 ◽

2009 ◽

Vol 114 (22) ◽

pp. 841-841 ◽

Cited By ~ 2

Author(s):

Jason C. Chandler ◽

Rebecca B. Klisovic ◽

Mitch A. Phelps ◽

Alison Walker ◽

Ramiro Garzon ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Leukemia ◽

Phase I ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Single Agent ◽

Allogeneic Transplantation ◽

Initial Therapy ◽

Trisomy 13 ◽

Acute Myeloid

Abstract Abstract 841 Lenalidomide is effective in myeloma and low-risk myelodysplastic syndromes (MDS), especially MDS with the 5q- cytogenetic abnormality, and may also have activity in acute leukemia. We designed a phase I dose escalation trial of lenalidomide in adults with relapsed or refractory acute leukemia to determine the maximum tolerable dose (MTD) and dose limiting toxicity (DLT), as well as to provide preliminary efficacy data in this setting. 35 adults with acute leukemia were enrolled: 31 with acute myeloid leukemia (AML) and 4 with acute lymphoblastic leukemia (ALL). Patients had a median age of 63 years (range, 22-79) and had received a median of 2 prior therapies (range, 1-4). 8 patients had relapsed after transplantation (7-allogeneic, 1-autologous). Patients were treated orally with lenalidomide on days 1-21 of 28 day cycles at the following dose levels: 25mg/day (N=4), 35mg/day (N=9), 50mg/day (N=19, including the expansion at the MTD), and 75mg/day (N=3). Patients were eligible to receive additional cycles of treatment beyond cycle 1 in the absence of disease progression defined as 25% increase in blasts relative to pretreatment. The median number of cycles received was 1 (range, 1-7). DLTs were assessed during cycle 1 of therapy. DLTs were sudden death (N=1, autopsy ruled out pulmonary embolism), rash (N=1), line-associated thrombosis (N=1), and fatigue (N=3). Grade 3 fatigue occurred in two patients at 75mg/day; 50mg/day was thus declared the recommended phase 2 dose and 10 additional patients were treated at this dose. The major toxicities associated with treatment were drug and disease associated myelosuppression and infection, as expected; these did not constitute DLT. In spite of concerns that higher dose lenalidomide would be associated with increased risk of thromboembolism, this toxicity was infrequent, even during multiple cycles of therapy. Two events occurred; both were line associated, and neither was life-threatening. Detailed pharmacokinetic results for the dose escalation cohorts in the trial are listed in the table below. Maximum plasma lenalidomide concentrations and area under the concentration-time curve (AUC) increased proportionally with dose. Drug clearance was independent of dose and correlated with calculated creatinine clearance. Of 31 patients with AML there were 5 complete responses (CR) (by IWG criteria for AML; Cheson, JCO 2003). 3/3 with cytogenetically abnormal AML achieved cytogenetic CR (cCR) as well. Achievement of CR was delayed beyond 2 months from initiation of therapy in each case. The duration of CR was 2.4-8.8 months, with two responders still in CR at 2.4+ and 4.7+ months, respectively. At 25mg, a 74 year old with AML in 2nd relapse with widespread leukemia cutis but no blood/marrow involvement had resolution of disease after 2 cycles. At 35mg, a 69 year old with AML and trisomy 13 achieved cCR after 2 cycles. At 50mg, there were three CRs, including two patients who received lenalidomide as initial therapy for relapsed AML following allogeneic stem cell transplant. In both of these cases, lenalidomide therapy was associated with the onset of skin rash requiring temporary discontinuation of drug; CR was achieved after 2 to 3 cycles of therapy and was preceded by cytogenetic remission before count recovery occurred. A third CR at the 50mg level occurred in a 70 year old with AML who had lenalidomide discontinued after 2 cycles due to no apparent response. Subsequently, CR was achieved 1 month later with no intervening therapy. In conclusion, single agent lenalidomide induced CR in 16% (5/31) of relapsed/ refractory AML patients. None of the responders had 5q-. The DLT was fatigue; the MTD was 50mg daily for days 1-21. Achievement of CR without donor leucocyte infusion in 2/4 patients who received lenalidomide as initial therapy for AML relapse following allogeneic transplantation suggests a possible allogeneic immunomodulatory effect. We are now developing a CTEP-sponsored study of lenalidomide as maintenance following allogeneic transplantation for AML. The promising single agent efficacy reported here supports further study of lenalidomide in combination with other agents in high risk AML. Disclosures: Blum: Celgene: Research Funding.

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VLA4 Blockade In Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v122.21.3944.3944 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3944-3944 ◽

Cited By ~ 6

Author(s):

Yao-Te Hsieh ◽

Enzi Jiang ◽

Jennifer Pham ◽

Hye-Na Kim ◽

Hisham Abdel-Azim ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Single Agent ◽

Leukemia Cell ◽

Chemotherapeutic Agents ◽

Bone Marrow Stroma ◽

Nsg Mice ◽

Marrow Stroma ◽

Acute Myeloid

Abstract Despite aggressive chemotherapy and early allogeneic transplantation, acute myeloid leukemia (AML) frequently relapses, so that over-all disease-free survival remains below 50%. Strategies to overcome the chemoresistance of relapse-initiating residual AML blasts are, therefore, warranted. Evidence has been provided that AML cells are sheltered from the insult of chemotherapeutic agents by interacting with bone marrow stroma. Integrin alpha4beta1 (VLA4) mediates adhesion of hematopoietic cells to bone marrow stroma cells and extracellular matrix and has been implicated in cell adhesion-mediated chemotherapy resistance. Based on the evidence thereof provided for ALL blasts, VLA4 is here proposed as a therapeutic target for refractory AML. For this purpose, VLA4 was functionally blocked in vitro and in vivo on patient-derived AML cells using an anti-functional humanized VLA4 antibody, Natalizumab (NZM). VLA4-positive (>90%) patient-derived (primary) AML cells were plated on immobilized human VCAM1 or human stromal cell line HS-5 and treated with control (IgG4) or Natalizumab (NZM) for 2 days. NZM de-adhered 94.0%±7.6 AML cells from its counter receptor VCAM-1, yet only 31.3%±13.8 from HS-5, indicating that stroma cells offer ligands for a wider panel of adhesion receptors besides VLA4. We tested also whether VLA4 blockade is beneficial against AML when combined with chemotherapy. For this purpose, primary AML cells were incubated with NZM and incubated on uncoated tissue culture plates or HS-5 stromal layers in the presence or absence of Ara-C (1µM) for two days. AML cells showed higher viability under Ara-C therapy when incubated with HS-5 cells compared to controls, indicating the chemoprotective effect of the stromal layer. The viability of the AML cells treated with combined Ara-C and NZM was similar to the controls, indicating that HS-5-mediated chemo-protection was completely abrogated by NZM. Significantly more AML cells treated with Ara-C+NZM stained AnnexinV+/7AAD- than after Ara-C+control Ig4 treatment (44.4%±5.6 vs. 29.8%±4.8, p=0.03) indicating increased apoptosis of AML cells. On its own, NZM did not induce apoptosis. Next, we tested NZM as a single agent in our NOD/SCIDIL2Rγ deficient (NSG) xenograft model of primary AML. Luciferase-labeled AML cells were intrafemorally injected into NSG mice (1x105 cells / mouse). NZM (5mg/kg) was given intraperitoneally once per week for 4 weeks. NZM-treated animals survived significantly longer than control Ig-treated animals (Median Survival Time, MST=107 days vs. MST=76 days; *p=0.008 by Log-rank Test.To determine effects of NZM on leukemia cell burden/distribution in different organs, primary AML cells were injected into NSG mice and allowed to engraft for 3 days, subsequently treated with a single dose of NZM or Ig control. 72 hours later, AML cell burden in femurs and spleens of NZM-treated animals was significantly decreased compared to control treated mice, however AML cells were not increased into the peripheral blood, so that whether leukemia cells were selectively killed ormobilized and then retained in non-hematopoietic organs remains to be determined. Further studies addressing molecular mechanisms of increased apoptosis after combined VLA4 blockade and chemotherapy are ongoing. Our data suggest that the paradigm of leukemia cell targeting by VLA4 blockade, previously demonstrated by us for ALL, can also be applied to AML. Disclosures: No relevant conflicts of interest to declare.

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A Phase I/II Trial of Combination of Midostaurin (PKC412) and 5-Azacytidine (5-AZA) for the Treatment of Patients with Refractory or Relapsed (R/R) Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v120.21.3587.3587 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3587-3587 ◽

Cited By ~ 1

Author(s):

Aziz Nazha ◽

Hagop M. Kantarjian ◽

Gautam Borthakur ◽

Guillermo Garcia-Manero ◽

Tapan M. Kadia ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Phase I ◽

Phase Ii ◽

Myeloid Leukemia ◽

Research Funding ◽

Response Rate ◽

Allelic Ratio ◽

Bone Marrow Blasts ◽

Acute Myeloid

Abstract Abstract 3587 Background: Midostaurin (PKC412) is a potent orally bioavailable FLT3 inhibitor with activity in acute myeloid leukemia (AML). 5-azacytidine (5-AZA) is a hypomethylating agent that plays an important role in the treatment of AML and MDS. We hypothesized that adding midostaurin to 5-AZA may improve the response rate with limited toxicity profile. Materials and Methods: Patients ≥18 years with MDS, chronic myelomonocytic leukemia (CMML) or AML, who failed prior therapies with performance status ≤ 2, adequate liver (bilirubin ≤ 2 × ULN, ALT ≤ 2.5× ULN) and renal (creatinine ≤2× ULN) functions were eligible. Patients were included in phase I regardless of FLT3 mutation status; only FLT3 mutated patients were included in phase II. Patients received 5-AZA 75 mg/m2 subcutaneously or intravenously for 7 days of each cycle (Days 1–7) and midostaurin at 25 mg (cohort 1) and 50 mg (cohort 2; target dose) orally twice daily for 14 days (Days 8–21) per cycle. Patients were planned to receive up to 12 cycles if benefit from treatment. Supportive care was standard. The study was approved by institutional IRB and conducted in accordance of the declaration of Helsinki. Results: 20 patients have been enrolled: 13 included in phase I (6 in cohort 1 and 7 in cohort 2) and 6 patients in phase II. One patient in cohort 1 was inevaluable for DLT (withdrawal before completing cycle #1). One patient in cohort 2 received midostaurin dose as per cohort 1 dose by patient error. Patients' characteristics and responses are summarized in table 1. Overall response rate (ORR) in phase I was 3/13 (21%) (2 CRi and 1 patient decreased BM blasts from 27% to 7% after 2 cycles and went to transplant). ORR in phase II was 2/6 (33%) (1 patient with AML achieved CRi, 1 patient with CMML {received prior sorafenib} achieved CR). In addition, 1 AML patient had bone marrow blasts improved form 77% to 10% after 1 cycle, completed 3 cycles of therapy and then refused further treatment, and 1 AML patient had bone marrow blasts improve from 34% to 7 % and was continued on treatment). A total of nine patients with FLT3-ITD mutations enrolled in the trial: four patients in phase I with a median allelic ratio of 0.44 (range, 0.219–0.726); 1/4 (25%) achieved CRi, 2 of the non-responders had received prior FLT3 inhibitors (1 had developed FLT3-D835). Five patients in phase II had FLT3-ITD (median allelic ratio 0.06, range 0.014–0.279; one with concomitant D835 mutation) and one patient had FLT3-D835 mutation only (allelic ratio 0.238). 4/6 patients in phase II had failed prior FLT 3 inhibitors. In total, the ORR among patients with FLT3-ITD mutations was 3/9 (33%). All toxicities were grade 1 and 2 with no difference between the 2 dose schedules of midostaurin. No DLT or deaths were identified. Conclusion: The combination of midostaurin/5-AZA is safe and well tolerated at the intended doses (midostaurin 50 mg PO twice daily). Good ORR in high risk patients with relapsed or primary refractory FLT3-ITD positive AML was observed. Schedule is being amended to allow uninterrupted midostaurin administration. Phase II study continues to enroll patients with FLT3 mutations and updated results will be presented at the meeting. Disclosures: Off Label Use: 5-azacytidine in AML. Cortes:Novartis: Consultancy, Research Funding; Celgene: Research Funding; Ambit: Research Funding.

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First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.19.03250 ◽

2020 ◽

Vol 38 (36) ◽

pp. 4260-4273

Author(s):

Olga Salamero ◽

Pau Montesinos ◽

Christophe Willekens ◽

José Antonio Pérez-Simón ◽

Arnaud Pigneux ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Phase I ◽

Myeloid Leukemia ◽

Single Agent ◽

Antileukemic Activity ◽

Open Label ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid

PURPOSE Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). METHODS This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor. RESULTS Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm. CONCLUSION Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).

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Preliminary Results from a Phase 1 Study of Cfi-400495, a PLK4 Inhibitor, in Patients with Acute Myeloid Leukemia and High Risk MDS

Blood ◽

10.1182/blood-2020-138822 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-2

Author(s):

Tracy Murphy ◽

Brian Leber ◽

Mark R Bray ◽

Steven M Chan ◽

Vikas Gupta ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Advisory Committees ◽

Once Daily ◽

Acute Myeloid ◽

Refractory Aml

Introduction: CFI-400945 is a first-in-class, potent, selective, orally active inhibitor of Polo-like kinase 4 (PLK4) (Ki=0.26nM), a master regulator of centriole duplication, necessary for genomic integrity (Mason et al. Cancer Cell 2014; 26:163-76). CFI-400945 has activity in leukemia cell lines and primary leukemia samples including those with complex karyotype, inversion 3 and monosomy 7 (Minden. personal communications). This suggests that CFI-400945 may provide an effective treatment of patients with AML. The objectives of this phase 1 trial was to establish the safety, tolerability, and recommend phase II dose (RP2D) of CFI-400945 in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods: Patients with relapsed/refractory AML or MDS and patients with untreated AML who refused induction chemotherapy or who are not candidates for intensive chemotherapy were eligible. Dose escalation followed a standard 3+3 design with a starting dose of 64 mg orally once daily. Plasma levels of CFI-400945 free base were measured on Days 1, 2, & 29 of Cycle 1 and Day 15 on all subsequent cycles. Peripheral blood and/or bone marrow were obtained at baseline, Day 8 of Cycle 1 and Day 1 of each subsequent cycle prior to dosing for pharmacodynamic monitoring. Safety assessments using the NCI CTCAE version 4.03 were performed. Results: From May 2018 to June 2019, nine patients have been enrolled on study across three pre-defined dose levels (64 mg [n=3], 96 mg [n=4], and 128 mg [n=2]). Three patients had untreated AML, five patients had relapsed/refractory AML and one patient had myelodysplastic syndrome/myeloproliferative disorder (MDS/MPN). Patient characteristics at diagnosis are outlined in Table 1. Six (67%) patients had baseline high throughput sequencing; the most frequent mutations were TP53 (33%), TET2 (33%), KRAS (33%) and DNMT3A (33%). A total of 20 cycles were administered with a median of 1 cycle (range, 0 to 7 cycles). The most common non-hematological drug related toxicities of any grade, which occurred in over 20%, were diarrhea (44%), headache (44%), colitis (33%), vomiting (33%), bilirubin increase (22%), dizziness (22%), fatigue (22%), and nausea (22%). One patient on the 96 mg dose level was not evaluable for DLT and hence, replaced. Both patients treated at the 128 mg/day dose level developed DLTs, consisting of grade 3 colitis and grade 5 sepsis and colitis. Pharmacokinetic profile indicated low interpatient variability between patients. Maximum exposure did not correlate with toxicity Six patients were evaluable for disease response. Two (33%) achieved complete remission (CR), 3 pts (50%) had stable disease (with one patient having a 78% reduction in marrow blast count). The patient with MDS/MPN who did not complete 1 cycle of therapy progressed to AML (Figure 1). Both patients who obtained a CR had an early response within 2 cycles. One CR has been durable for 218 days with no measurable residual disease (MRD) by flow cytometry. The additional patient, who obtained a CR with incomplete platelets recovery, with subsequent best response of CR, had a sustained response for 91 days before relapse was confirmed by bone marrow examination (Figure 1). Conclusion: Single agent CFI-400945 has activity in patients with poor risk AML. The RP2D in this population is 96 mg once daily. Dose expansion is occurring at the RP2D level. A phase 2 study with CFI-400945 single agent or in combination study with azacitidine or decitabine is planned. Disclosures Leber: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bray:Treadwell Therapeutics: Current Employment; TIO Discovery: Current Employment. Gupta:Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Maze:Novartis: Honoraria; Pfizer: Consultancy; Takeda: Research Funding. McNamara:Novartis: Honoraria. Schimmer:Jazz: Honoraria; Otsuka: Honoraria; Medivir AB: Research Funding; AbbVie Pharmaceuticals: Other: owns stock ; Takeda: Honoraria, Research Funding; Novartis: Honoraria.

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Arsenic Trioxide Reprograms the Bone-Marrow Microenvironment to Sensitize Minimal Residual Disease in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-153244 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1166-1166

Author(s):

Patric Teodorescu ◽

Yuya Nagai ◽

Guo Zhong ◽

Vikram Mathews ◽

Nina Isoherranen ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Arsenic Trioxide ◽

Minimal Residual Disease ◽

Myeloid Leukemia ◽

Residual Disease ◽

Single Agent ◽

Bone Marrow Niche ◽

Minimal Residual ◽

Acute Myeloid

Abstract Eliminating minimal residual disease (MRD) in order to prevent relapse is an unmet need in acute myeloid leukemia (AML). One of the success stories is acute promyelocytic leukemia (APL), a unique subtype of AML. The use of arsenic trioxide (ATO) in combination with all-trans retinoic acid (ATRA) has essentially eliminated disease relapse (<1% ATRA+ATO vs. ~18% ATRA+ chemotherapy - NEJM (2013), 369(2), 111-121). This is even more impressive as neither agent alone results in significant cure of patients with APL. In fact, single agent ATRA induces remission without cure due to bone marrow stroma expression of CYP26 enzymes (PloS one (2015), 10(6), e0127790), which are induced by ATRA, inactivate retinoids and protect APL MRD (Leukemia (2020), 34(11), 3077-3081). While ATO may synergize with ATRA by restoring PML nuclear bodies (Nature medicine (2014), 20(2), 167-174) and rescuing RAR-α dependent transcription (Nature reviews. Cancer (2018), 18(2), 117-127) in the bulk of the APL tumor cells, it is unclear how these mechanisms contribute to elimination of MRD, particularly given the hypothesized lack of ATRA in the bone marrow niche. It was previously reported that combination of ATRA with ATO may be associated with high incidence of transaminitis and headaches (NEJM (2013), 369(2), 111-121). Since these may be clinical signs of ATRA toxicity, we investigated if addition of ATO changes the pharmacokinetics (PKs) of ATRA in patients with APL. We determined the area under the plasma concentration versus time curve (AUC) for ATRA in patients suspected of APL and treated with single agent ATRA ("preATO") and in the same patients after the diagnoses of APL was confirmed and the patients received ATO ("postATO"). Even though ATRA should have an expected drop in AUC during the first 3-4 days of therapy (JPET (2017), 361(2), 246-258), addition of ATO resulted in improved ATRA PKs (Figure A). Since ATRA levels are mainly controlled by clearance via hepatic CYP26s, we tested if treatment with ATO changes the levels of CYP26 or its induction by ATRA. We found that exposure to ATO decreases both baseline and ATRA-induced upregulation of CYP26B1 in HepG2 cells (Figure B). Similarly, ATO decreases CYP26B1 levels in human bone marrow derived mesenchymal stroma cells (MSCs) at baseline (21%±7% of NO ATO control, n=3, p<0.01) and after ATRA-induced upregulation (66%±14% of ATRA only control, n=3, p<0.01). These changes resulted in improved ATRA PKs in vitro in the presence of bone marrow MSCs (Figure C). Next, we used NB4-EvAsR cells (NB4R), ATO-resistant APL cells to test if ATO-induced improvement of MSC-dependent ATRA PKs may contribute to elimination of APL MRD. We found that ATO sensitizes NB4R to ATRA in the presence of BM MSCs but not in stroma free conditions (Figure D). ATO had no effect on ATRA-induced differentiation of NB4R in the presence of CYP26B1 knockout stroma (this stroma offers no protection from ATRA) or if stroma expresses CYP26B1 under the control of a viral promoter and thus, resistant to ATO downregulation. This data suggest that ATO-induced changes of BM MSC expression of CYP26 may contribute to elimination of MRD in APL. Stromal CYP26 protects not only APL but also non-APL AML cells from retinoids (Leukemia (2020), 34(11), 3077-3081). Retinoids are synergistic with FLT3 inhibitors to eliminate mutant FLT3 AML cells (Blood (2016), 127(23), 2867-2878) and stromal CYP26 breaks this synergism (Blood (2015) 126 (23): 790). We tested if ATO sensitizes mutant FLT3 AML cells, MV4;11 to gilteritinib in the presence of BM MSCs. For this, we derived MV4.11 cells resistant to ATO (MV4.11R) via long term exposure to increasing concentration of ATO. As seen with NB4R, ATO treatment synergizes with gilteritinib to decrease the IC50 of gilteritinib against the clonogenic activity of MV4.11R in the presence of stroma but not in stroma free conditions (Figure E). In an effort to fully explore the translational potential of these findings, we are currently investigating the mechanism by which ATO changes CYP26 levels. Taken together these findings support a model in which ATO changes the bone marrow niche and it's ability to metabolize retinoids and thus, sensitizes MRD in AML to targeted therapy. Figure 1 Figure 1. Disclosures Mathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor. Ghiaur: Syros Pharmaceuticals: Consultancy; Menarini Richerche: Research Funding.

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Phase I/II Clinical Study of Tosedostat, an Inhibitor of Aminopeptidases, in Patients With Acute Myeloid Leukemia and Myelodysplasia

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.6295 ◽

2010 ◽

Vol 28 (28) ◽

pp. 4333-4338 ◽

Cited By ~ 50

Author(s):

Bob Löwenberg ◽

Gareth Morgan ◽

Gert J. Ossenkoppele ◽

Alan K. Burnett ◽

Pierre Zachée ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Platelet Count ◽

Phase I ◽

Phase Ii ◽

Myeloid Leukemia ◽

Hematologic Malignancies ◽

Maximum Tolerated Dose ◽

Antileukemic Activity ◽

Once Daily ◽

Acute Myeloid

Purpose To identify the maximum-tolerated dose (MTD) and to evaluate the antileukemic activity of tosedostat (formerly CHR-2797), an orally bioavailable aminopeptidase inhibitor. Patients and Methods In phase I, the MTD of once daily oral doses of tosedostat in hematologic malignancies was defined. In phase II, the therapeutic activity of the maximum-acceptable dose (MAD) of tosedostat was evaluated in elderly and/or relapsing patients with acute myeloid leukemia (AML) or myelodysplastic syndrome. Results In phase I, 16 patients were treated in four cohorts with tosedostat (60 mg to 180 mg) for 28 days. Three patients reported dose-limiting toxicities: two with reversible thrombocytopenia (> 75% reduction in platelet count) at 180 mg (MTD) and one with a Common Toxicity Criteria (CTC) grade 3 ALT elevation at 130 mg (MAD). In phase II, 41 patients were treated with 130 mg tosedostat. In phases I and II, the most common severe (CTC grades 3 to 5) adverse event was a reduction in the platelet count. Of the 51 AML patients in this study, seven reached complete marrow response (< 5% marrow blasts), with three achieving complete remission, and a further seven patients reaching a partial marrow response (between 5% and 15% marrow blasts). The overall response rate was therefore 27%. All responders were age > 60 years, and 79% had either relapsed or refractory AML. Conclusion This phase I/II study demonstrates that oral once daily dosing with 130 mg tosedostat is well tolerated and has significant antileukemic activity. The favorable risk-benefit profile suggests that further clinical trials are warranted.

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RHAMM/CD168-R3 Peptide Vaccination of HLA-A2+ Patients with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS) and Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v106.11.2781.2781 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2781-2781 ◽

Cited By ~ 2

Author(s):

Jochen Greiner ◽

Krzysztof Giannopoulos ◽

Li Li ◽

Peter Liebisch ◽

Christiane Wendl ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

T Cells ◽

Acute Myeloid Leukemia ◽

T Cell ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Hematological Malignancies ◽

Peptide Vaccination ◽

Acute Myeloid

Abstract The receptor for hyaluronic acid mediated motility (RHAMM/CD168) has been described as a leukemia-associated antigen (LAA) eliciting both humoral and cellular immune responses in patients with hematological malignancies. RHAMM/CD168 is expressed in more than 80% of patients with acute myeloid leukemia (AML) or multiple myeloma (MM). Recently, we characterized the RHAMM/CD168-derived peptide R3 (ILSLELMKL) as a CD8+ T cell epitope. R3-primed CD8+ T lymphocytes were able to lyse autologous RHAMM/CD168+ AML blasts in a MHC class I-restricted and epitope-specific manner. Therefore, we initiated a phase I/II R3 peptide vaccination trial for patients with AML, MDS or MM overexpressing RHAMM/CD168. Patients were included with positive RHAMM/CD168 expression but with a limited tumor load. 300 mcg RHAMM R3 peptide emulsified with the incomplete Freund’s adjuvant (ISA-51, Montanide; day 3) and GM-CSF (Leukine, days 1–5) was administrated four times subcutaneously at a biweekly interval. The primary aim of the study is safety and feasibility of this peptide vaccination, secondary aims the evaluation of a specific T cell immune response to RHAMM/CD168 R3 peptide and the assessment of the influence of the R3 peptide vaccination on the remission status. Since January 2005, ten patients were enrolled in this study. The first eight patients (2 AML, 3 MDS, 3 MM) have completed the course of four vaccinations and four patients have been evaluated. The only side effects observed under R3-peptide vaccination were erythema and induration of the skin at the site of injection (CTC I°). In 2/4 patients, we found in the peripheral blood a significant increase of specific CD8+ T cells (from 0.01% to 0.8%) recognizing the R3 peptide in ELISPOT analysis and tetramer staining, one patient showed already initially a high number of HLA-A2/R3 tetramer+CCR7-CD27-CD45RA+ effector T cells and maintained this level of T cell response. Clinical responses have been assessed by the examination of peripheral blood and bone-marrow samples before and after vaccination. Patients showed a reduction of the tumor-specific expressed antigen RHAMM/CD168 in real-time RT-PCR analysis after vaccination. 2/4 patients with myeloid disorders (1 AML, 1 MDS RAEB1) showed a reduction of CD33+ cells in FACS analysis of the bone-marrow after 4 vaccinations from 10 and 7 % to 1–2 and <1%, respectively. One patient with MM showed a reduction of plasma cells in bone-marrow and a stable quantity of light chains in peripheral blood, one patient with AML showed a progressive disease. In summary, RHAMM/CD168 is a promising target antigen for immunotherapies in patients with hematological malignancies.

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