scholarly journals 445 Trial in progress: A phase 1b/2 study of alrizomadlin (APG-115), alone or combined with 5-azacitidine, in patients with relapsed/refractory acute myeloid leukemia (R/R AML)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A474-A474
Author(s):  
Yifan Zhai ◽  
Tapan Kadia
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Maximum Tolerated Dose ◽  
Wild Type ◽  
Open Label ◽  
Durable Response ◽  
Link Type ◽  
Acute Myeloid

BackgroundAcute myeloid leukemia (AML) is the most common form of acute leukemia in adults, with an incidence that increases with age and a generally poor prognosis. This aggressive blood and bone-marrow malignancy is characterized by rapid and uncontrolled clonal proliferation of abnormal myeloid progenitor cells. Patients with R/R AML have very few approved effective treatment options, especially in the absence of a targetable mutation. Alrizomadlin is a novel, orally active, potent, small-molecule selective inhibitor that destabilizes the p53-MDM2 complex and activates p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. In acute leukemia human wild-type TP53 AML cell lines and xenograft models, alrizomadlin potently inhibited tumor cell growth when administered alone or with concomitant chemotherapy.MethodsThis US open-label study is evaluating the safety and tolerability of alrizomadlin, with or without 5-azacitidine, in adults with histologically confirmed R/R AML and adequate organ function. Eligible candidates will have AML with no known available therapies that are either indicated or expected to confer a durable response. In Part 1 of this trial, the safety and tolerability of alrizomadlin monotherapy are being assessed by evaluating the dose-limiting toxicity rate during the first 4 weeks of treatment, using a standard 3+3 design. The starting once-daily oral dose of alrizomadlin administered on Day 1 to 5 of every 28-day cycle is 100 mg, increasing to 150, 200, and 250 mg in each subsequent cohort. The severity of adverse events is being assessed using NCI CTCAE v5.0. Once the recommended phase 2 dose (RP2D) has been determined, 3 to 6 additional patients will be enrolled in the dose-expansion phase. In Part 2, alrizomadlin will be administered in combination with 5-azacitidine 75 mg/m2/day on Days 1–7 of a 28-day cycles. Alternatively, a 5-days-on, 2-days-off, 2-days-on schedule is allowed if consecutive day infusion is not available. A standard 3+3 design will also be implemented to determine the maximum tolerated dose/RP2D in the dose-escalation phase. Once the RP2D has been determined, there will be an expansion cohort of up to 15 patients. As of July 13, 2021, 2 patients have been enrolled in the alrizomadlin monotherapy dose-escalation phase. The overall estimated enrollment will be 69 study participants. Internal study identifier APG115AU101. ClinicalTrials.gov identifier: NCT04358393.Trial RegistrationClinicalTrials.gov identifier: NCT04358393

scholarly journals Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome

2020 ◽  
Vol 4 (9) ◽  
pp. 2032-2043 ◽  
Author(s):  
Je-Hwan Lee ◽  
Stefan Faderl ◽  
John M. Pagel ◽  
Chul Won Jung ◽  
Sung-Soo Yoon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Acute Myeloid

Abstract CWP232291 (CWP291) is a small-molecule inhibitor of Wnt signaling that causes degradation of β-catenin via apoptosis induction through endoplasmic reticulum stress activation. This first-in-human, open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of CWP291 enrolled 69 patients with hematologic malignancies (acute myeloid leukemia [AML], n = 64; myelodysplastic syndrome, n = 5) in 15 dose-escalation cohorts of 4 to 334 mg/m2 using a modified 3+3 design and 1 dose-expansion cohort. CWP291 was administered IV daily for 7 days every 21 days. The most common treatment-emergent adverse events (TEAEs) were nausea (n = 44, 64%), vomiting (n = 32, 46%), diarrhea (n = 25, 36%), and infusion-related reactions (n = 20, 29%). Grade ≥3 TEAEs in >3 patients (5%) were pneumonia (n = 8, 12%); hypophosphatemia (n = 6, 8%); leukocytosis, nausea, cellulitis, sepsis, and hypokalemia (n = 5 each, 7% each); and hypertension (n = 4, 6%). Dose-limiting toxicities included nausea (n = 3) and abdominal pain, anaphylactic reaction, myalgia, and rash (n = 1, each); the MTD was defined at 257 mg/m2. CWP232204, the active metabolite of CWP291, showed pharmacokinetic linearity on both days 1 and 7, and a terminal half-life of ∼12 hours. Among 54 response-evaluable AML patients, there was one complete response at a dose of 153 mg/m2 and one partial response at 198 mg/m2; bone marrow blast percentage reduced from a median of 58.3% to 3.5% and 15.0% to 4.2%, respectively. Future studies will explore CWP291, with a mechanism of action aimed at eradication of earlier progenitors via Wnt pathway blockade, as combination therapy. This trial was registered at www.clinicaltrials.gov as #NCT01398462.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 841-841 ◽  
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.

scholarly journals Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia

2019 ◽  
Vol 3 (13) ◽  
pp. 1939-1949 ◽  
Author(s):  
Harry P. Erba ◽  
Pamela S. Becker ◽  
Paul J. Shami ◽  
Michael R. Grunwald ◽  
Donna L. Flesher ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Open Label ◽  
Refractory Acute Myeloid Leukemia ◽  
Higher Doses ◽  
Acute Myeloid

AbstractThis open-label, phase 1 study evaluated the safety, pharmacokinetics, and maximum tolerated dose of AMG 232, an investigational oral, selective mouse double minute 2 homolog inhibitor in relapsed/refractory acute myeloid leukemia (AML). AMG 232 was administered orally once daily for 7 days every 2 weeks (7 on/off) at 60, 120, 240, 360, 480, or 960 mg as monotherapy (arm 1) or at 60 mg with trametinib 2 mg (arm 2). Dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics, clinical and pharmacodynamic response, and expression of p53 target genes were assessed. All 36 patients received AMG 232. No DLTs occurred in arm 1, and 360 mg was the highest test dose; dose escalation was halted due to gastrointestinal AEs at higher doses. One of ten patients in arm 2 had a DLT (grade 3 fatigue); 60 mg was the highest dose tested with trametinib. Common treatment-related AEs (any grade) included nausea (58%), diarrhea (56%), vomiting (33%), and decreased appetite (25%). AMG 232 exhibited linear pharmacokinetics unaffected by coadministration with trametinib. Serum macrophage inhibitor cytokine-1 and bone marrow expression of BAX, PUMA, P21, and MDM2 increased during treatment. Of 30 evaluable patients, 1 achieved complete remission, 4 had morphologic leukemia-free state, and 1 had partial remission. Four of 13 (31%) TP53-wild-type patients and 0 of 3 (0%) TP53-mutant patients were responders. AMG 232 was associated with gastrointestinal AEs at higher doses but had acceptable pharmacokinetics, on-target effects, and promising clinical activity warranting further investigation in patients with relapsed/refractory AML. This trial was registered at www.clinicaltrials.gov as #NCT02016729.

Determination of the Maximum Tolerated Dose of Panobinostat in Combination with Cytarabine and Mitoxantrone As Salvage Therapy for Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 423-423 ◽  
Author(s):  
Richard F. Schlenk ◽  
Jürgen Krauter ◽  
Markus Schaich ◽  
Didier Bouscary ◽  
Hervé Dombret ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Febrile Neutropenia ◽  
Dose Escalation ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Maximum Tolerated Dose ◽  
Refractory Acute Myeloid Leukemia ◽  
Grade 3 ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract Abstract 423 BACKGROUND: Relapsed/refractory acute myeloid leukemia (AML) is characterized by poor prognosis, with low complete remission (CR) rates after salvage therapy and low overall survival. A major challenge is to improve the CR rate, thereby increasing allogeneic hematopoietic stem cell transplantation (alloHSCT) rates. Panobinostat is a pan-deacetylase inhibitor that increases acetylation of proteins involved in cancer. Preclinical studies in AML demonstrated that panobinostat potentiates the activity of cytarabine (ara-C) and fludarabine and has synergistic activity in combination with doxorubicin in vitro. Single-agent panobinostat has induced CR in patients (pts) with AML. The addition of panobinostat to an active chemotherapeutic regimen in pts with relapsed/refractory AML has the potential to improve therapeutic outcomes in this setting. AIMS: This phase Ib, multicenter, open-label dose-escalation study was designed to determine the maximum tolerated dose (MTD) of panobinostat in combination with a fixed dose of ara-C and mitoxantrone in pts with relapsed/refractory AML. The secondary objectives were to characterize safety and tolerability during the dose-escalation phase and at the MTD and to evaluate anti-leukemic activity. METHODS: Successive cohorts of at least 3 pts with confirmed relapsed or refractory AML were treated with oral panobinostat (starting with 20 mg, escalated in 10-mg steps) thrice weekly on days 1, 3, 5, 8, 10, and 12, in combination with intravenous ara-C (1 g/m2) on days 1–6 and mitoxantrone (5 mg/m2) on days 1–5 of a 28-day cycle. The MTD was determined on the basis of the observed dose-limiting toxicities (DLTs), safety assessment, and tolerability during the first 28 days after starting panobinostat. A DLT was defined as any adverse event (AE) or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications with the following criteria: neutropenia lasting > 28 days after cycle 1 for hematologic DLTs; grade 4 AST/ALT or grade 3 AST/ALT for > 7 days; grade 3/4 bilirubin, vomiting, diarrhea, or any non-hematologic toxicity for non-hematologic DLTs. Safety and tolerability were described as type, duration, frequency, relatedness, and severity of AEs according to CTCAE v3.0. The adaptive Bayesian logistic regression model was used to guide dose escalation with overdose control. RESULTS: Of 5 dose levels, 40 pts (median age, 55 years; range, 19–73 years) were treated at panobinostat dosages of 20 to 60 mg, with 5 pts at 20 mg, 8 at 30 mg, 10 at 40 mg, 11 at 50 mg, and 6 at 60 mg. Of 6 DLTs observed, 1 was at 40 mg (sepsis and tachyarrhythmia), 2 were at 50 mg (vomiting/nausea; diarrhea), and 3 were at 60 mg (neutropenic colitis; 2 hypokalemic events). Frequent AEs of all grades, regardless of causality, included nausea (32 [80%]), diarrhea (31 [78%]), vomiting (26 [65%]), hypokalemia (25 [63%]), thrombocytopenia (24 [60%]), abdominal pain (22 [55%]), decreased appetite, and febrile neutropenia (21 each [53%]). The most frequent grade 3/4 treatment-related AEs were thrombocytopenia (20 [50%]), anemia (9 [23%]), leukopenia, and neutropenia (7 each [18%]). Serious AEs, regardless of causality, were reported in 23 pts, with febrile neutropenia (12 [30%]) being the most common. The MTD was determined to be 50 mg of panobinostat on the basis of observed DLTs and safety and tolerability in cycle 1 of the dose-escalation phase. Clinical responses were observed in 22 pts (55%), including 13 CR, 5 morphological CR, and 4 partial remissions. In pts receiving 40- and 50-mg doses of panobinostat, the preliminary efficacy was promising, with a response in 11 of 21 pts (52%). An alloHSCT was performed in 8 pts after the start of salvage therapy. CONCLUSIONS: The combination of panobinostat, ara-C, and mitoxantrone showed no unexpected toxicities and promising anti-leukemic activity in pts with relapsed/refractory AML. The MTD was determined to be 50 mg of panobinostat; enrollment at this dose is ongoing for the dose-expansion phase to further assess safety, tolerability, and activity. Thrombocytopenia and anemia were the principal treatment-related hematologic AEs. Treatment-related non-hematologic AEs were primarily gastrointestinal toxicities and fatigue. Disclosures: Krauter: Novartis: Consultancy, Honoraria. Winiger:Novartis AG: Employment, Equity Ownership, Honoraria. Squier:Novartis Corporation: Employment. Zahlten:Novartis AG: Employment. Wang:Novartis Corporation: Employment. Ottmann:Novartis Corporation: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.

The Mll PTD and Flt3 ITD Double Knock-In Mouse Develops Acute Leukemia and Recapitulates Phenotypic, Molecular and Epigenetic Characteristics of the Counterpart Human Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 150-150 ◽  
Author(s):  
Nicholas Zorko ◽  
Susan P. Whitman ◽  
Kelsie Bernot ◽  
Myntee T. Ngangana ◽  
Ronald Siebenaler ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Fold Increase ◽  
Global Dna Methylation ◽  
Wild Type ◽  
Single Mutant ◽  
Acute Myeloid

Abstract Abstract 150 Background. The Mll PTD and Flt3 ITD are co-present in a subset of adult patients (pts) with cytogenetically normal (CN) acute myeloid leukemia (AML) and poor clinical outcomes. While the single mutant knock-in (KI) mice (Mll PTD or Flt3 ITD) exhibit enhanced myeloid progenitor self-renewal or reduced apoptosis, respectively, neither model develops acute leukemia. We hypothesized that with mutant expression driven via the endogenous promoters, the two mutations may cooperate in vivo to induce an acute leukemia that mimics the human counterpart. Methods. Single mutant heterozygous KI mice were crossed to produce the PTD/ITD double KI. PTD/ITD mice were bred with the homozygous Flt3 ITD to generate the PTD/ITD2 genotype. An AML diagnosis was based on blood differentials, immunophenotyping, tissue pathology and transplantability. Real time RT-PCR and 5'-methylcytosine LC/MS assays measured gene expression and global DNA methylation levels, respectively. Results. PTD/ITD and PTD/ITD2 mice developed transplantable, CN-AML/undifferentiated leukemia exhibiting expansion of monocytic/myelomonocytic Gr1±/Mac1+ and/or immature CD3−/CD19−/CD117+/Mac1−/B220lo cell populations, splenomegaly, leukocytosis, anemia and thrombocytopenia. PTD/ITD mice had significantly reduced lifespans compared to mice with single mutant PTD and ITD KIs and wild-type (Wt) controls (medians: 50, 99, 88, 94 weeks, respectively; P<0.001) (Figure 1). Increased ITD gene dosage (PTD/ITD2) was associated with an even shorter lifespan (median: 16 weeks) (Figure 1). This is consistent with the poor prognosis conferred by high FLT3 ITD-to-FLT3 wild-type (WT) gene ratio in diagnostic leukemia blasts from AML pts treated with intensive chemotherapy. As in human MLL PTD AML, the Mll WT allele was downregulated in the murine model. Mll WT expression was >2-fold lower in bone marrow (BM) of leukemic PTD/ITD mice compared to age-matched single mutant KIs or Wt controls. HoxA9 and its cofactor Meis1 were upregulated 15- and 5-fold, respectively, in PTD/ITD mice with leukemia versus Wt BM. Yet, compared to Wt BM, single PTD KI exhibited increased HoxA9 (∼6-fold) but not Meis1, implicating an expression threshold for HoxA9 and a crucial role for Meis1 for the development of acute leukemia in the double KI. Consistent with Flt3 being a downstream transcriptional target of Meis1, total Flt3 mRNA (WT and ITD) levels increased 3-fold in the leukemic PTD/ITD mice relative to either single mutant KIs or Wt controls. Furthermore, one consequence of constitutive Flt3 ITD kinase activity is the upregulation of the anti-apoptotic kinase, Pim1, in human AML. Compared to Wt BM, a 2-fold increase in Pim-1 expression was observed in single ITD KI and a 6-fold increase was observed in leukemic PTD/ITD BM, while expression was unchanged in the single PTD KI BM. Finally, MLL PTD presence in human AML associates with increased global DNA methylation and silencing of tumor suppressor genes. We observed 3-fold higher transcript levels of a de novo methyltransferase, DNA methyltransferase 3b (DNMT3b), increased global DNA methylation and ≥2-fold decrease in the expression of tumor suppressors Id4, Shp1 and Cdkn1b in BM of leukemia PTD/ITD mice compared to age-matched single mutant KIs and Wt controls. Conclusion. The Flt3 ITD and Mll PTD, expressed via their endogenous promoters, cooperate in vivo to give rise to AML and acute undifferentiated leukemia. Elevations of Meis1 and DNMT3b solely in PTD/ITD animals appear to be critical points of dysregulation leading to development of acute leukemia. This novel murine model phenotypically, molecularly, and epigenetically mimics the human AML counterpart, thus making it highly relevant for examining critical pathways in acute myeloid leukemogenesis, investigating leukemia stem/initiating cell biology and microenvironment contributions, and testing novel targeting therapeutics. Disclosures: No relevant conflicts of interest to declare.

Determination of the Maximum Tolerated Dose of Panobinostat in Combination with a 5-Day Schedule of Azacitidine in High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia: Planned Interim Analysis of a Phase Ib/II Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1529-1529 ◽  
Author(s):  
Peter T. Tan ◽  
Kate Reed ◽  
Patricia A. Walker ◽  
Sharon Avery ◽  
Sushrut S. Patil ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Maximum Tolerated Dose ◽  
Patient Choice ◽  
Phase Ib ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Abstract 1529 Background: The management options for patients with high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy remain limited. The combination of hypomethylating agent and deacetylase inhibitor (DACi) has been shown to be synergistic, both in terms of leukaemia cell killing and gene reactivation in vitro. Aim: To investigate the safety, tolerability and preliminary efficacy of combining the oral pan-DACi panobinostat (LBH589) with azacitidine in previously untreated MDS or AML, not fit for standard induction therapy. Methods: Phase Ib/II multi-center open label dose-escalation and expansion study. Inclusion criteria: untreated IPSS intermediate-2 or high risk MDS, or AML (marrow blasts ≥20%), not eligible for standard induction therapy. Patients received azacitidine 75 mg/m2 SC on days 1–5 of each 28-day cycle with 10, 20, 30 or 40mg panobinostat orally 3 days per week (M/W/F) for 7 doses per cycle commencing on day 5. The safety and tolerability of the combination was assessed. Results: This preliminary analysis includes 26 patients (M 17, F 9), median age 69 years (36–81). 18 AML patients had intermediate (11/18) or poor cytogenetic risk (7/18); 8 MDS patients with intermediate-2 (7/8) or high risk (1/8) IPSS. Patients were enrolled into panobinostat dose-escalation cohorts of 10mg (4 patients), 20mg (7), 30mg (6) or 40mg (6); and expansion study 30mg (3). All grade non-hematologic adverse events regardless of relatedness to study treatment (>10%) were: subcutaneous injection site redness or pain (57%), fatigue (48%), nausea (30%), anorexia (22%), diarrhoea (22%), dyspnoea (13%), fever (13%), hyperbilirubinemia (13%), hyperglycaemia (13%), hyponatremia (13%), leg oedema (13%) and light headedness (13%). There were no unexpected adverse events or drug reactions. The principal dose-limiting toxicity (DLT) was fatigue, as haematological toxicity was not considered dose-limiting. In the dose-escalation phase, the grade 3/4 DLTs were: panobinostat 10mg cohort (0/4 DLT), panobinostat 20mg cohort (1/7 DLT; grade 3 fatigue), panobinostat 30mg cohort (1/6 DLT; grade 3 fatigue), panobinostat 40mg (4/6 DLTs; all grade 3: fatigue (1), syncope (1), hyponatremia (1) and somnolence/reduced level of consciousness (1)). Therefore, in combination with the 5-day schedule of azacitidine, the maximum tolerated dose (MTD) of panobinostat was defined at 30mg; this dose level has been selected for expanded accrual. At present 10/26 patients (38%) remain on combination study therapy. The panobinostat dose has been reduced by one dose level in 5/26 patients (19%) due to fatigue; 3 patients from panobinostat 40mg cohort. In 16 patients taken off study, the most common cause was disease progression (9), infection (2), atrial fibrillation treated with panobinostat interacting medication (2), patient choice (2) and fatigue (1). The median number of treatment cycles initiated was 4 (1–16). Preliminary efficacy in 18 AML patients, 3 achieved PR, 7 SD, 7 PD and 1 death unrelated to disease or therapy. In 8 MDS patients, 2 achieved CR, 3 PR, 2 SD, and 1 not evaluable (withdrawal due to patient choice). After a median follow-up of 276 days, the median OS is 239 days (22–472). Conclusion: In previously untreated MDS/AML, panobinostat and azacitidine is well tolerated and preliminary assessments demonstrate clinical activity. The MTD was determined to be 30mg of panobinostat in combination with a 5-day azacitidine schedule of 75mg/m2 daily. Further evaluation of this combination with panobinostat 30mg dose is ongoing in the dose-expansion phase of the study. Disclosures: Mollee: Celgene: Membership on an entity's Board of Directors or advisory committees. Gervasio:Novartis: Employment. Winiger:Novartis AG: Employee, Employment, Equity Ownership, Honoraria. Hönemann:Celgene Pty Ltd: Employment. Wei:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Spencer:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

scholarly journals Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia

2020 ◽  
Vol 38 (5) ◽  
pp. 1430-1441
Author(s):  
Geoffrey L. Uy ◽  
Sarit Assouline ◽  
Anne-Marie Young ◽  
Steven Blotner ◽  
Brian Higgins ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Active Principle ◽  
Wild Type ◽  
Antileukemic Activity ◽  
Platelet Recovery ◽  
Mdm2 Antagonist ◽  
Acute Myeloid

Abstract In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120–300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment–related adverse events in >20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%–47% (22%–54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967.

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