APG-115 + APG-2575 for Leukemia
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Ascentage Pharma Group Inc.
Must not be taking: CYP2C8 inhibitors, CYP3A4 inhibitors
Disqualifiers: CNS malignancy, Graft versus host, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial tests two experimental drugs, APG-115 and APG-2575, in patients with a rare type of leukemia called T-PLL. APG-115 aims to stop cancer cells from growing, while APG-2575 targets and kills cancer cells. The study will help determine if these drugs are safe and effective.
Will I have to stop taking my current medications?
The trial requires that you stop taking chemotherapy or antibody therapy 7 days before starting the study drugs. If you are taking strong CYP2C8 inhibitors or moderate/strong CYP3A4 inhibitors or inducers, you must stop them at least 14 days or 7 half-lives before starting the study drugs, whichever is longer.
What data supports the effectiveness of the drug APG-115 + APG-2575 for treating leukemia?
While there is no direct data on APG-115 and APG-2575 for leukemia, similar drugs like venetoclax have shown effectiveness in treating acute myeloid leukemia (AML), especially in combination with other agents. Venetoclax, a BCL-2 inhibitor like APG-2575, has been effective in achieving remission in AML patients, suggesting potential for similar drugs.
12345What makes the drug combination APG-115 and APG-2575 unique for treating leukemia?
The combination of APG-115 and APG-2575 is unique because it targets specific proteins involved in cancer cell survival, potentially offering a novel approach compared to traditional chemotherapy. APG-115 is known to inhibit MDM2, a protein that regulates the tumor suppressor p53, while APG-2575 targets BCL-2, a protein that helps cancer cells avoid death, making this combination potentially more effective in inducing cancer cell death.
678910Eligibility Criteria
Adults with T-PLL leukemia who've had at least one prior therapy can join. They must be in good enough health, not have received certain treatments recently, and agree to use contraception. People with severe allergies to the drugs, active infections like HIV or COVID-19, heart problems, other untreated cancers or those needing strong immune system drugs can't participate.Inclusion Criteria
My lab tests for tumor lysis syndrome are within safe limits and any symptoms are mild.
Total bilirubin ≤ 1.5 × upper limit of normal (ULN), unless related to leukemic involvement
I am not pregnant and agree to use contraception during the study.
+10 more
Exclusion Criteria
I have been diagnosed with HIV.
I haven't taken strong medication that affects liver enzymes in the last 14 days or 7 half-lives.
I have tested positive for COVID-19.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive APG-115 as a single agent or in combination with APG-2575 to evaluate pharmacokinetics, safety, and efficacy
21 days
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing APG-115 alone or combined with APG-2575 on patients with T-PLL leukemia. It's an open-label phase IIa study looking at how the body processes these drugs and their safety and effectiveness across multiple centers involving 24-36 participants.
3Treatment groups
Experimental Treatment
Group I: APG-115 monotherapy partExperimental Treatment1 Intervention
APG-115 will be given alone
Group II: APG-115 + APG-2575 combination dose expansion partExperimental Treatment2 Interventions
APG-115 is given in combination with APG-2575
Group III: APG-115 + APG-2575 combination dose escalation partExperimental Treatment2 Interventions
APG-115 is given in combination with APG-2575
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Ohio State UniversityColumbus, OH
MD AndersonHouston, TX
City of HopeDuarte, CA
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Who Is Running the Clinical Trial?
Ascentage Pharma Group Inc.Lead Sponsor
References
[Clinical efficacy and safety of venetoclax combined with multidrug chemotherapy in the treatment of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia]. [2023]Objective: To explore the efficacy and safety of Venetoclax combined with multidrug chemotherapy in patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia (R/R ETP-ALL) . Methods: This study retrospectively analyzed 15 patients with R/R ETP-ALL who received Venetoclax combined with multidrug chemotherapy from December 2018 to February 2022. Among them, eight cases were combined with demethylated drugs, four cases were combined with demethylated drugs and HAAG chemotherapy regimen, two cases were combined with demethylated drugs and CAG regimen, and one case was combined with Cladribine. Specific usage and dosage of Venetoclax: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3-28, orally; when combined with azole antifungal drugs, dosage was reduced to 100 mg/d. Results: Fifteen patients (10 males and 5 females) with R/R ETP-ALL were treated with Venetoclax and multidrug chemotherapy with a median age of 35 (12-42) years old. Of 4 refractory and 11 relapsed patients, the efficacy was evaluated on the 21th day following combined chemotherapy: the overall response rate, the complete response (CR) rate, and the CR with incomplete hematological recovery (CRi) rate were 67.7% (10/15), 60.0% (9/15), and 6.7% (1/15), respectively. For the overall study population, the 12-month overall survival (OS) rate was 60.0%, and the median OS was 17.7 months. The disease-free survival (DFS) rate of all CR patients at 12 months was 60.0%, and the median DFS did not reach. About 14 patients had Ⅲ-Ⅳ hematological toxicity, but these adverse reactions were all controllable. No adverse reaction in the nervous system and tumor lysis syndrome occurred in this study, and no adverse reaction of organs above grade Ⅲ occurred. Conclusion: Venetoclax combined with multidrug chemotherapy may be a safe and promising treatment option for patients with R/R ETP-ALL.
225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. [2021]Label="PURPOSE">Despite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new therapy approved for use in combination with a hypomethylating agent or with low-dose cytarabine for the treatment of newly diagnosed older AML patients or those ineligible for intensive chemotherapy. 225 Actinium-lintuzumab (225 Ac-lintuzumab) is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single-agent activity in relapsed/refractory AML. Increased expression of MCL-1 is a mediator of resistance to venetoclax in cancer.
Hymeglusin Enhances the Pro-Apoptotic Effects of Venetoclax in Acute Myeloid Leukemia. [2022]Venetoclax is used for the priority treatment of elderly patients with acute myeloid leukemia (AML). Resistance or intolerance to venetoclax offsets its clinical benefits in some patients. Combination strategies with other drugs are promising alternatives to overcome the current complications associated with venetoclax use. Hymeglusin, a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1), regulates the mevalonate pathway, which is vital for AML growth and chemosensitivity. The effects of the combination of venetoclax and hymeglusin on AML were explored in this study. The correlations between HMGCS1 and apoptosis-related genes were analyzed using the Gene Expression Profiling Interactive Analysis 2 and The Cancer Genome Atlas databases. Apoptosis and cell viability were detected in HL-60 and KG-1 cells after treatment with gradient concentrations of venetoclax or hymeglusin. The transcriptomic profiles of HL-60 and KG-1 cells were compared via RNA-Seq analysis. The effects of venetoclax and hymeglusin on apoptosis were validated in primary cells. The results showed that HMGCS1 expression was closely associated with apoptosis-related genes based on the data from large clinical databases. B cell lymphoma (BCL)-2 expression was elevated in AML and negatively associated with overall survival. Hymeglusin decreased BCL2 expression levels in HL-60 and KG-1 cells. Venetoclax and hymeglusin inhibited cell viability in both cell lines, but induced apoptosis in HL-60 cells. This discrepancy in sensitivity to hymeglusin may be attributed to the positive increase in the expression levels of HMGCS1 and multiple upregulated pro-leukemia genes in KG-1 cells. Combination treatment with venetoclax and hymeglusin significantly increased the apoptotic rates compared to single-agent treatment in both AML cell lines and primary AML cells. Furthermore, the combination strategy did not result in remarkably enhanced toxicity in normal mononuclear cells. Collectively, hymeglusin enhanced the effects of venetoclax on apoptosis. This combination strategy showed enhanced antileukemic activity with acceptable toxicity in AML.
Venetoclax for the treatment of elderly or chemotherapy-ineligible patients with acute myeloid leukemia: a step in the right direction or a game changer? [2022]Acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis and high rates of relapse, especially in elderly patients who are ineligible to receive intensive chemotherapy. Venetoclax, an oral BCL-2 inhibitor, is approved by the Food and Drug Administration in combination with hypomethylating agents or low-dose cytarabine in newly-diagnosed AML patients who are ineligible to receive intensive chemotherapy. Confirmatory phase III VIALE-A and VIALE-C trials showed a composite complete remission rate of 66.4% and 48%, respectively. Thus, further validating venetoclax as an attractive therapeutic option in the AML treatment landscape.
Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. [2022]Objectives: Venetoclax combinations are a new standard for patients with acute myeloid leukemia (AML). We aimed to evaluate the safety and efficacy of these combinations in a period of accelerated approval in Latin-America.Methods: This observational study evaluated adults with acute myeloid leukemia who received venetoclax-based therapy in 11 public or private centers in Mexico and Peru for both newly diagnosed or relapsed and refractory AML.Results: Fifty patients were included; 28 with newly diagnosed (ND) AML and 22 with relapsed/refractory (RR) disease. ND patients were older (64 vs. 40 years; p < 0.001) with a lower functional capacity (ECOG ≥2 64.3% vs 9%; p < 0.001). Venetoclax was frequently combined with azacytidine (60%) and prophylactic azoles (82%) with a median maximum dose of 200 mg (range, 100-600 mg). Hematologic toxicities were common. Complete response rates including patients with incomplete hematopoietic recovery were 78.6% in ND and 45.5% in RR patients, with a median overall survival of 9.6 (95% CI 3.7-15.5) and 8 months (95% CI 4.8-11.2).Discussion: Our study showed a preferred use of venetoclax plus azacytidine over cyatrabine. Patients in the first-line setting were similar to those in the landmark studies, while most patients with relapsed disease had received prior intensive therapies. Responses were favorable, with a median survival in agreement to other reports, albeit shorter than that observed in the randomized phase-3 trials.Conclusion: Venetoclax-based therapy in AML was effective despite dose reductions and prophylactic antifungals in two middle-income countries outside of a clinical trial setting.
Treatment of severe aplastic anemia by immunosuppressor anti-lymphocyte globulin/anti-thymus globulin as the chief medicine in combination with Chinese drugs. [2021]To study the therapeutic effect of combined therapy with Chinese drugs and immuno-suppressors, mainly anti-lymphocyte globulin/anti-thymus globulin (ALG/ATG), for the treatment of severe aplastic anemia (SAA), the efficacy associated factors and adverse effects as well.
Interindividual variability in the concentration-effect relationship of antilymphocyte globulins - a possible influence of FcgammaRIIIa genetic polymorphism. [2018]Polyclonal antilymphocyte globulins (ALGs) are currently used in transplantation, but the sources of interindividual variability of their effect are poorly understood. No pharmacokinetic-pharmacodynamic (PK-PD) study of ALG is available. Moreover, the genetic polymorphism of FcgammaRIIIa, a receptor for the Fc portion of immunoglobulins involved in antibody-dependent cellular cytotoxicity (ADCC), may influence their concentration-effect relationship.
Anti-lymphocyte globulin therapy in acquired aplastic anaemia. [2004]Thirty five patients with acquired aplastic anaemia (AAA) were treated with anti-lymphocyte globulin (ALG). Fifteen (42.9%) had non-severe aplastic anaemia (NSAA), 14 (40%) severe aplastic anaemia (SAA) and 6 very severe aplastic anaemia (VSAA). There were 17 (48.6%) responders to the first course of ALG while 2 out of 5 (40%) responded to a second course, the overall response rate being 54.3%. Eleven out of 15 (73.3%) with NSAA responded, 8 out of 20 (40%) with SAA responded while none of VSAA responded. All the non-responders have died. Out of the responders, 1 died of non-A non-B hepatitis, and 1 with relapse of AA and sepsis. One has developed paroxysmal nocturnal haemoglobinuria (PNH) and one myelodysplasia. Another 2 needed infrequent red cell transfusion support. Remaining 13 (37.1%) are asymptomatic and without any external support since 18-78 months (35 +/- 21). We conclude that ALG is an effective modality of treatment for patients with AAA.
Biological and immunological characterization of ATG and ALG. [2021]Antithymocyte globulin (ATG) and antilymphocyte globulin (ALG) are effective therapies in aplastic anemia; their mechanism of action is undefined. We assayed multiple properties of ATG and ALG to address the biological and immunological bases for differences between ATG and ALG and lot variation. In addition, we studied a lot reported to be inactive in an American clinical trial; however in retrospect, this lot appeared to be active in patients treated in Europe. Immunoprecipitation of thymocyte and lymphocyte membrane proteins with ATG and ALG showed between 14 and 18 major bands on SDS-PAGE, but the patterns for ATG and ALG were not identical. The ability of ATG and ALG to block binding of labeled monoclonal antibodies was assessed using flow cytometry and a radioimmunoassay. In general, there was more lot variation among ALGs than ATGs; however, all ALG lots were more potent blockers of binding of anti-HLA-DR and anti-Leu 1 antibodies than was ATG. Both ALG and ATG effectively blocked binding of anti-Leu 2a, anti-Leu 3a, anti-Leu 4, anti-Leu 5b, and anti-IL 2 receptor abs; neither blocked binding of anti-Leu 7. All preparations were capable of inducing T-cell blastogenesis, although there was considerable lot variation. All lots lysed 60% to 75% T cells in a rabbit complement-mediated cytotoxicity assay, with most having a plateau of activity at 5 to 10 ug/mL. Two lots of ALG, including the lot reported to be clinically inactive, showed less toxicity at suboptimal concentrations and did not plateau even at 80 ug/mL. In total, these results indicate important differences between ATG and ALG in general, more lot variation among ALGs than ATGs and only differences in cytotoxicity between an "inactive" lot of ALG and most, but not all, other active ATG and ALG preparations.
Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo Osseo (GITMO) [2019]About 30% of patients with severe aplastic anaemia (SAA) unresponsive to one course of immunosuppressive (IS) therapy with antithymocyte or antilymphocyte globulin can achieve complete or partial remission after a second IS treatment. Among various second-line treatments, rabbit ATG (r-ATG) could represent a safe and effective alternative to horse ALG (h-ALG). In a multicentre study, 30 patients with SAA (17 males and 13 females, median age 21 years, range 2-67) not responding to a first course with h-ALG plus cyclosporin (CyA) and granulocyte colony stimulating factor (G-CSF), were given a second course using r-ATG (3.5 mg/kg/d for 5 d), CyA (5 mg/kg orally from day 1 to 180) and G-CSF (5 microg/kg subcutaneously from day 1 to 90). The median interval between first and second treatment was 151 d (range 58-361 d). No relevant side-effects were observed, but one patient died early during treatment because of sepsis. Overall response, defined as transfusion independence, was achieved in 23/30 (77%) patients after a median time of 95 d (range 14-377). Nine patients (30%) achieved complete remission (neutrophils >/=2.0 x 109/l, haemoglobin >/=11 g/dl and platelets >/=100 x 109/l). The overall survival rate was 93% with a median follow-up of 914 d (range 121-2278). So far, no patient has relapsed. Female gender was significantly associated with a poorer likelihood to respond (P = 0.0006). These data suggest that r-ATG is a safe and effective alternative to h-ALG for SAA patients unresponsive to first-line IS treatment.