User login
In heavily pretreated pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), venetoclax plus navitoclax with chemotherapy was well tolerated with promising responses, according to results of a phase 1 trial. Delayed count recovery, however, stated lead author Jeffrey E. Rubnitz, MD, PhD, St. Jude’s Children’s Research Hospital, Memphis, remained a key safety concern.
Unmet medical need
Despite intensive chemotherapy and novel therapeutics, Dr. Rubnitz said in a virtual oral presentation at the annual meeting of the American Society of Hematology, patients with relapsed or refractory ALL and LL have a poor prognosis and represent an unmet medical need. Venetoclax, a potent, highly selective oral B-cell lymphoma 2 inhibitor, and navitoclax, an oral BCL-2, BCL-XL, and BCL-W inhibitor, directly bind their BCL-2 family member targets to promote apoptosis. In ALL preclinical models, venetoclax and navitoclax have demonstrated antileukemic effects, which suggests dependence on BCL-2 family members. Venetoclax efficacy associated with BCL-2 family inhibition may be potentiated and dose-limiting thrombocytopenia associated with standard-dose navitoclax monotherapy may be avoided by adding venetoclax to low-dose navitoclax. Previous reports of an ongoing phase 1, multicenter, open-label, dose-escalation study in an adult and pediatric population (NCT03181126), Dr. Rubnitz noted, showed the venetoclax/navitoclax/chemotherapy combination to be well tolerated with promising response rates. In the current report, Dr. Rubnitz presented data on the safety, tolerability, pharmacokinetics, and antitumor activity of the triplet regimen in the subgroup of pediatric patients.
The study included pediatric patients (ages, 4-18 years and weight ≥20 kg) receiving venetoclax (weight-adjusted equivalent of 400 mg daily) and navitoclax at three dose levels (25, 50, 100 mg) for patients weighing ≥45 kg and two dose levels (25, 50 mg) for patients weighing <45 kg. At investigator’s discretion, patients could receive chemotherapy (polyethylene glycosylated–asparaginase, vincristine, and dexamethasone). The primary outcomes were safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetics. A safety expansion cohort assessed a 21-day dosing schedule of venetoclax at 400 mg followed by 7 days off plus navitoclax at 50 mg (patients ≥45 kg) or 25 mg (patients <45 kg).
Investigators enrolled 18 patients <18 years (median age, 10 years; range, 6-16; 56% male), with 12 in the dose-escalation cohort and 6 in the safety-expansion cohort. Three patients had prior chimeric antigen receptor (CAR) T treatment and four had received prior stem cell transplantation. In the overall cohort, B-cell ALL was most common (n = 13, 72%), with T-cell ALL (n = 3, 17%) and LL (n = 2, 11%) following. The median number of prior therapies was 2 (range 1-6). All patients received chemotherapy.
Grade 3-4 adverse events
Venetoclax-related grade 3-4 adverse events occurred in 56% of patients. Similarly, navitoclax-related grade 3-4 events were reported in 56% of patients. Navitoclax dose-limiting toxicities occurred in two patients (11%), delayed count recovery on 25 mg and sepsis on 50 mg. No grade 5 adverse events and tumor lysis syndrome were reported.
Among secondary endpoint efficacy parameters, complete responses, CRs with incomplete marrow recovery (CRi) and CRs without platelet recovery (CRp) combined occurred in 62% of B-ALL patients (8/13), 33% of T-cell ALL patients (1/3) and in 50% of LL patients (1/2). Separately, CRs/CRis/CRps occurred in 33%/22%/0% of all patients, respectively.
Subsequently, 5 of 18 (28%) of patients proceeded to stem cell transplantation and 3 (17%) to CAR T. Eight patients (44%) died from disease progression.
BH3 profiling
BH3 profiling revealed that at baseline, patients with B-cell ALL had more diversity in BCL-2 and BCL-XL dependency than did patients with T-cell ALL or early T-cell precursor ALL. The fact that responses were observed in patients who were BCL-2 or BCL-XL dependent, Dr. Rubnitz said, supports the use of venetoclax plus navitoclax in these patients. Analysis of these results led to a recommended phase 2 dose for pediatric patients of 400 mg venetoclax with 25 mg navitoclax (for patients weighing <45 kg) or 50 mg navitoclax (for patients weighing 45 kg or more).
Dr. Rubnitz concluded: “Venetoclax plus navitoclax plus chemotherapy was well tolerated in pediatric patients with relapsed/refractory ALL or LL, with promising response rates observed in a heavily pretreated pediatric population.”
Asked whether the combination might be used also before the refractory setting, in a minimal residual disease (MRD) setting, Dr. Rubnitz replied: “We have a lot of safety data on venetoclax but very little on navitoclax. The next trial, being developed by Seth Karol, MD, will include relapsed patients. MRD-positive patients will also be eligible for enrollment.” To a further question as to whether guiding titration via BH3 profiling would lead to improved outcomes, Dr. Rubnitz said, “I think BH3 profiling can be used to identify which patients will respond to these drugs, but we are still a long way from using it for titrating the doses and dose ratios for the two drugs.”
Dr. Rubnitz disclosed research funding from AbbVie.
SOURCE: Rubnitz JE et al. ASH 2020, Abstract 466.
In heavily pretreated pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), venetoclax plus navitoclax with chemotherapy was well tolerated with promising responses, according to results of a phase 1 trial. Delayed count recovery, however, stated lead author Jeffrey E. Rubnitz, MD, PhD, St. Jude’s Children’s Research Hospital, Memphis, remained a key safety concern.
Unmet medical need
Despite intensive chemotherapy and novel therapeutics, Dr. Rubnitz said in a virtual oral presentation at the annual meeting of the American Society of Hematology, patients with relapsed or refractory ALL and LL have a poor prognosis and represent an unmet medical need. Venetoclax, a potent, highly selective oral B-cell lymphoma 2 inhibitor, and navitoclax, an oral BCL-2, BCL-XL, and BCL-W inhibitor, directly bind their BCL-2 family member targets to promote apoptosis. In ALL preclinical models, venetoclax and navitoclax have demonstrated antileukemic effects, which suggests dependence on BCL-2 family members. Venetoclax efficacy associated with BCL-2 family inhibition may be potentiated and dose-limiting thrombocytopenia associated with standard-dose navitoclax monotherapy may be avoided by adding venetoclax to low-dose navitoclax. Previous reports of an ongoing phase 1, multicenter, open-label, dose-escalation study in an adult and pediatric population (NCT03181126), Dr. Rubnitz noted, showed the venetoclax/navitoclax/chemotherapy combination to be well tolerated with promising response rates. In the current report, Dr. Rubnitz presented data on the safety, tolerability, pharmacokinetics, and antitumor activity of the triplet regimen in the subgroup of pediatric patients.
The study included pediatric patients (ages, 4-18 years and weight ≥20 kg) receiving venetoclax (weight-adjusted equivalent of 400 mg daily) and navitoclax at three dose levels (25, 50, 100 mg) for patients weighing ≥45 kg and two dose levels (25, 50 mg) for patients weighing <45 kg. At investigator’s discretion, patients could receive chemotherapy (polyethylene glycosylated–asparaginase, vincristine, and dexamethasone). The primary outcomes were safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetics. A safety expansion cohort assessed a 21-day dosing schedule of venetoclax at 400 mg followed by 7 days off plus navitoclax at 50 mg (patients ≥45 kg) or 25 mg (patients <45 kg).
Investigators enrolled 18 patients <18 years (median age, 10 years; range, 6-16; 56% male), with 12 in the dose-escalation cohort and 6 in the safety-expansion cohort. Three patients had prior chimeric antigen receptor (CAR) T treatment and four had received prior stem cell transplantation. In the overall cohort, B-cell ALL was most common (n = 13, 72%), with T-cell ALL (n = 3, 17%) and LL (n = 2, 11%) following. The median number of prior therapies was 2 (range 1-6). All patients received chemotherapy.
Grade 3-4 adverse events
Venetoclax-related grade 3-4 adverse events occurred in 56% of patients. Similarly, navitoclax-related grade 3-4 events were reported in 56% of patients. Navitoclax dose-limiting toxicities occurred in two patients (11%), delayed count recovery on 25 mg and sepsis on 50 mg. No grade 5 adverse events and tumor lysis syndrome were reported.
Among secondary endpoint efficacy parameters, complete responses, CRs with incomplete marrow recovery (CRi) and CRs without platelet recovery (CRp) combined occurred in 62% of B-ALL patients (8/13), 33% of T-cell ALL patients (1/3) and in 50% of LL patients (1/2). Separately, CRs/CRis/CRps occurred in 33%/22%/0% of all patients, respectively.
Subsequently, 5 of 18 (28%) of patients proceeded to stem cell transplantation and 3 (17%) to CAR T. Eight patients (44%) died from disease progression.
BH3 profiling
BH3 profiling revealed that at baseline, patients with B-cell ALL had more diversity in BCL-2 and BCL-XL dependency than did patients with T-cell ALL or early T-cell precursor ALL. The fact that responses were observed in patients who were BCL-2 or BCL-XL dependent, Dr. Rubnitz said, supports the use of venetoclax plus navitoclax in these patients. Analysis of these results led to a recommended phase 2 dose for pediatric patients of 400 mg venetoclax with 25 mg navitoclax (for patients weighing <45 kg) or 50 mg navitoclax (for patients weighing 45 kg or more).
Dr. Rubnitz concluded: “Venetoclax plus navitoclax plus chemotherapy was well tolerated in pediatric patients with relapsed/refractory ALL or LL, with promising response rates observed in a heavily pretreated pediatric population.”
Asked whether the combination might be used also before the refractory setting, in a minimal residual disease (MRD) setting, Dr. Rubnitz replied: “We have a lot of safety data on venetoclax but very little on navitoclax. The next trial, being developed by Seth Karol, MD, will include relapsed patients. MRD-positive patients will also be eligible for enrollment.” To a further question as to whether guiding titration via BH3 profiling would lead to improved outcomes, Dr. Rubnitz said, “I think BH3 profiling can be used to identify which patients will respond to these drugs, but we are still a long way from using it for titrating the doses and dose ratios for the two drugs.”
Dr. Rubnitz disclosed research funding from AbbVie.
SOURCE: Rubnitz JE et al. ASH 2020, Abstract 466.
In heavily pretreated pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), venetoclax plus navitoclax with chemotherapy was well tolerated with promising responses, according to results of a phase 1 trial. Delayed count recovery, however, stated lead author Jeffrey E. Rubnitz, MD, PhD, St. Jude’s Children’s Research Hospital, Memphis, remained a key safety concern.
Unmet medical need
Despite intensive chemotherapy and novel therapeutics, Dr. Rubnitz said in a virtual oral presentation at the annual meeting of the American Society of Hematology, patients with relapsed or refractory ALL and LL have a poor prognosis and represent an unmet medical need. Venetoclax, a potent, highly selective oral B-cell lymphoma 2 inhibitor, and navitoclax, an oral BCL-2, BCL-XL, and BCL-W inhibitor, directly bind their BCL-2 family member targets to promote apoptosis. In ALL preclinical models, venetoclax and navitoclax have demonstrated antileukemic effects, which suggests dependence on BCL-2 family members. Venetoclax efficacy associated with BCL-2 family inhibition may be potentiated and dose-limiting thrombocytopenia associated with standard-dose navitoclax monotherapy may be avoided by adding venetoclax to low-dose navitoclax. Previous reports of an ongoing phase 1, multicenter, open-label, dose-escalation study in an adult and pediatric population (NCT03181126), Dr. Rubnitz noted, showed the venetoclax/navitoclax/chemotherapy combination to be well tolerated with promising response rates. In the current report, Dr. Rubnitz presented data on the safety, tolerability, pharmacokinetics, and antitumor activity of the triplet regimen in the subgroup of pediatric patients.
The study included pediatric patients (ages, 4-18 years and weight ≥20 kg) receiving venetoclax (weight-adjusted equivalent of 400 mg daily) and navitoclax at three dose levels (25, 50, 100 mg) for patients weighing ≥45 kg and two dose levels (25, 50 mg) for patients weighing <45 kg. At investigator’s discretion, patients could receive chemotherapy (polyethylene glycosylated–asparaginase, vincristine, and dexamethasone). The primary outcomes were safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetics. A safety expansion cohort assessed a 21-day dosing schedule of venetoclax at 400 mg followed by 7 days off plus navitoclax at 50 mg (patients ≥45 kg) or 25 mg (patients <45 kg).
Investigators enrolled 18 patients <18 years (median age, 10 years; range, 6-16; 56% male), with 12 in the dose-escalation cohort and 6 in the safety-expansion cohort. Three patients had prior chimeric antigen receptor (CAR) T treatment and four had received prior stem cell transplantation. In the overall cohort, B-cell ALL was most common (n = 13, 72%), with T-cell ALL (n = 3, 17%) and LL (n = 2, 11%) following. The median number of prior therapies was 2 (range 1-6). All patients received chemotherapy.
Grade 3-4 adverse events
Venetoclax-related grade 3-4 adverse events occurred in 56% of patients. Similarly, navitoclax-related grade 3-4 events were reported in 56% of patients. Navitoclax dose-limiting toxicities occurred in two patients (11%), delayed count recovery on 25 mg and sepsis on 50 mg. No grade 5 adverse events and tumor lysis syndrome were reported.
Among secondary endpoint efficacy parameters, complete responses, CRs with incomplete marrow recovery (CRi) and CRs without platelet recovery (CRp) combined occurred in 62% of B-ALL patients (8/13), 33% of T-cell ALL patients (1/3) and in 50% of LL patients (1/2). Separately, CRs/CRis/CRps occurred in 33%/22%/0% of all patients, respectively.
Subsequently, 5 of 18 (28%) of patients proceeded to stem cell transplantation and 3 (17%) to CAR T. Eight patients (44%) died from disease progression.
BH3 profiling
BH3 profiling revealed that at baseline, patients with B-cell ALL had more diversity in BCL-2 and BCL-XL dependency than did patients with T-cell ALL or early T-cell precursor ALL. The fact that responses were observed in patients who were BCL-2 or BCL-XL dependent, Dr. Rubnitz said, supports the use of venetoclax plus navitoclax in these patients. Analysis of these results led to a recommended phase 2 dose for pediatric patients of 400 mg venetoclax with 25 mg navitoclax (for patients weighing <45 kg) or 50 mg navitoclax (for patients weighing 45 kg or more).
Dr. Rubnitz concluded: “Venetoclax plus navitoclax plus chemotherapy was well tolerated in pediatric patients with relapsed/refractory ALL or LL, with promising response rates observed in a heavily pretreated pediatric population.”
Asked whether the combination might be used also before the refractory setting, in a minimal residual disease (MRD) setting, Dr. Rubnitz replied: “We have a lot of safety data on venetoclax but very little on navitoclax. The next trial, being developed by Seth Karol, MD, will include relapsed patients. MRD-positive patients will also be eligible for enrollment.” To a further question as to whether guiding titration via BH3 profiling would lead to improved outcomes, Dr. Rubnitz said, “I think BH3 profiling can be used to identify which patients will respond to these drugs, but we are still a long way from using it for titrating the doses and dose ratios for the two drugs.”
Dr. Rubnitz disclosed research funding from AbbVie.
SOURCE: Rubnitz JE et al. ASH 2020, Abstract 466.
FROM ASH 2020