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At present, the main drugs for early treatment of multiple myeloma (MM) include proteasome inhibitors (such as bortezomib) and immunomodulators (such as lenalidomide).
In the past two decades, these drugs have significantly improved the prognosis of patients.
However, as the treatment continues, the depth of remission and the duration of remission tend to gradually decrease, and over time, patients may be resistant to multiple drugs.
Therefore, patients with relapsed and refractory MM (RRMM) need new treatment options that can overcome resistance and produce deep and lasting remissions.
Histone deacetylase (HDAC) inhibitors and bortezomib have a synergistic effect and show the ability to induce remission in patients with bortezomib refractory.
Panobinostat is currently the only pan-HDAC inhibitor approved in the United States and Europe to be used in combination with bortezomib and dexamethasone for relapsed or relapsed and refractory MM that has previously received ≥2 lines of treatment.
The approval of this indication is based on the results of the subgroup analysis of the key phase 3 PANORAMA 1 study: among patients with relapsed or relapsed and refractory MM who have previously received ≥2 line treatments (including bortezomib and immunomodulators), compared with placebo The median progression-free survival (PFS) of the panobinostat + bortezomib (intravenous infusion) + dexamethasone group increased by 7.
8 months (12.
5) compared with the treatment + bortezomib (intravenous infusion) + dexamethasone group Month [95%CI 7.
3-14.
0] vs 4.
7 months [95%CI 3.
7-6.
1], hazard ratio [HR] 0.
47[95%CI 0.
31-0.
72]).
Although the efficacy data is encouraging, the hematology and gastrointestinal toxicity of panobinostat and intravenous bortezomib overlap, and the incidence of grade 3-4 adverse events in the panobinostat group is higher than that in the placebo group.
In 2012, the subcutaneous administration of bortezomib was approved, and the results of its phase 3 study showed that subcutaneous injection has better safety than intravenous infusion.
In addition, in the PANORAMA 1 study, patients received bortezomib treatment twice a week, but in recent years in clinical practice, elderly patients ≥ 60 years old often receive bortezomib treatment once a week.
Therefore, the PANORAMA 1 study cannot well reflect the safety of panobinostat+bortezomib+dexamethasone in current clinical practice.
Based on this, the PANORAMA 3 study optimized the dosing regimen in order to reduce overlapping toxicity, extend the treatment time, and improve the prognosis of patients.
The study evaluated the efficacy and safety of three different dosing regimens of oral panobinostat + subcutaneous bortezomib + oral dexamethasone, and evaluated the reduction of bortezomib administration according to age (≤75 years vs >75 years) The effect of frequency on efficacy.
Research Method The PANORAMA 3 study (NCT02654990) is an open-label, randomized phase 2 study conducted in 71 hospitals/medical centers in 21 countries/regions.
Patients with relapsed or relapsed and refractory MM who have received 1-4 line therapy (including immunomodulators) in the past, and the Eastern Cooperative Oncology Group Performance Status Score (ECOG PS) ≤ 2 (according to the International Myeloma Work Group [IMWG] 2014 standard) was included in this study, stratified according to the number of previous treatment lines and age, and were randomly assigned (1:1:1) to receive oral panobinostat combined with subcutaneous bortezomib and oral dexamethasone treatment.
21 days is a treatment cycle.➤panobinostat 20mg 3 times a week [q3w], d1, 3, 5, 8, 10, 1220mg 2 times a week [q2w], d1, 4, 8, 1110mg q3w, d1, 3, 5, 8, 10, 12 ➤ Bortezomib: 1.
3 mg/m2 ≤ 75 years old, 1-4 cycles q2w (d1, 4, 8, 11), 5-8 cycles once a week (qw, d1, 8)> 75 years old, once a week (qw , D1, 8) ➤ Dexamethasone ≤ 75 years old, 20 mg for 1-4 cycles (d1, 2, 4, 5, 8, 9, 11, 12), 20 mg for 5-8 cycles (d1, 2, 8, 9) >75 years old, 10mg (d1, 2, 8, 9) The primary endpoint is the total response rate (ORR, analysis of all randomly assigned patients according to treatment intention) after up to 8 treatment cycles.
The safety analysis included all patients who received at least one dose of any study medication.
Study results From April 27, 2016 to January 17, 2019, 248 patients were enrolled and randomly assigned (panobinostat: 82 cases in the 20 mg q3w group, 83 cases in the 20 mg q2w group, and 83 cases in the 10 mg q3w group).
The median follow-up period for all treatment groups was 14.
7 months (IQR 7.
8-24.
1).
The patient's baseline characteristics are shown in the figure below.
After up to 8 treatment cycles, the ORR of the 20 mg q3w group was 62.
2% (95% CI 50.
8-72.
7; 51/82 cases), and the 20 mg q2w group was 65.
1% (95% CI 53.
8-75.
2; 54/83 cases).
The 10 mg q3w group was 50.
6% (95% CI 39.
4-61.
8; 42/83 cases).
In the post-hoc subgroup analysis, after up to 8 cycles of treatment, the ORRs of patients ≤75 years old and >75 years old in the 20mg q3w group were similar (62.
5%[45/72] vs 60.
0%[6/10]); the 20mg q2w group Compared with the 10mg q3w group, patients> 75 years old (40.
0%[4/10] and 25.
0%[3/12]) had higher ORRs (68.
5%[50/73] and 54.
9%[ 39/71]). There were 71/78 cases (91%) in the 20 mg q3w group, 69/83 cases (83%) in the 20 mg q2w group, and 60/80 cases (75%) in the 10 mg q3w group.
Grade 3-4 adverse events occurred; the most common ( Grade 3-4 adverse events in each group ≥20%) were thrombocytopenia (33/78 [42%], 26/83 [31%], 19/80 [24%]) and neutropenia (18/78 [23%], 13/83 [16%], 6/80 [8%]).
Serious adverse events occurred in 42/78 cases (54%) in the 20 mg q3w group, 40/83 cases (48%) in the 20 mg q2w group, and 35/80 cases (44%) in the 10 mg q3w group; the most common (all groups were ≥10%) serious adverse event was pneumonia (9/78 [12%], 10/83 [12%], 9/80 [11%]).
During the study period, 14 patients died (5/78 patients in the 20mg q3w group [6%], 3/83 patients in the 20mg q2w group [4%], and 6/80 patients in the 10mg q3w group [8%]); deaths It has nothing to do with treatment.
Conclusion The safety of Panobinostat 20mg q3w group is better than previous studies of this regimen (bortezomib is intravenous infusion), which shows that subcutaneous injection of bortezomib improves the tolerance of panobinostat+bortezomib+dexamethasone regimen.
And can guarantee the curative effect.
The results of the study showed that in elderly patients and all patients after 4 cycles of treatment, the use of once a week subcutaneous injection of bortezomib can improve tolerance and patient prognosis.
References: Laubach, Jacob P et al.
Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study.
The Lancet Oncology, Volume 22, Issue 1, 142 – 154.
Stamp "read the original text", we make progress together
In the past two decades, these drugs have significantly improved the prognosis of patients.
However, as the treatment continues, the depth of remission and the duration of remission tend to gradually decrease, and over time, patients may be resistant to multiple drugs.
Therefore, patients with relapsed and refractory MM (RRMM) need new treatment options that can overcome resistance and produce deep and lasting remissions.
Histone deacetylase (HDAC) inhibitors and bortezomib have a synergistic effect and show the ability to induce remission in patients with bortezomib refractory.
Panobinostat is currently the only pan-HDAC inhibitor approved in the United States and Europe to be used in combination with bortezomib and dexamethasone for relapsed or relapsed and refractory MM that has previously received ≥2 lines of treatment.
The approval of this indication is based on the results of the subgroup analysis of the key phase 3 PANORAMA 1 study: among patients with relapsed or relapsed and refractory MM who have previously received ≥2 line treatments (including bortezomib and immunomodulators), compared with placebo The median progression-free survival (PFS) of the panobinostat + bortezomib (intravenous infusion) + dexamethasone group increased by 7.
8 months (12.
5) compared with the treatment + bortezomib (intravenous infusion) + dexamethasone group Month [95%CI 7.
3-14.
0] vs 4.
7 months [95%CI 3.
7-6.
1], hazard ratio [HR] 0.
47[95%CI 0.
31-0.
72]).
Although the efficacy data is encouraging, the hematology and gastrointestinal toxicity of panobinostat and intravenous bortezomib overlap, and the incidence of grade 3-4 adverse events in the panobinostat group is higher than that in the placebo group.
In 2012, the subcutaneous administration of bortezomib was approved, and the results of its phase 3 study showed that subcutaneous injection has better safety than intravenous infusion.
In addition, in the PANORAMA 1 study, patients received bortezomib treatment twice a week, but in recent years in clinical practice, elderly patients ≥ 60 years old often receive bortezomib treatment once a week.
Therefore, the PANORAMA 1 study cannot well reflect the safety of panobinostat+bortezomib+dexamethasone in current clinical practice.
Based on this, the PANORAMA 3 study optimized the dosing regimen in order to reduce overlapping toxicity, extend the treatment time, and improve the prognosis of patients.
The study evaluated the efficacy and safety of three different dosing regimens of oral panobinostat + subcutaneous bortezomib + oral dexamethasone, and evaluated the reduction of bortezomib administration according to age (≤75 years vs >75 years) The effect of frequency on efficacy.
Research Method The PANORAMA 3 study (NCT02654990) is an open-label, randomized phase 2 study conducted in 71 hospitals/medical centers in 21 countries/regions.
Patients with relapsed or relapsed and refractory MM who have received 1-4 line therapy (including immunomodulators) in the past, and the Eastern Cooperative Oncology Group Performance Status Score (ECOG PS) ≤ 2 (according to the International Myeloma Work Group [IMWG] 2014 standard) was included in this study, stratified according to the number of previous treatment lines and age, and were randomly assigned (1:1:1) to receive oral panobinostat combined with subcutaneous bortezomib and oral dexamethasone treatment.
21 days is a treatment cycle.➤panobinostat 20mg 3 times a week [q3w], d1, 3, 5, 8, 10, 1220mg 2 times a week [q2w], d1, 4, 8, 1110mg q3w, d1, 3, 5, 8, 10, 12 ➤ Bortezomib: 1.
3 mg/m2 ≤ 75 years old, 1-4 cycles q2w (d1, 4, 8, 11), 5-8 cycles once a week (qw, d1, 8)> 75 years old, once a week (qw , D1, 8) ➤ Dexamethasone ≤ 75 years old, 20 mg for 1-4 cycles (d1, 2, 4, 5, 8, 9, 11, 12), 20 mg for 5-8 cycles (d1, 2, 8, 9) >75 years old, 10mg (d1, 2, 8, 9) The primary endpoint is the total response rate (ORR, analysis of all randomly assigned patients according to treatment intention) after up to 8 treatment cycles.
The safety analysis included all patients who received at least one dose of any study medication.
Study results From April 27, 2016 to January 17, 2019, 248 patients were enrolled and randomly assigned (panobinostat: 82 cases in the 20 mg q3w group, 83 cases in the 20 mg q2w group, and 83 cases in the 10 mg q3w group).
The median follow-up period for all treatment groups was 14.
7 months (IQR 7.
8-24.
1).
The patient's baseline characteristics are shown in the figure below.
After up to 8 treatment cycles, the ORR of the 20 mg q3w group was 62.
2% (95% CI 50.
8-72.
7; 51/82 cases), and the 20 mg q2w group was 65.
1% (95% CI 53.
8-75.
2; 54/83 cases).
The 10 mg q3w group was 50.
6% (95% CI 39.
4-61.
8; 42/83 cases).
In the post-hoc subgroup analysis, after up to 8 cycles of treatment, the ORRs of patients ≤75 years old and >75 years old in the 20mg q3w group were similar (62.
5%[45/72] vs 60.
0%[6/10]); the 20mg q2w group Compared with the 10mg q3w group, patients> 75 years old (40.
0%[4/10] and 25.
0%[3/12]) had higher ORRs (68.
5%[50/73] and 54.
9%[ 39/71]). There were 71/78 cases (91%) in the 20 mg q3w group, 69/83 cases (83%) in the 20 mg q2w group, and 60/80 cases (75%) in the 10 mg q3w group.
Grade 3-4 adverse events occurred; the most common ( Grade 3-4 adverse events in each group ≥20%) were thrombocytopenia (33/78 [42%], 26/83 [31%], 19/80 [24%]) and neutropenia (18/78 [23%], 13/83 [16%], 6/80 [8%]).
Serious adverse events occurred in 42/78 cases (54%) in the 20 mg q3w group, 40/83 cases (48%) in the 20 mg q2w group, and 35/80 cases (44%) in the 10 mg q3w group; the most common (all groups were ≥10%) serious adverse event was pneumonia (9/78 [12%], 10/83 [12%], 9/80 [11%]).
During the study period, 14 patients died (5/78 patients in the 20mg q3w group [6%], 3/83 patients in the 20mg q2w group [4%], and 6/80 patients in the 10mg q3w group [8%]); deaths It has nothing to do with treatment.
Conclusion The safety of Panobinostat 20mg q3w group is better than previous studies of this regimen (bortezomib is intravenous infusion), which shows that subcutaneous injection of bortezomib improves the tolerance of panobinostat+bortezomib+dexamethasone regimen.
And can guarantee the curative effect.
The results of the study showed that in elderly patients and all patients after 4 cycles of treatment, the use of once a week subcutaneous injection of bortezomib can improve tolerance and patient prognosis.
References: Laubach, Jacob P et al.
Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study.
The Lancet Oncology, Volume 22, Issue 1, 142 – 154.
Stamp "read the original text", we make progress together
