Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Panobinostat (LBH589), LBH589, PAN, LBH, LBH589 (i.v. panobinostat), LBH581, Farydak
Panobinostat · 39 trials · 46 indications
Safety monitoring was conducted throughout the study.
Overall response rate is percentage of participants with complete (CR), very good partial (VGPR), partial (PR), or minimal response (MR) as best response during treatment. CR * Disappearance of monoclonal protein by immunofixation * No histologic evidence of bone marrow involvement * Resolution of any adenopathy/organomegaly (confirmed by CT scan), or signs or symptoms attributable to WM. * Second immunofixation required for confirmation. VGPR -At least 90% reduction of serum monoclonal IgM concentration on protein electrophoresis. PR * At least 50% reduction of serum monoclonal IgM concentration on protein electrophoresis and at least 50% decrease in adenopathy/organomegaly on physical examination or on CT scan. * No new symptoms or signs of active disease. MR * At least 25% but less than 50% reduction of serum monoclonal IgM by protein electrophoresis. * No new symptoms or signs of active disease.
nCR plus CR rate after 8 cycles of therapy as defined by the modified European Society for Bone and Marrow Transplantation (EBMT) criteria per investigator assessment as the proportion of participants with nCR or CR as their best overall response.
Adverse events were collected from baseline up to 30 days post treatment at scheduled visits. Severity of adverse events was assessed according to the current version of Common Terminology Criteria for Adverse Events (CTCAE). If CTCAE grading did not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, was used
The primary endpoint will be the best overall response rate (ORR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
The primary endpoint will be the best overall response rate (ORR)
Overall response rate=(PR+nCR+CR) CR= \< 5% plasma cells in bone marrow. No confirmation on bone marrow plasma cell (additional assessment) is needed to document CR except patients with non-secretory myeloma where the bone marrow examination must be repeated after an interval of at least 6 weeks, Absence of M-protein in serum and urine by immunofixation,nCR same as CR without out Absence of M-protein in serum and urine by immunofixation,PR+ 50% reduction of serum M-protein and sofft tissue Plasmacytomas all for more than 6 weeks.
Response to treatment was defined as complete remission rate (CRR). CRR is complete remission (CR) and morphologic CR with incomplete blood count recovery (residual neutropenia or thrombocytopenia) (CRi). To stop or to proceed with Stage 2 of a given stratum of the Simon's optimal 2-stage design was based on the number of patients with CR/CRi and a safety evaluation of the patients from Stage 1 in that stratum. If early results clearly indicated that the drug was not active or worthy of further investigation, enrollment of that particular stratum would be terminated. CR and CRi were assessed by the Investigator according to IWG response Criteria for AML (Cheson et al 2003). As per protocol we would continue to stage II if ≥ 4 patients out of 26 patients enrolled to stage I had a CR or a CRi. As per response observed there was only 1 patient with CR/CRi in stratum A and 2 patients with CR/CRi in Stratum B.
ORR was number of participants with best overall disease response of complete response(CR)/partial response(PR).Best overall disease response was best disease response recorded from start of treatment until disease progression/recurrence.CR=complete normalization of all index nodal,extranodal lesions,complete disappearance of all extranodal lesions.PR=50% decrease in SPD for up to 6 identified dominant lesions (splenic,hepatic nodules) from baseline.Stable=neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease (PD), reference smallest sum diameters while on study.Progression=50% increase in sum of longest diameter of all target lesions,from smallest sum of longest diameter of all target lesions recorded at or after baseline/a new lesion/progression of non-target lesions.Unknown is progression not documented,one/more of index lesions not assessed or have been assessed using a different method than baseline at the time of radiologic evaluation.
Objective response rate measured according to the RECIST (Response Evaluation Criteria In Solid Tumours).
The PFS rate was defined as the percentage of participants that were alive without documented disease progression at the end of 24 weeks from first study treatment. Disease Progression as per response evaluation criteria in solid tumors (RECIST) criteria: Measurable lesions: If target lesion was lymph node then it had to be at least 2 centimeter (cm) at baseline to assess change in size. Bone lesions: (non-target lesions) appearance of greater than or equal to (\>=) 2 unequivocal new lesions confirmed on a second scan at least 6 weeks later.
Progression-free survival was defined as the interval from the date of first treatment with panobinostat until the date that disease progression or death occurred. Progressive disease (PD): 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.
Skin response was primarily classified based on an assessment using mSWAT, provided there was documented evidence of stable disease or better in lymph node/viscera.The mSWAT is a tool specifically developed to evaluate the extent of skin disease in CTCL (Olsen et al 2007). Responses in the skin based on SWAT are defined as: * Complete Response (CR): no evidence of skin disease * Partial Response (PR): ≥ 50% decrease of the modified SWAT score compared with baseline * Stable Disease (SD): Neither CR, PR, or PD as compared with baseline, i.e. change from baseline is less than a 50% decrease but also less than a 25 % increase in the modified SWAT score * Progressive Disease (PD): ≥ 25% increase in the modified SWAT score compared with baseline.
MTD for Capecitabine, BID
DLT will be assessed during PK run-in period (up to 7 days) and 1st cycle (28 days)
To determine the DLTs and MTD of panobinostat given in combination with bortezomib.
Dose limiting toxicity (DLT) was defined as a toxicity requiring treatment withdrawal and included the following: Non-hematologic toxicity qualifying for DLT and Hematologic toxicity qualifying for DLT
Dose limiting toxicity (DLT) was defined as a toxicity requiring treatment withdrawal and included the following: Non-hematologic toxicity qualifying for DLT and Hematologic toxicity qualifying for DLT
Composite complete response is defined as complete response (CR), Complete response with incomplete blood count recovery (CRi) or bone marrow complete response (BM-CR) as defined by the International Working Group (IWG) response criteria.
The MTD LBH589 in combination with bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached but the highest dose received may be the Recommended Phase II Dose (RP2D). The MTD was not reached with 0 of 6 DLTs observed in the highest dose cohort but due to safety concerns higher doses of LBH589 with bevacizumab were neither planned nor tested. The RP2D was 30 mg/day orally, 3x per week, every other week.
A DLT was defined as an adverse event that (a) is related to the LBH589 and/or bevacizumab with an attribution of possible, probable, or definite, and (b) occurs during and/or begins during the first 30 days of the study treatment, and (c) meets any of the following criteria: grade 3 thrombocytopenia; grade 4 neutropenia lasting 7 days; grade 4 anemia lasting 7 days despite transfusion or growth factors; febrile neutropenia if ANC\<0.5 x10\^9/L; a QT interval corrected for heart rate (QTc) of 500-515 msec that did not stabilize to \<480 msec after one week; a second occurrence of QTc 500-515 msec; any QTc \>515 msec; any deep vein thrombosis (DVT) or pulmonary embolism (PE) while on fully therapeutic anticoagulation therapy; Grade 3 proteinuria lasting 14 days; or any other clinically significant Grade 3 toxicity despite maximal medical therapy lasting 7 days, any Grade 4 toxicity despite maximal medical therapy; or any Grade 3 or 4 toxicity resulting in study drug discontinuation.
PFS6 is the proportion of patients remaining alive and progression-free at 6-months from study entry. Progressive disease was established based on RANO criteria (Wen et al JCO 2010).
oral dose of \[14C\] LBH589
Maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) for consecutive dosing schedule (MWF weekly). A 3-parameter version of a Bayesian logistic regression model with overdose control (Babb, Rogatko, and Zacks 1998) was used during the dose escalation phase for dose level selection and determination of the MTD.
Maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) for intermittent dosing schedule (MWF weekly). A 3-parameter version of a Bayesian logistic regression model with overdose control (Babb, Rogatko, and Zacks 1998) was used during the dose escalation phase for dose level selection and determination of the MTD.
| Arm | Type | Description |
|---|---|---|
| Panobinostat (PAN) | EXPERIMENTAL | Participants received 45 mg orally 3 times a week (TIW), every other week (QOW), |
| Placebo | PLACEBO_COMPARATOR | Participants received matching placebo to PAN TIW, QOW. |
| Panobinostat + Bortezomib + Dexamethasone | EXPERIMENTAL | - |
| Placebo + Bortezomib + Dexamethasone | PLACEBO_COMPARATOR | - |
| LBH589 | EXPERIMENTAL | 30 mg three days a week (Mondays, Wednesdays and Fridays). 1 cycle was 28 days Dose modifications for attributable toxicities allowed for reduction to: * 25 mg, 20 mg three times a week every week * Or 20 mg three times a week every other week. No dose re-escalation was allowed. * The protocol was amended on 6/15/2010 because of concerns of toxicity to allow a starting dose of 25 mg; 12/36 (33%) patients were enrolled on the 25 mg dose. |
| LBH589 + bortezomib + dexamethasone | EXPERIMENTAL | Participants were administered LBH589 (panobinostat)in combination with bortezomib and dexamethasone 2 weeks on/1 week off. |
| Panobinostat - 10 to 40 mg/day TIW QoW | EXPERIMENTAL | 10 to 40mg/day TIW QoW (3 times/week every other week) as per parent protocol design |
| Panobinostat, Lenalidomide and Dexamethasone | EXPERIMENTAL | All patients will receive oral panobinostat, lenalidomide and dexamethasone as per protocol. |
| LBH589 plus Rituximab | EXPERIMENTAL | - |
| panobinostat + bortezomib & dexamethasone | EXPERIMENTAL | panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma |
| Stratum A | EXPERIMENTAL | patients with refractory acute myelogenous leukemia (AML) initially diagnosed as de novo AML received 60 mg of panobinostat per day on three discontinuous days per week. |
| Stratum B | EXPERIMENTAL | patients with refractory AML initially diagnosed as AML secondary to myelodysplastic syndrome (MDS)/antecedent hematologic disorder (AHD) received 60 mg of panobinostat per day on three discontinuous days per week. |
| Panobinostat | EXPERIMENTAL | Participants received panobinostat 40 mg, capsules, orally, thrice every week (i.e. days 1, 3 and 5), in each cycle of 21 days until unacceptable toxicity, disease progression, start of new anti-cancer therapy or withdrawal of consent (up to approximately 48 months). |
| Treatment | OTHER | LBH589 will be administered orally at a dose of 45 mg (1 - 5 mg capsule and 2 - 20 mg capsules) on Monday and Thursday of each week (twice weekly). To enable patients to undergo cardiac monitoring, all patients must begin treatment on a Monday, and continue Monday/Thursday dosing during subsequent treatment cycles. Patients with objective response or stable disease after re-evaluation at week 8 will continue LBH589 at the same dose until disease progression, unacceptable toxicity and/or at the discretion of the investigator. |
| Previously treated with oral bexarotene | EXPERIMENTAL | Participants received Panobinostat 20 milligrams per day (mg/day) capsule orally, once a day (OD) on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). |
| No prior oral bexarotene treatment | EXPERIMENTAL | Participants received Panobinostat 20 milligrams per day (mg/day) capsule orally, once a day (OD) on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). |
| LBH589 with Capecitabine | EXPERIMENTAL | MTD, LBH589 with Capecitabine |
| LBH589 and Lapatinib | EXPERIMENTAL | LBH589 and Lapatinib |
| LBH589, Capecitabine and Lapatinib | EXPERIMENTAL | LBH589, Capecitabine and Lapatinib (Breast Cancer Patients) |
| Panobinostat and Azacitidine | EXPERIMENTAL | combination regimen |
| Cohort 1 | EXPERIMENTAL | Subjects will be treated with ruxolitinib 5 mg twice daily (BID) and panobinostat 10 mg three times per week (TIW) every other week (QOW) on a 28 day cycle |
| Cohort 2 | EXPERIMENTAL | Subjects will be treated with ruxolitinib 10 mg twice daily (BID) and panobinostat 10 mg three times per week (TIW) every other week (QOW) on a 28 day cycle |
| Cohort 3 | EXPERIMENTAL | Subjects will be treated with ruxolitinib 15 mg twice daily (BID) and panobinostat 10 mg three times per week (TIW) every other week (QOW) on a 28 day cycle |
| Cohort 4 | EXPERIMENTAL | Subjects will be treated with ruxolitinib 15 mg twice daily (BID) and panobinostat 15 mg three times per week (TIW) every other week (QOW) on a 28 day cycle |
| Cohort 5 | EXPERIMENTAL | Subjects will be treated with ruxolitinib 15 mg twice daily (BID) and panobinostat 20 mg three times per week (TIW) every other week (QOW) on a 28 day cycle |
| Cohort 6/6+ | EXPERIMENTAL | Subjects will be treated with ruxolitinib 15 mg twice daily (BID) and panobinostat 25 mg three times per week (TIW) every other week (QOW) on a 28 day cycle |
| Open Label Drug Therapy | EXPERIMENTAL | Single arm |
| HDACi | EXPERIMENTAL | - |
| Panobinostat + 5-Azacytidine | EXPERIMENTAL | In phase I: Panobinostat : Escalating doses starting with 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m\^2, subcutaneously Daily for Day 1 to Day 7. |
| 5-Azacytidine | ACTIVE_COMPARATOR | The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m\^2 subcutaneously daily from Day 1 to Day 7. |
| Phase I Cohort 1: Bevacizumab +LBH589 20 mg every week | EXPERIMENTAL | Phase I Cohort 1 participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and the original starting LBH589 dose of 20 mg/day orally, 3x per week, every week (days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26). Participants were treated until disease progression or unacceptable toxicity. |
| Phase I Cohort 2: Bevacizumab + LBH589 20 mg every other week | EXPERIMENTAL | Phase I Cohort 2 participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and the amended starting LBH589 dose of 20 mg/day orally, 3x per week, every other week (Days 1, 3, 5, 15, 17, 19). Participants were treated until disease progression or unacceptable toxicity. |
| Phase I Cohort 3: Bevacizumab + LBH589 30 mg every other week | EXPERIMENTAL | Phase I Cohort 3 participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and LBH589 30 mg/day orally, 3x per week, every other week (Days 1, 3, 5, 15, 17, 19). Participants were treated until disease progression or unacceptable toxicity. |
| All Phase I Participants | EXPERIMENTAL | All phase I participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and LBH589 according to the established dose escalation schedule. Participants were treated until disease progression or unacceptable toxicity. |
| Phase II GBM: Bevacizumab + LBH589 30 mg every other week | EXPERIMENTAL | Phase II glioblastoma (GBM) participants received the regimen established in the Phase I study (Feb 2011). Phase II participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and LBH589 30 mg/day orally, 3x per week, every other week (Days 1, 3, 5, 15, 17, 19). Participants were treated until disease progression or unacceptable toxicity. |
| Phase II AG: Bevacizumab + LBH589 30 mg every other week | EXPERIMENTAL | Phase II Anaplastic Glioma (AG) participants received the regimen established in the Phase I study (Feb 2011). Phase II participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and LBH589 30 mg/day orally, 3x per week, every other week (Days 1, 3, 5, 15, 17, 19). Participants were treated until disease progression or unacceptable toxicity. |
| All Phase II Participants | EXPERIMENTAL | All phase II participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and LBH589 30 mg/day orally, 3x per week, every other week (Days 1, 3, 5, 15, 17, 19). Participants were treated until disease progression or unacceptable toxicity. |
| IV LBH589 + trastuzumab + paclitaxel | EXPERIMENTAL | i.v. panobinostat |
| Oral LBH589 + trastuzumab + paclitaxel | EXPERIMENTAL | oral panobinostat |
| LBH589 (Panobinostat) | EXPERIMENTAL | - |
| PAN 5 mg | EXPERIMENTAL | Panobinostat 5 mg |
| PAN 10 mg | EXPERIMENTAL | Panobinostat 10 mg |
| PAN 20 mg | EXPERIMENTAL | Panobinostat 20 mg |
| PAN 25 mg | EXPERIMENTAL | Panobinostat 25 mg |
| Panobinostat (LBH589) | EXPERIMENTAL | - |
| Arm 1, Group X | EXPERIMENTAL | - |
| Arm 1, Group Y | EXPERIMENTAL | - |
| Arm 2, Group X | EXPERIMENTAL | - |
| Arm 2, Group Y | EXPERIMENTAL | Panobinostat was administered orally, once-a-day, on Monday-Wednesday-Friday (MWF), every other week, as part of a 28-day treatment cycle. Group Y is a sub-arm, based on disease indication. |
| Name | Type | Description |
|---|---|---|
| Panobinostat | DRUG | - |
| Placebo | DRUG | Placebo |
| Bortezomib | DRUG | Bortezomib was administered 2 x week ( 2weeks on 1 week off) |
| Dexamethasone | DRUG | Dexamethasone was adminstered on day of Bortezomib and the day after Bortezomib administration |
| LBH589 | DRUG | - |
| LBH589 (panobinostat) | DRUG | Panobinostat (PAN) capsules were supplied at dose strengths of 10 mg and 15 mg. and dosed at 20mg during treatment phase 1 (21 days) and treatment phase 2 (42 days) |
| Lenalidomide | DRUG | Each cycle is 28 days. Lenalidomide will be given 25 mg: Days 1-21. |
| Rituximab | DRUG | Patients randomized to Arm B will receive IV rituximab at a dose of 375 mg/m2 in combination with oral LBH589. Rituximab should be administered on the same day as LBH589, after the patient has taken their LBH589 dose. The appropriate amount of solution should be withdrawn from the vial for the following calculation: Volume (mL) = BSA (m2) × dose (375 mg/m2) / concentration of reconstituted solution ml/mL (100 mg/10 mL and/or 500 mg/50 mL). |
| Panobinostat/LBH589 | DRUG | - |
| LBH581 | DRUG | 25 mg/5 ml solution packaged in 6 ml type I glass vials and given as a 30 minutes infusion at the dose of 20 mg/m2 i.v., on day 1 and 8, every 21 days. |
| Capecitabine | DRUG | Capecitabine will be administered orally twice daily for 14 days out of every 21 days. |
| Lapatinib | DRUG | Lapatinib, 1000 mg PO daily will be added to this combination. |
| Cytarabine | DRUG | Induction - 100 mg/m2 continuous IV daily for 7 doses on day 3-9. Second induction - 100 mg/m2 continuous IV daily for 7 doses on day 3-7. Dosing for consolidation - 100 mg/m2 continuous IV daily for 7 doses on day 3-9. |
| Daunorubicin | DRUG | Induction - 60 mg/m2 IV over 15-30 minutes daily for 3 doses on day 3-5. Second induction - 60 mg/m2 IV over 15-30 minutes daily for 2 doses on day 3 and 4. Dosing for consolidation - 60 mg/m2 IV over 15-30 minutes daily for 3 doses on day 3-5. |
| ruxolitinib | DRUG | Given twice daily in 28-day cycles. |
| panobinostat (LBH589) | DRUG | - |
| 5-Azacytidine | DRUG | - |
| panobinostat/LBH589B | DRUG | - |
| bevacizumab | DRUG | - |
| IV LBH589 | DRUG | - |
| Oral LBH589 | DRUG | - |
| trastuzumab | DRUG | - |
| paclitaxel | DRUG | - |
| LBH589 (i.v. panobinostat) | DRUG | i.v. LBH589 dose levels: 10, 15, or 20 mg/m2 i.v. docetaxel 75 or 60 mg/m2 oral prednisone 5mg bid. LBH589 i.v. administered on days 1 and 8 in combination with docetaxel i.v. on day 1 and prednisone p.o 5mg bid every day of a 21-day cycle |
Inclusion Criteria: 1. Patient age is greater than or equal to 18 years 2. Patient has a history of histologically confirmed classical HL (i.e. Nodular sclerosing (NSHL), Mixed-cellularity (MCHL), Lymphocyte-rich (LRHL), Lymphocyte depleted (LDHL)) 3. Patient has achieved a complete response by CT/...
Panobinostat is a small molecule oncology drug developed by Novartis AG (ticker NVS). It is being studied in hematologic malignancies and advanced solid tumors, including acute myeloid leukemia, Hodgkin's lymphoma, cutaneous T-cell lymphoma, and multiple myeloma. It is an investigational agent in clinical development.
Panobinostat targets histone deacetylases, specifically HDAC1, HDAC2, HDAC3, HDAC5, HDAC6, and HDAC7. It acts as an HDAC inhibitor, a class of small molecule agents studied in oncology for their effects on gene expression and cell growth in hematologic and solid tumors.
Panobinostat is developed by Novartis AG, which trades under the ticker NVS. Novartis has sponsored the clinical studies of panobinostat, including trials in multiple myeloma, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia.
Panobinostat is in Phase 1 clinical development according to its current development stage. It is an investigational drug and is not described as approved. Studies have been conducted across Phase 1 and Phase 2, with completed trials in multiple myeloma and hematologic neoplasms.
Panobinostat has been studied in trials including NCT01965353, a Phase 1 study with lenalidomide, bortezomib, and dexamethasone in relapsed multiple myeloma; NCT01802879, a Phase 2 access study in hematologic neoplasms; NCT01651039, a Phase 2 study with lenalidomide and dexamethasone in multiple myeloma; and NCT01613976, a Phase 1b study with 5-azacitidine in MDS, CMML, or AML.
Yes, panobinostat is also known as LBH589. Other names used for the same compound include panobinostat (LBH589), panobinostat/LBH589B, and Panobinostat/LBH589. These refer to the same HDAC inhibitor developed by Novartis.