Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Romidepsin · 10 trials · 27 indications
PFS is defined as the time from randomization into the study to the first observation of documented disease progression (local assessment using Lugano Response Criteria 2014) or death due to any cause, whichever occurs first. If a participant has not progressed or died, PFS will be censored at the time of last visit with adequate assessment. C2 censoring rules were used per US FDA guidance 2015. Progression will be determined as per Response criteria for lymphoma: Lugano classification.
The endpoint for this objective will be objective response rate (ORR), defined per Cheson criteria. Response will be assessed by imaging after cycles 3 and 6, and then every 6 months thereafter. Response at 3 months (after cycle 3) will be used for purposes of the interim efficacy analysis.
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. Adverse events were assessed using National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4: On the following is the scale: Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe and Undesirable AE, Grade 4 = Life-threatening or Disabling AE, and Grade 5 = Death. Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention. A TEAE is defined as any AE occurring or worsening on or after the first dose of study drug and within 28 days after the last dose of study drug.
Complete Response (CR): \>75% decrease in size aggregate of nodal index lesions (large and small), complete disappearance of extranodal and non-index lesions; total disappearance of clinical disease including skin involvement; disease-related signs and symptoms, normalization of biochemical abnormalities and reduction in size of spleen or liver so no longer palpable. Unconfirmed CR: all above criteria except all nodal index lesions must have regressed \>75% in the sum of the product diameters (SPD) from baseline. Individual nodes previously confluent must have regressed by \>75% in their SPD.
The percent of pts with confirmed Objective Disease Response (confirmed best responses of complete response \[CR\], clinical complete response \[CCR\], or partial response \[PR\]). Responses were evaluated according to a composite assessment (Objective Primary Disease Response Evaluation Criteria - OPDREC).
Rate of objective disease control was defined as the proportion of patients with confirmed CR, PR, or SD for at least 6 months, as determined by the Response Evaluation Criteria for Solid Tumors (RECIST).
DLT was defined as an adverse event (AE) occurring in Cycle 1 in Phase 1 and judged that the causal relationship to the investigational product could not be denied. The severity of all AEs was graded based upon the NCI CTCAE version 3.0. DLTs were defined as: • Grade 4 Hemoglobin \<6.5 g/dL • Grade 4 Neutrophil \<500/μL continuing for at least 5 days • Febrile neutropenia (Grade 4 neutropenia caused by fever and ≥ 38.5° C for more than 1 hour) • Grade 4 thrombocyte (\< 25,000/μL), or thrombocytopenia with hemorrhage requiring platelet transfusion • Nausea, vomiting, or diarrhea at \> grade 3 in spite of treatment • Grade 3 ALT (alanine aminotransferase) or AST (aspartate aminotransferase) values continued for 7 days. • Grade 4 ALT or AST • Grade 2 arrhythmia • Grade 4 non-hematological AEs • Other grade 3 non-hematological AEs except transient fatigue, anorexia, hyponatremia, and tumor lysis syndrome • Other AEs leading to discontinuation of administration
Objective disease response in PTCL was defined as patients with a complete response (CR), unconfirmed complete response (CRu) or a partial response (PR) according to modified IWC 1999 criteria and assessed by an independent efficacy reviewer. A CR is \>75% decrease in size of maximum 6 largest target within nodal and extranodal lesions, complete disappearance of other nodal and extranodal; total disappearance of clinical disease; disease-related signs and symptoms, normalization of biochemical abnormalities, disappearance of spleen, liver, or kidney enlargement; no bone marrow (BM) involvement, no new sites of disease. CRu: all above criteria fulfilled except for BM involvement is indeterminate. PR: a ≥50% decrease in size of 6 largest target lesions and no increase other nodal and extranodal; no progression of clinical disease; disease-related signs and symptoms, normalization or biochemical abnormalities, no progression in size of liver, spleen, or kidney; and no new sites of disease
AUC0-t: area under the plasma concentration time-curve from Time 0 to the time of the last quantifiable concentration (Ct), calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. For AUC0-t, an analysis of variance (ANOVA) model was used to estimate the ratio of geometric means and its 90% CI between romidepsin alone and romidepsin in the presence to ketoconazole.
AUC 0-24: area under the plasma concentration time-curve from Time 0 to 24 hours, calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing; for AUC 0-24 an analysis of variance (ANOVA) model was used to estimate the ratio of geometric means and its 90% confidence interval (CI) between romidepsin alone and romidepsin in the presence of ketoconazole
AUC0-∞: area under the plasma concentration time-curve from Time 0 extrapolated to infinity, calculated as \[AUCt + Ct/λz\].
Cmax: maximum observed plasma concentration, obtained directly from the observed concentration versus time data; for Cmax, an analysis of variance (ANOVA) model was used to estimate the ratio of geometric means and its 90% confidence interval (CI) between romidepsin alone and romidepsin in the presence of ketoconazole
Tmax: time to maximum observed Tmax, obtained directly from the observed concentration versus time data
Terminal elimination half-life (t1/2) in plasma, was calculated as \[(ln 2)/λz\]
Apparent total plasma clearance, (CL) calculated as \[Dose/AUC 0-∞\].
Vz: apparent total volume of distribution, calculated as \[(CL)/λz\].
Individual and mean romidepsin plasma concentrations by treatment and scheduled time data were collected. AUC0-24: area under the plasma concentration time-curve from Time 0 to 24 hours, calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing.
AUC0-∞: area under the plasma concentration time-curve from Time 0 extrapolated to infinity, calculated as \[AUCt + Ct/λz\]. λz is the apparent terminal rate constant. No AUC extrapolation was performed with unreliable λz. If the percentage of AUC extrapolated is ≥ 25%, AUC0-∞ will not be reported.
Maximum observed plasma concentration (Cmax)was obtained directly from the observed concentration versus time data.
The apparent total plasma clearance (CL) was calculated as \[Dose/AUC0-∞\] for Romidepsin alone and co-administered with rifampin plasma concentrations.
Apparent total volume of distribution (Vz) was calculated as \[(CL)/λz\] for Romidepsin and co-administered with Rifampin.
Toxicities were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), V 3.0. A DLT was one of the following, if considered at least possibly related to study treatment: Grade 4 neutropenia for ≥5 days or febrile neutropenia; Grade 4 thrombocytopenia or need for a platelet transfusion; ≥ Grade 3 nausea and/or emesis despite using optimal antiemetic therapy; ≥ Grade 3 diarrhea despite using maximal supportive therapy; Any clinically significant Grade 3 or 4 nonhematologic toxicity; Inability to administer all doses in cycle 1.
AEs were graded for severity according to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), V 3.0: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe (prevents normal everyday activities); Grade 4: Life-threatening or disabling; Grade 5: Death. A serious AE is associated with events that pose a threat to a patient's life or functioning, require hospitalization, is a congenital anomaly/birth defect or is an important medical event or condition that may jeopardize the patient and may require medical or surgical intervention to prevent one of the above outcomes.
Disease response was determined by the Investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria using computed tomography or magnetic resonance imaging: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions or the appearance of ≥1 new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
| Arm | Type | Description |
|---|---|---|
| Administration of Oral Azacitidine (CC-486) | EXPERIMENTAL | Oral azacytidine 300 mg during 14 first days of 28-days cycle for European (EU) patients, Oral azacytidine 200 mg during 14 first days of 28-days cycle for Asian patients (Treatment until progression, patient decision or toxicity) |
| Investigator's choice therapy - Romidepsin | ACTIVE_COMPARATOR | Romidepsin 14mg/m2 on days 1, 8 and 15 of a 28-days cycle (Treatment until progression, patient decision or toxicity) |
| Investigator's choice therapy - Gemcitabine | ACTIVE_COMPARATOR | Gemcitabine 1000mg/m2 on days 1, 8 and 15 of a 28-days cycle (during 6 cycles) |
| Treatment (romidepsin, lenalidomide) | EXPERIMENTAL | Patients receive romidepsin IV over 4 hours on days 1, 8, and 15 and lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. |
| Romidepsin | EXPERIMENTAL | This study is an open-label, single-arm study. The study is divided into the Screening Period, Treatment Period, and Follow-up Period. |
| Romidepsin and ketoconazole | EXPERIMENTAL | Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 1 and Day 8. Ketoconazole 400 mg oral once daily on Days 4-8 |
| Romidepsin and rifampin | EXPERIMENTAL | Romidepsin 14 mg/m\^2 intravenous infused over 4 hours on Day 1 and Day 8. Rifampin 600 mg oral once daily on Days 4-8 |
| Romidepsin / Gemcitabine | EXPERIMENTAL | Participants were to receive 7, 10 or 12 mg/m\^2 of romidepsin intravenously on either Days 1, 8 and 15 (Schedule A) or Days 1 and 15 (Schedule B) of each 28-day cycle, followed by 800 or 1000 mg/m\^2 of gemcitabine. Subsequent doses of both drugs were based on treatment-related toxicities. The planned duration of study therapy was 6 cycles or until disease progression occurred. Patients who responded could continue beyond 6 cycles until disease progression or until a withdrawal criterion was met. |
| Name | Type | Description |
|---|---|---|
| Azacitidine | DRUG | Azacitidine |
| Romidepsin | DRUG | Romidepsin |
| Gemcitabine | DRUG | Gemcitabine |
| lenalidomide | DRUG | Given PO |
| laboratory biomarker analysis | OTHER | Correlative studies |
| romidepsin (depsipeptide, FK228) | DRUG | Study patients received romidepsin at a dose of 14 mg/m\^2 intravenously over 4 hours on Days 1, 8 and 15 of each 28-day cycle. The duration of study treatment was 6 cycles although patients who showed an objective response or stable disease could continue to receive therapy, at the discretion of the investigator, until disease progression or another withdrawal criterion was met. |
| Ketoconazole | DRUG | Ketoconazole 400 mg oral once daily on Days 4-8 |
| Rifampin | DRUG | 600 mg oral once daily on Days 4-8 |
Inclusion Criteria: 1. Patient is ≥ 18 years of age at the time of signing the informed consent form (ICF). 2. Patient must understand and voluntarily sign an ICF prior to any study-specific assessments/procedures being conducted. 3. Patient is willing and able to adhere to the study visit schedule...
| Company | Ticker | Trials | Lead Phase | Drugs |
|---|---|---|---|---|
| Incyte Corporation | INCY | 2 | PHASE2 | Ruxolitinib, Pembrolizumab |
| Takeda Pharmaceutical Co. Ltd. Sponsored ADR | TAK | 1 | - | Undisclosed |
Romidepsin is a small molecule oncology drug being studied for use in T-cell lymphomas, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, as well as pancreatic cancer, prostate cancer, and hematologic malignancies. It is currently in clinical development and is not yet approved for these indications.
Romidepsin is being developed by Bristol-Myers Squibb Company, which trades under the ticker BMY. The company is conducting clinical trials of the drug in oncology indications, including T-cell lymphomas and solid tumors.
Romidepsin is in Phase 1 clinical development. While some completed trials were Phase 2 studies, the current development stage is Phase 1. The drug is investigational and has not been approved by regulatory authorities for any indication.
Romidepsin has been studied in several completed trials, including NCT00106431 for cutaneous T-cell lymphoma, NCT00379639 for pancreatic cancer, NCT01456039 for peripheral T-cell lymphoma, and NCT02232516 for peripheral T-cell lymphoma in combination with lenalidomide. These trials are all completed.
Romidepsin is also known as depsipeptide and FK228. Clinical trial NCT00106431, a Phase 2 study in cutaneous T-cell lymphoma, refers to the drug as Romidepsin (Depsipeptide, FK228), confirming these names refer to the same compound.