T Cell Lymphoma
Conditions
Keywords
T cell Lymphoma, RP6530, Tenalisib, Romidepsin
Brief summary
To characterize safety, tolerability and to establish the maximum tolerated dose (MTD) of Tenalisib in combination with Romidepsin in patients with R/R T-cell lymphoma.
Interventions
DRUGTenalisib
Tenalisib, BID orally daily
DRUGRomidepsin
Romidepsin IV
Sponsors
Rhizen Pharmaceuticals SA
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Pathologically confirmed T-cell lymphomas at the enrolling institution. 2. Disease status as defined as relapsed or progressed patients who have received at least one systemic therapy. 3. The patients should have received NOT more than three prior systemic combination chemotherapies 4. PTCL patients must have measurable disease defined as at least one bidimensional measurable lesion with minimum measurement of \> 1.5 cm in the longest diameter. 5. Must have ECOG performance status ≤ 2 6. Adequate bone marrow, liver and renal function in line with below mentioned laboratory requirements. 1. Hemoglobin ≥8.0 g/dL 2. Absolute neutrophil count (ANC) ≥1,000/µL 3. Platelet count ≥75,000/μL 4. Total bilirubin ≤1.5 times the ULN (or ≤3 x ULN, if patient has Gilbert syndrome) 5. AST (SGOT) and ALT (SGPT) ≤ 3 x ULN; ≤ 5 ULN in case of liver involvement 6. Calculated creatinine clearance (CrCl) \> 50 ml/min by Cockcroft-Gault formula 7. Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential. 8. Provide written informed consent prior to any study-specific screening procedures. 9. Willingness and capability to comply with the requirements of the study
Exclusion criteria
1. Patient receiving anticancer therapy including any investigational therapy ≤3 weeks or 5 half-lives (whichever is shorter) prior to C1D1. 2. Patient who discontinued prior therapy with PI3K inhibitors or HDAC inhibitors due to drug toxicity. 3. PTCL patients with Allo-SCT on active GVHD or immunosuppression therapy within 3 months prior to C1D1. CTCL patients with the history of Allo-SCT will be excluded. 4. Patient with medical conditions requiring the use of systemic immunosuppressive medications (\> 20 mg/day of prednisone or equivalent). 5. Severe bacterial, viral or mycotic infection requiring systemic treatment. 6. Known seropositive requiring anti-viral therapy for human immunodeficiency virus (HIV) infection. 7. Known seropositive requiring anti-viral therapy for hepatitis B virus (HBV) infection OR evidence of active hepatitis B infection as defined by detectable viral load if the antibody tests are positive.. 8. Known seropositive requiring anti-viral therapy for hepatitis c virus (HCV) infection OR patients with positive hepatitis C virus Ab. 9. Subjects with active EBV unrelated to underlying lymphoma (positive serology for anti- EBV VCA IgM antibody and negative for anti-EBV EBNA IgG antibody, or clinical manifestations and positive EBV PCR consistent with active EBV infection. 10. Subject with active CMV (positive serology for anti-CMV IgM antibody and negative for anti-CMV IgG antibody and positive CMV PCR with clinical manifestations consistent with active CMV infection) and requiring therapy. 11. Uncontrolled or significant cardiovascular disease including, but not limited to: * Congenital long QT syndrome. * QTcF interval \> 450 msec * Myocardial infarction or stroke/TIA within the past 6 months * Uncontrolled angina within the past 3 months * Significant ECG abnormalities including 2nd degree atrio- ventricular (AV) block (AV) block type II, 3rd degree AV block. * History of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation or torsades de pointes), * History of other clinically significant heart disease (ie, cardiomyopathy, congestive heart failure with NYHA functional classification III-IV, pericarditis, significant pericardial effusion) * Requirement for daily supplemental oxygen therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With and Without Dose Limiting Toxicities (DLTs) | 28 days | The DLTs will be classified according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) With Tenalisib and Romidepsin Combination | 12 weeks | Overall response (ORR) = CR + PR) was assessed according to the Lugano classification with PTCL and according to the modified Severity Weighted Assessment Tool (mSWAT)/Global assessment in patients with CTCL. |
| Duration of Response (DoR) With Tenalisib and Romidepsin Combination | 28 weeks | The time period from the response achieved in patient until the disease progression |
| Maximum Observed Plasma Concentration (Cmax) | 8 days | Assessment of Cmax in subjects treated with Tenalisib and Romidepsin combination. Blood samples for measurement of RP6530 plasma concentrations were collected pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 11 hours after dosing on Day 8 of the first cycle. Maximum (peak) drug concentration (Cmax in nanograms/milliliter) was estimated using Single-Dose data. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose escalation_Cohort 1 RP6530 was administered at 400 mg BID orally daily and Romidepsin was administered at 12 mg/m2, IV on day 1, 8 and 15 | 3 |
| Dose escalation_Cohort 2 RP6530 was administered at 600 mg BID orally daily and Romidepsin was administered at 12 mg/m2, IV on day 1, 8 and 15 | 3 |
| Dose escalation_Cohort 3 RP6530 was administered at 800 mg BID orally daily and Romidepsin was administered at 14 mg/m2, IV on day 1, 8 and 15 | 3 |
| Dose expansion_Group 1 (PTCL) RP6530 was administered at 800 mg BID orally daily and Romidepsin was administered at 14 mg/m2, IV on day 1, 8 and 15 | 12 |
| Dose expansion_Group 2 (CTCL) RP6530 was administered at 800 mg BID orally daily and Romidepsin was administered at 14 mg/m2, IV on day 1, 8 and 15 | 12 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Premature discontinuation due to PD | 0 | 0 | 1 | 3 | 2 |
Baseline characteristics
| Characteristic | Dose escalation_Cohort 1 | Total | Dose expansion_Group 2 (CTCL) | Dose expansion_Group 1 (PTCL) | Dose escalation_Cohort 3 | Dose escalation_Cohort 2 |
|---|---|---|---|---|---|---|
| Age, Continuous | 69.79 years | 66.21 years | 69.67 years | 67.62 years | 49.03 years | 55.72 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 4 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 27 Participants | 10 Participants | 11 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 3 participants | 33 participants | 12 participants | 12 participants | 3 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 16 Participants | 7 Participants | 6 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 17 Participants | 5 Participants | 6 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 1 / 12 | 1 / 12 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 12 / 12 | 12 / 12 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 0 / 3 | 1 / 12 | 2 / 12 |
Outcome results
Primary
Number of Participants With and Without Dose Limiting Toxicities (DLTs)
The DLTs will be classified according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.
Time frame: 28 days
Population: DLT assessment performed in patients who participated in dose escalation phase; A toxicity will be considered dose-limiting if it occurs during the first cycle (4-weeks) of treatment with Tenalisib and Romidepsin combination and is considered related to combination.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose escalation_Cohort 1 | Number of Participants With and Without Dose Limiting Toxicities (DLTs) | No.of Participants with Dose Limiting Toxicities | 0 Participants |
| Dose escalation_Cohort 1 | Number of Participants With and Without Dose Limiting Toxicities (DLTs) | No.of Participants without Dose Limiting Toxicities | 3 Participants |
| Dose escalation_Cohort 2 | Number of Participants With and Without Dose Limiting Toxicities (DLTs) | No.of Participants with Dose Limiting Toxicities | 0 Participants |
| Dose escalation_Cohort 2 | Number of Participants With and Without Dose Limiting Toxicities (DLTs) | No.of Participants without Dose Limiting Toxicities | 3 Participants |
| Dose escalation_Cohort 3 | Number of Participants With and Without Dose Limiting Toxicities (DLTs) | No.of Participants with Dose Limiting Toxicities | 0 Participants |
| Dose escalation_Cohort 3 | Number of Participants With and Without Dose Limiting Toxicities (DLTs) | No.of Participants without Dose Limiting Toxicities | 3 Participants |
| Dose expansion_Group 1 (PTCL) | Number of Participants With and Without Dose Limiting Toxicities (DLTs) | No.of Participants without Dose Limiting Toxicities | 0 Participants |
| Dose expansion_Group 1 (PTCL) | Number of Participants With and Without Dose Limiting Toxicities (DLTs) | No.of Participants with Dose Limiting Toxicities | 0 Participants |
| Dose expansion_Group 2 (CTCL) | Number of Participants With and Without Dose Limiting Toxicities (DLTs) | No.of Participants with Dose Limiting Toxicities | 0 Participants |
| Dose expansion_Group 2 (CTCL) | Number of Participants With and Without Dose Limiting Toxicities (DLTs) | No.of Participants without Dose Limiting Toxicities | 0 Participants |
Secondary
Duration of Response (DoR) With Tenalisib and Romidepsin Combination
The time period from the response achieved in patient until the disease progression
Time frame: 28 weeks
Population: Duration of Response (DoR) is defined as the time when the measurement criteria are first met for PR or CR (whichever is reported first) until the date of documented disease progression or death. Overall number of Participants analyzed for DoR will be the participants who met response as CR or PR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose escalation_Cohort 1 | Duration of Response (DoR) With Tenalisib and Romidepsin Combination | 151 days |
| Dose escalation_Cohort 2 | Duration of Response (DoR) With Tenalisib and Romidepsin Combination | 151 days |
| Dose expansion_Group 1 (PTCL) | Duration of Response (DoR) With Tenalisib and Romidepsin Combination | 151 days |
| Dose expansion_Group 2 (CTCL) | Duration of Response (DoR) With Tenalisib and Romidepsin Combination | 114 days |
Secondary
Maximum Observed Plasma Concentration (Cmax)
Assessment of Cmax in subjects treated with Tenalisib and Romidepsin combination. Blood samples for measurement of RP6530 plasma concentrations were collected pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 11 hours after dosing on Day 8 of the first cycle. Maximum (peak) drug concentration (Cmax in nanograms/milliliter) was estimated using Single-Dose data.
Time frame: 8 days
Population: Peak Plasma Concentration (Cmax) of RP6530 at Cycle 1 day 8.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose escalation_Cohort 1 | Maximum Observed Plasma Concentration (Cmax) | 1544.42 nanogram/millilitre | Standard Deviation 1609.44 |
| Dose escalation_Cohort 2 | Maximum Observed Plasma Concentration (Cmax) | 2152.17 nanogram/millilitre | Standard Deviation 748.83 |
| Dose escalation_Cohort 3 | Maximum Observed Plasma Concentration (Cmax) | 5791.11 nanogram/millilitre | Standard Deviation 2426.44 |
Secondary
Overall Response Rate (ORR) With Tenalisib and Romidepsin Combination
Overall response (ORR) = CR + PR) was assessed according to the Lugano classification with PTCL and according to the modified Severity Weighted Assessment Tool (mSWAT)/Global assessment in patients with CTCL.
Time frame: 12 weeks
Population: Patients were considered for efficacy analysis as per protocol only if they had one post treatment efficacy assessment at C3D1
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose escalation_Cohort 1 | Overall Response Rate (ORR) With Tenalisib and Romidepsin Combination | 2 Participants |
| Dose escalation_Cohort 2 | Overall Response Rate (ORR) With Tenalisib and Romidepsin Combination | 2 Participants |
| Dose escalation_Cohort 3 | Overall Response Rate (ORR) With Tenalisib and Romidepsin Combination | 0 Participants |
| Dose expansion_Group 1 (PTCL) | Overall Response Rate (ORR) With Tenalisib and Romidepsin Combination | 7 Participants |
| Dose expansion_Group 2 (CTCL) | Overall Response Rate (ORR) With Tenalisib and Romidepsin Combination | 6 Participants |