Relapsed or Refractory Peripheral T Cell Lymphoma
Conditions
Brief summary
This is a multinational, non-randomized, open-label, Phase 1/2 clinical study to evaluate the safety, tolerability and anti-tumor efficacy of AZD4205 as monotherapy in patients with peripheral T cell lymphoma (PTCL), who have relapsed from or are refractory/intolerant to standard systemic treatment. Phase 1 part: Around 20\ 40 patients will be subsequently enrolled into 2 different dose ascending cohorts. Additional 10\ 20 patients may be enrolled to further explore a selected dose defined by dose escalation cohorts. Phase 2 part: After the recommended phase 2 dose (RP2D) is defined, a phase 2 single-arm open-label pivotal study will be conducted to assess anti-tumor efficacy and safety of AZD4205 at RP2D in patients with refractory or relapsed PTCL.
Interventions
DRUGgolidocitinib
golidocitinib will be administered orally as capsules. golidocitinib treatment will be continued until disease progression or intolerant adverse reactions
Sponsors
Dizal Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Obtained written informed consent 2. Patients must have histologically confirmed peripheral T-cell lymphoma according to the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Tumor samples are required for central pathology review to confirm the diagnosis. 3. Patients must have measurable disease according to the Lugano criteria. 4. Patients should be transplant-ineligible upon their entry into this study, and must have relapsed after or been refractory/intolerant to ≥ 1 (but not \> 3) prior systemic therapy(ies) for PTCL. 5. Adequate bone marrow reserve and organ system functions.
Exclusion criteria
1. Any unsolved toxicity \> Common Terminology Criteria for Adverse Events (CTCAE) grade 1 from previous anti-cancer therapy (except alopecia). 2. Active infections, active or latent tuberculosis. 3. Patients with severely decreased lung function. 4. History of heart failure or QT interval prolongation. 5. Central nervous system (CNS) or leptomeningeal lymphoma. 6. History of treatment with Janus kinase (JAK) or signal transducer and activator of transcription 3 (STAT3) inhibitor. 7. Patient has undergone an allogeneic stem cell transplant. Patient had autologous stem cell transplant within 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part B: CT-based Objective Response Rate (ORR) by Independent Review Committee (IRC) | Up to approximately 3 years | ORR is the percentage of patients with at least one visit response of Complete Response (CR) or Partial Response (PR) based on CT scans evaluated by IRC per Lugano criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Duration of Response (DoR) Assessed by IRC | Up to approximately 3 years | DoR is the time from the date of first documented response until the date of documented progression or death due to any cause. Documented response and progression are both identified based on CT scans evaluated by IRC per Lugano criteria. |
| Part B: Complete Response Rate (CRR) Assessed by IRC | Up to approximately 3 years | CRR is the percentage of patients with at least one visit response of CR based on CT scans evaluated by IRC per Lugano criteria. |
| Part B: Progression Free Survival (PFS) Assessed by IRC | Up to approximately 3 years | PFS is the time from the date of first dosing until the date of objective disease progression or death (by any cause) regardless of whether the participant discontinues the study treatments. Progression is identified based on CT scans evaluated by IRC per Lugano criteria. |
| Part B: Time to Response (TTR) Assessed by IRC | Up to approximately 3 years | TTR is the time from the date of first dosing to the time of the initial response of PR or CR. Response is identified based on CT scans evaluated by IRC per Lugano criteria. |
| Part A and Part B: ORR Assessed by Investigator | Up to approximately 3 years | ORR is the percentage of patients with at least one visit response of CR or PR based on CT and/or PET scans evaluated by investigator per Lugano criteria. |
| Part A and Part B: DoR Assessed by Investigator | Up to approximately 3 years | DoR is the time from the date of first documented response until the date of documented progression or death due to any cause. Documented response and progression are both identified based on CT and/or PET scans evaluated by investigator per Lugano criteria. |
| Part A and Part B: Number of Participants With Adverse Events | The first dose until 28 days after last dose, up to approximately 3 years | To evaluate the safety and tolerability of AZD4205 in patients with PTCL in terms of adverse events (AEs), such as number of participants with AEs |
| Part A and Part B: PFS Assessed by Investigator | Up to approximately 3 years | PFS is the time from the date of first dosing until the date of objective disease progression or death (by any cause) regardless of whether the participant discontinues the study treatments. Progression is identified based on CT and/or PET scans evaluated by investigator per Lugano criteria. |
| Part B: TTR Assessed by Investigator | Up to approximately 3 years | TTR is the time from the date of first dosing to the time of the initial response of PR or CR. Response is identified based on CT scans evaluated by investigator per Lugano criteria. |
| Part A and Part B: Maximum Plasma Concentration (Cmax) of AZD4205 | Cycle 1 Day 1 (each cycle = 21 days): 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 24 hours postdose (for Group A, B and C); 0 (predose), 1, 2, 4, 6, 8, and 24 hours postdose (for Group D). | Maximum observed plasma concentration, obtained directly from the observed concentration versus time data. Calculated for the single dose. |
| Part A and Part B: Area Under the Plasma Concentration-time Curve From Zero to the Last Measurable Concentration (AUC0-t) of AZD4205 | Cycle 1, Day 1 (each cycle = 21 days): 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 24 hours postdose (for Group A, B and C); 0 (predose), 1, 2, 4, 6, 8, and 24 hours postdose (for Group D). | Area under the plasma concentration-time curve from time zero to the last quantifiable time point, calculated by the linear up/log down rule. |
| Part A and Part B: Cmax,ss, at Steady State of AZD4205 | Cycle 2 Day 1 (each cycle = 21 days): 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 24 hours postdose (for Group A, B and C); 0 (predose), 1, 2, 4, 6, 8, and 24 hours postdose (for Group D). | Maximum observed plasma concentration (ng/mL) at steady state, obtained directly from the observed concentration versus time data. Calculated for the multiple doses. |
| Part A and Part B: AUCss, at Steady State of AZD4205 | Cycle 2 Day 1 (each cycle = 21 days): 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 24 hours postdose (for Group A, B and C); 0 (predose), 1, 2, 4, 6, 8, and 24 hours postdose (for Group D). | Area under the plasma concentration-time curve from time zero to the last quantifiable time point at steady state, calculated by the linear up/log down rule |
| Part A and Part B: CRR Assessed by Investigator | Up to approximately 3 years | CRR is the percentage of patients with at least one visit response of CR based on CT and/or PET scans evaluated by investigator per Lugano criteria. |
Countries
Australia, China, South Korea, United States
Participant flow
Recruitment details
DZ2019J0005 study includes 2 parts: Part A, the dose escalation and extension part (group A, B, C), and part B, dose expansion part (group D). 51 and 120 participants were recruited in Part A and Part B respectively, based on physician referral at 31 sites in the U.S., Australia, China and South Korea. The first participant was enrolled on 10-Sep-2019 and the last participant was enrolled on 23-Aug-2023.
Pre-assignment details
171 enrolled participants met inclusion criteria and received study drug.
Participants by arm
| Arm | Count |
|---|---|
| AZD4205 Group A Group A: Open label AZD4205 at 150 mg, once daily (Phase 1)
AZD4205: AZD4205 will be administered orally as capsules. AZD4205 treatment will be continued until disease progression or intolerant adverse reactions | 28 |
| AZD4205 Group B Group B: Open label AZD4205 at 250 mg, once daily (Phase 1)
AZD4205: AZD4205 will be administered orally as capsules. AZD4205 treatment will be continued until disease progression or intolerant adverse reactions | 16 |
| AZD4205 Group C Group C: Open label AZD4205 at 150 mg, once daily (Phase 1)
AZD4205: AZD4205 will be administered orally as capsules. AZD4205 treatment will be continued until disease progression or intolerant adverse reactions | 7 |
| AZD4205 Group D Group D: Open label AZD4205 at the 150 mg (RP2D), once daily (Phase 2)
AZD4205: AZD4205 will be administered orally as capsules. AZD4205 treatment will be continued until disease progression or intolerant adverse reactions | 120 |
| Total | 171 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 3 | 1 | 1 | 54 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 4 |
| Overall Study | Other reason | 4 | 7 | 0 | 19 |
| Overall Study | Withdrawal by Subject | 8 | 1 | 1 | 4 |
Baseline characteristics
| Characteristic | AZD4205 Group A | Total | AZD4205 Group D | AZD4205 Group C | AZD4205 Group B |
|---|---|---|---|---|---|
| Age, Continuous | 62.5 years | 58.0 years | 58.0 years | 55.0 years | 61.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 28 Participants | 151 Participants | 100 Participants | 7 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 4 Participants | 4 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 14 Participants | 14 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 11 Participants | 61 Participants | 44 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 17 Participants | 110 Participants | 76 Participants | 4 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 28 | 2 / 16 | 1 / 7 | 54 / 120 |
| other Total, other adverse events | 26 / 28 | 16 / 16 | 6 / 7 | 114 / 120 |
| serious Total, serious adverse events | 12 / 28 | 9 / 16 | 1 / 7 | 44 / 120 |
Outcome results
Primary
Part B: CT-based Objective Response Rate (ORR) by Independent Review Committee (IRC)
ORR is the percentage of patients with at least one visit response of Complete Response (CR) or Partial Response (PR) based on CT scans evaluated by IRC per Lugano criteria.
Time frame: Up to approximately 3 years
Population: Evaluable for CT-based Response Set (all dosed and central pathology confirmed Peripheral T Cell Lymphoma (PTCL) patients with baseline measurable disease assessed by IRC using CT imaging)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD4205 Group D | Part B: CT-based Objective Response Rate (ORR) by Independent Review Committee (IRC) | 43.1 percentage of participants |
p-value: <0.0001Binomial test against a null
Secondary
Part A and Part B: Area Under the Plasma Concentration-time Curve From Zero to the Last Measurable Concentration (AUC0-t) of AZD4205
Area under the plasma concentration-time curve from time zero to the last quantifiable time point, calculated by the linear up/log down rule.
Time frame: Cycle 1, Day 1 (each cycle = 21 days): 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 24 hours postdose (for Group A, B and C); 0 (predose), 1, 2, 4, 6, 8, and 24 hours postdose (for Group D).
Population: PK population with Intensive PK sampling on Cycle 1, Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD4205 Group D | Part A and Part B: Area Under the Plasma Concentration-time Curve From Zero to the Last Measurable Concentration (AUC0-t) of AZD4205 | 3592 h*ng/mL | Geometric Coefficient of Variation 26 |
| AZD4205 Group B | Part A and Part B: Area Under the Plasma Concentration-time Curve From Zero to the Last Measurable Concentration (AUC0-t) of AZD4205 | 6755 h*ng/mL | Geometric Coefficient of Variation 25 |
| AZD4205 Group C | Part A and Part B: Area Under the Plasma Concentration-time Curve From Zero to the Last Measurable Concentration (AUC0-t) of AZD4205 | 3276 h*ng/mL | Geometric Coefficient of Variation 21.1 |
| AZD4205 Group D | Part A and Part B: Area Under the Plasma Concentration-time Curve From Zero to the Last Measurable Concentration (AUC0-t) of AZD4205 | 3271 h*ng/mL | Geometric Coefficient of Variation 35.24 |
Secondary
Part A and Part B: AUCss, at Steady State of AZD4205
Area under the plasma concentration-time curve from time zero to the last quantifiable time point at steady state, calculated by the linear up/log down rule
Time frame: Cycle 2 Day 1 (each cycle = 21 days): 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 24 hours postdose (for Group A, B and C); 0 (predose), 1, 2, 4, 6, 8, and 24 hours postdose (for Group D).
Population: PK population with Intensive PK sampling on Cycle 2, Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD4205 Group D | Part A and Part B: AUCss, at Steady State of AZD4205 | 11978 h*ng/mL | Geometric Coefficient of Variation 27.1 |
| AZD4205 Group B | Part A and Part B: AUCss, at Steady State of AZD4205 | 20991 h*ng/mL | Geometric Coefficient of Variation 33.5 |
| AZD4205 Group C | Part A and Part B: AUCss, at Steady State of AZD4205 | 11822 h*ng/mL | Geometric Coefficient of Variation 29.2 |
| AZD4205 Group D | Part A and Part B: AUCss, at Steady State of AZD4205 | 10000 h*ng/mL | Geometric Coefficient of Variation 36.85 |
Secondary
Part A and Part B: Cmax,ss, at Steady State of AZD4205
Maximum observed plasma concentration (ng/mL) at steady state, obtained directly from the observed concentration versus time data. Calculated for the multiple doses.
Time frame: Cycle 2 Day 1 (each cycle = 21 days): 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 24 hours postdose (for Group A, B and C); 0 (predose), 1, 2, 4, 6, 8, and 24 hours postdose (for Group D).
Population: PK population with Intensive PK sampling on Cycle 2, Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD4205 Group D | Part A and Part B: Cmax,ss, at Steady State of AZD4205 | 673.5 ng/mL | Geometric Coefficient of Variation 28.9 |
| AZD4205 Group B | Part A and Part B: Cmax,ss, at Steady State of AZD4205 | 1152 ng/mL | Geometric Coefficient of Variation 30.6 |
| AZD4205 Group C | Part A and Part B: Cmax,ss, at Steady State of AZD4205 | 665.9 ng/mL | Geometric Coefficient of Variation 27.4 |
| AZD4205 Group D | Part A and Part B: Cmax,ss, at Steady State of AZD4205 | 539.0 ng/mL | Geometric Coefficient of Variation 35.92 |
Secondary
Part A and Part B: CRR Assessed by Investigator
CRR is the percentage of patients with at least one visit response of CR based on CT and/or PET scans evaluated by investigator per Lugano criteria.
Time frame: Up to approximately 3 years
Population: Part A: Evaluable for Response Set Part B: Evaluable for CT-based Response Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD4205 Group D | Part A and Part B: CRR Assessed by Investigator | 28.6 percentage of participants |
| AZD4205 Group B | Part A and Part B: CRR Assessed by Investigator | 12.5 percentage of participants |
| AZD4205 Group C | Part A and Part B: CRR Assessed by Investigator | 14.3 percentage of participants |
| AZD4205 Group D | Part A and Part B: CRR Assessed by Investigator | 14.7 percentage of participants |
Secondary
Part A and Part B: DoR Assessed by Investigator
DoR is the time from the date of first documented response until the date of documented progression or death due to any cause. Documented response and progression are both identified based on CT and/or PET scans evaluated by investigator per Lugano criteria.
Time frame: Up to approximately 3 years
Population: Part A: Subset of CR or PR responders in Evaluable for Response Set Part B: Subset of CR or PR responders in Evaluable for CT-based Response Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD4205 Group D | Part A and Part B: DoR Assessed by Investigator | 5.09 months |
| AZD4205 Group B | Part A and Part B: DoR Assessed by Investigator | NA months |
| AZD4205 Group C | Part A and Part B: DoR Assessed by Investigator | 3.19 months |
| AZD4205 Group D | Part A and Part B: DoR Assessed by Investigator | NA months |
Secondary
Part A and Part B: Maximum Plasma Concentration (Cmax) of AZD4205
Maximum observed plasma concentration, obtained directly from the observed concentration versus time data. Calculated for the single dose.
Time frame: Cycle 1 Day 1 (each cycle = 21 days): 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 24 hours postdose (for Group A, B and C); 0 (predose), 1, 2, 4, 6, 8, and 24 hours postdose (for Group D).
Population: PK population (all dosed patients with at least one reportable AZD4205 plasma concentrations and no important AEs or protocol deviations that may impact PK) with Intensive PK sampling on Cycle 1, Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD4205 Group D | Part A and Part B: Maximum Plasma Concentration (Cmax) of AZD4205 | 279.8 ng/mL | Geometric Coefficient of Variation 29.2 |
| AZD4205 Group B | Part A and Part B: Maximum Plasma Concentration (Cmax) of AZD4205 | 512.0 ng/mL | Geometric Coefficient of Variation 27.7 |
| AZD4205 Group C | Part A and Part B: Maximum Plasma Concentration (Cmax) of AZD4205 | 258.8 ng/mL | Geometric Coefficient of Variation 36.9 |
| AZD4205 Group D | Part A and Part B: Maximum Plasma Concentration (Cmax) of AZD4205 | 229.2 ng/mL | Geometric Coefficient of Variation 40.91 |
Secondary
Part A and Part B: Number of Participants With Adverse Events
To evaluate the safety and tolerability of AZD4205 in patients with PTCL in terms of adverse events (AEs), such as number of participants with AEs
Time frame: The first dose until 28 days after last dose, up to approximately 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AZD4205 Group D | Part A and Part B: Number of Participants With Adverse Events | 26 Participants |
| AZD4205 Group B | Part A and Part B: Number of Participants With Adverse Events | 16 Participants |
| AZD4205 Group C | Part A and Part B: Number of Participants With Adverse Events | 6 Participants |
| AZD4205 Group D | Part A and Part B: Number of Participants With Adverse Events | 115 Participants |
Secondary
Part A and Part B: ORR Assessed by Investigator
ORR is the percentage of patients with at least one visit response of CR or PR based on CT and/or PET scans evaluated by investigator per Lugano criteria.
Time frame: Up to approximately 3 years
Population: Part A: Evaluable for Response Set (All dosed patients with baseline measurable disease) Part B: Evaluable for CT-based Response Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD4205 Group D | Part A and Part B: ORR Assessed by Investigator | 46.4 percentage of participants |
| AZD4205 Group B | Part A and Part B: ORR Assessed by Investigator | 37.5 percentage of participants |
| AZD4205 Group C | Part A and Part B: ORR Assessed by Investigator | 14.3 percentage of participants |
| AZD4205 Group D | Part A and Part B: ORR Assessed by Investigator | 38.2 percentage of participants |
Secondary
Part A and Part B: PFS Assessed by Investigator
PFS is the time from the date of first dosing until the date of objective disease progression or death (by any cause) regardless of whether the participant discontinues the study treatments. Progression is identified based on CT and/or PET scans evaluated by investigator per Lugano criteria.
Time frame: Up to approximately 3 years
Population: Part A: Safety Analysis Set Part B: Evaluable for Survival Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD4205 Group D | Part A and Part B: PFS Assessed by Investigator | 3.29 months |
| AZD4205 Group B | Part A and Part B: PFS Assessed by Investigator | 2.50 months |
| AZD4205 Group C | Part A and Part B: PFS Assessed by Investigator | 3.32 months |
| AZD4205 Group D | Part A and Part B: PFS Assessed by Investigator | 3.4 months |
Secondary
Part B: Complete Response Rate (CRR) Assessed by IRC
CRR is the percentage of patients with at least one visit response of CR based on CT scans evaluated by IRC per Lugano criteria.
Time frame: Up to approximately 3 years
Population: Evaluable for CT-based Response Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD4205 Group D | Part B: Complete Response Rate (CRR) Assessed by IRC | 21.6 percentage of participants |
Secondary
Part B: Duration of Response (DoR) Assessed by IRC
DoR is the time from the date of first documented response until the date of documented progression or death due to any cause. Documented response and progression are both identified based on CT scans evaluated by IRC per Lugano criteria.
Time frame: Up to approximately 3 years
Population: Subset of CR or PR responders in Evaluable for CT-based Response Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD4205 Group D | Part B: Duration of Response (DoR) Assessed by IRC | NA months |
Secondary
Part B: Progression Free Survival (PFS) Assessed by IRC
PFS is the time from the date of first dosing until the date of objective disease progression or death (by any cause) regardless of whether the participant discontinues the study treatments. Progression is identified based on CT scans evaluated by IRC per Lugano criteria.
Time frame: Up to approximately 3 years
Population: Evaluable for Survival Set (all dosed and central pathology confirmed PTCL patients)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD4205 Group D | Part B: Progression Free Survival (PFS) Assessed by IRC | 5.5 months |
Secondary
Part B: Time to Response (TTR) Assessed by IRC
TTR is the time from the date of first dosing to the time of the initial response of PR or CR. Response is identified based on CT scans evaluated by IRC per Lugano criteria.
Time frame: Up to approximately 3 years
Population: Subset of CR or PR responders in Evaluable for CT-based Response Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD4205 Group D | Part B: Time to Response (TTR) Assessed by IRC | 1.4 months |
Secondary
Part B: TTR Assessed by Investigator
TTR is the time from the date of first dosing to the time of the initial response of PR or CR. Response is identified based on CT scans evaluated by investigator per Lugano criteria.
Time frame: Up to approximately 3 years
Population: Subset of CR or PR responders in Evaluable for CT-based Response Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD4205 Group D | Part B: TTR Assessed by Investigator | 1.4 months |