Relapsed/Refractory Classical Hodgkins Lymphoma, Relapsed/Refractory Peripheral T-cell Lymphoma
Conditions
Keywords
AZD4573, Modular study, Dose confirmation, Dose expansion
Brief summary
This is a modular dose confirmation and expansion study. The core study design is to assess the efficacy of AZD4573, administered as monotherapy or combination therapy, to participants with either r/r PTCL or r/r cHL and to confirm the safety profiles and PK in these populations. Module 1 of this study will evaluate the efficacy, safety, and tolerability of AZD4573 monotherapy in participants with r/r PTCL or r/r cHL. If AZD4573 monotherapy is found to have promising anti-tumour efficacy in Module 1, an AZD4573 monotherapy Phase II expansion may be added via a substantial protocol amendment.
Detailed description
Module 1 will consist of two r/r PTCL cohorts and one cHL cohort; and each cohort includes 21 participants. A comprehensive initial review of all safety and PK/PD data will be conducted in approximately the first 6 participants of each cohort (safety run-in), with separate Safety Review Committees (SRCs) for each cohort executed independently. The safety assessment will be undertaken by the SRC. Each cohort will have a separate dose confirmation, assessed independently by the SRC, to assess safety and PK/PD data compared to the known profiles in the first time in human study (Study D8230C00001) lymphoma population. These SRC reviews will confirm whether the recommended phase II dose for lymphoma (IV infusion 12 mg once weekly, including intra-participant ramp-up) is safe and tolerable or if additional dose optimisation is indicated at a revised dose and/or schedule. All cohorts can be opened and delivered independently of each other.
Interventions
DRUGAZD4573
AZD4573 will be given intravenously
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Participants who are diagnosed with one of the following, as defined by the World Health Organisation: * Peripheral T-cell Lymphoma * Classical Hodgkin Lymphoma * Eastern Cooperative Oncology Group performance status of ≤ 2. * Must have received at least 1 prior line of therapy for the treatment of current disease and have documented relapsed or refractory active disease requiring treatment, defined as: * Recurrence of disease after response to prior line(s) of therapy, or * Progressive disease after completion of or on the treatment regimen preceding entry into the study, or * Disease which did not achieve an objective response (CR or PR). * Uric acid level \< ULN at screening. If hyperuricaemia is present at screening, SoC therapy should be administered (including IV fluid and rasburicase or allopurinol) to reduce the uric acid levels to \< ULN before the start of study intervention. * Willing and able to participate in all required evaluations and procedures in this study protocol including receiving IV administration of study drug and being admitted, if required, for at least 24 hours during study drug administration. * Fresh tumour tissue or archival tumour tissue must be confirmed to be available at screening. * Adequate haematologic function at screening. * PTCL Only: All participants with PTCL must be willing and able to provide baseline bone marrow aspirate and/or biopsy no older than 3 months and agree to undergo post-treatment bone marrow biopsy when required to confirm response. Additional Module 1 Inclusion Criteria Prior lines of therapy: * PTCL: Participants must have failed at least 1 prior therapy for the treatment of PTCL. * Non NK-PTCL (Cohort 1): Prior therapy must have included an alkylating agent and/or anthracycline. In addition, ALCL participants must have received brentuximab vedotin (BV) as part of prior therapy. * NKTCL (Cohort 2): Prior treatment must have included a platinum agent and/or asparaginase. * cHL (Cohort 3): Participants must have failed at least 2 prior therapies for the treatment of cHL (including BV and anti-PD1) except where unable to receive BV or anti-PD1 due to neuropathy or autoimmune disease. * Presence of at least 1 radiographically measurable, FDG-avid lymphoma disease lesion \> 1.5 cm (according to the Lugano (2014) criteria \[Cheson et al 2014\]).
Exclusion criteria
Type of Participant and Disease Characteristics: * PTCL only: Presence of bulky disease (defined as largest lymphoma lesion ≥ 10 cm) or a LDH value \> 3 x ULN. * PTCL only: Diagnosis of any of the following: Lymphoblastic/precursor T-cell lymphoma or leukaemia; T-cell prolymphocytic leukaemia; T-cell large granular lymphocytic leukaemia; Cutaneous T-cell lymphoma (eg, primary cutaneous type ALCL, mycosis fungoide/Sezary syndrome). Medical Conditions: * With the exception of alopecia and neuropathy, presence of any unresolved non haematological toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment. * Presence of, or history of, CNS lymphoma, leptomeningeal disease, or spinal cord compression. * History of prior non-haematological malignancy except for the following: * Malignancy treated with curative intent and with no evidence of active disease present for more than 1 year prior to screening and felt to be at low risk for recurrence by treating physician. * Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer. * Adequately treated carcinoma in situ without current evidence of disease. * Any evidence of: * Severe or uncontrolled systemic disease (eg, severe hepatic impairment, interstitial lung disease \[bilateral, diffuse, parenchymal lung disease\]). * Current unstable or uncompensated respiratory or cardiac conditions. * Uncontrolled hypertension. * Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment). * IV anti-infective treatment within 1 week before first dose of study drug. * Known history of infection with HIV. * Serologic status reflecting active hepatitis B or C infection: * Participants who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative PCR result before enrolment. Those who are hepatitis B surface antigen positive or hepatitis B PCR-positive will be excluded. * Participants who are hepatitis C antibody positive will need to have a negative PCR result before enrolment. Those who are hepatitis C PCR-positive will be excluded. * Any of the following cardiac criteria: * Resting QT interval corrected using Fridericia's formula (QTcF) ≥ 470 msec obtained from a single ECG. * Any clinically important abnormalities in rhythm (except for participants with a pacemaker in place), conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block). * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age. * Documented confirmation and ongoing treatment of adrenal gland insufficiency or pancreatitis. * Undergone any of the following procedures or experienced any of the following conditions within 6 months prior to first dose: * Coronary artery bypass graft * Angioplasty * Vascular stent * Myocardial infarction * Angina pectoris * CHF (New York Heart Association Class ≥ 2) * Ventricular arrhythmias requiring continuous therapy * Atrial fibrillation, which is judged as uncontrolled by the treating physician * Haemorrhagic or thrombotic stroke, including transient ischemic attacks or any other CNS bleeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months) | Objective response rate is defined as the proportion of participants who have a tumour response of complete response \[CR\] or partial response \[PR\] according to the Lugano (2014) response criteria for malignant lymphoma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DoR) | From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months). | Duration of response is defined as the time from the first objective response to the time of documented disease progression or death due to any cause, whichever occurs first. |
| Progression-free Survival (PFS) | From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months). | Progression-free survival is defined as the time from the date of first dose to documented disease progression, or death from any cause, whichever occurs first. |
| Overall Survival (OS) | From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months). | Overall survival is defined as the time from the date of first dose to death from any cause. |
| Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | From treatment period (Cycle 1) to follow up visit (30 [± 7] ) days from the last dose (upto 26 months). | The safety and tolerability of AZD4573 was assessed. |
| Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1. | The plasma PK of AZD4573 when administered in participants was assessed. |
| Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1. | The plasma PK of AZD4573 when administered in participants was assessed. |
| Complete Response (CR) Rate | From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months). | Complete response rate is defined as proportion of participants who have a complete response according to the Lugano (2014) response criteria. |
| Time to Reach Peak Observed Concentration Following Drug Administration (Tmax) | Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1. | The plasma PK of AZD4573 when administered in participants was assessed. |
| Half-life (t1/2) of AZD4573 | Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1. | The plasma PK of AZD4573 when administered in participants was assessed. |
| Systematic Clearance (CL) | Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1. | The plasma PK of AZD4573 when administered in participants was assessed. |
| Volume of Distribution at Terminal Phase (Vz) | Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1. | The plasma PK of AZD4573 when administered in participants was assessed. |
| Volume of Distribution at Steady State (Vss) | Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1. | The plasma PK of AZD4573 when administered in participants was assessed. |
| Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573 | Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1. | The plasma PK of AZD4573 when administered in participants was assessed. |
Countries
Australia, France, Italy, South Korea, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted from 15 December 2021 and completed on 16 February 2024. The study was conducted at 27 sites in 7 countries worldwide (Australia, France, Italy, South Korea, Taiwan, United Kingdom and United States).
Pre-assignment details
Participants who met the inclusion criteria and none of the exclusion criteria were enrolled to the study. All study assessments were performed as per the schedule of assessment.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Non-NK PTCL Participants with non-NK PTCL received 12 mg dose of AZD4573 once weekly until disease progression. | 31 |
| Cohort 2 NK PTCL Participants with NK PTCL received 12 mg dose of AZD4573 once weekly until disease progression. | 2 |
| Cohort 3 cHL Participants with cHL received 12 mg dose of AZD4573 once weekly until disease progression. | 19 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 3 | 0 | 0 |
| Overall Study | Investigator decision | 1 | 0 | 0 |
| Overall Study | Other | 4 | 0 | 1 |
| Overall Study | Progressive disease | 20 | 1 | 12 |
| Overall Study | Subjective disease progression | 2 | 1 | 0 |
| Overall Study | Unknown at data cut-off | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 4 |
| Overall Study | Withdrawal of consent | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Cohort 3 cHL | Cohort 2 NK PTCL | Cohort 1 Non-NK PTCL |
|---|---|---|---|---|
| Age, Continuous | 55.2 Years STANDARD_DEVIATION 14.5 | 46.5 Years STANDARD_DEVIATION 14.7 | 61.0 Years STANDARD_DEVIATION 8.5 | 60.1 Years STANDARD_DEVIATION 12.2 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 4 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Ethnicity Missing | 9 Participants | 2 Participants | 0 Participants | 7 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 38 Participants | 16 Participants | 2 Participants | 20 Participants |
| Race/Ethnicity, Customized Ethnicity Other | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 11 Participants | 6 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Black or African American | 4 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Missing | 6 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Not reported | 4 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Other | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 25 Participants | 7 Participants | 0 Participants | 18 Participants |
| Sex: Female, Male Female | 23 Participants | 10 Participants | 0 Participants | 13 Participants |
| Sex: Female, Male Male | 29 Participants | 9 Participants | 2 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 17 / 31 | 1 / 2 | 2 / 19 |
| other Total, other adverse events | 31 / 31 | 2 / 2 | 18 / 19 |
| serious Total, serious adverse events | 21 / 31 | 2 / 2 | 11 / 19 |
Outcome results
Primary
Objective Response Rate (ORR)
Objective response rate is defined as the proportion of participants who have a tumour response of complete response \[CR\] or partial response \[PR\] according to the Lugano (2014) response criteria for malignant lymphoma.
Time frame: From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months)
Population: Response evaluable set included all dosed participants who had measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 Non-NK PTCL | Objective Response Rate (ORR) | 22.6 Percentage of participants |
| Cohort 2 NK PTCL | Objective Response Rate (ORR) | 0 Percentage of participants |
| Cohort 3 cHL | Objective Response Rate (ORR) | 21.1 Percentage of participants |
Secondary
Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573
The plasma PK of AZD4573 when administered in participants was assessed.
Time frame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
Population: PK set included all participants who received any amount of study intervention with at least 1 reportable concentration. Here, 'n (number analyzed in each row) signifies the participants with available data that were analyzed for each timepoint of this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Non-NK PTCL | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573 | Cycle 1 week 1 day 1 | 1294 h*ng/mL | Geometric Coefficient of Variation 82.9 |
| Cohort 1 Non-NK PTCL | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573 | Cycle 1 week 2 day 1 | 1711 h*ng/mL | Geometric Coefficient of Variation 86.8 |
| Cohort 1 Non-NK PTCL | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573 | Cycle 1 week 3 day 1 | 1490 h*ng/mL | Geometric Coefficient of Variation 71.5 |
| Cohort 1 Non-NK PTCL | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573 | Cycle 2 day 1 | 1885 h*ng/mL | Geometric Coefficient of Variation 72.9 |
| Cohort 2 NK PTCL | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573 | Cycle 1 week 3 day 1 | NA h*ng/mL | — |
| Cohort 2 NK PTCL | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573 | Cycle 1 week 2 day 1 | NA h*ng/mL | — |
| Cohort 3 cHL | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573 | Cycle 1 week 2 day 1 | 1984 h*ng/mL | Geometric Coefficient of Variation 62.9 |
| Cohort 3 cHL | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573 | Cycle 2 day 1 | 1899 h*ng/mL | Geometric Coefficient of Variation 89 |
| Cohort 3 cHL | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573 | Cycle 1 week 1 day 1 | 1872 h*ng/mL | Geometric Coefficient of Variation 59.3 |
| Cohort 3 cHL | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573 | Cycle 1 week 3 day 1 | 2643 h*ng/mL | Geometric Coefficient of Variation 88.2 |
Secondary
Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast)
The plasma PK of AZD4573 when administered in participants was assessed.
Time frame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
Population: PK set included all participants who received any amount of study intervention with at least 1 reportable concentration. Here, 'n (number analyzed in each row) signifies the participants with available data that were analyzed for each timepoint of this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Non-NK PTCL | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Cycle 1 week 1 day 1 | 913.3 hours (h)*ng/mL | Geometric Coefficient of Variation 95 |
| Cohort 1 Non-NK PTCL | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Cycle 1 week 2 day 1 | 1695 hours (h)*ng/mL | Geometric Coefficient of Variation 102.3 |
| Cohort 1 Non-NK PTCL | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Cycle 2 day 1 | 1933 hours (h)*ng/mL | Geometric Coefficient of Variation 81.2 |
| Cohort 1 Non-NK PTCL | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Cycle 1 week 3 day 1 | 1651 hours (h)*ng/mL | Geometric Coefficient of Variation 76.5 |
| Cohort 2 NK PTCL | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Cycle 1 week 2 day 1 | NA hours (h)*ng/mL | — |
| Cohort 2 NK PTCL | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Cycle 1 week 1 day 1 | NA hours (h)*ng/mL | — |
| Cohort 2 NK PTCL | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Cycle 1 week 3 day 1 | NA hours (h)*ng/mL | — |
| Cohort 3 cHL | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Cycle 2 day 1 | 2083 hours (h)*ng/mL | Geometric Coefficient of Variation 115.9 |
| Cohort 3 cHL | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Cycle 1 week 1 day 1 | 1039 hours (h)*ng/mL | Geometric Coefficient of Variation 113.5 |
| Cohort 3 cHL | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Cycle 1 week 2 day 1 | 1646 hours (h)*ng/mL | Geometric Coefficient of Variation 86.7 |
| Cohort 3 cHL | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Cycle 1 week 3 day 1 | 2228 hours (h)*ng/mL | Geometric Coefficient of Variation 75 |
Secondary
Complete Response (CR) Rate
Complete response rate is defined as proportion of participants who have a complete response according to the Lugano (2014) response criteria.
Time frame: From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months).
Population: Response evaluable set included all dosed participants who had measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 Non-NK PTCL | Complete Response (CR) Rate | 19.4 Percentage of participants |
| Cohort 2 NK PTCL | Complete Response (CR) Rate | 0 Percentage of participants |
| Cohort 3 cHL | Complete Response (CR) Rate | 15.8 Percentage of participants |
Secondary
Duration of Response (DoR)
Duration of response is defined as the time from the first objective response to the time of documented disease progression or death due to any cause, whichever occurs first.
Time frame: From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months).
Population: Response evaluable set included all dosed participants who have measurable disease at baseline and had objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Non-NK PTCL | Duration of Response (DoR) | NA Months |
| Cohort 3 cHL | Duration of Response (DoR) | 5.2 Months |
Secondary
Half-life (t1/2) of AZD4573
The plasma PK of AZD4573 when administered in participants was assessed.
Time frame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
Population: PK set included all participants who received any amount of study intervention with at least 1 reportable concentration. Here, 'n (number analyzed in each row) signifies the participants with available data that were analyzed for each timepoint of this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 Non-NK PTCL | Half-life (t1/2) of AZD4573 | Cycle 1 week 2 day 1 | 5.448 Hour |
| Cohort 1 Non-NK PTCL | Half-life (t1/2) of AZD4573 | Cycle 2 day 1 | 6.669 Hour |
| Cohort 1 Non-NK PTCL | Half-life (t1/2) of AZD4573 | Cycle 1 week 3 day 1 | 5.435 Hour |
| Cohort 1 Non-NK PTCL | Half-life (t1/2) of AZD4573 | Cycle 1 week 1 day 1 | 5.772 Hour |
| Cohort 2 NK PTCL | Half-life (t1/2) of AZD4573 | Cycle 1 week 3 day 1 | NA Hour |
| Cohort 2 NK PTCL | Half-life (t1/2) of AZD4573 | Cycle 1 week 2 day 1 | NA Hour |
| Cohort 3 cHL | Half-life (t1/2) of AZD4573 | Cycle 2 day 1 | 4.323 Hour |
| Cohort 3 cHL | Half-life (t1/2) of AZD4573 | Cycle 1 week 1 day 1 | 5.858 Hour |
| Cohort 3 cHL | Half-life (t1/2) of AZD4573 | Cycle 1 week 2 day 1 | 5.250 Hour |
| Cohort 3 cHL | Half-life (t1/2) of AZD4573 | Cycle 1 week 3 day 1 | 5.499 Hour |
Secondary
Maximum Observed Plasma (Peak) Drug Concentration (Cmax)
The plasma PK of AZD4573 when administered in participants was assessed.
Time frame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
Population: Pharmacokinetic (PK) set included all participants who received any amount of study intervention with at least 1 reportable concentration. Here, 'n (number analyzed in each row) signifies the participants with available data that were analyzed for each timepoint of this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Non-NK PTCL | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Cycle 1 week 2 day 1 | 312.4 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 84.5 |
| Cohort 1 Non-NK PTCL | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Cycle 1 week 1 day 1 | 159.9 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 53.2 |
| Cohort 1 Non-NK PTCL | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Cycle 1 week 3 day 1 | 265.5 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 54.1 |
| Cohort 1 Non-NK PTCL | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Cycle 2 day 1 | 308.6 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 65.9 |
| Cohort 2 NK PTCL | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Cycle 1 week 2 day 1 | NA Nanogram per milliliter (ng/mL) | — |
| Cohort 2 NK PTCL | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Cycle 1 week 3 day 1 | NA Nanogram per milliliter (ng/mL) | — |
| Cohort 2 NK PTCL | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Cycle 1 week 1 day 1 | NA Nanogram per milliliter (ng/mL) | — |
| Cohort 3 cHL | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Cycle 2 day 1 | 381.8 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 82.5 |
| Cohort 3 cHL | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Cycle 1 week 3 day 1 | 376.3 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 89.9 |
| Cohort 3 cHL | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Cycle 1 week 2 day 1 | 278.2 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 73.8 |
| Cohort 3 cHL | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Cycle 1 week 1 day 1 | 201.8 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 82.1 |
Secondary
Number of Participants With Adverse Events (AE) and Serious AEs (SAE)
The safety and tolerability of AZD4573 was assessed.
Time frame: From treatment period (Cycle 1) to follow up visit (30 [± 7] ) days from the last dose (upto 26 months).
Population: Safety set included all participants who received at least 1 dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 Non-NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE | 31 Participants |
| Cohort 1 Non-NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE possibly related to treatment | 31 Participants |
| Cohort 1 Non-NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher | 29 Participants |
| Cohort 1 Non-NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE of CTCAE grade 3 or higher, possibly related to treatment | 27 Participants |
| Cohort 1 Non-NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE with outcome = death | 2 Participants |
| Cohort 1 Non-NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE with outcome = death, possibly related to treatment | 2 Participants |
| Cohort 1 Non-NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any SAE (including events with outcome = death) | 21 Participants |
| Cohort 1 Non-NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any SAE (including events with outcome = death), possibly related to treatment | 16 Participants |
| Cohort 2 NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher | 2 Participants |
| Cohort 2 NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any SAE (including events with outcome = death) | 2 Participants |
| Cohort 2 NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE of CTCAE grade 3 or higher, possibly related to treatment | 2 Participants |
| Cohort 2 NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE with outcome = death | 1 Participants |
| Cohort 2 NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE with outcome = death, possibly related to treatment | 0 Participants |
| Cohort 2 NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE | 2 Participants |
| Cohort 2 NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE possibly related to treatment | 2 Participants |
| Cohort 2 NK PTCL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any SAE (including events with outcome = death), possibly related to treatment | 1 Participants |
| Cohort 3 cHL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher | 15 Participants |
| Cohort 3 cHL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE possibly related to treatment | 16 Participants |
| Cohort 3 cHL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE | 18 Participants |
| Cohort 3 cHL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE of CTCAE grade 3 or higher, possibly related to treatment | 13 Participants |
| Cohort 3 cHL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any SAE (including events with outcome = death) | 11 Participants |
| Cohort 3 cHL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE with outcome = death, possibly related to treatment | 0 Participants |
| Cohort 3 cHL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any AE with outcome = death | 0 Participants |
| Cohort 3 cHL | Number of Participants With Adverse Events (AE) and Serious AEs (SAE) | Any SAE (including events with outcome = death), possibly related to treatment | 8 Participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from the date of first dose to death from any cause.
Time frame: From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months).
Population: Full analysis set included all participants who received any amount of any study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Non-NK PTCL | Overall Survival (OS) | 8.6 Months |
| Cohort 2 NK PTCL | Overall Survival (OS) | NA Months |
| Cohort 3 cHL | Overall Survival (OS) | NA Months |
Secondary
Progression-free Survival (PFS)
Progression-free survival is defined as the time from the date of first dose to documented disease progression, or death from any cause, whichever occurs first.
Time frame: From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months).
Population: Full analysis set included all participants who received any amount of any study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Non-NK PTCL | Progression-free Survival (PFS) | 1.8 Months |
| Cohort 2 NK PTCL | Progression-free Survival (PFS) | 0.7 Months |
| Cohort 3 cHL | Progression-free Survival (PFS) | 1.9 Months |
Secondary
Systematic Clearance (CL)
The plasma PK of AZD4573 when administered in participants was assessed.
Time frame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
Population: PK set included all participants who received any amount of study intervention with at least 1 reportable concentration. Here, 'n (number analyzed in each row) signifies the participants with available data that were analyzed for each timepoint of this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Non-NK PTCL | Systematic Clearance (CL) | Cycle 1 week 1 day 1 | 4.636 Liter/hour | Geometric Coefficient of Variation 82.9 |
| Cohort 1 Non-NK PTCL | Systematic Clearance (CL) | Cycle 1 week 2 day 1 | 5.137 Liter/hour | Geometric Coefficient of Variation 82.3 |
| Cohort 1 Non-NK PTCL | Systematic Clearance (CL) | Cycle 1 week 3 day 1 | 7.799 Liter/hour | Geometric Coefficient of Variation 69.5 |
| Cohort 1 Non-NK PTCL | Systematic Clearance (CL) | Cycle 2 day 1 | 6.367 Liter/hour | Geometric Coefficient of Variation 72.9 |
| Cohort 2 NK PTCL | Systematic Clearance (CL) | Cycle 1 week 3 day 1 | NA Liter/hour | — |
| Cohort 2 NK PTCL | Systematic Clearance (CL) | Cycle 1 week 2 day 1 | NA Liter/hour | — |
| Cohort 3 cHL | Systematic Clearance (CL) | Cycle 1 week 2 day 1 | 4.537 Liter/hour | Geometric Coefficient of Variation 62.9 |
| Cohort 3 cHL | Systematic Clearance (CL) | Cycle 2 day 1 | 6.064 Liter/hour | Geometric Coefficient of Variation 85.9 |
| Cohort 3 cHL | Systematic Clearance (CL) | Cycle 1 week 1 day 1 | 3.205 Liter/hour | Geometric Coefficient of Variation 59.3 |
| Cohort 3 cHL | Systematic Clearance (CL) | Cycle 1 week 3 day 1 | 4.965 Liter/hour | Geometric Coefficient of Variation 74.7 |
Secondary
Time to Reach Peak Observed Concentration Following Drug Administration (Tmax)
The plasma PK of AZD4573 when administered in participants was assessed.
Time frame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
Population: PK set included all participants who received any amount of study intervention with at least 1 reportable concentration. Here, 'n (number analyzed in each row) signifies the participants with available data that were analyzed for each timepoint of this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 Non-NK PTCL | Time to Reach Peak Observed Concentration Following Drug Administration (Tmax) | Cycle 1 week 1 day 1 | 2.000 Hour |
| Cohort 1 Non-NK PTCL | Time to Reach Peak Observed Concentration Following Drug Administration (Tmax) | Cycle 1 week 2 day 1 | 2.083 Hour |
| Cohort 1 Non-NK PTCL | Time to Reach Peak Observed Concentration Following Drug Administration (Tmax) | Cycle 2 day 1 | 2.133 Hour |
| Cohort 1 Non-NK PTCL | Time to Reach Peak Observed Concentration Following Drug Administration (Tmax) | Cycle 1 week 3 day 1 | 2.083 Hour |
| Cohort 2 NK PTCL | Time to Reach Peak Observed Concentration Following Drug Administration (Tmax) | Cycle 1 week 2 day 1 | NA Hour |
| Cohort 2 NK PTCL | Time to Reach Peak Observed Concentration Following Drug Administration (Tmax) | Cycle 1 week 1 day 1 | NA Hour |
| Cohort 2 NK PTCL | Time to Reach Peak Observed Concentration Following Drug Administration (Tmax) | Cycle 1 week 3 day 1 | NA Hour |
| Cohort 3 cHL | Time to Reach Peak Observed Concentration Following Drug Administration (Tmax) | Cycle 2 day 1 | 2.083 Hour |
| Cohort 3 cHL | Time to Reach Peak Observed Concentration Following Drug Administration (Tmax) | Cycle 1 week 1 day 1 | 2.083 Hour |
| Cohort 3 cHL | Time to Reach Peak Observed Concentration Following Drug Administration (Tmax) | Cycle 1 week 2 day 1 | 2.083 Hour |
| Cohort 3 cHL | Time to Reach Peak Observed Concentration Following Drug Administration (Tmax) | Cycle 1 week 3 day 1 | 2.133 Hour |
Secondary
Volume of Distribution at Steady State (Vss)
The plasma PK of AZD4573 when administered in participants was assessed.
Time frame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
Population: PK set included all participants who received any amount of study intervention with at least 1 reportable concentration. Here, 'n (number analyzed in each row) signifies the participants with available data that were analyzed for each timepoint of this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Non-NK PTCL | Volume of Distribution at Steady State (Vss) | Cycle 1 week 1 day 1 | 35.80 Liter | Geometric Coefficient of Variation 51.1 |
| Cohort 1 Non-NK PTCL | Volume of Distribution at Steady State (Vss) | Cycle 1 week 2 day 1 | 39.25 Liter | Geometric Coefficient of Variation 51.3 |
| Cohort 1 Non-NK PTCL | Volume of Distribution at Steady State (Vss) | Cycle 1 week 3 day 1 | 50.32 Liter | Geometric Coefficient of Variation 27.8 |
| Cohort 1 Non-NK PTCL | Volume of Distribution at Steady State (Vss) | Cycle 2 day 1 | 55.93 Liter | Geometric Coefficient of Variation 36.8 |
| Cohort 2 NK PTCL | Volume of Distribution at Steady State (Vss) | Cycle 1 week 3 day 1 | NA Liter | — |
| Cohort 2 NK PTCL | Volume of Distribution at Steady State (Vss) | Cycle 1 week 2 day 1 | NA Liter | — |
| Cohort 3 cHL | Volume of Distribution at Steady State (Vss) | Cycle 1 week 2 day 1 | 33.20 Liter | Geometric Coefficient of Variation 36.9 |
| Cohort 3 cHL | Volume of Distribution at Steady State (Vss) | Cycle 2 day 1 | 37.29 Liter | Geometric Coefficient of Variation 54.6 |
| Cohort 3 cHL | Volume of Distribution at Steady State (Vss) | Cycle 1 week 1 day 1 | 24.20 Liter | Geometric Coefficient of Variation 54.3 |
| Cohort 3 cHL | Volume of Distribution at Steady State (Vss) | Cycle 1 week 3 day 1 | 37.99 Liter | Geometric Coefficient of Variation 66.3 |
Secondary
Volume of Distribution at Terminal Phase (Vz)
The plasma PK of AZD4573 when administered in participants was assessed.
Time frame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
Population: PK set included all participants who received any amount of study intervention with at least 1 reportable concentration. Here, 'n (number analyzed in each row) signifies the participants with available data that were analyzed for each timepoint of this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Non-NK PTCL | Volume of Distribution at Terminal Phase (Vz) | Cycle 1 week 1 day 1 | 38.59 Liter | Geometric Coefficient of Variation 49 |
| Cohort 1 Non-NK PTCL | Volume of Distribution at Terminal Phase (Vz) | Cycle 1 week 2 day 1 | 45.96 Liter | Geometric Coefficient of Variation 53.8 |
| Cohort 1 Non-NK PTCL | Volume of Distribution at Terminal Phase (Vz) | Cycle 1 week 3 day 1 | 58.92 Liter | Geometric Coefficient of Variation 33.1 |
| Cohort 1 Non-NK PTCL | Volume of Distribution at Terminal Phase (Vz) | Cycle 2 day 1 | 63.45 Liter | Geometric Coefficient of Variation 41.6 |
| Cohort 2 NK PTCL | Volume of Distribution at Terminal Phase (Vz) | Cycle 1 week 3 day 1 | NA Liter | — |
| Cohort 2 NK PTCL | Volume of Distribution at Terminal Phase (Vz) | Cycle 1 week 2 day 1 | NA Liter | — |
| Cohort 3 cHL | Volume of Distribution at Terminal Phase (Vz) | Cycle 1 week 2 day 1 | 37.68 Liter | Geometric Coefficient of Variation 37.5 |
| Cohort 3 cHL | Volume of Distribution at Terminal Phase (Vz) | Cycle 2 day 1 | 43.38 Liter | Geometric Coefficient of Variation 59 |
| Cohort 3 cHL | Volume of Distribution at Terminal Phase (Vz) | Cycle 1 week 1 day 1 | 26.45 Liter | Geometric Coefficient of Variation 54.2 |
| Cohort 3 cHL | Volume of Distribution at Terminal Phase (Vz) | Cycle 1 week 3 day 1 | 44.34 Liter | Geometric Coefficient of Variation 55.7 |