Clinical trial NCT05140382: AZD4573 as Monotherapy or in Combinations With Anti-cancer Agents in Patients With r/r PTCL or r/r cHL
Official title: A Modular Phase II, Open-label, Multicentre Study to Assess AZD4573 Efficacy and Safety as Monotherapy or in Combination With Anti-cancer Agents in Patients With Relapsed/Refractory Peripheral T-cell Lymphoma or Classical Hodgkin Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Relapsed/Refractory Peripheral T-cell Lymphoma
Relapsed/Refractory Classical Hodgkins Lymphoma
Keywords: AZD4573
Modular study
Dose confirmation
Dose expansion
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2021-12-01
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months)
Secondary outcomes:
measure: Complete Response (CR) Rate
timeFrame: From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months).
measure: Duration of Response (DoR)
timeFrame: From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months).
measure: Progression-free Survival (PFS)
timeFrame: From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months).
measure: Overall Survival (OS)
timeFrame: From Screening (Day -30 to Day-1) until disease progression or survival until death (26 months).
measure: Number of Participants With Adverse Events (AE) and Serious AEs (SAE)
timeFrame: From treatment period (Cycle 1) to follow up visit (30 [± 7] ) days from the last dose (upto 26 months).
measure: Maximum Observed Plasma (Peak) Drug Concentration (Cmax)
timeFrame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
measure: Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast)
timeFrame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
measure: Area Under Plasma Concentration Time Curve From Zero to Infinity (AUC0-inf) of AZD4573
timeFrame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
measure: Time to Reach Peak Observed Concentration Following Drug Administration (Tmax)
timeFrame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
measure: Half-life (t1/2) of AZD4573
timeFrame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
measure: Systematic Clearance (CL)
timeFrame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
measure: Volume of Distribution at Terminal Phase (Vz)
timeFrame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
measure: Volume of Distribution at Steady State (Vss)
timeFrame: Cycle 1 (Cycle length is 35 days), Day 1 of Weeks 1-3 and Cycle 2 (Cycle length is 21 Days), Day 1.
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Hackensack
country: United States
facility: Research Site
state: New Jersey
city: Houston
country: United States
facility: Research Site
state: Texas
city: Salt Lake City
country: United States
facility: Research Site
state: Utah
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Clayton
country: Australia
facility: Research Site
city: Melbourne
country: Australia
facility: Research Site
city: Nedlands
country: Australia
facility: Research Site
city: Besançon
country: France
facility: Research Site
city: Clermont Ferrand
country: France
facility: Research Site
city: Creteil
country: France
facility: Research Site
city: Lille Cedex
country: France
facility: Research Site
city: MONTPELLIER Cedex 5
country: France
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Lund
country: Sweden
facility: Research Site
city: Kaohsiung City
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Headington
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
Study officials:
References: