AZD4573 as Monotherapy or in Combinations With Anti-cancer Agents in Patients With r/r PTCL or r/r cHL

Sponsor

AstraZeneca (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05140382

Collaborator

(none)

Enrollment

Locations

Arms

25.5

Anticipated Duration (Months)

2.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Relapsed/Refractory Peripheral T-cell Lymphoma Relapsed/Refractory Classical Hodgkins Lymphoma	Drug: AZD4573	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

81 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Dec 15, 2021

Anticipated Primary Completion Date :

Jan 31, 2024

Anticipated Study Completion Date :

Jan 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1: non-natural killer (NK) PTCL (Non-NK PTCL) Eligible participants with PTCL, all comers (excluding NKTCL) will receive AZD4573 monotherapy	Drug: AZD4573 AZD4573 will be given intravenously
Experimental: Cohort 2: NK PTCL Eligible participants with PTCL (NKTCL only) will receive AZD4573 monotherapy	Drug: AZD4573 AZD4573 will be given intravenously
Experimental: Cohort 3: cHL Eligible participants with cHL will receive AZD4573 monotherapy	Drug: AZD4573 AZD4573 will be given intravenously

Arm

Intervention/Treatment

Experimental: Cohort 1: non-natural killer (NK) PTCL (Non-NK PTCL)

Eligible participants with PTCL, all comers (excluding NKTCL) will receive AZD4573 monotherapy

Drug: AZD4573

AZD4573 will be given intravenously

Experimental: Cohort 2: NK PTCL

Eligible participants with PTCL (NKTCL only) will receive AZD4573 monotherapy

Drug: AZD4573

AZD4573 will be given intravenously

Experimental: Cohort 3: cHL

Eligible participants with cHL will receive AZD4573 monotherapy

Drug: AZD4573

AZD4573 will be given intravenously

Outcome Measures

Primary Outcome Measures

Objective Response Rate (ORR) [From Screening (Day -30 to Day-1) until disease progression or survival until death (approximately 6 months)]
The efficacy of AZD4573 will be assessed by evaluation of ORR. Proportion of participants who have a tumour response (complete response [CR] and partial response [PR]) according to the Lugano response criteria for malignant lymphoma.

Secondary Outcome Measures

Complete response (CR) rate [From Screening (Day -30 to Day-1) until disease progression or survival until death (approximately 6 months)]
Efficacy of AZD4573 will be assessed by evaluation of tumour response. Proportion of participants who have a complete response according to the Lugano response criteria.
Duration of response (DoR) [From Screening (Day -30 to Day-1) until disease progression or survival until death (approximately 6 months)]
Efficacy of AZD4573 will be assessed by evaluation of tumour response. The time from the first objective response of CR or PR 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 (approximately 6 months)]
Efficacy of AZD4573 will be assessed by evaluation of tumour response. The time from first dose date 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 (approximately 6 months)]
Efficacy of AZD4573 will be assessed by evaluation of overall survival. The time from first dose date to death from any cause.
Frequency of Adverse events (AE) and Serious AEs (SAE) [From Cycle 1 (this cycle is 35 days in length) until Safety follow-up (30 days after the last dose of all study drug) and long term follow-up (upto 2 years)]
The safety and tolerability of AZD4573 will be assessed
Maximum observed plasma (peak) drug concentration (Cmax) 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 and Day 2]
The plasma PK of AZD4573 will be assessed.
Area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) 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 and Day 2]
The plasma PK of AZD4573 will be assessed.
Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) 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 and Day 2]
The plasma PK of AZD4573 will be 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 and Day 2]
The plasma PK of AZD4573 will be assessed.
Time to reach peak or maximum observed concentration or response following drug administration (tmax) 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 and Day 2]
The plasma PK of AZD4573 will be 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 and Day 2]
The plasma PK of AZD4573 will be assessed.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 mandatory 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 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 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Duarte	California	United States	91010
2	Research Site	Ventura	California	United States	93003
3	Research Site	Boston	Massachusetts	United States	02215
4	Research Site	Hackensack	New Jersey	United States	07601
5	Research Site	Houston	Texas	United States	77030
6	Research Site	Seattle	Washington	United States	98104
7	Research Site	Clayton		Australia	3168
8	Research Site	Melbourne		Australia	3000
9	Research Site	Nedlands		Australia	6009
10	Research Site	Besançon		France	25000
11	Research Site	Clermont Ferrand		France	63003
12	Research Site	Creteil		France	94010
13	Research Site	Lille Cedex		France	59037
14	Research Site	MONTPELLIER Cedex 5		France	34295
15	Research Site	Bologna		Italy	40138
16	Research Site	Milano		Italy	20133
17	Research Site	Napoli		Italy	80131
18	Research Site	Seoul		Korea, Republic of	03080
19	Research Site	Seoul		Korea, Republic of	03722
20	Research Site	Seoul		Korea, Republic of	05505
21	Research Site	Seoul		Korea, Republic of	06351
22	Research Site	Singapore		Singapore	119074
23	Research Site	Singapore		Singapore	169608
24	Research Site	Singapore		Singapore	322605
25	Research Site	Lund		Sweden	221 85
26	Research Site	Solna		Sweden	111 35
27	Research Site	Kaohsiung City		Taiwan	83301
28	Research Site	Taichung		Taiwan	40447
29	Research Site	Tainan		Taiwan	70403
30	Research Site	Taipei		Taiwan	100
31	Research Site	Headington		United Kingdom	0X3 7LJ
32	Research Site	London		United Kingdom	NW1 2PG