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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05205161




Registration number
NCT05205161
Ethics application status
Date submitted
5/01/2022
Date registered
25/01/2022

Titles & IDs
Public title
A Phase I/II Study of AZD0466 as Monotherapy or in Combination With Anticancer Agents in Advanced Non-Hodgkin Lymphoma
Scientific title
A Modular Phase I/II, Open-label, Dose Escalation and Expansion, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of AZD0466 as Monotherapy or in Combination With Anticancer Agents in Patients With Advanced Non-Hodgkin Lymphoma.
Secondary ID [1] 0 0
2021-003410-39
Secondary ID [2] 0 0
D8242C00001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-Hodgkin Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - AZD0466

Experimental: Part A (Dose Escalation): Dose Level (DL)-1 - Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.

Experimental: Part A (Dose Escalation): DL1 - Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.

Experimental: Part A (Dose Escalation): DL2 - Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.

Experimental: Part A (Dose Escalation): DL3 - Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.

Experimental: Part A (Dose Escalation): DL4 - Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.

Experimental: Part B (Dose Expansion): Cohort B1 (R/R MCL) - Participants with advanced R/R MCL will receive AZD0466 at the recommended phase 2 dose (RP2D) until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.

Experimental: Part B (Dose Expansion): Cohort B2 (R/R FL or MZL) - Participants with advanced R/R FL or MZL will receive AZD0466 at the recommended phase 2 dose (RP2D) until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.

Experimental: Part B (Dose Expansion): Cohort B3 (R/R DLBCL) - Participants with advanced R/R DLBCL will receive AZD0466 at the recommended phase 2 dose (RP2D) until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.


Treatment: Drugs: AZD0466
All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Part A: Incidence of adverse events (AEs) and dose-limiting toxicities (DLTs)
Timepoint [1] 0 0
From Screening until for 28 days Post-treatment follow-up visit (upto 2 years)
Primary outcome [2] 0 0
Part B: Objective Response Rate (ORR)
Timepoint [2] 0 0
From Screening until for 28 days Post-treatment follow-up visit (upto 2 years)
Secondary outcome [1] 0 0
Part B: Incidence of adverse events (AEs) and serious adverse events (SAEs)
Timepoint [1] 0 0
From screening until for 28 days Post-treatment follow-up visit and every 3 month (Q3M) after post-treatment follow-up visit (upto 2 years)
Secondary outcome [2] 0 0
Part B: Complete Response (CR) Rate
Timepoint [2] 0 0
From screening until for 28 days Post-treatment follow-up visit and the Q3M after post-treatment follow-up visit (upto 2 years)
Secondary outcome [3] 0 0
Part B: Duration of Response (DoR)
Timepoint [3] 0 0
From screening until for 28 days Post-treatment follow-up visit and the Q3M after post-treatment follow-up visit (upto 2 years)
Secondary outcome [4] 0 0
Part B: Time to Response (TTR)
Timepoint [4] 0 0
From screening until for 28 days Post-treatment follow-up visit and the Q3M after post-treatment follow-up visit (upto 2 years)
Secondary outcome [5] 0 0
Part B: Progression-free Survival (PFS)
Timepoint [5] 0 0
From screening until for 28 days Post-treatment follow-up visit and the Q3M after post-treatment follow-up visit (upto 2 years)
Secondary outcome [6] 0 0
Part B: Overall Survival (OS)
Timepoint [6] 0 0
From screening until for 28 days Post-treatment follow-up visit and the Q3M after post-treatment follow-up visit (upto 2 years)
Secondary outcome [7] 0 0
Part A and Part B: Maximum observed plasma (peak) drug concentration (Cmax)
Timepoint [7] 0 0
Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days)
Secondary outcome [8] 0 0
Part A and Part B: Time to reach peak or maximum observed concentration or response following drug administration (tmax)
Timepoint [8] 0 0
Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days)
Secondary outcome [9] 0 0
Part A and Part B: Terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (?z)
Timepoint [9] 0 0
Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days)
Secondary outcome [10] 0 0
Part A and Part B: Half-life associated with terminal slope (?z) of a semi-logarithmic concentration-time curve (t1/2?z)
Timepoint [10] 0 0
Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days)
Secondary outcome [11] 0 0
Part A and Part B: Partial area under the plasma concentration-time curve from time 0 to 24 hours after the start of infusion (AUC0-24)
Timepoint [11] 0 0
Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days)
Secondary outcome [12] 0 0
Part A and Part B: Partial area under the plasma concentration-time curve from time 0 to 72 hours after the start of infusion (AUC0-72)
Timepoint [12] 0 0
Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days)
Secondary outcome [13] 0 0
Part A and Part B: Area under the plasma concentration-curve from time 0 to the last quantifiable concentration (AUClast)
Timepoint [13] 0 0
Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days)
Secondary outcome [14] 0 0
Part A and Part B: Time of last observed (quantifiable) concentration (tlast)
Timepoint [14] 0 0
Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days)
Secondary outcome [15] 0 0
Part A and Part B: Concentration prior to dosing (Ctrough)
Timepoint [15] 0 0
Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days)
Secondary outcome [16] 0 0
Part A and Part B (total AZD4320 only): Area under the plasma concentration-time curve from time 0 to time of last quantifiable analyte concentration divided by the dose administered (Dose normalised AUClast)
Timepoint [16] 0 0
Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days)
Secondary outcome [17] 0 0
Part A and Part B (total AZD4320 only): Area under the plasma concentration-time curve from time 0 to 72 hours after the start of infusion (Dose normalised AUC0-72)
Timepoint [17] 0 0
Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days)
Secondary outcome [18] 0 0
Part A and Part B (total AZD4320 only): Maximum observed plasma (peak) drug concentration divided by the dose administered (Dose normalised Cmax)
Timepoint [18] 0 0
Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days)

Eligibility
Key inclusion criteria
Inclusion Criteria- Core

* Patient must be aged = 18 years at the time of signing the informed consent. In some countries, parental consent may be required in addition to an assent form for patients who are 18 years of age.
* Patient must have histologically documented diagnosis of B-cell non-Hodgkin lymphoma (B-NHL) as defined by a B-cell neoplasm in the World Health Organisation classification scheme except as noted in the exclusion criteria.
* Patient has relapsed after or failed to respond to at least 2 but no more than 5 prior systemic treatment regimens (including investigational therapy) and for whom there is no available therapy expected to improve survival (eg, standard chemotherapy, autologous stem cell transplantation (SCT), chimeric antigen receptor T cell (CAR-T) cell therapy).
* Documented active disease requiring treatment that is relapsed or refractory defined as:

* Recurrence/relapse of disease after response to prior line(s) of therapy.
* Progressive disease (refractory) on/after completion of the treatment regimen preceding entry into the study.
* Must have at least one measurable, fluorodeoxyglucose positron emission tomography (FDG-PET) avid lesion (except for MZL), based on bi-dimensional assessment on PET and computed tomography (CT)/magnetic resonance imaging (MRI) scan. A measurable lesion is defined as:

* For nodal lesions: longest diameter > 1.5 cm
* For extranodal lesions: longest diameter > 1 cm
* Eastern Cooperative Oncology Group (ECOG) performance status score = 2. Performance status must not have deteriorated by = 2 levels within 2 weeks after providing informed consent.
* Adequate haematologic, hepatic, and renal function
* Adequate cardiac function as demonstrated by left ventricular ejection fraction > 50% on screening cardiac multigated acquisition, magnetic resonance imaging, or echocardiogram.
* Women of childbearing potential and men should use protocol defined contraceptive measures.
* Willing and able to participate in all required study evaluations and procedures including receiving IV administration of study intervention and admission to the hospital, when required, for administration of study treatment and monitoring.
* All patients must be willing to undergo an incisional or excisional lymph node or tissue biopsy or to provide a lymph node or tissue biopsy from the most recent available archival tissue.
* For inclusion in the genetic component of the study, patients must fulfil protocol defined criteria.

Inclusion Criteria- Module 1

Additional Inclusion Criteria for Cohort B1 (R/R mantle cell lymphoma [MCL]):

* Histologically confirmed MCL, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1, as assessed by Investigator or local pathologist.
* Must have relapsed after or failed to respond to at least 2 prior lines of treatment, including one anti-CD20 monoclonal antibody (mAb) and a Bruton's tyrosine kinase inhibitor.

Additional Inclusion Criteria for Cohort B2 (R/R FL or MZL):

* Histologically confirmed diagnosis of FL Grade 1, 2, or 3a OR histologically confirmed MZL including splenic, nodal, and extranodal subtypes, as assessed by Investigator or local pathologist.
* For FL patients: Previously received at least 2 prior systemic treatment regimens (including anti-CD20 mAb and an alkylating agent).
* For MZL patients: Previously received at least 2 prior lines of systemic therapy including at least one anti-CD20 mAb-directed regimen either as monotherapy or as chemoimmunotherapy (Helicobacter pylori eradication and radiation therapy alone will not be considered a systemic treatment regimen).

Additional Inclusion Criteria for Cohort B3 (R/R DLBCL):

* Histologically confirmed DLBCL (including transformed FL) OR FL Grade 3b.
* Must have received 2 lines of systemic therapy including at least one anti-CD20 mAb-directed regimen and must have failed or are ineligible for stem cell transplantation (if indicated per local institutional guidelines).
Minimum age
18 Years
Maximum age
130 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria- Core

* Diagnosis of post-transplant lymphoproliferative disease, Richter's transformation, Burkitt's lymphoma, Burkitt-like lymphoma, lymphoblastic lymphoma/leukaemia, chronic lymphocytic leukaemia, small lymphocytic lymphoma.
* High risk of TLS according to Howard modification of Cairo-Bishop criteria and/or the presence of bulky disease.
* Unresolved toxicity from prior anticancer therapy. Patients with Grade 2 neuropathy or Grade 2 alopecia are eligible.
* Active idiopathic thrombocytopenic purpura.
* Active central nervous system (CNS) involvement by lymphoma, leptomeningeal disease or spinal cord compression.
* Known history of infection with human immunodeficiency virus.
* Known serologic status reflecting active hepatitis B or C infection; concurrent infection with cytomegalovirus (CMV).
* Patients must be tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and those with active infection in accordance with local testing guidelines will be excluded.
* Any evidence of severe or uncontrolled systemic diseases; current unstable or uncompensated respiratory or cardiac conditions; uncontrolled hypertension; history of, or active, bleeding diatheses; uncontrolled active systemic fungal, bacterial, or other infection.
* Any of the following cardiac criteria at screening: patients with a history of myocarditis within one year of study entry, or heart failure; mean resting corrected QT interval (QTcF) = 470 msec obtained from 3 electrocardiograms (ECGs), in the absence of a cardiac pacemaker; any factors that increase the risk of QTc prolongation or risk of arrhythmic events; any clinically important abnormalities in rhythm, conduction or morphology of resting ECG.
* History of another life-threatening malignancy = 2 years prior to first dose of study intervention.
* Any of the following currently or in the 6 months prior to the first dose of study intervention: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris; haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other CNS bleeding.
* Treatment with any of the following: radiotherapy less than 2 weeks prior to the first dose of study intervention; any investigational agents or study drugs from a previous clinical study within = 14 days or 5 half-lives prior to the first dose of study intervention; any other chemotherapy, immunotherapy, immunosuppressant medication or anticancer agents within 21 days of the first dose of study intervention; Prior allogenic haematopoietic stem cell transplantation (HSCT) within 6 months from the first dose of study intervention (patients > 6 months after allogenic HSCT are eligible in the absence of active graft-versus host disease and concomitant immune-suppressive therapy). Eligible patients must have stopped immunosuppression at least 2 months prior to study entry; prior cellular therapies such as CAR-T and/or autologous HSCT within 3 months prior to the first dose of study intervention; major surgery = 21 days, or minor surgical procedures = 7 days, prior to the first dose of study intervention; prescription or non-prescription drugs or other products known to be sensitive substrates of BCRP, OCT2, OAT3, OATP1B1, OATP1B3, CYP2B6, CYP2C8, CYP2C9 or CYP2D6, or reversible moderate or strong cytochrome 3A (CYP3A) inhibitors, which cannot be discontinued within 5 half-lives of the first dose of study intervention and withheld throughout the study until 14 days after the last dose of AZD0466; moderate or strong mechanism-based inhibitors or inducers of CYP3A4 which cannot be discontinued within 5 half-lives plus 12 days of the drug prior to the first dose of study intervention and withheld until 14 days after the last dose of AZD0466; concurrent anticoagulation therapy, including aspirin, which cannot be stopped; medications with known risk of Torsades de Pointes within 5 half-lives of the first dose of study intervention and continuing until 5 half-lives after the last dose of AZD0466.
* Administration of a live, attenuated vaccine within 4 weeks before first dose of study intervention.
* Administration of inactivated vaccines or protein/RNA immunogen vaccines.
* Patients with a known hypersensitivity to polyethylene glycol, pegylated products, or drugs with a similar chemical structure or class to AZD0466 or other BH3 mimetic.

Exclusion Criteria- Module 1

Additional Exclusion Criteria for Cohort B1:

- Patients with known blastoid or pleiomorphic variant at study entry/most recent relapse.

Additional Exclusion Criteria for Cohort B2:

* Histologically confirmed diagnosis of FL grade 3B.
* Known transformation to aggressive lymphoma, eg, large cell lymphoma.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
5/07/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
17/08/2023
Sample size
Target
Accrual to date
Final
7
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Heidelberg
Recruitment postcode(s) [1] 0 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
France
State/province [2] 0 0
Lille Cedex
Country [3] 0 0
Italy
State/province [3] 0 0
Milan
Country [4] 0 0
Korea, Republic of
State/province [4] 0 0
Seoul
Country [5] 0 0
Portugal
State/province [5] 0 0
Porto
Country [6] 0 0
Spain
State/province [6] 0 0
Palma de Mallorca
Country [7] 0 0
Spain
State/province [7] 0 0
Pamplona
Country [8] 0 0
Spain
State/province [8] 0 0
Salamanca

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AstraZeneca
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
When will data be available (start and end dates)?
AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.
Available to whom?
When a request has been approved AstraZeneca will provide access to the de-identified individual patientlevel data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://astrazenecagroup-dt.pharmacm.com/DT/Home


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT05205161