This study has been transitioned to CTIS with ID 2022-502774-17-00 check the CTIS register for the current data. Part A Dose Escalation: To assess the safety and tolerability, characterize the dose-limiting toxicities (DLTs), and determine the…
ID
Source
Brief title
Condition
- Other condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Health condition
Maagdarmstelselneoplasmata benigne
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part A Dose Escalation:
To assess the safety and tolerability, characterize the DLTs, and determine the
MTD or OBD and a RP2D of AZD7789 in
participants with advanced or metastatic solid tumors
Part B Expansion:
To assess the safety and tolerability of AZD7789 in participants with advanced
or metastatic solid tumors
To assess the preliminary antitumor activity of AZD7789 in participants with
advanced or metastatic solid tumors
Secondary outcome
Part A Dose Escalation
To assess the preliminary antitumor activity of AZD7789 in participants with
advanced or metastatic solid tumors
Part B Dose Expansion
To further assess the preliminary antitumor activity of AZD7789 in participants
with advanced or metastatic solid tumors
Part A Dose Escalation and Part B Dose Expansion
To assess the pharmacokinetics (PK) of AZD7789 in participants with advanced or
metastatic solid tumors
To assess the immunogenicity of AZD7789 in participants with advanced or
metastatic solid tumors
Background summary
While PD-1/PD-L1 targeting strategies have yielded a breakthrough in cancer
therapeutics, the majority of cancers progress even after initial response to
anti-PD-1/PD-L1 antibody therapy suggesting that additional immune therapies
are required to further improve patient outcome.
Multiple reports have identified a high correlation in PD-1 and TIM-3
expression on tumor infiltrating lymphocytes associated with diminished
functionality. Additionally, recent studies suggest that TIM-3 is upregulated
on T cells following PD-1 receptor blockade and acts as a compensatory
inhibitory mechanism to downregulate antitumor T cell responses.
Dual targeting of PD-1 and TIM-3 has the potential to reinvigorate an immune
response in participants who develop progression on prior PD-1/PD-L1
monotherapies and also may lead to more durable responses in participants who
have not been previously treated with PD-1/PD-L1 checkpoint inhibitors, thereby
resulting in a clinical benefit.
Study objective
This study has been transitioned to CTIS with ID 2022-502774-17-00 check the CTIS register for the current data.
Part A Dose Escalation:
To assess the safety and tolerability, characterize the dose-limiting
toxicities (DLTs), and determine the maximum tolerared dose (MTD) or optimal
biological dose (OBD) and a recommended phase 2 dose (RP2D) of AZD7789 in
participants with advanced or metastatic solid tumors
Part B Expansion:
To assess the safety and tolerability of AZD7789 in participants with advanced
or metastatic solid tumors
To assess the preliminary antitumor activity of AZD7789 in participants with
advanced or metastatic solid tumors
Study design
This is a first-time-in-human (FTIH), multicenter, open-label, dose-escalation
and dose-expansion study to evaluate the safety, tolerability, PK,
pharmacodynamics, and antitumor activity of AZD7789 in adult participants with
advanced or metastatic non-small cell lung cancer (NSCLC) and other solid
tumors. The study includes 2 parts: Part A Dose Escalation and Part B Dose
Expansion. Initially, participants with Stage IIIB to IV NSCLC will be enrolled
in the study; additional tumor types may be explored and added in a future
amendment to the clinical study protocol.
Approximately 192 participants will receive treatment with AZD7789 in the study
at approximately 20 sites globally.
Part A Dose Escalation will evaluate approximately 8 dose levels of AZD7789 in
approximately 41 participants with Stage IIIB to IV NSCLC with PD-L1 tumor
proportion score (TPS) <1% or >=1% who have anti-PD-1/PD-L1 immune-oncology (IO)
acquired resistance in order to determine a MTD or OBD and a RP2D.
Dose escalation for the first 5 dose levels of AZD7789 (2, 7, 22.5, 75, and 225
mg) is planned to follow an accelerated titration design (ATD) consisting of 5
single-participant cohorts. Dose escalation for subsequent dose levels of
AZD7789 (750, 1500, and 2000 mg) will follow the modified toxicity probability
interval (mTPI-2) algorithm consisting of a minimum of 3 and a maximum of 12
participants per dose level. If predefined safety criteria are met in an ATD
cohort, dose escalation will switch to the mTPI-2 algorithm for all subsequent
dose levels.
Intermediate dose levels (50, 150, 450, 1000, 1250, and 1750 mg) may be
explored if warranted by emerging safety, PK, pharmacodynamic, biomarker, and
response data. Participants will be evaluated for DLTs during a 21-day
DLT-evaluation period.
Part B Dose Expansion may be initiated once the MTD or OBD and a RP2D is
established in Part A Dose Escalation and will evaluate the safety,
tolerability, PK, pharmacodynamics, and antitumor activity of AZD7789 at the
RP2D determined during Part A Dose Escalation in 3 cohorts (Cohorts B1, B2 and
B3) described below.
Cohort B1: Approximately 20 participants with Stage IIIB to IV NSCLC with PD-L1
expression >= 1% who have received at least 1 prior line of treatment and have
anti-PD-1/PD-L1 IO acquired resistance.
Cohort B2: Approximately 20 participants with Stage IIIB to IV NSCLC with PD-L1
expression >= 50% who have received no prior therapy including IO therapy (ie,
IO naïve).
Cohort B3: Approximately 20 participants with Stage IIIB to IV NSCLC with PD-L1
expression >= 1% who have received at least 1 prior line of treatment and have
anti-PD-1/PD-L1 IO acquired resistance. Cohort B3 and B1 are the same, only
dosing differs.
Cohort B4: Approximately 20 participants with advanced or metastatic gastric
and GEJC who must have received at least one but no more than two prior lines
of systemic therapy in the advanced/metastatic setting, of which only one prior
line of therapy contained an approved anti-PD-1/PD-L1 therapy.
Intervention
Part A Dose Escalation:
Ascending dose levels of AZD7789 (2, 7, 22.5, 75, 225, 750, 1500, and 2000 mg)
will be given IV every 3 weeks
Part B Dose Expansion:
The recommended phase II dose will be given IV every 3 weeks
Study burden and risks
Patients have to visit the hospital more often and the visits take longer. On
several days during the study, patients will undergo the following assessments:
- Anamnesis (inclusive medical history)
- ECHO/MUGA scan (LVEF)
- ECG
- Vital signs (blood pressure, heart rate, body temperature, respiratory rate,
SpO2)
- Length and weight
- ECOG performance status
- Physical examination
- Blood and urine examination
- Pregnancy test (if applicable)
- AE/SAE
- CT/MRI at screening and during the first 54 weeks of the study every 6 weeks
and every 12 weeks thereafter
- MRI brain (at screening and if applicable thereafter)
- Bone scan (at screening and if applicable thereafter)
- Admission of study medication
- Tumour Biopsy at screening and at cycle 3 day 1 (mandatory for patients at
part A: dose escalation backfill cohorts)
- Tumour Biopsy (optional tumour biopsy at progression)
The risks of AZD7789 are not fully known at this time. Using information
available about drugs that work in a similar way to AZD7789 and information
from studies of AZD7789 given to animals, the Sponsor has determined the
following side effects that could occur when AZD7789 is administered in
patients.
Immune-mediated side effects that may occur include, but are not limited to:
• Skin disorders causing rash, pruritus (itching), raised patchy skin lesions,
or skin blisters.
• Colitis
• Endocrine abnormalities: thyroiditis, adrenal insufficiency, or type 1
diabetes mellitus
• Hepatitis
• Pneumonitis
• Myositis
• Increased pancreatic enzymes (including amylase and lipase)
• Nephritis
• Myocarditis
• Encephalitis
Other side effects include:
• Infusion-related reactions, these reactions include fever, chills, myalgia,
nausea, vomiting, pruritus, rash, headache, flushing, sweating, increased heart
rate, difficulty breathing, decreased blood pressure, dizziness, or
light-headedness.
• Anaphylaxis
• Immune complex disease
• Cytokine release syndrome
• Cytokine storm syndrome
• Tumor Lysis Syndrome
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Listed location countries
Age
Inclusion criteria
General Inclusion Criteria for all cohorts:
• Must be >= 18 years of age
• Part A, B1, B2 and B3: Histologically or cytologically documented Stage IIIB
to IV non-small cell lung carcinoma (NSCLC) not amenable to curative surgery or
radiation
• Part B4: Histologically or cytologically documented advanced or metastatic
gastric and GEJC not amendable to curative surgery
• Must have at least one measurable lesion according to Response Evaluation
Criteria in Solid Tumors (RECIST) v1.1
• Provision of fresh tumor tissue sample and consent to undergo mandatory
on-treatment biopsy for participants enrolled in Part A Dose-escalation
participants
• Provision of archival tumor tissue sample or fresh tissue sample for Part B
Dose-expansion participants
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Non-pregnant women and willingness of female participants to avoid pregnancy
or male participants willing to avoid fathering children through highly
effective methods of contraception
• Adequate organ and bone marrow function measured within 28*days prior to
first dose.
Part A Dose Escalation Additional Inclusion Criteria:
• May have squamous or non-squamous NSCLC
• Must have received at least one prior line of systemic therapy, of which at
least one prior line of therapy contained approved anti-PD-1/PD-L1
• Must have had immune-oncology (IO) acquired resistance
• PD-L1 <1% of >1% documented
Part B Dose Expansion Cohort B1 and B3 Additional Inclusion Criteria:
• May have squamous or non-squamous NSCLC
• Must have received at least one prior line of systemic therapy, of which only
one prior line of therapy contained approved anti-PD-1/PD-L1
• Must have had IO acquired resistance
• PD- L1 expression >= 1% as determined by IHC
Part B Dose Expansion Cohort B2 Additional Inclusion Criteria:
• May have squamous or non-squamous NSCLC
• Must not have received prior systemic therapy including IO therapy in the
first-line setting
• PD-L1 expression >= 50% as determined by IHC
Part B Dose Expansion Cohort B4 Additional Inclusion Criteria:
• Must not have received at least one but no more than two prior lines of
systemic therapy in the advanced/metastatic setting, of which only one prior
line of therapy contained an approved anti-PD-1/PD-L1 therapy
• Must have had IO acquired resistance
• There are no PD-L1 status requirements for this cohort
Exclusion criteria
• Patients with sensitizing epidermal growth factor receptor (EGFR) mutations
or anaplastic lymphoma kinase (ALK) fusions
• Documented test result for any other known genomic alteration for which a
targeted first line therapy is approved per local standard of care (SoC)
• Part B dose-expansion Cohort B4: documented HER2 amplification (unless an SoC
including an anti-HER2 therapy has been received)
• Unresolved toxicities of >= Grade 2 from prior therapy
• Any prior >= Grade 3 immune-mediated adverse event (imAE) while receiving
immunotherapy or any unresolved imAE >= Grade 2
• Must not have experienced a toxicity that led to permanent discontinuation of
prior immunotherapy
• Symptomatic central nervous system (CNS) metastasis or leptomeningeal disease
• History of symptomatic and objectively confirmed arterial (including
myocardial infarction) or venous thromboembolic event within 6 months prior to
study drug dosing, unless participant is on treatment with adequate
antithrombotic medication and is considered to be stable by the investigator.
• History of organ transplant or allogenic hematopoietic stem cell transplant.
• Infectious disease exclusions: Active infection including TB, HIV, hepatitis
A, chronic or active hepatitis B, chronic or active hepatitis C, active
COVID-19 infection
• History of clinically significant arrhythmia as judged by the Investigator.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, cardiomyopathy of any etiology, symptomatic congestive heart
failure, uncontrolled hypertension, uncontrolled diabetes mellitus, unstable
angina pectoris, history of myocardial infarction within the past 6 months,
serious chronic gastrointestinal conditions associated with diarrhea, active
non infectious skin disease. For Part B Dose-expansion Cohort B4,
medication-resistant ascites requiring drainage in the last 28 days prior the
start of AZD7789 and/or the occurrence of active gastro-intestinal bleeding, as
judged by the Investigator.
• Active or prior documented autoimmune or inflammatory disorders, including
inflammatory bowel disease (eg, colitis or Crohn's disease), diverticulitis
(with the exception of diverticulosis), systemic lupus erythematosus,
Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis),
Graves' disease, rheumatoid arthritis, Hypophysitis, uveitis, etc.. Some
exceptions have been specified in the protocol.
• Past medical history of interstitial lung disease (ILD), drug-induced ILD,
radiation pneumonitis requiring steroid treatment, or any evidence of
clinically active ILD
• Major surgical procedure within 28 days prior to the first dose of study
intervention or still recovering from prior surgery
• Other invasive malignancy within 2 years prior to screening
• Congenital long QT syndrome or history of QT prolongation associated with
other medications that cannot be changed or discontinued based on a
cardiologist assessment
• Any previous treatment with anti-TIM-3 therapy in any setting is not
permitted. For Part A, B1 and B3: treatment with investigational therapy prior
to initiation of study treatment except where the most recent line of therapy
was investigational agents added to approved anti-PD-1/PD-L1 as part of
standard of care. Investigational agents may be given as prior lines of therapy
(other than the most recent line) and as a monotherapy, they must be given in
combination with approved anti-PD-1/PD-L1. For Part B4: investigational agents,
other than investigational immune checkpoint inhibitors or other IO agents, may
be given as any prior lines of
therapy
• Current or prior use of immunosuppressive medication within 14 days prior to
the first dose of study intervention
• Any concurrent chemotherapy, radiotherapy, investigational, biologic, or
hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for
noncancer-related conditions is acceptable.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of
study intervention. Note: Participants should not receive live vaccine while
receiving study intervention and up to 30 days after the last dose of study
intervention
• Radiotherapy treatment to the lung within <= 4 weeks of the first dose of
AZD7789. Palliative bone radiotherapy is allowed if >= 2 weeks prior to the
first dose of AZD7789.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2022-502774-17-00 |
| EudraCT | EUCTR2021-000036-57-NL |
| ClinicalTrials.gov | NCTnummernognietbekend |
| CCMO | NL77084.031.21 |