EudraCT-Nr.: 2021-003410-39
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
AZD0466 monotherapy, potential for combination therapy after completion of Phase 1 component
Frau Marlene Piontek Jordan
marlene.jordan@astrazeneca.com
AstraZeneca GmbH (Unternehmen, 12264)
Tinsdaler Weg 183
22880 Wedel
Primary
Part A
• To assess the safety and tolerability and identify the MTD and/or RP2D of AZD0466 as monotherapy or in combination with anticancer agents in patients with R/R B-NHL
Part B
• To assess the preliminary efficacy of AZD0466 as monotherapy or in combination with other anticancer agents in patients with R/R B-NHL
Parts A and B
• To characterise the PK profile of study drug(s)
Part B
• To assess the safety and tolerability of AZD0466 as monotherapy or in combination with anticancer agents in patients with R/R B NHL
• To assess the efficacy of AZD0466 as monotherapy or in combination with anticancer agents by evaluation of tumour response and OS in patients with R/R B-NHL
Patients with selected lymphoid malignancies, including R/R Mantel Cell Lymphoma, R/R Follicular or Marginal Zone Lymphoma, and R/R DLBCL.
In Module 1 Part A, a minimum of 3 patients will be enrolled in a dose cohort and evaluated through the Dose Limiting Toxicity evaluation period of 28 days before a dose escalation/dose expansion/de-escalation decision can be made (unless unacceptable toxicity is encountered prior to enrolment of 3 patients).
The maximum number of patients at any given dose cohort will be capped at 9 patients.
In Module 1 Part B, up to 67 patients will be enrolled (26 patients for Cohort B1 and for Cohort B2, and 15 patients for Cohort B3).
Part A
• Incidence of AEs and DLTs
• Changes from baseline in laboratory parameters, electrocardiograms, and vital signs
Part B
• • ORR
Endpoint based on revised response criteria for malignant lymphoma (Cheson et al 2014)
Part B
Incidence of AEs and SAEs
• Changes from baseline in laboratory parameters, physical examinations, performance status, electrocardiograms, and vital signs
• CR rate
• DoR
• TTR
• PFS
• OS
Tumour response endpoints based on revised response criteria for malignant lymphoma (Cheson et al 2014)
Parts A and B
• Plasma concentrations and derived PK parameters for study drug(s), to be specified for each module
Part B
Patients are eligible to be included in the study only if all of the core criteria below and all criteria from the relevant individual modules apply. Where specific module criteria differ from core inclusion criteria, the most stringent criteria should be applied.
Informed Consent
1 Provision of signed and dated written informed consent, as described in Appendix A, prior to any study-specific procedures, sampling, and analyses. Informed consent includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
Age
2 Patient must be aged e 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.
Type of Patient and Disease Characteristics
3 Patient must have histologically documented diagnosis of B-NHL as defined by a B-cell neoplasm in the World Health Organisation classification scheme except as noted in the exclusion criteria.
4 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 SCT, CAR-T cell therapy).
5 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.
6 Must have at least one measurable, FDG-PET avid, lesion based on bi-dimensional assessment on PET and CT/MRI scan. A measurable lesion is defined as:
- For nodal lesions: longest diameter > 1.5 cm
- For extranodal lesions: longest diameter > 1 cm
7 ECOG performance status score d 2. Performance status must not have deteriorated by e 2 levels within 2 weeks after providing informed consent.
8 Adequate haematologic, hepatic, and renal function as defined in Table 3.
Table 3 Criteria for Adequate Organ and Marrow Function
Parameter Criteria
Haematologic Haemoglobin e 8.0 g/dL (5.59 mmol/L) with no whole blood transfusions within 14 days prior first dose of AZD0466
Platelet count e 75 × 109/L (e 100 × 109/L for Module 1 Part A) with no platelet transfusions within 7 days prior to first dose of AZD0466
ANC e 1.0 × 109/L. The use of growth factors is not permitted within 14 days prior to first dose of AZD0466 (long-acting pegylated growth factors are not permitted during study intervention).
Coagulation INR < 1.5 × ULN
Hepatic Total bilirubin d 1.5 × ULN (or d 3.0 × ULN in presence of Gilbert’s syndrome) d 3 × ULN if the patient has Gilbert’s syndrome ALT and AST d 2.5 × ULN
Pancreatic Lipase and amylase d 1.5 × ULN and absence of clinical pancreatitis
Renal Serum creatinine OR Calculated creatinine clearance d 1.5 × ULN
e 50 mL/min by the Cockcroft-Gault equation (Cockcroft and Gault 1976) or the estimated glomerular filtration rate e 50 mL/min/1.73 m2 using the MDRD formula
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; INR= international normalised ratio; MDRD = Modification of Diet in Renal Disease; ULN = upper limit of normal.
9 Adequate cardiac function as demonstrated by left ventricular ejection fraction > 50% on screening cardiac multigated acquisition, magnetic resonance imaging, or echocardiogram.
Reproduction
10 Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
(a) Female patients:
o Female patients of childbearing potential must be willing to use 2 forms of highly reliable methods of contraception (Appendix I) from the time of screening until 6 months after the last dose of study intervention or patients must have evidence of an inability to bear children by fulfilling 1 of the following criteria at screening:
* Postmenopausal, defined as aged > 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments.
* Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation.
o Female patients must not be lactating, breastfeeding, and must have a negative pregnancy test (serum) prior to start of dosing.
(b) Male patients:
o Male patients must be willing to use barrier contraception (ie, condoms) and refrain from sperm donation from the time of screening until 6 months after the last dose of study intervention. If not done previously, storage of sperm before receiving AZD0466 will be advised to male patients with a desire to have children.
Other
11 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 intervention and/or monitoring.
12 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.
13 For inclusion in the optional genetic component of the study, patients must fulfil the following additional criteria:
- Provision of signed, written, and dated informed consent for genetic research. If a patient declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this protocol, as long as they consented to the main study.
Patients assigned to Module 1 must meet all of the criteria in the core protocol (Section 5.1) and all of the relevant criteria below.
10.5.1.1 Additional Inclusion Criteria for Cohort B1 (R/R MCL)
1 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.
2 Must have relapsed after or failed to respond to at least 2 prior lines of treatment, including one anti-CD20 mAb and a Bruton’s tyrosine kinase inhibitor.
10.5.1.2 Additional Inclusion Criteria for Cohort B2 (R/R FL or MZL)
1 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.
2 For FL patients: Previously received at least 2 prior systemic treatment regimens (including anti-CD20 mAb and an alkylating agent).
3 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).
10.5.1.3 Additional Inclusion Criteria for Cohort B3 (R/R DLBCL)
1 Histologically confirmed DLBCL OR FL Grade 3b.
2 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).
Medical Conditions
1 Diagnosis of post-transplant lymphoproliferative disease, Richter’s transformation, Burkitt's lymphoma, Burkitt-like lymphoma, lymphoblastic lymphoma/leukaemia, chronic lymphocytic leukaemia, small lymphocytic lymphoma.
2 Unresolved toxicity from prior anticancer therapy of CTCAE Grade e 2. Patients with Grade 2 neuropathy or Grade 2 alopecia are eligible.
3 Active idiopathic thrombocytopenic purpura.
4 Active CNS involvement by lymphoma, leptomeningeal disease or spinal cord compression. Patients with a prior history of CNS localization of lymphoma who received treatment are eligible provided that there is no evidence of CNS involvement at study entry as documented by cerebrospinal fluid cytology and/or brain MRI.
5 Known history of infection with human immunodeficiency virus.
6 Known serologic status reflecting active hepatitis B or C infection.
- Patients who are anti-HBc antibody 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.
- Patients 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.
7 Known uncontrolled infection with CMV.
8 Patients must be tested for SARS-CoV-2 and those with active infection detected using either molecular or antigen tests in accordance with local testing guidelines will be excluded.
9 As judged by the Investigator:
- Any evidence of severe or uncontrolled systemic diseases, (eg, severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease]).
- Current unstable or uncompensated respiratory or cardiac conditions.
- Uncontrolled hypertension.
- History of, or active, bleeding diatheses (eg, haemophilia or von Willebrand disease).
- Uncontrolled active systemic fungal, bacterial, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
10 Any of the following cardiac criteria at screening:
- Patients with a history of myocarditis within one year of study entry, or heart failure New York Heart Association Functional Classification Class 3 or 4 (Appendix J).
- Mean resting corrected QT interval (QTcF) e 470 msec obtained from 3 ECGs, in the absence of a cardiac pacemaker.
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.
- Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third-degree heart block, intermittent or persistent bundle branch block, atrioventricular block II to III, or clinically significant sinus pause).
11 History of another life-threatening malignancy d 2 years prior to first dose of study intervention. The following are permitted:
- Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and considered to be at low risk of recurrence by the treating physician.
- Adequately treated lentigo malignant melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer.
- Adequately treated carcinoma in situ without current evidence of disease.
12 Any of the following procedures or any of the following conditions 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
Prior/Concomitant Therapy
13 Treatment with any of the following:
- Radiotherapy less than 2 weeks prior to the first dose of study intervention. Radiation therapy for palliative care to focal sites is allowed.
- Any investigational agents or study drugs from a previous clinical study within d 14 days or 5 half-lives (whichever is shorter) prior to the first dose of study intervention, with the exception of strong CYP3A inducers or inhibitors as outlined in Section 6.5.2. Treatment with high-dose steroids for primary malignancy control is permitted, but must be discontinued at least 2 days prior to the first dose of study intervention.
- Any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents within 21 days of the first dose of study intervention. A longer washout may be required for drugs with a long half-life (eg, biologics) as agreed by the Sponsor.
- Prior allogenic HSCT within 6 months from the first dose of study drug (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 4 weeks 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 (excluding placement of vascular access) d 21 days, or minor surgical procedures d 7 days, prior to the first dose of study intervention. No waiting is required following implantable port or catheter placement.
- 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 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 (Section 6.5.2).
- 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 (Appendix H) within 5 half lives of the first dose of study intervention and continuing until 5 half-lives after the last dose of AZD0466. Some of the medications listed as a possible risk of Torsades de Pointes may be allowed at the Investigator’s discretion after approval by the Study Physician when the patient has unmet medical need to continue receiving prohibited medication(s), no suitable alternative treatments are available, and the benefit-risk ratio is acceptable in the Investigator’s opinion.
14 Administration of a live, attenuated vaccine within 4 weeks before first dose of study intervention.
15 Administration of inactivated vaccines or protein/RNA immunogen vaccines, including COVID-19 vaccines, within 7 days before first dose of study intervention.
Prior/Concurrent Clinical Study Experience
16 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.
Other Exclusions
17 Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
18 Judgement by the Investigator or Study Physician that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
19 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
Patients assigned to Module 1 must not meet any of the criteria in the core protocol (Section 5.2) and any of the criteria below.
10.5.2.1 Additional Exclusion Criteria for Part A
1 High risk of TLS according to Howard modification of Cairo-Bishop criteria and/or the presence of bulky disease (defined as any lesion e 10 cm on the screening CT scan).
10.5.2.2 Additional Exclusion Criteria for Cohort B1 (R/R MCL)
1 Patients with known blastoid or pleiomorphic variant at study entry/most recent relapse.
10.5.2.3 Additional Exclusion Criteria for Cohort B2 (R/R FL or MZL)
1 Histologically confirmed diagnosis of FL grade 3B.
2 Known transformation to aggressive lymphoma, eg, large cell lymphoma.
Patients will receive treatment with AZD0466 until disease progression or up to a maximum of 2 years. If patients are still receiving benefit after 2 years, there may be the possibility to continue treatment.
Approximately 25 total sites , with ~ 3-5 investigators in Germany
AstraZeneca
unknown
0
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