Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Hodgkin Disease

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Hodgkin Lymphoma

In Part A, participants with Relapsed/Refractory classical Hodgkin Lymphoma (cHL) will take AZD3470 tablets orally until PD, unacceptable toxicity, or withdrawal of consent.

In Part B, adult and adolescent participants with r/r cHL will take AZD3470 tablets orally until PD, unacceptable toxicity, or withdrawal of consent.

AZD3470 is a novel, potent and selective, secondgeneration, Methylthioadenosine (MTA)-selective, small molecule inhibitor of PRMT5.

AZD3470

AstraZeneca Clinical Study Information Center

This study is designed to evaluate the safety, tolerability, PK and preliminary efficacy following oral administration of AZD3470 as a monotherapy, and in combination with other anticancer agents in participants with haematologic malignancies.

This is a FTiH modular, Phase I/II, open-label, multicentre, dose escalation and expansion study in participants with r/r haematologic malignancies. The study is designed to evaluate the safety, tolerability, PK and preliminary efficacy following oral administration of AZD3470 as a monotherapy, and in combination with other anticancer agents in participants with haematologic malignancies.

This study will follow a modular protocol design evaluating AZD3470 as monotherapy and in combination with other anticancer agents. New cohorts (including further monotherapy expansion) and new modules for combination treatments may be added as protocol amendments in the future based on emerging supportive preclinical and/or clinical data.

Module 1 Part A includes a dose escalation of AZD3470 monotherapy in participants with r/r haematologic malignancies, initially focused on r/r cHL. Dose escalation cohorts will evaluate the safety, tolerability, PK, and preliminary efficacy in participants with r/r cHL.

Module 1 Part B optimization/expansion cohorts may be opened at selected dose levels. These cohorts will further characterise the safety, PK, and preliminary efficacy of AZD3470 to support dose optimization. Both adult and adolescent participants with r/r cHL will be eligible for this part of the study. Adolescent participants will only be enrolled once there is sufficient PK and safety data in adults. A preliminary effect of food on AZD3470 pharmacokinetics will be explored in this part of the study.

The protocol may be amended in the future to incorporate further expansion of cHL at the RP2D, additional monotherapy cohorts in other hematologic malignancies, and/or additional modules investigating AZD3470 in combination with other anticancer agents.

AZD3470 as Monotherapy and in Combination With Anticancer Agents in Participants With Relapsed/Refractory Haematologic Malignancies.

A Modular Phase I/II, Open-label, Multicentre Study to Evaluate the Safety, Tolerability, and Efficacy of AZD3470, a PRMT5 Inhibitor, as Monotherapy and in Combination With Anticancer Agent(s) in Participants With Relapsed/Refractory Haematologic Malignancies

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.

AEs: Number of patients with adverse events by system organ class and preferred term.

SAEs: Number of patients with serious adverse events by system organ class and preferred term.

In the Dose Escalation cohorts in Part A, the number of participants with at least 1 dose-limiting toxicity (DLT), which is any toxicity defined as a DLT in the Clinical Study Protocol

ORR is defined as the proportion of participants who have a CR or PR and CRR is defined as the proportion of participants who have a CR.

Assessment of ORR/CRR will be done according to the Lugano Classification for cHL.

The time from the date of first documented response until the date of documented progression as assessed by the investigator according to the Lugano classification for cHL, or death due to any cause

Time from date of first dose (non- randomised study parts) or date of randomization (randomised study parts) until progression as assessed by the investigator according to the Lugano Classification for cHL, or death due to any cause.

Time from date of first dose (non-randomised study parts) or date of randomization (randomised study parts) until the date of death due to any cause.

Assessed to characterize the plasma PK profile of AZD3470.

Assessed to characterize the urine PK profile of AZD3470.

Preliminary food effect on plasma PK of AZD3470 administered as a monotherapy in participants enrolled in dose expansion.

AstraZeneca

Hematologic Neoplasms

Hematologic Diseases

All Drugs and Chemicals

Immunomodulating Agents

Data collection

Jeremie Zerbit, PharmD

Marie BENHAMMANI-GODARD

Jeremie ZERBIT, PharmD

Immunotherapies have substantially improved the prognosis of patients with haematological malignancies. While clinical trial data suggest durable complete response rates, markers associated with non-response to treatment are still poorly described. The identification of predictive markers using demographic, physiologic, biologic, immunologic data as well as patients' treatment history, might enable the optimization of therapeutic sequences and the reduction of treatment toxicity.

This study aim to assess markers of toxicity and response following an immunotherapy in patients with a haematological malignancy using real life data.

It will allow the development of clinical and therapeutic benchmarks to guide medical decisions in relation to the therapeutic strategies to be implemented for patients benefiting from real-life conditions, in addition to the results obtained in randomized studies.

Predictive Markers of Response and Toxicity in Patients With a Haematological Malignancy Treated With Immunotherapy.

Treatment response : Explore the proportion of complete response

Treatment response : Explore the proportion of partial response

Treatment response : Explore the proportion of stable disease

Treatment response : Explore the proportion of progress disease

Toxicity : Explore the cumulative incidence of grade III and IV adverse events

Toxicity : Explore the interruption and discontinuation rates of immunotherapy

Assistance Publique - Hôpitaux de Paris

Infections

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Herpes Simplex

Herpes Zoster

Communicable Diseases

Herpesviridae Infections

Virus Diseases

DNA Virus Infections

Skin Diseases

Skin Diseases, Viral

Skin Diseases, Infectious

Chickenpox

Varicella Zoster Virus Infection

Vaccines

Subjects will receive the candidate HZ vaccine (GSK 1437173A).

Subjects will receive the placebo vaccine.

2 doses administered intramuscularly (IM) in deltoid region of non-dominant arm. Dose 1 administered at Day 0. Dose 2 administered 1-2 months post Dose 1.

Herpes zoster vaccine (GSK 1437173A)

Placebo

GSK Clinical Trials

The purpose of this study is to evaluate the safety and immunogenicity of GSK Biologicals' vaccine GSK1437173A in subjects aged 18 years and older with blood cancers. The study will evaluate safety-related events and antibody and cellular immune responses to the study vaccine, as compared to placebo.

Amendment to protocol posting:

Increase in sample size, update of country/region-specific information (Sections 5, 6 and 9).

Promotion of secondary to primary objective; related update of primary and secondary outcome measures (Sections 4 and 7).

Study to Assess the Safety and Immunogenicity of GlaxoSmithKline (GSK) Biologicals' Herpes Zoster Subunit (HZ/su) Vaccine in Adults Aged 18 Years and Older With Blood Cancers

Study to Evaluate Safety and Immunogenicity of GSK Biologicals' Herpes Zoster Vaccine GSK1437173A in Adults Aged 18 Years and Older With Haematologic Malignancies

Vaccine response rate refers to the percentage of subjects with a vaccine response, as determined by Enzyme-Linked Immunosorbent Assay (ELISA). Vaccine response was defined as: For initially seronegative subjects, antibody concentration at Month 2 greater than or equal to (≥) 4 fold the cut-off for Anti-gE \[4x97 milli-international units per milliliter (mIU/mL)\]. For initially seropositive subjects, antibody concentration at Month 2 ≥ 4 fold the pre-vaccination antibody concentration.

This analysis was performed on subjects with haematologic malignancies excluding subjects with Non-Hodgkin B-cell Lymphoma and Chronic Lymphocytic Leukaemia.

The Adjusted geometric mean concentration was measured in all subjects excluding those with Non-Hodgkin B-cell Lymphoma and Chronic Lymphocytic Leukaemia.

Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site.

Solicited local symptoms: pain, redness, swelling and their number of days were recorded after each vaccination dose.

Assessed solicited general symptoms were fatigue, gastrointestinal symptoms (included nausea, vomiting, diarrhoea and/or abdominal pain), headache, myalgia, shivering and fever \[defined as oral, axillary or tympanic route measured temperature equal to or above 37.5 degrees Celsius (°C)\]. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever \> 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination.

Solicited general symptoms: fatigue, gastrointestinal symptoms, headache, myalgia, shivering, temperature and their number of days were recorded after each vaccination dose.

An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study. It also included any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 AE = an AE which prevented normal, everyday activities. Related = AE assessed by the investigator as related to the vaccination.

A Serious adverse event (SAE) is any untoward medical occurrence that result in death, is life threatening, requires hospitalisation or prolongation of existing hospitalisation, results in disability/incapacity, or is a congenital anomaly/birth defect in the offspring of a study subject. Related = SAEs assessed by the investigator as causally related to the study vaccination

Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology. Related = pIMds assessed by the investigator as causally related to the study vaccination

Vaccine response rate refers to the percentage of subjects with a vaccine response, as determined by ELISA. Vaccine response was defined as: For initially seronegative subjects, antibody concentration at Month 2 ≥ 4 fold the cut-off for Anti-gE (4x97 mIU/mL). For initially seropositive subjects, antibody concentration at Month 2 ≥ 4 fold the pre -vaccination antibody concentration. This analysis was performed on subjects with haematologic malignancies, excluding subjects with Non-Hodgkin B-cell Lymphoma.

Antibody concentrations were determined by ELISA, presented as geometric mean concentrations (GMCs) and expressed in milli-international units per milliliter (mIU/mL).This parameter was assessed in subjects with haematologic malignancies, excluding subjects with Non-Hodgkin B-cell Lymphoma.

Time to occurrence of any confirmed HZ case is expressed in terms of incidence rate of subjects with at least one event. Hence, person-year rate = number of episodes (n)/ sum of follow-up period (censored at the first occurrence of an event) expressed in years (T\[year)\]). Follow-up period starts Day 1 of vaccination.

Any clinically suspected case of HZ (defined as (1) a new rash characteristic of HZ (e.g., unilateral, dermatomal and accompanied by pain broadly defined to include allodynia, pruritus or other sensations), or a vesicular rash suggestive of Varicella Zoster Virus (VZV) infection regardless of the distribution, and no alternative diagnosis; or (2) a clinical presentation (symptoms and/or signs) and specific laboratory findings suggestive of VZV infection in the absence of characteristic HZ or VZV rash.) The endpoint is confirmed in two ways: (1) By Polymerase Chain Reaction (PCR) or (2) By the HZ Ascertainment Committee. The PCR is used as primary classification method.

Antibody concentrations were determined by ELISA, presented as geometric mean concentrations (GMCs) and expressed in milli-international units per milliliter (mIU/mL). This parameter was assessed in all vaccinated subjects.

Vaccine response rate refers to the percentage of subjects with a vaccine response, as determined by ELISA. Vaccine response was defined as: For initially seronegative subjects, antibody concentration at Month 2 ≥ 4 fold the cut-off for anti-gE (4x97 mIU/mL). For initially seropositive subjects, antibody concentration at Month 2 ≥ 4 fold the pre -vaccination antibody concentration. Vaccine response was measured in all subjects.

Among markers expressed were interferon-gamma (IFN-γ), interleukin-2 (IL-2), tumour necrosis factor-alpha (TNF-α) and cluster of differentiation 40 ligand (CD40L), as determined by in vitro intracellular cytokine staining (ICS).

Among markers expressed were IFN-γ, IL-2, TNF-α and CD40L, as determined by in vitro ICS. Vaccine response was defined as:

For initially subjects with pre-vaccination T-cell frequencies below the threshold, at least a 2-fold increase as compared to the threshold (2x\<320\> Events/106 CD4+ T cells).

For initially subjects with pre-vaccination T-cell frequencies above the threshold, at least a 2-fold increase as compared to pre-vaccination T-cell frequencies.

Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology

GMCs of anti-gE antibodies were tabulated per study group and HZ confirmed/non-confirmed status and expressed in milli-international units per milliliter (mIU/mL).

MGI was tabulated per study group and HZ confirmed/non-confirmed status. MGI was defined as the Geometric mean of the within subject ratios of the post-vaccination reciprocal anti-gE concentration to the Month 0 reciprocal anti-gE concentration.

GlaxoSmithKline

Subjects who received GSK1437173A vaccine according to a 0, 1 Months schedule (The second dose of study vaccine could be administered 1 - 2 months after the first dose).

GSK1437173A Group

Subjects who received placebo doses according to a 0, 1 Months schedule (The second dose of placebo could be administered 1 - 2 months after the first dose).

Placebo Group

Total

Age, Continuous

Sex: Female, Male

Geographic ancestry

Race/Ethnicity, Customized

GSK Response Center

Subjects who received placebo doses according to a 0, 1 Months schedule. (The second dose of placebo could be administered 1 - 2 months after the first dose).

The analysis was performed on the According-to-Protocol (ATP) cohort for Humoral immunogenicity, which included all subjects who met all eligibility criteria, who received the full vaccination course, complied with the protocol and and for whom data concerning immunogenicity outcome measures were available up to the Month 2 visit.

Vaccine Response Rates (VRR) for Anti-glycoprotein E (Anti-gE) Antibody Concentrations

The objective aimed to evaluate anti-gE humoral immune responses at Month 2 following a two-dose administration of the GSK1437173A vaccine, as compared to placebo, in subjects with haematologic malignancies excluding subjects with Non-Hodgkin B-cell Lymphoma and Chronic Lymphocytic Leukaemia.

The analysis was performed on the According-to-Protocol (ATP) cohort for Humoral immunogenicity, which included all subjects who met all eligibility criteria, who received the full vaccination course, complied with the protocol and for whom data concerning immunogenicity outcome measures were available up to the Month 2 visit.

Adjusted Geometric Mean Concentration of Anti-gE Antibodies

Any Pain, Dose 1

Grade 3 Pain, Dose 1

Any Redness, Dose 1

Grade 3 Redness, Dose 1

Any Swelling, Dose 1

Grade 3 Swelling, Dose 1

Any Pain, Dose 2

Grade 3 Pain, Dose 2

Any Redness, Dose 2

Grade 3 Redness, Dose 2

Any Swelling, Dose 2

Grade 3 Swelling, Dose 2

Any Pain, Across doses

Grade 3 Pain, Across doses

Any Redness, Across doses

Grade 3 Redness, Across doses

Any Swelling, Across doses

Grade 3 Swelling, Across doses

The analysis was performed on the Total Vaccinated cohort, which included all subjects with at least one vaccine dose administered, who had their symptom sheets completed.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
AZD3470 as Monotherapy and in Combination With Anticancer Agents in Participants With Relapsed/Refractory Haematologic Malignancies.	NCT06137144	Lymphoma Non-Hodgkin Hodgkin Lymphom...	AZD3470	15 Years - 130 Years	AstraZeneca
AZD3470 as Monotherapy and in Combination With Anticancer Agents in Participants With Relapsed/Refractory Haematologic Malignancies.	NCT06137144	Lymphoma Non-Hodgkin Hodgkin Lymphom...	AZD3470	15 Years - 130 Years	AstraZeneca
Predictive Markers of Response and Toxicity in Patients With a Haematological Malignancy Treated With Immunotherapy.	NCT05450367	Blood Cancer	Data collection	18 Years -	Assistance Publique - Hôpitaux de Paris
Predictive Markers of Response and Toxicity in Patients With a Haematological Malignancy Treated With Immunotherapy.	NCT05450367	Blood Cancer	Data collection	18 Years -	Assistance Publique - Hôpitaux de Paris
Study to Assess the Safety and Immunogenicity of GlaxoSmithKline (GSK) Biologicals' Herpes Zoster Subunit (HZ/su) Vaccine in Adults Aged 18 Years and Older With Blood Cancers	NCT01767467	Herpes Zoster	Herpes zoster v... Placebo	18 Years -	GlaxoSmithKline
Study to Assess the Safety and Immunogenicity of GlaxoSmithKline (GSK) Biologicals' Herpes Zoster Subunit (HZ/su) Vaccine in Adults Aged 18 Years and Older With Blood Cancers	NCT01767467	Herpes Zoster	Herpes zoster v... Placebo	18 Years -	GlaxoSmithKline

Spots Global Cancer Trial Database for haematologic malignancies