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

Inclusion criteria

• Core Inclusion criteria:
• Adequate adult (ECOG) or adolescent (Karnofsy or Lanksy) Performance Score assessments
• Adequate organ and bone marrow function. Module 1 Cohort 1:
• Part A (dose escalation): aged ≥ 18 years at the time of signing the informed consent.
• Part B (optimization): aged ≥ 12 years of age. Adolescent participants must weigh ≥ 40 kg.
• Histologically confirmed diagnosis of cHL based on WHO criteria
• Previous treatment with at least 2 prior lines of therapy for the treatment of cHL (including at least 2 cycles of BV and anti-PD1) and have documented r/r active disease requiring treatment.
• Participants must provide FFPE baseline tumour tissue.
• At least 1 radiographically measurable, and/or FDG-avid lymphoma lesion ( \>1.5 cm for nodal lesion and \>1 cm for extranodal lesion). Module 1 Cohort 2:
• Participants must be at least 50 years of age or older at study entry.
• Histologically confirmed diagnosis of cHL based on WHO criteria
• Ann Arbor stages III or IV.
• Participant must have previously received at least 4 cycles of SoC combination therapy with A-AVD, N-AVD, AVD, or ABVD (based on regional SOC, per investigator) as finite first-line induction therapy, and achieved at least a PR post-induction therapy.
• Participants must provide FFPE baseline tumour tissue. Module 1 Cohort 3:
• Participants must be aged ≥ 18 years at the time of signing the informed consent.
• Histologically confirmed diagnosis of PTCL NOS, systemic ALCL, or AITL based on WHO criteria.
• Participants must have received at least 1 prior line of therapy for the treatment of PTCL and have exhausted all available therapies with demonstrated clinical benefit. Participants with ALCL must have received prior BV treatment.
• Participants must provide FFPE baseline tumour tissue a. Ability to provide an on-treatment biopsy (if the tumour is suitable for biopsy).
• At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (\> 1.5 cm for nodal lesion and \>1 cm for extranodal lesion). Module 2 Cohort 1:
• Participants must be aged ≥ 18 years at the time of signing the informed consent.
• Histologically confirmed diagnosis of cHL based on WHO criteria
• At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (\> 1.5 cm for nodal lesion and \>1 cm for extranodal lesion).
• Participant must have received at least 1 prior line of therapy for the treatment of cHL and have documented r/r active disease requiring treatment.
• Participants must provide FFPE baseline tumour tissue.

Exclusion criteria

• Core Exclusion criteria:
• Any significant laboratory finding or any severe and uncontrolled medical condition.
• Active CNS involvement by lymphoma, leptomeningeal disease, or spinal cord compression.
• Serologic active HBV or HCV infection.
• Known to have tested positive for HIV.
• Active gastrointestinal disease or other condition that will interfere with oral therapy.
• Any of the following ECG cardiac criteria: Mean resting QTcF \> 470 msec, clinically important abnormalities in rhythm, conduction or morphology, and/or any factors that increase the risk of QTc prolongation or risk of arrhythmic events.
• Undergone any of the following procedures within 6 months prior to first dose:
• Coronary artery bypass graft,
• Percutaneous coronary intervention or heart valve replacement or repairment,
• Vascular stent implantation (venous stent is eligible),
• Acute coronary syndrome / myocardial infarction,
• Unstable or poorly controlled angina pectoris,
• Ventricular arrhythmias requiring continuous therapy,
• Uncontrolled atrial fibrillation,
• Haemorrhagic or thrombotic stroke (including transient ischaemic attacks) or any other CNS bleeding.
• Acute venous or atrial thromboembolic event (unless considered stable or adequately treated with at least 3months of therapeutic anticoagulation).
• Severe valvular heart disease.
• Congestive heart failure Grade II to Grade IV.
• Prior or current cardiomyopathy.
• Uncontrolled hypertension.
• History of significant haemoptysis or haemorrhage within4 weeks of the first dose of study treatment.
• Unresolved toxicities of Grade \> 1 from prior anti cancer therapy (excluding peripheral neuropathy, vitiligo, alopecia and endocrine disorders that are controlled with replacement hormone therapy, and asymptomatic laboratory abnormalities), unless immune-mediated.
• History of another primary malignancy.
• Received the following anticancer therapies: anti-lymphoma therapy (within 21 days), radiation therapy(within 28 days), allo-HSCT (within 180 days), auto-HSCT/cellular therapy (within 60 days), or MAT2A or PRMT5 inhibitor
• Requires ongoing immunosuppressive therapy, including systemic corticosteroids. Module 2 Cohort 1:
• History of confirmed ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment or any evidence of clinically active ILD or pneumonitis.
• ≥Grade 3 immune-mediated AE while receiving prior checkpoint inhibitor immunotherapy, or any unresolved ≥Grade 2 immune-mediated AE.
• History of immune-mediated myocarditis or pericarditis.
• Experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
• Active or prior documented pathologically confirmed autoimmune or inflammatory disorders
• Refractory to prior checkpoint inhibitor therapy (within 12 weeks of last dose)
• Eligible for allogeneic or autologous stem cell transplant.
• Received an allogeneic HSCT within 5 years of the first dose of study treatment; must not have active Graft-versus-host disease.
• Participants with a known hypersensitivity to pembrolizumab or any of the excipients of the product.