AZD3470 as Monotherapy or in Combination with Anticancer Agent(s) in Participants With Haematologic Malignancies. - PRIMAVERA

Inclusion Criteria

• Inclusion Criteria:
• Core Inclusion criteria:
• 1- Adequate adult (ECOG) or adolescent (Karnofsy or Lanksy) Performance Score assessments
• 2- Adequate organ and bone marrow function.
• Module 1 Cohort 1:
• 1- Age:
• a. Part A (dose escalation): aged ≥ 18 years at the time of signing the informed consent.
• b. Part B (optimization): aged ≥ 12 years of age. Adolescent participants must weigh ≥ 40 kg.
• 2- Histologically confirmed diagnosis of cHL based on WHO criteria
• 3- 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.
• 4- Participants must provide FFPE baseline tumour tissue.
• 5- 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:
• 1- Participants must be at least 50 years of age or older at study entry.
• 2- Histologically confirmed diagnosis of cHL based on WHO criteria
• 3- Ann Arbor stages III or IV.
• 4- 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.
• 5- Participants must provide FFPE baseline tumour tissue.
• Module 1 Cohort 3:
• 1- Participants must be aged ≥ 18 years at the time of signing the informed consent.
• 2- Histologically confirmed diagnosis of PTCL NOS, systemic ALCL, or AITL based on WHO criteria.
• 3- 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.
• 4- Participants must provide FFPE baseline tumour tissue
• a. Ability to provide an on-treatment biopsy (if the tumour is suitable for biopsy).
• 5- 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:
• 1- Participants must be aged ≥ 18 years at the time of signing the informed consent.
• 2- Histologically confirmed diagnosis of cHL based on WHO criteria
• 3- At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (> 1.5 cm for nodal lesion and >1 cm for extranodal lesion).
• 4- 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.
• 5- Participants must provide FFPE baseline tumour tissue.
• Exclusion Criteria:
• Core Exclusion criteria:
• 1- Any significant laboratory finding or any severe and uncontrolled medical condition.
• 2- Active CNS involvement by lymphoma, leptomeningeal disease, or spinal cord compression.
• 3- Serologic active HBV or HCV infection.
• 4- Known to have tested positive for HIV.
• 5- Active gastrointestinal disease or other condition that will interfere with oral therapy.
• 6- 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.
• 7-Undergone any of the following procedures within 6 months prior to first dose:
• a) Coronary artery bypass graft,
• b) Percutaneous coronary intervention or heart valve replacement or repairment,
• c) Vascular stent implantation (venous stent is eligible),
• d) Acute coronary syndrome / myocardial infarction,
• e) Unstable or poorly controlled angina pectoris,
• f) Ventricular arrhythmias requiring continuous therapy,
• g) Uncontrolled atrial fibrillation,
• h) Haemorrhagic or thrombotic stroke (including transient ischaemic attacks) or any other CNS bleeding.
• i) Acute venous or atrial thromboembolic event (unless considered stable or adequately treated with at least 3months of therapeutic anticoagulation).
• 8- Severe valvular heart disease.
• 9- Congestive heart failure Grade II to Grade IV.
• 10- Prior or current cardiomyopathy.
• 11- Uncontrolled hypertension.
• 12- History of significant haemoptysis or haemorrhage within4 weeks of the first dose of study treatment.
• 13- 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.
• 14- History of another primary malignancy.
• 15- 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
• 16- Requires ongoing immunosuppressive therapy, including systemic corticosteroids.
• Module 2 Cohort 1:
• 1- History of confirmed ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment or any evidence of clinically active ILD or pneumonitis.
• 2- ≥Grade 3 immune-mediated AE while receiving prior checkpoint inhibitor immunotherapy, or any unresolved ≥Grade 2 immune-mediated AE.
• 3- History of immune-mediated myocarditis or pericarditis.
• 4- Experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
• 5- Active or prior documented pathologically confirmed autoimmune or inflammatory disorders
• 6- Refractory to prior checkpoint inhibitor therapy (within 12 weeks of last dose)
• 7- Eligible for allogeneic or autologous stem cell transplant.
• 8- Received an allogeneic HSCT within 5 years of the first dose of study treatment; must not have active Graft-versus-host disease.
• 9- Participants with a known hypersensitivity to pembrolizumab or any of the excipients of the product.