This study is designed to evaluate the safety, tolerability, PK, pharmacodynamics, 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 modular, Phase I/II, open-label, multicentre study of AZD3470 in participants with haematologic malignancies. The study consists of several study modules, each evaluating the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of orally administered AZD3470 as a monotherapy and in combination with other anticancer agent(s).

Module 1 Cohort 1 will evaluate AZD3470 monotherapy in adults and adolescents with r/r cHL who have received at least 2 prior lines of anticancer therapy. Part A (dose escalation) will assess AZD3470 at increasing doses to determine Maximum Tolerated Dose and Recommended Dose for Expansion in participants aged 18 years or older. Part B (dose optimization/expansion) will include participants to selected dose levels that were evaluated in Part A to support the recommended phase II dose (RP2D). Safety, tolerability, PK, preliminary efficacy, and food effect will be assessed. Adolescent participants (aged 12 years and older) will only be enrolled in Part B once sufficient supportive adult safety/PK data is reviewed and agreed upon with Safety Review Committee.

Module 1 Cohort 2 will evaluate AZD3470 monotherapy as a consolidation therapy in advanced stage (Stage III/IV) cHL participants aged 50 years or older, who have achieved a response (CR or PR) after at least 4 cycles of frontline standard of care therapy. Safety and tolerability, PK, Pharmacodynamics and preliminary efficacy will be evaluated.

Module 1 Cohort 3 will evaluate AZD3470 monotherapy in participants with r/r PTCL (PTCL NOS, ALCL, AITL) aged 18 years or older, who have received at least one prior anticancer therapy. Safety and tolerability, PK, Pharmacodynamics, and preliminary efficacy will be evaluated.

Module 2 Cohort 1 will evaluate AZD3470 in combination with pembrolizumab in r/r cHL participants aged 18 years or older, who have received at least one prior anticancer therapy. Part A (dose escalation) will include participants at select dose levels below or at the highest tolerable monotherapy dose in Module 1 Cohort 1.

Part B (dose optimization/expansion) will include participants to selected dose levels that were evaluated in Part A to support the recommended combination phase II dose (RP2D). Safety, tolerability, PK, Pharmacodynamics and preliminary efficacy, will be evaluated.

The protocol may be amended in the future to incorporate additional cohorts in combination with pembrolizumab or new modules evaluating AZD3470 in combination with other anticancer agents in haematologic malignancies.

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:

   1. Part A (dose escalation): aged ≥ 18 years at the time of signing the informed consent.
   2. 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:

   1. Coronary artery bypass graft,
   2. Percutaneous coronary intervention or heart valve replacement or repairment,
   3. Vascular stent implantation (venous stent is eligible),
   4. Acute coronary syndrome / myocardial infarction,
   5. Unstable or poorly controlled angina pectoris,
   6. Ventricular arrhythmias requiring continuous therapy,
   7. Uncontrolled atrial fibrillation,
   8. Haemorrhagic or thrombotic stroke (including transient ischaemic attacks) or any other CNS bleeding.
   9. 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.

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.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the de-identified individual patientlevel data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.