A first time in man study to look at the safety of the experimental drug CCS1477 and what effects it has on cancers that affect the blood, bone marrow, lymph and lymphatic system.

Prior treatment

• With the exception of alopecia, and CTCAE Grade 2 neuropathy, any unresolved toxicities from prior therapy > Grade 1 at the time of starting study treatment.

Other illness

• History of prior malignancy except for the following: • Adequately treated carcinoma in situ or non-melanomatous skin cancer • Malignancy treated with curative intent or in remission for >6 months after the last therapy may be eligible. Maintenance treatment is allowed. Note: Patients with a history of any haematological malignancy (other than indications included in the protocol) may be included following discussion with the medical monitor
• History of severe allergic or anaphylactic reactions or any known severe allergies to any active or inactive ingredients in the study medications (CCS1477 and/or pomalidomide, lenalidomide,dexamethasone, isatuximab, ixazomib, bortezomib, elranatamab, teclistamab, posaconazole, azacitidine or venetoclax as applicable).

Lab values

• Treatment with any of the following: • Any investigational agent, chemotherapy, immunotherapy or anticancer agents from a previous clinical study within 14 days or 5 half-lives of first dose of study treatment. • Strong inducers of CYP3A4 taken within 4 weeks of the first dose of study treatment or whilst on study treatment • Strong inhibitors of CYP3A4 and or P-gp taken within 2 weeks of the first dose of study treatment or while on study treatment. The potent CYP3A4 inihibitor posaconazole is allowed in patients participating in the posaconazole DDI part of the study. Following review of the posaconazole DDI data, and with the agreement of the Safety Review Committee, concomitant use of posaconazole may be permitted thereafter in the study. • CYP3A4 and/or CYP2B6 and/or P-gp and/or OATP1B1 sensitive substrates and substates with narrow therapeutic index taken within 2 weeks of the first dose of study treatment & during Cycle 1. Note - Patients may receive pravastatin or fluvastatin (with monitoring for potential toxicities), or atorvastatin or simvastatin at 10mg daily dose only. • CYP2C8 sensitive and moderate substrates taken within 2 weeks of the first dose of study treatment and duryng Cycle 1. • Herbal medications taken within 7 days of the first dose of study treatment (4 weeks for St John's wort) or while on study treatment. • Radiotherapy with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks of the first dose of study treatment; palliative radiotherapy to ≤30% of the bone marrow within 2 weeks of the first dose of study treatment. • Steroids use >10mg daily (or 20mg daily for NHL) prednisolone or equivalent within 2 weeks of the first dose of study treatment. Replacement therapy steroids (even exceeding the above daily dose), given in the context of a transfusion, inhaled, nasal, topical and ophthalmic steroids are allowed. Note: For control of lymphoma related symptoms, patients may have received a brief (<7days) course of systemic steroids (≤ 100 mg prednisone equivalent per day) prior to initiation of study therapy. MM patients may receive >10mg daily if discussed and agreed with the medical monitor. • Medications with known risk of QT/QTc interval prolongation should be avoided concomitantly with CCS1477 unless essential in clinical management of the patient. If unavoidable, additional monitoring of potential QT/QTc interval prolongation is warranted • Major surgery within 4 weeks of the first dose of study treatment. • Shorter wash-out may be considered for some medications or palliative radiotherapy after discussion with medical monitor.
• Any evidence of severe or uncontrolled systemic disease (e.g. current unstable or uncompensated respiratory or cardiac conditions; recent history of significant cardiac incidents, eg. significant cardiac dysfunction (congestive heart failure [NY Heart Association Class III or IV]; myocardial infarction within 12 months of starting study; unstable or poorly controlled angina pectoris) history of risk factors for torsades de pointes (e.g. heart failure, hypokalemia, family history of long QT syndrome or clinically significant arrhythmia; uncontrolled diabetes; history of, or active, bleeding diatheses; uncontrolled active systemic infection, including hepatitis B&C and human immunodeficiency virus (HIV), or active HBV, HCV, SARS-CoV2 (for patients receiving elranatamab or teclistamab) which in the investigator’s opinion makes it undesirable for the patient to participate in the study or which would jeopardise compliance with the protocol.

Other

• Active or unresolved spinal cord compression or CNS infiltration.
• Repeatable QTcF prolongation (>470 msec).
• Female patients who are pregnant or breast-feeding at any time during the study.
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements. Refer the protocol for additional exclusion criteria for combination arms.

• Written informed consent
• Females must agree to use highly effective contraceptive measures (if sexually active), must not be breast feeding & must have a negative serum pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: • Post-menopausal defined as aged more than 50 years & 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. • Amenorrhoeic for 12 months & serum follicle-stimulating hormone, luteinizing hormone & plasma oestradiol levels in the postmenopausal range for the institution. Note: All patients receiving pomalidomide or lenalidomide must fulfil the conditions of the Pregnancy Prevention Programme. Refer to the protocol for additional inclusion criteria for combination arms.
• Willing&able to participate in all required evaluations and procedures
• Men&women ≥18 years
• ECOG performance status of ≤1 - for multiple myeloma patients in Part D3 and ECOG ≤ 2 for all other arms.
• Patients with confirmed relapsed or refractory haematological malignancies (NHL, MM, AML & higher risk MDS). Patients will include: • B-cell non-Hodgkin lymphoma - DLBCL, FL, MCL & Burkitt lymphoma • T-cell non-Hodgkin lymphoma • Multiple myeloma o Patients must have measurable disease by IMWG criteria defined as either serum M protein ≥0.5g/dL, or urine ≥200mg/24h, or involved SFLC ≥ 10mg/dL with abnormal FLC ratio • AML/secondary AML (patients with acute promyelocytic leukemia (APL) (FAB subtype M3) will be excluded) • Higher-risk MDS; according to revised IPSS-R
• Must have received standard therapy. Must not require urgent cytoreductive therapy • NHL – patients must have exhausted or be ineligible for standard therapeutic options as available in the relevant geographical region; patient should not be eligible for hematopoietic stem cell transplantation; DLBCL patients should have received, or waiting for, CAR T cell treatment, if eligible and available; patients with indolent lymphomas must meet criteria for systemic therapy treatment. Patients should not be eligible for allogenic transplantation. • MM patients (except Parts D3), selected cohorts in D2; and D15-D18)) must have exhausted or be ineligible for standard therapeutic options as available in the relevant geographical region. For Parts D3 - (and selected small cohorts expansions in D2) MM patients must have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor. • For Parts D15-D18 – patients must be triple class exposed (a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody), and where treatment with elranatamb or teclistamab is recommended per local standard practice. • AML–relapsed or refractory following standard therapeutic options, including non-intensive therapy and targeted agents, as applicable considering disease and patient characteristics as well as availability of therapy in the relevant geographical region • Higher-risk MDS patients must have previously failed treatment with at least 4 cycles of a hypomethylating agent (if applicable).
• Adequate haematologic function • Absolute neutrophil count (ANC) ≥1000 cells/mm3 (1.0 x 109/L) or ≥750 cells/mm3 in patients with Duffy null phenotype if this is considered their normal baseline • Platelet count ≥75,000 cells/mm3 (75 x 109/L), screening result should be independent of platelet transfusion for at least 3 days. • Haemoglobin level ≥80 g/L. • For further details on supportive medications see restrictions (Section 4.3.3) This criterion does not apply to AML/MDS patients. Patients with other malignancies involving bone marrow with parameters below the threshold may be considered eligible following discussion with the medical monitor • For AML, WBC must be <10,000/μl
• Adequate organ function at screening
• Duration of the study & for 1 week after the last study medication administration (CCS1477 or combination agent), sexually active male patients must be willing to use barrier contraception i.e. condoms (with spermicide if locally approved for use) with all sexual partners. Where the sexual partner is a 'woman of child-bearing potential' who is not using effective contraception, men must use a condom (with spermicide if locally approved for use) & another form of contraception during the study & for 6 months after the last dose of study medication (CCS1477 or combination agent)