An open-label Phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy in patients with advanced haematological malignancies.

Study ID: 41027
Short Title: Phase I/IIa study to evaluate CCS1477 in haem. malignancies v1.0
Trust Name: UHS
Recruitment Site: Southampton General Hospital
Disease Area: Haematology
Phase: II
I
Expected End Date: 31/12/2021
Postcode: SO16 6YD
Contact Name: Amanda Pattie
Contact Email: studysupport1and3.crnwessex@nihr.ac.uk
Active: Yes

Inclusion criteria, exclusion criteria and study summary

1. Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses. 2. Willing and able to participate in all required evaluations and procedures in this study protocol. 3. Men and women ≥ 18 years of age. 4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 5. Patients with confirmed (per standard disease specific diagnostic criteria), relapsed or refractory haematological malignancies (NHL, MM and AML). Patients will include but are not limited to the following: • B-cell non-Hodgkin lymphoma (including Richter’s Syndrome) • T-cell non-Hodgkin lymphoma • Multiple myeloma • AML/secondary AML (patients with acute promyelocytic leukemia (APL) (FAB subtype M3) will be excluded). • High-risk MDS; according to revised International Prognostic Scoring System (IPSS-R). 6. Must have received standard therapy (for the majority of therapeutic indications - at least 2 prior lines of therapy) - refer to relevant disease guidelines, such as European Society for Medical Oncology (ESMO), International Myeloma Working Group (IMWG) or National Comprehensive Cancer Network (NCCN) guidelines. In circumstances where there may be no standard of care, or intensive treatment would not be tolerable or is refused, patients may be considered eligible for the study upon consultation and agreement between the medical monitor and the treating Investigator. 7. Adequate haematologic function defined as: • Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 (1.0 x 10^9/L). • Platelet count without requiring ongoing blood product support ≥ 75,000 cells/mm3 (75 x 10^9/L). Platelet transfusions are not permitted within 3 days of screening. • Haemoglobin level ≥ 80 g/L. 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. 8. Adequate organ function at screening defined as: • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN), or AST/ALT ≤ 5 x ULN (with underlying liver involvement following discussion with the medical monitor). • Total bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin, patients with borderline elevation due to underlying liver involvement may be eligible following discussion with the medical monitor). • Serum creatinine < 1.5 x ULN, OR creatinine clearance ≥ 50 mL/min as measured or calculated by Cockcroft and Gault equation, or ≥ 30 mL/min in patients with kidney function affected by the underlying malignancy • Serum albumin > 2.5 g/dL.

Patients must not enter the study if any of the following exclusion criteria are fulfilled 1. 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. Shorter wash-out may be considered for immunotherapies after discussion with medical monitor. • Strong inducers of CYP3A4 taken within 4 weeks of the first dose of study treatment or whilst on study treatment. • Strong inhibitors of CYP3A4 or CYP3A4 substrates with a narrow therapeutic range taken within 2 weeks of the first dose of study treatment or while on study treatment. • CYP2C8 substrates with a narrow therapeutic range taken within 2 weeks of the first dose of study treatment 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. • 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. • Statins; patients should discontinue statins prior to starting study treatment. • Steroids use > 10mg daily prednisolone or equivalent within 2 weeks of the first dose of study treatment. • Major surgery within 4 weeks of the first dose of study treatment. 2. 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. 3. Presence of, or history of, CNS lymphoma, symptomatic leptomeningeal disease, or spinal cord compression. 4. History of prior non-haematologic 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 after discussion with medical monitor. Maintenance treatment (eg. hormonal therapy) is allowed. 5. Any evidence of severe or uncontrolled systemic disease (e.g. current unstable or uncompensated respiratory or cardiac conditions; history of, or active, bleeding diatheses; uncontrolled active systemic infection, including hepatitis B, hepatitis C and human immunodeficiency virus (HIV)*), 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. *Active viral infection is defined as requiring antiviral therapy. Screening for chronic conditions is not required. 6. Repeatable QTcF prolongation (> 480 msec). 7. History of severe allergic or anaphylactic reactions or history of hypersensitivity to active or inactive excipients of CCS1477. 8. Female patients who are pregnant or breast-feeding at study entry. 9. 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.

CCS1477 is a new experimental medication (sponsored by CellCentric Ltd) for a group of cancers that effect the blood and/or bone marrow. These include Acute Myeloid Leukaemia (AML), high-risk Myelodysplastic Syndrome (MDS), Multiple Myeloma (MM) and Non-Hodgkin Lymphoma (NHL). It is aimed at tumours that are not responsive to, or have become resistant to, existing medications used in late stage disease. The purpose of this study is to examine the safety, tolerability, pharmacokinetics (PK) and efficacy of CCS1477 when treating patients with the above disorders. It is expected that approximately 90 patients will be recruited from up to 10 hospitals in the UK. The study has 5 parts consisting of dose escalation and expansion cohorts. Patients will have regular clinic visits for various safety and clinical benefit assessments, to monitor any side effects and to find out how CCS1477 is handled by the body and affects this group of cancers. The information gained in this study will help the sponsor to determine whether CCS1477 is suitable for further studies in humans.

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