A Phase 1/2 Study of STP938 (Dencatistat) for Adult Subjects With Relapsed/Refractory B-Cell and T-Cell Lymphomas

Official title

An Open-Label, First in Human, Phase 1/2 to Evaluate Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of the CTPS1 Inhibitor STP938 In Adult Subjects With Relapsed/Refractory B-Cell and T-Cell Lymphomas

Overview

The Phase 1 part of the study is a dose escalation of STP938 as monotherapy. The Phase 2 part of the study is cohort expansion of STP938 as a monotherapy in 5 different B and T cell lymphomas.

Detailed description

The drug STP938 is an inhibitor of an enzyme called cytidine triphosphate synthase 1 (CTPS1). CTPS1, and a very similar enzyme cytidine triphosphate synthase 2 (CTPS2), control the final step in the production of the cytidine triphosphate (CTP). CTP is an essential building block of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Studies of people with inherited mutations of the CTPS1 gene indicate that certain types of blood cells required CTPS1 in order to divide rapidly, whereas other cells in the body use the CTPS2 enzyme. Based on these observations, it is expected that blocking CTPS1, using the drug STP938, may be an effective treatment for certain types of cancer that arise from blood cells.

The purpose of this study is to see if STP938 is effective at treating different types of lymphoma. STP938 will be given as a tablet. Blood samples will be taken during the study in order to understand the effects of STP938 on the lymphoma and on the rest of the body. The main outcome of the first part of the study is to see if STP938 can be given safely to patients with lymphoma, and to work out the best dose of STP938. The main outcome of the second part of the study is to see if ST938 is effective in treating different types of lymphoma.

Interventions

• Drug STP938
  Small molecule

Primary outcome measures

• Safety and Tolerability (Phase 1 / Dose Escalation) [Time frame: Through study completion, an average of 9 months]
• Objective Response Rate (ORR) (Phase 2 / Dose Expansion) [Time frame: Through study completion, an average of 9 months]

Secondary outcome measures (10)

• Maximum plasma concentration (Cmax) of STP938 including effects of food on absorption (Phase 1 / Dose Escalation) [Time frame: 16 Days]
• Time to reach maximum concentration (TMax) of STP938 including effects of food on absorption (Phase 1 / Dose Escalation) [Time frame: 16 Days]
• Area under the curve (AUC) of STP938 including effects of food on absorption (Phase 1 / Dose Escalation) [Time frame: 16 Days]
• Evaluate preliminary clinical activity of STP938 (Phase 1) [Time frame: Through study completion, an average of 9 months]
• Evaluate best overall response of STP938 (Phase 1 / Phase 2) [Time frame: Through study completion, an average of 9 months]
• Evaluation Time To Respond (Phase 1 / Phase 2) [Time frame: Through study completion, an average of 9 months]
• Evaluation Duration of Response (Phase 1 / Phase 2) [Time frame: Through study completion, an average of 9 months]
• Evaluation Progression Free Survival (Phase 1 / Phase 2) [Time frame: Through study completion, an average of 9 months]
• Evaluation of Complete Response Rate (Phase 2) [Time frame: Through study completion, an average of 9 months]
• Safety and Tolerability (Phase 2 / Dose Expansion) [Time frame: Through study completion, an average of 9 months]

Eligibility criteria

Main Inclusion Criteria:

• Signed and dated informed consent, and able to comply with the study procedures and any locally required authorization.
• Male or female aged ≥ 18 years.
• Relapsed/refractory patients with histologically confirmed diagnosis of B cell or T cell lymphoma
• Must have received at least 2 prior systemic therapies and have no treatment options known to provide clinical benefit
• Must have measurable disease per Lugano lymphoma classification except for cutaneous T-cell lymphoma (CTCL) which is measured via International Society for Cutaneous Lymphomas (ISCL)/ European Organization of Research and Treatment of Cancer (EORTC).
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
• Life expectancy > 3 months as assessed by the Investigator.
• Adequate organ function (bone marrow, hepatic, renal function and coagulation).
• All toxicities (except alopecia) from prior cancer treatments or procedures must have resolved to ≤Grade 1 or returned to baseline levels prior to enrollment.

Main Exclusion Criteria:

• Pregnant or breastfeeding females and women of child bearing potential or males unwilling to comply with contraception requirements.
• Known carcinomatous meningitis or central nervous system (CNS) involvement with lymphoma.
• Active malignancy within 2 years of study enrollment
• Prior radiation or surgical resection of their lymphoma without additional sites of measurable disease outside of the radiation field or subjects who have received prior radiation or surgical resection of their lymphoma ≤2 weeks prior to the first dose of study drug.
• Systemic cancer treatments, monoclonal antibody-directed therapies, other investigational agents within 4 weeks before enrollment, or <5 half-lives since completion of previous investigational therapy, whichever is shorter.
• Uncontrolled intercurrent illness.
• Immunocompromised subjects with increased risk of opportunistic infections or history of opportunistic infection in the last 12 months.
• Known active or chronic hepatitis B or active hepatitis C virus (HCV) infection.
• Subjects who have received a live vaccine within 30 days prior to study enrollment or whilst participating in the study.
• Subjects with corrected QT interval >470 msec based on averaged triplicate electrocardiogram (ECG) readings at the Screening Visit using the QT interval corrected for heart rate using Fridericia's method (QTcF).
• Subjects who received a severe acute respiratory syndrome coronavirus 2 vaccine ≤3 weeks prior to study drug dosing.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 7 centers

• University Hospitals of Leicester NHS Trust — Leicester
• Imperial College / Clinical Trials Unit, Hammersmith Hospital — London
• The Christie — Manchester
• Nottingham City Hospital — Nottingham
• Churchill Hospital — Oxford
• Derriford Hospital — Plymouth
• The Royal Marsden — Sutton

France · 5 centers

• Hôpital Saint-Louis — Paris
• The Centre Léon Bérard — Lyon
• Institut Paoli Calmettes — Marseille
• CHU de Nantes — Nantes
• Institut Gustave Roussy — Villejuif

United States · 3 centers

• Colorado Blood Cancer Institute — Denver
• Florida Cancer Specialists — Sarasota
• Memorial Sloan Kettering — New York

Publications

• Asnagli H, Minet N, Pfeiffer C, Hoeben E, Lane R, Laughton D, Birch L, Jones G, Novak A, Parker AE, Ludwig H, Fischer A, Latour S, Beer PA. CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma. Hemasphere. 2023 Mar 28;7(4):e864. doi: 10.1097/HS9.0000000000000864. eCollection 2023 Apr. PMID 37008165

Identifiers

NCT: NCT05463263 · STP938-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗