A Phase 1/2, Open-Label, Multicenter Study to Investigate the Safety, Pharmacokinetics and Efficacy of CYC140, an Oral PLK1 Inhibitor, in Subjects with Advanced Solid Tumors and Lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cyclacel Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

3 Aug 2022 → 7 Jan 2025

Decision date (initial)

2024-08-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516290-67-00

EudraCT number

2022-000222-24

ClinicalTrials.gov

NCT03884829

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Dose response, Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, Therapy, Others

Phase 1: dose escalation • To determine the maximum-tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of CYC140 when administered orally once daily (QD) in 28-day cycles in adult subjects with advanced solid tumors and lymphoma
Phase 2: proof of concept • To evaluate the preliminary efficacy of CYC140 as measured by overall response rate (ORR) in subjects with locally advanced, recurrent or metastatic, histologically confirmed advanced solid tumors or lymphoma who have failed all standard therapies or for whom standard therapy does not exist

Secondary objectives 2

1. Phase 1 dose escalation: To assess safety and tolerability of CYC140. To investigate clinical pharmacokinetics (PK) of CYC140. To evaluate overall response rate (ORR) in subjects receiving CYC140. Phase 2 proof of concept:To assess the safety and tolerability of CYC140. To evaluate the DCR, DOR, PFS, and OS in subjects receiving CYC140.
2. Exploratory: Phase 1 dose escalation: To investigate the clinical pharmacodynamics of CYC140. To investigate the clinical pharmacogenomics (PGx) of CYC140. Phase 2 proof of concept: To investigate the clinical PGx of CYC140.

Conditions and MedDRA coding

ADVANCED SOLID TUMORS AND LYMPHOMA

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Male or females aged # 18 years or per local regulatory guidance
2. Subjects with histological or cytologically-confirmed advanced cancer who have progressed on (or have not been able to tolerate) standard therapy or for whom no standard anticancer therapy is available a. For phase 1, all tumor types may be enrolled b. For phase 2, subjects will be enrolled as mentioned in the ‘study design’ section c. For phase 2, subjects should also meet the following criteria: i. Radiological progression as per RECIST (Lugano criteria for lymphoma, modified severity-weighted assessment tool [mSWAT] for CTCL) criteria on the last line of therapy before entering the trial must be documented ii. At least one measurable lesion as defined by the RECIST criteria (version 1.1) for solid tumors iii. For subjects with lymphoma based on Lugano Criteria (Cheson et al. 2014) and CTCL subjects based on mSWAT (Olsen)
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2
4. Subjects who relapsed post-autologous or post-allogeneic transplant are eligible. Post-transplant subjects must be without active fungal disease or significant acute graft-versus-host disease.
5. WOCBP must have a negative pregnancy test (urine/serum) within 7 days prior initiating the study drug. Both males and females must agree to use effective birth control during the study (prior receiving first dose and for 6 months after the last dose) if conception is possible during this interval. Female subjects are considered to not be of childbearing potential if they have a history of hysterectomy or are postmenopausal (no menses for 12 months without an alternative medical cause). For both males and females, see Section 5.5 for the definitions of contraceptive methods considered effective for this protocol
6. Subjects must be able to swallow and retain orally administered medication, and not have any clinically significant GI abnormalities that may alter absorption, such as malabsorption syndrome or major resection of the stomach or bowels
7. Ability to agree to and sign the informed consent form, and comply with the protocol

Exclusion criteria 8

1. Subjects with a history of brain metastases or with signs/symptoms attributable to brain metastases and those who have not been assessed with radiologic imaging to rule out the presence of brain metastases. Subjects with treated brain metastases that are asymptomatic and have been clinically stable for at least 4 weeks will be eligible
2. Subjects who have not received vaccines for SARS-COV-2 and have suspected signs and symptoms of the novel coronavirus infection (COVID-19) or have confirmed COVID-19 Exclusions owing to medical conditions
3. Subjects with a history of another primary malignancy other than: a. In situ carcinomas (e.g., breast, cervix and prostate) b. Locally excised non-melanoma skin cancer c. No evidence of the disease from another primary cancer for 2 or more years and has not taken any anti-cancer treatment in 2 years. Exceptions are gonadotropin-releasing hormone (GnRH) therapy for prostate cancer and hormonal maintenance therapy for breast cancer
4. Presence of an active infection requiring IV antibiotics
5. Presence of a known history of human immunodeficiency virus-1/2 with uncontrolled viral load and on medications that might interfere with metabolism
6. Presence of active hepatitis B virus (HBV) or hepatitis C virus (HCV). In subjects with a history of HBV, hepatitis B core antibody (HBcAb) testing is required and if positive, HBV DNA testing will be performed and if positive, the subject will be excluded. For subjects with HCV Ab positive, HCV viral load must be below the limit of quantification
7. Chemotherapy, biological therapy, targeted therapy, immunotherapy, extended-field radiotherapy or investigational agents within 5 half-lives or 3 weeks (whichever is shorter), prior administering the first dose of study drug on Day 1 or in those who have not recovered from the side-effects of such therapy
8. Major surgery/surgical therapy for any cause within 4 weeks of the first dose

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase 1: dose escalation • The incidence rate of dose-limiting toxicities (first cycle only) at each dose level
2. Phase 2: proof of concept • ORR according to Response Evaluation Criteria in Solid Tumors: RECIST guidelines (version 1.1, 2009) (Lugano Criteria for lymphoma, mSWAT for CTCL) for each tumor type. The overall response rate is defined as proportion of subjects who had the best overall response (BOR) of complete response (CR) or partial response (PR)

Secondary endpoints 7

1. Phase 1 dose escalation, Phase 2 proof of concept: Safety: Type, frequency and severity of adverse drug reactions according to National Cancer Institute CTCAE (version 5.0).
2. DCR is defined as the proportion of subjects who achieve a response of CR, PR and stable disease according to RECIST.
3. Response rate as per Lugano Criteria for lymphoma, mSWAT for CTCL.
4. Progression-free survival (PFS) is defined as the time from the first dose date to objectively documented disease progression or death.
5. Duration of response, computed for subjects with a BOR of CR or PR, is defined as the time between the date of first response and the subsequent date of objectively documented disease progression or death.
6. Overall survival is defined as the time between the first dosing date and the date of death.
7. Exploratory: Phase 1 dose escalation, Phase 2 proof of concept • Pharmacodynamics: PLK1 and BRD4 inhibition assessed by differential expression of target genes (such as MYC, PLK1, CDKN1A, HEXIM1) relative to baseline (Phase 1 only) • PGx: Plasma cell-free DNA mutation and copy number variation profile determined by NGS.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cyclacel Limited

Sponsor organisation

Cyclacel Limited

Address

2 London Wall Place

City

London

Postcode

EC2Y 5AU

Country

United Kingdom

Scientific contact point

Organisation

Cyclacel Limited

Contact name

Julius Huang

Public contact point

Organisation

Cyclacel Limited

Contact name

Julius Huang

Third parties 6

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications