A Study of MTL-CEBPA in Combination With a PD-1 Inhibitor in Patients With Advanced Solid Tumours (TIMEPOINT)

NCT04105335 | Completed Phase 1

• 2 other identifiers: MNA-3521-0122019-002231-28
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 3

Brief Summary

This is an open label Phase 1a/1b study in patients who have advanced solid cancer tumours. Patients will receive MTL-CEBPA (an experimental drug) in combination with pembrolizumab (a drug which has been given approval for use for some tumour types). The Phase 1a dose escalation part of the study is designed to establish which doses of MTL-CEBPA are safe and well-tolerated when combined with the standard dose of pembrolizumab. Patients recruited to this part of the study will be those whose cancer progressed on standard treatment(s) or for whom no treatments are available. Phase 1b the dose expansion part of the study will further explore how safe and well-tolerated these two drugs are when combined and will assess if the combination of drugs could potentially reduce the size of tumours. Participants in this part of the study will receive the experimental drug (MTL-CEBPA) at a dose which is considered safe and well-tolerated based on data from the first part of the study (Phase 1a). Participants will remain in the study taking study drugs until either death, or they choose to withdraw from the study.

Conditions

Solid Tumor, Adult

Keywords

Oligonucleotide; saRNA; Pembrolizumab; Tumour microenvironment; Myeloid-derived suppressor cells; C/EBP-a; CEBPA

Outcome Measures

Primary Outcomes (2)

• Adverse events

  Frequency of adverse events graded according to toxicity criteria (NCI CTCAE v 5.0) and categorised by body system and diagnosis.

  From screening visit through study completion, an average of 1 year

• Anti-tumour activity

  Change from baseline CT scan using the revised Response Evaluation Criteria in Solid Tumours (RECIST) guideline version 1.1 modified RECIST(mRECIST) and irRECIST

  information on how the event is determined and over what estimated period of time (e.g., "From date of sceening visit until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months

Secondary Outcomes (1)

• Pharmokinetic analysis of the study drug MTL-CEBPA when co administered with pembrolizumab

  Blood samples will be collected on Days 1, 2, 3, 4, 8, 9 10, and 11 of the study

Study Arms (4)

Cohort 1 MTL-CEBPA in combination with pembrolizumab

EXPERIMENTAL

MTL-CEBPA 70mg/m2 administered weekly over 3 weeks followed by 1 week of rest combined with pembrolizumab 200mg administered every 3 weeks.

Drug: MTL-CEBPA; Drug: Pembrolizumab

Cohort 2 MTL-CEBPA in combination with pembrolizumab

EXPERIMENTAL

MTL-CEBPA 98mg/m2 administered weekly over 3 weeks followed by 1 week of rest combined with pembrolizumab 200mg administered every 3 weeks.

Drug: MTL-CEBPA; Drug: Pembrolizumab

Cohort 3 MTL-CEBPA in combination with pembrolizumab

EXPERIMENTAL

MTL-CEBPA 130mg/m2 administered weekly over 3 weeks followed by 1 week of rest combined with pembrolizumab 200mg administered every 3 weeks.

Drug: MTL-CEBPA; Drug: Pembrolizumab

Expansion Cohort MTL-CEBPA in combination with pembrolizumab

EXPERIMENTAL

MTL-CEBPA RP2D administered once every 3 weeks on Day 1 of every 3 week cycle. Pembrolizumab 200mg administered once 3 weeks on Day 8 of every 3 week cycle.

Drug: MTL-CEBPA; Drug: Pembrolizumab

Interventions

MTL-CEBPA DRUG

Intravenous administration

Cohort 1 MTL-CEBPA in combination with pembrolizumab; Cohort 2 MTL-CEBPA in combination with pembrolizumab; Cohort 3 MTL-CEBPA in combination with pembrolizumab; Expansion Cohort MTL-CEBPA in combination with pembrolizumab

Pembrolizumab DRUG

Intravenous administration

Also known as: Keytruda

Cohort 1 MTL-CEBPA in combination with pembrolizumab; Cohort 2 MTL-CEBPA in combination with pembrolizumab; Cohort 3 MTL-CEBPA in combination with pembrolizumab; Expansion Cohort MTL-CEBPA in combination with pembrolizumab

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female ≥ 18 years
• Histologically or cytologically confirmed diagnosis of any solid tumour
• Participants with advanced solid tumours who have progressed on standard of care therapy or for whom no standard therapy is available
• Participants with advanced pancreatic cancer may also be eligible if they are considered by the treating physician to be unsuitable or have chosen not to take chemotherapy treatment.
• Participants with high grade serous ovarian, fallopian tube and peritoneal ovarian cancer should have been previously treated with a poly adenosine diphosphate ribose polymerase (PARP)inhibitor and should have received no more than 3 prior lines of systemic therapy.
• Participants who are naïve to a prior treatment with an immune checkpoint inhibitor. Participants with lung cancer, renal cancer, mesothelioma or melanoma who have received prior PD-1/PD-L1 or a CTLA4 inhibitor containing treatment will be eligible if they have experienced objective response to this treatment (as defined by Response Evaluation Criteria in Solid Tumours \[RECIST\] 1.1) as part of their most recent treatment line and have had progressive disease occurring within 6 months of the last dose of their checkpoint inhibitor containing treatment.
• Eastern Cooperative Oncology Group (ECOG)Performance Score0 or 1
• Life expectancy greater than 3 months at the time of recruitment
• Measurable disease as per RECIST 1.1 (Response Assessment in Neuro-Oncology \[RANO\]for glioblastoma multiforme \[GBM\]) as assessed by the investigator. Lesions situated in a previously irradiated area are considered measurable if progression hasbeen demonstrated in such lesions.
• In Part 1b of the study, at least one lesion suitable for biopsy (with the exception of brain tumours). If participants have only 1 measurable lesion per RECIST 1.1, the biopsy specimen should be obtained from a non-target lesion.
• Haematology and clotting profile at screening with no clinically significant findings:
• Platelet count \> 70 x 109/L
• Absolute neutrophil count ≥ 1.5 x 109/dl
• ≥ 9.0 Serum albumin ≥ 26 g/Lg/dL
• International Normalised Ratio (INR) \< 1.5

You may not qualify if:

• Participants who received any prior systemic anticancer therapy investigational drug(s)including vaccines,within the last 30 days prior to study treatment initiation (Cycle1 Day 1)
• Grade \> 1 prior treatment-related toxicity at the time of screening, with the exception of alopecia or Grade 2 neuropathy which may be eligible if recovered tobaseline and upon discussion with the Sponsor.
• Participants received prior radiotherapy within 2 weeks of start of study treatment
• Participants not recovered adequately from major surgery or radiotherapy.
• Participants with history of clinically significant haemorrhage or gastrointestinal perforation•Participants with history of bilateral portal vein occlusion
• Known infection with human immunodeficiency virus (HIV)withCD4+ T-cell counts \<350 cells/μL or with a history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infection
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases and/or carcinomatous meningitis, with the exception of participants with GBM. Participants with previously treated metastases may participate provided they are radiologically stable for at least 4 weeks by repeat imaging performed during study screening, clinically stable, and without requirement for steroid treatment above 10mg/day (prednisone) for at least 28days prior to the first dose of study intervention. An MRI brain scan for all participants with stable brain metastases at screening (CT scan will be allowed if MRI is contraindicated).
• Participants with clinically significant, progressing malignant ascites except for those with ovarian tumours•Participants with known history of non-infectious pneumonitis, myocarditis, or nephritis•Signs and symptoms of heart failure within the last 12 months characterised as greater than New York Heart Association (NYHA) Class I or other clinically significant cardiac abnormalities (such as myocardial infarction) including stable abnormalities.
• Major surgery within the last 30 days prior to study treatment initiation. Participants must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.
• Participants with history of solid organ or haematological transplantation•Participants with sepsis, ineffective biliary drainage with or without cholangitis, obstructive jaundice or encephalopathy at screening visit or within the last 2weeks prior to study treatment initiation, whichever is earlier
• Evidence of spontaneous bacterial peritonitis or renal failure, or allergic reaction at screening visit or within the last 2 weeks prior to study treatment initiation, whichever is earlier•Pregnant or lactating women
• Received systemic corticosteroids and other immunosuppressants in the 4 weeks prior to enrolment into the study (please see note on exception details in Section 6.3.1).
• Received live (attenuated) vaccine in the 30 days prior to first dose of study drug.Live vaccines include, but are not limited to: measles, mumps, rubella, varicella/zoster chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza and COVID-19 vaccines for injection are generally inactive/not viablevirus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\]requiring immunosuppressive treatment, diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:
• Participants with vitiligo or alopecia.

Sponsors & Collaborators

• Mina Alpha Limited: lead

Study Sites (3)

Guys and St Thomas NHS Foundation Trust

London, SE1 9RT, United Kingdom

Location

Imperial College Healthcare NHS Trust

London, W12 0HS, United Kingdom

Location

Freeman Hospital, Newcastle Upn Tyne Hospitals NHS Foundation Trust

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (2)

• Plummer R, Sodergren MH, Hodgson R, Ryan BM, Raulf N, Nicholls JP, Reebye V, Voutila J, Sinigaglia L, Meyer T, Pinato DJ, Sarker D, Basu B, Blagden S, Cook N, Jeffrey Evans TR, Yachnin J, Chee CE, Li D, El-Khoueiry A, Diab M, Huang KW, Pai M, Spalding D, Talbot T, Noel MS, Keenan B, Mahalingam D, Song MS, Grosso M, Arnaud D, Auguste A, Zacharoulis D, Storkholm J, McNeish I, Habib R, Rossi JJ, Habib NA. TIMEPOINT, a phase 1 study combining MTL-CEBPA with pembrolizumab, supports the immunomodulatory effect of MTL-CEBPA in solid tumors. Cell Rep Med. 2025 Apr 15;6(4):102041. doi: 10.1016/j.xcrm.2025.102041. Epub 2025 Mar 31.

  PMID: 40168999 DERIVED

• Hashimoto A, Sarker D, Reebye V, Jarvis S, Sodergren MH, Kossenkov A, Sanseviero E, Raulf N, Vasara J, Andrikakou P, Meyer T, Huang KW, Plummer R, Chee CE, Spalding D, Pai M, Khan S, Pinato DJ, Sharma R, Basu B, Palmer D, Ma YT, Evans J, Habib R, Martirosyan A, Elasri N, Reynaud A, Rossi JJ, Cobbold M, Habib NA, Gabrilovich DI. Upregulation of C/EBPalpha Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer. Clin Cancer Res. 2021 Nov 1;27(21):5961-5978. doi: 10.1158/1078-0432.CCR-21-0986. Epub 2021 Aug 18.

  PMID: 34407972 DERIVED

Related Links

• Company web page

MeSH Terms

Interventions

pembrolizumab

Study Officials

• Nagy Habib, ChM, FRCS

  Mina Alpha Limited

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: The principal objective of the first part of the study (Phase 1a) is to establish if a combination of an experimental drug (MTL-CEBPA) with pembrolizumab (PD-1 inhibitor) is safe and well-tolerated in patients with advanced solid tumours. Phase 1b will aim to confirm the doses of the drugs obtained in Phase 1a in a larger population and if it has potential to reduce the size of the tumour and/or extend the life of participants.

Study Record Dates

• First Submitted: August 16, 2019
• First Posted: September 26, 2019
• Study Start: November 13, 2019
• Primary Completion: January 25, 2025
• Study Completion: January 25, 2025
• Last Updated: March 6, 2025

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3)