Clinical Trials /

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

NCT04105335

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of MTL-CEBPA in Combination With a PD-1 Inhibitor in Patients With Advanced Solid Tumours (TIMEPOINT)
  • Official Title: An Open Label Phase 1a/b Study of MTL-CEBPA in Combination With a PD-1 Inhibitor (Pembrolizumab) in Adult Patients With Advanced Solid Tumours

Clinical Trial IDs

  • ORG STUDY ID: MNA-3521-012
  • SECONDARY ID: 2019-002231-28
  • NCT ID: NCT04105335

Conditions

  • Solid Tumor, Adult

Interventions

DrugSynonymsArms
MTL-CEBPACohort 1 MTL-CEBPA in combination with pembrolizumab
PembrolizumabKeytrudaCohort 1 MTL-CEBPA in combination with pembrolizumab

Purpose

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.

Detailed Description

      Phase 1a comprises three planned dose cohorts (ascending dose, 3+3 design, at the following
      dose levels: 70 mg/m2 QW, 98 mg/m2 QW, and 130 mg/m2 QW) of MTL-CEBPA combined with standard
      dose of pembrolizumab (given every 3 weeks). The aim is to assess the safety and tolerability
      of MTL-CEBPA in combination with pembrolizumab, recruiting patients whose disease progressed
      on standard of care therapy or for whom no therapy is available.

      In the first dose cohort the first participant enrolled will receive MTL-CEBPA treatment at
      the 70mg/m2 QW dose level. Pembrolizumab (200mg) will be administered on Day 2 of the first
      cycle and subsequently every 3 weeks whilst participant is on treatment. MTL-CEBPA and
      pembrolizumab will not be administered on the same day.

      Phase 1b of the study will further evaluate safety, tolerability, and assess the clinical
      activity of MTL-CEBPA and a PD-1 inhibitor (pembrolizumab) in combination.

      Participants will receive MTL-CEBPA at a dose considered most appropriate, with regards to
      safety, tolerability, and efficacy, for further development (based on data from Phase 1a of
      the study).

      Patients with the following (but not limited to) solid tumours will be specifically targeted:
      breast, lung, ovarian, pancreatic, gall bladder, HCC, neuroendocrine, and cholangiocarcinoma.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1 MTL-CEBPA in combination with pembrolizumabExperimentalMTL-CEBPA 70mg/m2 administered weekly over 3 weeks followed by 1 week of rest combined with pembrolizumab 200mg administered every 3 weeks.
  • MTL-CEBPA
  • Pembrolizumab
Cohort 2 MTL-CEBPA in combination with pembrolizumabExperimentalMTL-CEBPA 98mg/m2 administered weekly over 3 weeks followed by 1 week of rest combined with pembrolizumab 200mg administered every 3 weeks.
  • MTL-CEBPA
  • Pembrolizumab
Cohort 3 MTL-CEBPA in combination with pembrolizumabExperimentalMTL-CEBPA 130mg/m2 administered weekly over 3 weeks followed by 1 week of rest combined with pembrolizumab 200mg administered every 3 weeks.
  • MTL-CEBPA
  • Pembrolizumab
Expansion Cohort MTL-CEBPA in combination with pembrolizumabExperimentalMTL-CEBPA RP2D administered weekly over 3 weeks followed by 1 week of rest combined with pembrolizumab 200mg administered every 3 weeks.
  • MTL-CEBPA
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed diagnosis of any solid tumour

          -  Patients with progressive disease, refractory to standard of care with no standard
             therapy available or patient refused standard therapy

          -  Patients who are naïve to PD-1 / PD-L1 inhibitors

          -  ECOG PS 0 - 1

          -  Life expectancy greater than 3 months at the time of recruitment

          -  At least one measurable tumour lesion with target lesion size ≥ 1.0 cm as measured by
             CT

          -  Negative blood pregnancy test for women of childbearing potential (within 10 days
             prior to first drug administration)

          -  For women who are of child-bearing potential (see definition below) agreement to
             remain abstinent or use single or combined contraceptive methods with a failure rate
             of < 1% per year during the treatment period and for at least three months after the
             last dose of MTL-CEBPA or four months after the last dose of pembrolizumab, whichever
             is longer.

          -  Examples of contraceptive methods with a failure rate of < 1% per year include
             bilateral tubal occlusion, male sterilization, hormone implants, established/proper
             use of combined oral or injected hormonal contraceptives and certain intrauterine
             devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a
             cervical cap) may be combined to achieve a failure rate < 1% per year. Barrier methods
             must always be supplemented with the use of a spermicide.

          -  Male participants with partners of child-bearing potential are required to use barrier
             contraception plus an additional contraceptive method that together result in a
             failure rate of < 1% per year during the treatment period and for at least three
             months after the last dose of MTL-CEBPA or four months after the last dose of
             pembrolizumab, whichever is longer. Male participants will also be advised to abstain
             from sexual intercourse with pregnant or lactating women, or to use condoms.

          -  Abstinence is only acceptable if it is line with the preferred and usual lifestyle of
             the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
             post-ovulation methods), declaration of abstinence for the duration of exposure to
             IMP, and withdrawal are not acceptable methods of contraception.

          -  Note: a woman is considered of child-bearing potential following menarche and until
             becoming post-menopausal unless permanently sterile. Permanent methods of
             sterilization include hysterectomy, bilateral salpingectomy, and bilateral
             oophorectomy. A post-menopausal state is defined as no menses for 12 months without an
             alternative medical cause.

          -  Able to comply with all the requirements of the protocol

        Exclusion Criteria:

          -  Patients who received investigational drug(s) including vaccines within the last 30
             days prior to study treatment initiation (Cycle 1 Day 1)

          -  Grade > 1 prior treatment-related toxicity (excluding alopaecia) at the time of
             screening

          -  Cancer ascites related to liver failure on physical examination

          -  Patients with history of haemorrhage or gastrointestinal perforation

          -  Patients with history of bilateral portal vein occlusion

          -  Known infection with human immunodeficiency virus (HIV)

          -  Patients with known history of infection with hepatitis B (defined as hepatitis B
             surface antigen [HBsAg] reactive) or known infection with hepatitis C (defined as
             detectable HCV RNA via qualitative nucleic acid testing)

          -  Patients with central nervous system (CNS) or peritoneal metastasis

          -  Patients with known history of non-infectious pneumonitis, myocarditis, or nephritis

          -  Patients presenting with a marked baseline prolongation of QT/QTc interval defined as
             repeated demonstration of a QTc interval≥ 450ms (males) and ≥ 460ms (females) using
             Fridericia's correction formula.

          -  Signs and symptoms of heart failure 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

          -  Patients with history of solid organ or haematological transplantation

          -  Patients with sepsis, ineffective biliary drainage with or without cholangitis,
             obstructive jaundice or encephalopathy at screening visit or within the last two weeks
             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 two 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 note exceptions detailed in Prohibited medication
             section).

          -  Received live (attenuated) vaccine in the 30 days prior to first dose of study drug.

          -  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:

          -  Patients with vitiligo or alopecia.

          -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone
             replacement.

          -  Any chronic skin condition that does not require systemic therapy.

          -  Patients without active disease in the last 2 years may be included but only after
             consultation with the study physician.

          -  Patients with coeliac disease controlled by diet alone.

          -  Patients with an active infection requiring systemic therapy.

          -  Known hypersensitivity to the active substance (pembrolizumab) or to any of the
             excipients.

          -  Known hypersensitivity to the active substance (MTL-CEBPA) or to any of the
             excipients.

          -  Any other condition (e.g., known or suspected poor compliance, etc.) that, in the
             judgment of the investigator, may affect the participant's ability to follow the
             protocol specific procedures
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Adverse events
Time Frame:From screening visit through study completion, an average of 1 year
Safety Issue:
Description:Frequency of adverse events graded according to toxicity criteria (NCI CTCAE v 5.0) and categorised by body system and diagnosis.

Secondary Outcome Measures

Measure:Pharmokinetic analysis of the study drug MTL-CEBPA when co administered with pembrolizumab
Time Frame:Blood samples will be collected on Days 1, 2, 3, 4, 8, 9 10, and 11 of the study
Safety Issue:
Description:Blood sampling Blood samples collected at pre-defined timepoints will be analysed to define the maximum plasma concentration (Cmax) of MTL-CEBPA after intravenous administration.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mina Alpha Limited

Trial Keywords

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

Last Updated

January 22, 2020