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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

Description

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.


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.

Phase

N/A

Inclusion and Exclusion 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

  • 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

Sites

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