Live Biotherapeutic Product MRx0518 and Pembrolizumab Combination Study in Solid Tumors

A Phase I/II Open Label, Safety And Preliminary Efficacy Study of MRx0518 In Combination With Pembrolizumab In Patients With Advanced Malignancies Who Have Progressed On PD-1/PD-L1 Inhibitors

This is an open label, safety and preliminary efficacy study of MRx0518 in combination with pembrolizumab in patients with solid tumours (non small cell lung cancer, renal cell carcinoma, bladder cancer or melanoma).

Subjects will be treated with IV pembrolizumab every 3 weeks and 1 capsule twice daily of MRx0518. Treatment will continue as long as clinically relevant, until disease progression, unacceptable AEs or withdrawal of consent up to a maximum of 35 cycles (approx. 2 years).

Inclusion Criteria:

• Willing and able to provide written informed consent/assent for the trial.

• ≥18 years of age on day of signing informed consent.

• Histological or cytological evidence of advanced and/or metastatic or recurrent NSCLC, renal cell carcinoma, bladder cancer or melanoma.

• At least one measurable lesion per RECIST v 1.1 criteria.

• Failure to respond or intolerance to standard therapy or for whom no appropriate therapies are known to provide clinical benefit (per the judgement of the Investigator).

• Subjects must have progressed on treatment with a PD-1/PD-L1 inhibitor administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. PD-1/PD-L1 inhibitor treatment progression is defined by meeting all of the following criteria:

  1. Has received at least 2 doses of a PD-1/PD-L1 inhibitor.
  2. Has demonstrated disease progression after PD-1/PD-L1 therapy as defined by RECIST v1.1, iRECIST or irRECIST. The initial evidence of disease progression (PD) is to be confirmed by a second assessment no less than four weeks from the date of the first documented PD, in the absence of rapid clinical progression.
  3. Progressive disease has been documented within 12 weeks from the last dose of a PD-1/PD-L1 inhibitor.

• Have adequate organ function

• Be willing to provide archival tissue

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Female subjects of childbearing potential should have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥2 years.

• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication

• Male subjects with female partners of childbearing potential should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria:

• Subjects who failed to show any response to initial treatment with PD-1/PD-L1 inhibitor (i.e. no Response or no Stable Disease).
• Has active brain metastases or leptomeningeal disease. Subjects with asymptomatic CNS metastases which have been stable (defined as without evidence of progression by MRI for at least 28 days prior to initiation of therapy and any neurologic symptoms have returned to baseline) following treatment with surgery or radiation therapy are allowed.
• Prior solid organ or hematologic transplant.
• Treatment-related immune-mediated (or immune related) AEs from immune-modulatory agents (including but not limited to anti-PD1/PD-L1 agents, anti-CTLA4 monoclonal antibodies) that caused permanent discontinuation of the agent, or that were grade 3 or 4 in severity.
• Subjects treated with chemotherapy, immunotherapy, biologic therapy, or other investigational agent within <5 times the half-life of the agent or <21 days (whichever is shorter) of starting study drug. Continuation of hormone replacement therapy is permitted. Stable regimens of hormonal therapy i.e. for prostate cancer (e.g. leuprolide, a GnRH agonist), ovarian, or breast cancer are not exclusionary.
• Subjects treated with tyrosine kinase inhibitor therapy or completed palliative radiotherapy <14 days from initiation of therapy.
• Comorbidity requiring corticosteroid therapy (>10mg prednisone/day or equivalent) within 7 days of starting experimental therapy. Physiologic replacement doses are allowed if they are ≤10mg of prednisone/day or equivalent, as long as they are not being administered for immunosuppressive intent. Inhaled or topical steroids are permitted, provided that they are not for treatment of an autoimmune disorder.
• Significant cardiac dysfunction, New York Heart Association classification for chronic heart failure III-IV, symptomatic coronary artery disease, significant ventricular arrhythmias; myocardial infarction within 6 months; unstable, poorly controlled angina pectoris
• Active, known or suspected autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs), except for replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.). Note: corticosteroids given within 24 hours of an imaging study for purposes of pre-medication in subjects with hypersensitivity to radiologic contrast agents are allowed
• Has a serious active infection requiring systemic therapy
• Subjects who have completed a course of antibiotics within the two weeks prior to dosing
• Has a known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the trial
• Receipt of a live-virus vaccination within 28 days of planned treatment start
• Known HIV infection, or active infection with hepatitis A, B or C
• Has a history of (non-infectious) pneumonitis that required steroids or has current active pneumonitis
• Known additional malignancy either progressing r requiring active treatment (except for non-melanoma skin cancer, in situ cervical cancer or prostate intraepithelial neoplasia) within the last 2 years
• Female subjects who are breastfeeding
• Known intolerance or hypersensitivity to study drugs
• Subjects who are allergic to amoxicillin/clavulanic acid, erythromycin and imipenem
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has a known inability for oral intake of capsules