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).

Study Overview

• Status: Terminated
• Conditions: Melanoma; Renal Cell Carcinoma; Solid Tumor; Non Small Cell Lung Cancer; Bladder Cancer; Oncology
• Intervention / Treatment: Drug: MRx0518; Drug: Pembrolizumab 25 MG/1 ML Intravenous Solution [KEYTRUDA]

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Hillman Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Houston Methodist Cancer Center
  • Washington
    • Spokane, Washington, United States, 99208
      • Summit Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: MRx0518 with pembrolizumab; Subjects will receive IV infusion of pembrolizumab once every 3 weeks until disease progression, unacceptable AEs or withdrawal of consent up to a maximum of 35 cycles (approx. 2 years). Starting on the day of first pembrolizumab dose, subjects will take one capsule of MR0518 twice daily until the end of the treatment period.

Drug: MRx0518; MRx0518 is a live biotherapeutic product consisting of a lyophilised formulation of a proprietary strain of bacterium. The study dosing regimen is one capsule two times per day for the duration of the treatment period.; Drug: Pembrolizumab 25 MG/1 ML Intravenous Solution [KEYTRUDA]; Pembrolizumab is a potent humanised immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD1) receptor , thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). The study dosing regimen is 200mg (two 4ml vials of 25mg/ml solution) for IV infusion once every three weeks.; Other Names: Keytruda; Pembrolizumab; MK3475

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: To assess the safety and tolerability of MRx0518 in combination with pembrolizumab through the collection of adverse events	Adverse events will be assessed as per CTCAE v4	Baseline to treatment discontinuation up to a maximum of 35 treatment cycles (one cycle = 21 days)
Part B: To assess safety and tolerability of MRx0518 in combination with pembrolizumab through the collection of adverse events	Adverse events will be assessed as per CTCAE v4	Baseline to treatment discontinuation up to a maximum of 35 treatment cycles (one cycle = 21 days)
Part B: To assess the clinical benefit of MRx0518 in combination with pembrolizumab	To determine preliminary evidence of anti-tumor activity	Baseline to treatment discontinuation up to a maximum of 35 treatment cycles (one cycle = 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antitumour effect	Antitumour effect is assessed through tumour imaging and measurement of lesions per RECIST and iRECIST (ORR, DOR, DCR, PFS)	Baseline and every 3 weeks until treatment discontinuation up to a maximum of 35 treatment cycles (one cycle = 21 days)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers of treatment effect - blood	Blood samples will be analysed for changes in immune status and biomarkers of treatment effect	Day 1 of Cycle 1 and Cycle 2 and time of treatment discontinuation up to a maximum of 35 treatment cycles (one cycle = 21 days)
Biomarkers of treatment effect - tumour	Tissue biopsies will be taken to analyse for tumour biomarkers	Baseline, Day 1 of Cycle 4 and time of treatment discontinuation up to a maximum of 35 treatment cycles (one cycle = 21 days)
Microbiota and metabolome	Faecal and urine samples will be collected and analysed for microbiota and metabolomics using the MicroDx platform	Day 1 of Cycle 1 and Cycle 2, time of treatment discontinuation up to a maximum of 35 treatment cycles (one cycle = 21 days), and 30 Day follow up
Overall survival	Survival of the subjects will be recorded	From start of treatment until death due to any cause up to a maximum of 35 treatment cycles (one cycle = 21 days)

Collaborators and Investigators

• Sponsor: 4D pharma plc
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Shubham Pant, MD, M.D. Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2019
• Primary Completion (Actual): May 8, 2023
• Study Completion (Actual): May 8, 2023

Study Registration Dates

• First Submitted: August 3, 2018
• First Submitted That Met QC Criteria: August 16, 2018
• First Posted (Actual): August 20, 2018

Study Record Updates

• Last Update Posted (Actual): June 1, 2023
• Last Update Submitted That Met QC Criteria: May 30, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Oncology; pembrolizumab; MK-3475; PD-1 Inhibitor; Live Biotherapeutic Product; MRx0518
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: MRx0518-I-002; Keynote MK3475-823 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No