POTENT - Tepotinib in Combination With Pembrolizumab in NSCLC

Overview

This clinical study is looking at the combination of two experimental drugs called tepotinib and pembrolizumab. Pembrolizumab, also known as Keytruda, is licenced and available by prescription to treat a variety of cancers. Tepotinib is currently licensed in the UK for use in non-small cell lung cancer (NCSLC) and is being investigated for this purpose.

Cancer immunotherapy drugs hold great promise but still do not work for many patients. Laboratory studies on cancers that do not respond well to immunotherapy reveal that most of these tumours do not have any immune cells. This suggests that the cancer has successfully hidden itself and avoided being recognised by the immune system. This study aims to use a novel approach using a targeted drug, tepotinib, to target the gene involved with NSCLC.

Tepotinib is a type of drug called a kinase inhibitor. Kinase inhibitors are a newer type of drug being used to try to treat cancers. They act by blocking some of the chemical messengers that are part of the signalling process within cancer cells that control their growth. Tepotinib is used in adults to treat NSCLC that can have certain abnormal changes in the mesenchymal-epithelial transition factor gene (MET) and which has spread and/or cannot be removed by surgery. The changes in the MET gene can make an abnormal protein which can lead to uncontrolled cell growth and cancer. By blocking this abnormal protein, tepotinib may slow or stop the cancer from growing as well as potentially shrinking the cancer. This study will include patients with and without the MET exon 14 mutations.

In this clinical study, the investigators aim to test our ideas in a small number of people for the first time, specifically in those patients with cancers which do not respond to cancer immunotherapy.

Eligibility

Inclusion Criteria:

1. Male or female patients aged 18 or over.
2. Non-small cell lung cancer histologically confirmed
3. Part A:

   Either

   1. Exon 14 MET mutation (on tissue or ctDNA testing)
   2. Patients have not received systemic therapy for advanced non-small cell lung cancer Or
   3. Patient has received at least one line of systemic anticancer therapy for metastatic disease
   4. Patient has received at least two cycles of immune checkpoint inhibitor and has demonstrated disease progression within 12 weeks of last dose
4. Part B:

   Cohort 1 c) Exon 14 MET mutation (on tissue or ctDNA testing) d) Patients have not received systemic therapy for advanced non-small cell lung cancer

5. Measurable disease as assessed by iRECIST
6. Life expectancy of at least 12 weeks.
7. World Health Organisation (WHO) performance status of 0 or 1.
8. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) prior to the patient's first dose of IMP.
9. Written (signed and dated) study informed consent and be capable of co-operating with treatment and follow-up. If patient does not comply with study procedures such that safety of the trial is affected then they will be withdrawn from the study.
10. Female patients with reproductive potential must have a negative urine or serum pregnancy test performed within 7-days prior to start of trial.

Laboratory test requirements:

Haemoglobin (Hb)

• 9.0 g/dL Absolute neutrophil count
• 1.5 x 109/L Platelet count
• 100 x 109/L Serum bilirubin
  • 1.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
  • 2.5 x (ULN) unless raised due to tumour in which case up to 5 x ULN is permissible Renal function

    Either

Serum creatinine

        ≤ 1.5 x upper limit of normal (ULN) Or Calculated creatinine clearance (using the Wright,
        Cockcroft & Gault formula) GFR ≥ 50 mL/min (uncorrected value) Coagulation INR < 1.5 APTT
        <1.5x ULN Unless participant is receiving anticoagulant therapy as long as PT or aPTT is
        within therapeutic range of intended use of anticoagulants
        Exclusion Criteria:
          1. Radiotherapy, endocrine therapy, immunotherapy or chemotherapy during the previous
             four weeks (six weeks for nitrosoureas, Mitomycin-C) and four weeks for
             investigational medicinal products), except for bisphosphonates or RANK ligand
             antagonists that are permitted for the management of bone metastases. Radiotherapy at
             radical doses within 6 months.
          2. Ongoing Grade 2 or greater toxicities of previous treatments. Exceptions to this are
             alopecia and ongoing anticoagulation therapy due to prior thromboembolic episodes.
          3. History of ILD or interstitial pneumonitis requiring steroid administration.
          4. Ability to become pregnant (or already pregnant or lactating). However, those female
             patients who have a negative serum or urine pregnancy test before enrolment and agree
             to use two highly effective forms of contraception (oral, injected or implanted
             hormonal contraception and condom, have an intra-uterine device and condom) for four
             weeks before entering the trial, during the trial and for six months afterwards are
             considered eligible.
          5. Male patients with partners of child-bearing potential (unless they agree to take
             measures not to father children by using a barrier method of contraception [condom
             plus spermicide] or to sexual abstinence effective from the first administration of
             IMP throughout the trial and for six months afterwards. Men with partners of
             child-bearing potential must also be willing to ensure that their partner uses an
             effective method of contraception for the same duration for example, hormonal
             contraception, intrauterine device, diaphragm with spermicidal gel or sexual
             abstinence). Men with pregnant or lactating partners must be advised to use barrier
             method contraception (for example, condom plus spermicidal gel) to prevent exposure of
             the foetus or neonate.
             NB. Abstinence is only considered to be an acceptable method of contraception when
             this is in line with the preferred and usual lifestyle of the subject. Periodic
             abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and
             withdrawal are not acceptable methods of contraception.
          6. Known untreated or active central nervous system (CNS) metastases (progressing or
             requiring corticosteroids for symptomatic control). Patients with a history of treated
             CNS metastases are eligible, provided they meet all of the following criteria:
               -  Evaluable or measurable disease outside the CNS is present.
               -  Radiographic stability upon the completion of CNS-directed therapy and no
                  evidence of interim progression between the completion of CNS-directed therapy
                  and the baseline disease assessment
               -  Not requiring corticosteroids.
          7. Major surgery within four weeks of the first dose of study treatment.
          8. At high medical risk because of non-malignant systemic disease including active
             uncontrolled infection.
          9. Known to be serologically positive for hepatitis B, hepatitis C or human
             immunodeficiency virus (HIV).
         10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 14 days prior to the first dose of
             trial treatment.
         11. Has an active autoimmune disease that has required systemic treatment in past 3 months
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment. Patients with a history of inflammatory bowel diseases
             such as Crohn's disease or ulcerative colitis will be excluded from the study.
             Patients with Sjogren's syndrome will not be excluded from the study. In addition,
             patients that experienced a Grade 2 or higher immune-related AEs on treatment with
             immunotherapy will be excluded from the study. Patients with inactive autoimmune
             disease which has previously required systemic therapy, may be considered on a
             case-by-case basis after discussion with the chief investigator.
         12. Has a known history of severe allergic anaphylactic reactions to chimeric, human or
             humanized antibodies, or fusion proteins.
         13. Has received a live vaccine within 30 days of planned start of study therapy. Note:
             The killed virus vaccines used for seasonal influenza vaccines for injection are
             allowed; however intranasal influenza vaccines (e.g. FluMist®) are live attenuated
             vaccines and are not allowed.
         14. Previous treatment with tepotinib or other selective/unselective MET inhibitor
         15. Experience hypersensitivity to tepotinib, pembrolizumab or any of their excipients.
         16. Any of the following cardiac criteria:
               -  Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutive
                  electrocardiograms (ECGs) within 5 minutes of each other. Known congenital QT
                  syndrome or history of torsades de pointes.
               -  Any clinically significant abnormalities in rhythm, conduction or morphology of
                  resting ECG, e.g. complete left bundle branch block, third degree heart block.
                  Controlled atrial fibrillation is allowed.
               -  Experience of any of the following procedures or conditions in the preceding 6
                  months: coronary artery bypass graft, angioplasty, vascular stent, myocardial
                  infarction, angina pectoris, congestive heart failure New York Heart Association
                  [NYHA Grade 2 or above], severe valvular disease, uncontrolled hypertension
                  despite optimal therapy.
         17. Prior bone marrow transplant or have had extensive radiotherapy to greater than 25% of
             bone marrow within eight weeks.
         18. Current malignancies of other types, with the exception of adequately treated cone
             biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of
             the skin. An exception to this criteria are cancer survivors, who have undergone
             potentially curative therapy for a prior malignancy, have no evidence of that disease
             for three years or more and are deemed at negligible risk for recurrence, are eligible
             for the trial.
         19. Is a participant or plans to participate in another interventional clinical trial,
             whilst taking part in this Phase I study. Participation in an observational trial
             would be acceptable.
         20. Any other condition which in the Investigator's opinion would not make the patient a
             good candidate for the clinical trial.
         21. Symptoms of active COVID-19 and/or documented active COVID-19 infection at the time of
             screening.