A Proof-of-concept Trial With Safety Run of Tepotinib and Pembrolizumab in NSCLC Patients With and Without MET Exon 14 Mutations (POTENT)
A Proof-of-concept Trial With Safety Run of Tepotinib and Pembrolizumab in NSCLC Patients With and Without MET Exon 14 Mutations (POTENT)
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.
Inclusion criteria:
1. Male or female patients aged 18 or over; 2. Non-small cell lung cancer histologically confirmed; 3.
Part A:
Either
a) Exon 14 MET mutation (on tissue or ctDNA testing); b) Patients have not received prior immunotherapy; c) Patients who have received previous MET inhibitor therapy must have PD-L1 TPS≥50% (not required in those naïve to MET inhibitors).
Or a) Patient has received at least one line of systemic anticancer therapy for metastatic disease; b) 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
a) Exon 14 MET mutation (on tissue or ctDNA testing); b) Patients have not received prior immunotherapy; c) Patients who have received previous MET inhibitor therapy must have PD-L1 TPS≥50% (not required in those naïve to MET inhibitors).
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(Appendix 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.
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 GFR ≥ 50 mL/min (uncorrected value) Calculated creatinine clearance (using the Wright, Cockcroft & Gault formula) 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
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.
Exclusion Criteria:
1. 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 and at palliative doses within 2 weeks. Patients already receiving tepotinib prior to trial are not required to cease tepotinib prior to trial entry.
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:
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. Has experienced hypersensitivity to tepotinib, pembrolizumab or any of their excipients.
15.
Any of the following cardiac criteria:
Prior bone marrow transplant or have had extensive radiotherapy to greater than 25% of bone marrow within eight weeks.
17. 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.
18. 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.
19. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
20. Symptoms of active COVID-19 and/or documented active COVID-19 infection at the time of screening.