Bexmarilimab plus nivolumab in solid tumors, melanoma, and NSCLC

Inclusion Criteria:

1. Part A:

   Histologically proven solid tumour, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient

   Part B1: Histologically proven NSCLC.
   * Patient has received at least one but not more than three lines of systemic anticancer therapy for metastatic disease.
   * Patient has received at least two cycles of immune checkpoint inhibitor and has demonstrated disease progression within 12 weeks of last dose.
   * Patient has had a benefit to prior immune checkpoint inhibitor defined as greater than 6 months of treatment or partial response.
   * Patients with actionable EGFR, ALK, or other known genomic alterations must have received at least 1 relevant targeted therapy treatment if available.

   Part B2: Histologically proven cutaneous melanoma.
   * Patient has received at least one but not more than three lines of systemic anticancer therapy for metastatic disease.
   * Patient has received at least two cycles of immune checkpoint inhibitor and has demonstrated disease progression within 12 weeks of last dose.
   * Patients with BRAF mutations must have received relevant targeted therapy.
   * Patient has had a benefit to prior immune checkpoint inhibitor defined as greater than 6 months of treatment or partial response
2. Life expectancy of at least 12 weeks
3. World Health Organisation (WHO) performance status of 0-1 (Appendix 2)
4. Measurable disease as assessed by iRECIST
5. Biologically female patients are eligible to participate in the trial if they are not pregnant, not breast feeding and meet one of the following criteria:

   1. a biological woman of childbearing potential (WOCB) who has a negative serum or urine pregnancy test before enrolment and agrees to use a highly effective form of contraception (refer to Appendix 3) from signing the consent form, throughout the trial and for six months afterwards. A biological woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
   2. A biological woman of non-childbearing potential; a postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in biological women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
6. Biologically male patients are eligible to participate in the trial if they meet one of the following criteria:

   1. is fertile and agrees to use and ensure their partners (if WOCBP) use a highly effective form of contraception (refer to Appendix 3) from signing the consent form, throughout the trial and for six months afterwards. Biological men with pregnant or lactating partners must be advised to use barrier method contraception (refer to Appendix 3) to prevent exposure of the foetus or neonate; a biological man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy
   2. is infertile
7. Negative serology for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV)
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

   Laboratory Test Value required 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 ULN; with the following exception:

   Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled

   ALT ≤ 2.5 x ULN unless raised due to tumour in which case up to 5 x ULN is permissible AST ≤ 2.5 x ULN unless raised due to tumour in which case up to 5 x ULN is permissible Renal function Calculated creatinine clearance (using the Wright, Cockcroft \& Gault formula) Glomerular filtration rate ≥ 30 mL/min (uncorrected value)
9. 18 years or over
10. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up

Exclusion Criteria:

1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and 4 weeks for investigational medicinal products) before treatment.
2. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia/vitiligo, treated endocrinopathies (i.e. on physiological doses of endocrine replacement) or certain Grade 1 toxicities, which in the opinion of the Investigator and the CI should not exclude the patient.
3. 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.
4. Major thoracic or abdominal surgery from which the patient has not yet recovered.
5. At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
6. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus.
7. 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
8. 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) or is at risk of recurrence. 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.
9. Are receiving chronic systemic steroids (\> 10 mg/day prednisone equivalent). Use of topical, inhalational, intranasal, and intraocular steroids will be permitted.
10. Patients that experienced a Grade 3 or higher immune-related AEs from prior treatment with immunotherapy will be excluded from the study.
11. Has received a live vaccine within 30 days of planned start of study therapy. Note: The inactivated 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.
12. 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.
13. Prior bone marrow transplant, allogenic tissue/solid organ transplant or have had extensive radiotherapy to greater than 25% of bone marrow within eight weeks.
14. 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.
15. Is a patient or plans to participate in another interventional clinical trial, whilst taking part in this study. Participation in an observational trial would be acceptable.
16. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
17. Symptoms of COVID-19 and/or documented COVID-19 infection
18. Hypersensitivity to the active substance or to any of the IMP excipients
19. Active or known pre-existing or history of non-infectious/interstitial lung disease/pneumonitis