Mobilize Trial

1. Males or females ≥ 18 years of age who have provided written informed consent prior to completing any study-specific procedure.

2. Dose Escalation (Arm 1a): Participant has histologically confirmed locally advanced or metastatic cancer (cutaneous melanoma, NSCLC, non-muscle invasive bladder cancer, head and neck squamous cell carcinoma, MSS CRC, basal cell carcinoma, or triple negative breast cancer) with measurable disease as determined by RECIST v1.1. Arm 1a participants must have received, and then progressed, relapsed, or been intolerant to, or ineligible for, at least 1 standard treatment regimen in the advanced or metastatic setting. Participants with a known driver mutation must have also received or been offered a mutation-directed therapy, where indicated. Participants must have a tumor lesion amenable to biopsy and must provide fresh tumor biopsy samples at all timepoints if medically feasible and must have another lesion that can be followed for response.

3. Dose Confirmation (Arm 1b), PD Arm Group 1, and PD Arm Group 2: Participant has histologically confirmed locally advanced or metastatic, and checkpoint inhibitor refractory melanoma or locally advanced or metastatic, and checkpoint inhibitor refractory NSCLC with measurable disease as determined by RECIST v1.1 who have disease progression after, at least one line of standard therapy (no limit to prior lines of therapy), and have been treated with or refused standard of care treatment. Must have primary refractory or acquired secondary resistance to prior immune checkpoint treatments. Primary refractory is defined as prior exposure to anti PD-1/PD-L1 antibody for at least six weeks but no more than six months with demonstration of progression on two separate scans at least four weeks apart but no more than 12 weeks apart and progression occurring within six months after first dose of anti-PD-1 antibody. Acquired secondary resistance must have confirmed objective response or prolonged SD (> 6 months), followed by disease progression in the setting of ongoing treatment and confirmed progression on scans at least four weeks apart. Participants must have a tumor lesion amenable to biopsy and must provide fresh tumor biopsy samples at all timepoints if medically feasible and must have another lesion that can be followed for response.

a. For NSCLC patients with known epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), proto-oncogen tyrosine-protein kinase reactive oxygen species (ROS1), or other actionable mutations for which there are approved targeted therapies, must have received prior approved targeted therapy or have been offered and declined approved targeted therapy.

4. Dose Expansion Arm (Arm 2) only: Participant has histologically confirmed locally advanced or metastatic melanoma (Cohort 1), locally advanced or metastatic NSCLC with a PD-L1 TPS of ≥ 1% (Cohort 2), with measurable disease as determined by RECIST v1.1 and have not had any prior therapy for this cancer in this setting (ie, first line therapy). Participants must have a tumor lesion amenable to biopsy and must provide tumor biopsy sample at baseline (archival formalin-fixed, paraffin-embedded [FFPE] tissue collected within 60 days of informed consent is accepted as long as no intervening therapy is received, see the Laboratory Manual for full tissue specifications) and optionally at all on-treatment timepoints (including response or progression) if medically feasible. If the participant is undergoing a new biopsy, they must have another lesion that can be followed for response.

5. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.

6. Participant has adequate haematological and biological function, confirmed by the following laboratory values:

Bone marrow function:

a. Absolute neutrophil count ≥ 1.5 × 109/L.

b. Haemoglobin ≥ 9 g/dL or ≥ 6.2 mmol/L. Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within two weeks of being consented for study.

c. Platelets ≥ 100 × 109/L without transfusion support.

Hepatic function:

a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN) (5 × ULN if hepatic involvement of tumor).

b. Bilirubin ≤ 1.5 × ULN (< 3.0 mg/dL if participant has Gilbert’s disease).

Renal function:

a. Serum creatinine ≤ 1.5 × ULN or creatinine clearance of > 50 mL/min (using Cockcroft-Gault formula).

Coagulation function:

a. Prothrombin time/international normalized ratio and activated partial thromboplastin time ≤ 1.5 × ULN.

Thyroid function:

a. Clinical euthyroid status based on thyroid-stimulating hormone or free triiodothyronine/free thyroxine within normal range. Participants are permitted to be on thyroid supplementation. 

1. Participant has active central nervous system tumors or metastases.

Note: Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging [using the identical imaging modality for each assessment, either computerized tomography or magnetic resonance imaging scan] for at least 28 days before the first dose of study intervention and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days before the first dose of study intervention. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. Brain metastases will not be recorded as RECIST target lesions at baseline.

2. Participant has received treatment with prohibited medications (eg, concurrent anticancer therapy including other chemotherapy, radiation [local radiation for palliative care is permitted with approval from the Sponsor], hormonal anticancer treatment, biologic therapy, or immunotherapy) or investigational agents within five half-lives or 14 days prior to the first day of study intervention (C1D1), whichever is shorter.

3. Participant has reversible toxicities from prior cancer therapy that have not recovered to Grade 1 or baseline. Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in Inclusion Criterion #6.

4. Participants with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after documented consultation with the Sponsor.

5. Participants with irreversible toxicity not reasonably expected to be exacerbated by treatment with study intervention may be included only after documented consultation with the Sponsor.

6. Participant has received prior radiotherapy within 14 days prior to the first dose of study intervention. Participants must have recovered from all radiation related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 7 day washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non central nervous system disease.

7. Participant has a history of severe allergic reactions to any of the study intervention components.

8. Participant has a history of primary immunodeficiency, solid organ transplantation, or tuberculosis.

9. Participant has received immunosuppressive doses of systemic steroids or absorbed topical steroids (doses > 10 mg prednisone daily equivalent) within two weeks before study intervention administration.

10. Participant has any plan to receive a live attenuated vaccine during study intervention or has received a live vaccine within 30 days before the first dose of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines and non-live coronavirus disease 2019 (COVID-19) for injection are generally allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

11. Participant has history of severe injection-related reactions (such as anaphylaxis) to any components of the study intervention, requiring medical evaluation and management.

12. Participant has had any major surgical procedure ≤ 28 days or non-study-related minor procedures ≤ 7 days prior to C1D1. In all cases, the participant must be sufficiently recovered and stable before treatment administration.

13. Participant has any of the following cardiac abnormalities:

a. Medically uncontrolled hypertension.

b. New York Heart Association Class III or IV heart failure.

c. Myocardial infarction within prior 6 months.

d. Unstable angina pectoris.

e. Unstable arrhythmias or prolonged corrected QT interval > 480 ms (unless a pacemaker is in place).

14. Participant has had other invasive cancer within the past, with the exception of the following:

a. Malignancy treated with curative intent and with no known active disease ≥ 3 years before the first dose of study intervention and of low potential risk for recurrence.

b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.

c. Adequately treated carcinoma in situ without evidence of disease.

15. For participants who have received prior anti PD 1, anti PD L1, or anti cytotoxic T lymphocyte-associated protein 4 therapy, the participant will be excluded if they have experienced any of the following:

a. A toxicity that led to permanent discontinuation of prior immunotherapy.

b. Any AEs while receiving prior immunotherapy that have not completely resolved or recovered to baseline prior to screening for this study.

c. A Grade ≥ 3 immune-related AE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy. Note: Participants with endocrine AEs of Grade ≤ 2 are permitted to enroll if they are stable while maintained on appropriate replacement therapy and are asymptomatic.

16. Participant has required the use of additional immunosuppression other than corticosteroids for the management of an AE, has experienced recurrence of an AE if rechallenged, and currently requires maintenance doses of > 10 mg prednisone or equivalent per day.

17. Participant requires active systemic anticoagulation at the time of biopsy.

18. Participant has active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive hepatitis B surface antigen [HBsAg] result), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) (positive HIV subtypes 1 & 2 [HIV-1/HIV-2] antibodies). Participants with a past or resolved hepatitis B virus infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

19. Participant has active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis], Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis) within the past 2 years. The following are exceptions to this criterion:

a. Participants with vitiligo or alopecia.

b. Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.

c. Participants with any chronic skin condition that does not require systemic therapy.

d. Participants without active disease in the last five years may be included but only after consultation with the Sponsor’s Medical Monitor.

e. Participants with celiac disease controlled by diet alone.

20. Participant has a history of leptomeningeal carcinomatosis.

21. Female participant who is pregnant or breastfeeding.

22. Participant is a woman of childbearing potential (WCBP), defined as all women capable of becoming pregnant unless they are using two highly effective methods of contraception during dosing and for 90 days after the last dose administrations. Highly effective contraception methods include:

a. Total abstinence.

b. Female sterilization at least eight weeks before taking study intervention.

c. Sterilization of a female participant’s monogamous male partner at least six months prior to screening.

d. Use of oral, injected, or implanted hormonal methods of contraception or placement of an intrauterine device or other forms of hormonal contraception that have comparable efficacy (failure rate < 1% per year). In case of use of oral contraception, women should have been stable on the same oral contraception for a minimum of six months before taking study intervention.

23. Sexually active males who refuse to use a condom during intercourse while taking study intervention and for 90 days after stopping study intervention and should not father a child in this period. Male participants must also refrain from sperm donation from the time of the first study intervention administration and for 90 days after stopping study intervention.

24. Participant has any unstable or clinically significant concurrent medical condition (eg, substance abuse, uncontrolled intercurrent illness including active infection, arterial thrombosis, and symptomatic pulmonary embolism, etc) that would, in the opinion of the Investigator, jeopardize the safety of a participant, impact their expected survival through the end of the study participation, and/or impact their ability to comply with the protocol. Also including but not limited to, ongoing or active infection, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, active gastrointestinal bleeding or hemoptysis or history of bleeding disorder, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs, or compromise the ability of the participant to give written informed consent.

25. Participant is involved in the planning and/or conduct of the study.

26. Participant has concurrent enrollment in another clinical study (unless it is an observational noninterventional clinical study) or during the follow-up period of an interventional study. 

Research Nurse: Lizzie Coates (x2031) Elizabeth.Coates@LTHTR.nhs.uk