Advanced Solid Tumor, Cutaneous Melanoma, Uveal Melanoma, Metastatic
Conditions
Brief summary
The Phase I trial is evaluating safety, tolerability, pharmacokinetics and preliminary efficacy of MBS8(1V270) in subjects with advanced solid tumours. The trial is designed to provide data for further clinical development of MBS8(1V270)
Detailed description
This is a prospective, open-label, two arms, multinational, multicenter Phase I trial in subjects with advanced solid tumors. The trial consists of two stages: Stage I is a dose escalation stage which will include up to eight cohorts with escalating doses of MBS8(1V270) to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Stage II is an expansion phase in which safety and tolerability of MBS8(1V270) will be assessed at the recommended phase 2 dose established in Stage I of the trial. Stage II comprices two cohorts: One cohort in which MBS8(1V270) will be evaluated in combination with pembrolizumab (Keytruda) in cutaneous melanoma patients with acquired resistance to PD-1 therapy; and one cohort in which MBS8(1V270) will be evaluated as monotherapy in uveal melanoma patients previously treated with T-cell engagers. The dose-escalation in stage 1 is based on the 1+2 design for the first cohort and on the 3+3 design for the following cohorts. The investigational medicinal product is a TLR7 agonist and will be administered intravenously by infusion. Subjects will be treated in cycles. Plasma cytokine levels will be assessed, and tumor biopsies will be taken and evaluated. Radiological tumor assessment by MRI or CT will be performed. Safety will be evaluated by the incidence of adverse events (AEs), serious adverse events (SAEs), DLTs, and use of concomitant medications. Anti-tumor activity of MBS8(1V270) will be evaluated via imaging using RECIST and iRECIST criteria, with iRECIST being the leading tumor evaluation criteria.
Interventions
DRUGMBS8(1V270)
MBS8(1V270) monotherapy
DRUGMBS8(1V270) and pembrolizumab combination
MBS8(1V270) and pembrolizumab combination
Sponsors
MonTa Biosciences ApS
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective, open-label, two arms, multinational, multicenter Phase I trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Stage I Inclusion Criteria 1. Male or female aged ≥18 years. 2. Diagnosis of a histologically or cytologically confirmed solid tumour that was advanced and with progression. No standard treatment existed, or the participant refused standard treatment. Experimental immunotherapy appeared as a feasible exploratory treatment option as per Investigator's assessment. 3. Tumour lesion(s) accessible to serial biopsies. 4. Was willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and tumour biopsies. Mandatory Baseline and on-treatment tumour biopsies were required. However, a biopsy may have been omitted if the procedure was deemed medically unsafe or not feasible, based on the Investigator's clinical judgment and after discussion with the Medical Monitor (or Sponsor's designee). 5. Measurable disease according to RECIST v1.1. Previously irradiated lesions were measurable if subsequent progression was documented. 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. 7. Life expectancy \>3 months as assessed by the Investigator. 8. Adequate bone marrow, cardiopulmonary, renal and hepatic functions: • Haemoglobin ≥5.6 mmol/L (≥90 g/dL) (without transfusion or erythropoietin therapy within 4 weeks prior to therapy) • Neutrophils ≥1.5×109/L, without growth factor stimulation within 3 weeks prior to the blood test • Platelet count ≥75×109/L • Serum creatinine ≤1.25×ULN or creatinine clearance ≥50 mL/min (by CKD-EPI formula) • Hepatic function: AST and ALT ≤2.5×ULN; (5×ULN in the case of liver metastases); bilirubin ≤1.5×ULN except in the case of Gilbert's syndrome and 2×ULN in the case of liver metastases. 9. All participants of childbearing potential (defined as \<2 years after last menstruation or not surgically sterile) must have had a negative highly sensitive pregnancy test at Screening (urine/serum) and agreed to use highly effective method for contraception according to the European Union (EU) Clinical Trial Facilitation Group guidance from time of signing the informed consent form (ICF) until at least 120 days after the last administration of trial drug. The partners of participants with childbearing potential must have also applied contraceptive methods and were recommended not to donate sperm. 10. Ability to understand and sign the ICF. Stage II General Inclusion Criteria The following general inclusion criteria apply to all participants unless cohort criteria specify otherwise. 1. Male and female aged ≥18 years. 2. Eastern Cooperative Oncology Group performance status 0 to 1. 3. Life expectancy ≥3 months as assessed by the Investigator. 4. Adequate organ function within 7 to 14 days prior to Day 1. • Absolute neutrophil count ≥1.5×10⁹/L; platelets ≥100×10⁹/L; haemoglobin ≥9 g/dL (transfusion allowed per site's policy) • Aspartate transaminase/ALT ≤3×ULN (≤5×ULN in case of liver metastases) • Total bilirubin ≤1.5×ULN (≤3×ULN in case of Gilbert's syndrome) * Creatinine clearance ≥50 mL/min (Cockcroft-Gault or measured) * International normalised ratio (INR)/activated partial thromboplastin time (APTT) within institutional limits (unless on stable anticoagulation). 5. Prior systemic anti-cancer therapy with a washout period of ≥14 days plus resolution of drug-related AEs before C1D1. Participants should have recovered from prior therapy-related toxicities to Baseline or Grade ≤1 (except alopecia and other non-clinically significant AEs) and meet all Baseline laboratory criteria. Any deviation requires documented approval from the Sponsor/Medical Monitor with justification in the source record. 6. Major surgery ≥4 weeks, palliative radiotherapy ≥2 weeks, stereotactic body radiation therapy to lung/liver ≥3 weeks. 7. No systemic steroids \>10 mg/day prednisone-equivalent within 14 days before C1D1. Note: Physiologic/replacement doses (e.g., adrenal insufficiency) up to 10 mg/day prednisone-equivalent, topical, inhaled, intra-articular, intranasal, or ophthalmic steroids are allowed. 8. All participants of childbearing potential (defined as \<2 years after last menstruation or not surgically sterile) must have a negative highly sensitive pregnancy test at Screening (urine/serum) and agree to use highly effective method for contraception according to the EU Clinical Trial Facilitation Group guidance from the time of signing the ICF until at least 120 days after the last administration of trial drug. The partners of participants with childbearing potential must also apply contraceptive methods and are recommended not to donate sperm. 9. Ability to provide informed consent and comply with trial procedures. 10. Lactate dehydrogenase ≤2.0×ULN at Screening (single repeat allowed, if confounded). Stage II - Cohort A (Cutaneous Melanoma; Pembrolizumab in Combination with MBS8(1V270)) Specific Inclusion Criteria The following inclusion criteria apply specifically to Stage II - Cohort A. 11A. Histologically/cytologically confirmed metastatic cutaneous melanoma. 12A. Prior exposure to pembrolizumab, nivolumab, nivolumab + ipilimumab, or nivolumab + relatlimab with documented SD lasting ≥6 months, or any CR or PR followed by disease progression. 13A. No untreated or unstable brain metastases. Participants with treated/stable CNS metastasis are eligible if the condition is radiographically stable for ≥4 weeks, no new/worsening neurologic symptoms, and off steroids or on stable/declining ≤10 mg/day prednisone-equivalent for ≥14 days. 14A. Last dose of pembrolizumab, nivolumab, nivolumab + ipilimumab, or nivolumab + relatlimab was given ≤12 weeks prior to Screening, and with no other therapy started. 15A. No prior Grade ≥3 irAE leading to permanent discontinuation of prior anti-PD1/PD L1. 16A. Willing to receive pembrolizumab per SmPC/label-concordant schedule. Stage II - Cohort B (Uveal Melanoma; MBS8(1V270) Monotherapy) Specific Inclusion Criteria The following inclusion criteria apply specifically to Stage II - Cohort B. 11B. Histologically/cytologically confirmed metastatic uveal (ocular) melanoma. 12B. Prior tebentafusp exposure with subsequent progression. * With documented SD lasting ≥6 months, or any CR or PR * RECIST v1.1 progression on tebentafusp. * Washout ≥14 days from the last tebentafusp dose, tebentafusp-related AEs recovered to Grade ≤1/Baseline. * No new organ crisis (e.g., hepatic failure risk, spinal cord compromise) in the prior 4 weeks. * No escalation of corticosteroids for tumour-related symptoms within 14 days. 13B. Prior exposure to pembrolizumab, nivolumab, or nivolumab + ipilimumab with documented SD lasting ≥6 months, or any CR or PR followed by disease progression, independent of prior tebentafusp therapy.
Exclusion criteria
A participant was not eligible for the trial if any of the following applied. Stage I
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events | 42 days | Type and number of adverse events |
| Dose limiting toxicities | 23 days | Dose limiting toxicities (DLTs) and the MTD for determination of RP2D of MBS8(1V270). Stage I only |
| Safety related biomarkers | 23 days | Plasma levels of safety related cytokines IL-6 and TNF-alpha wil be assessed |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best overall response | 42 days | Complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), unconfirmed (iUPD) and confirmed PD (iCPD), assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) and immune RECIST (iRECIST |
| Pharmacokinetic profile of drug substance | 22 days | The plasma concentration time profile of MBS8(1V270) will be assessed |
Countries
Denmark, Spain
Contacts
CONTACTSimon S Jensen, PhD
CONTACTSteven Glazer, MD
PRINCIPAL_INVESTIGATORKristoffer S Rohrberg, MD PhD
University Hospital of Denmark, Department of Oncology
Outcome results
None listed